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Melanoma Clinical Trials

SLUHN 2015-97

A Phase 1b/2 Study of PV-10 Intralesional Injection in Combination with Immune Checkpoint Inhibition for Treatment of Metastatic Melanoma (PV-10-MM-1201)

  • Physician & Study Coordinator
  • Synopsis
  • Inclusion Criteria
  • Exclusion Criteria
  • Study Coordinator

    Robyn Rex, RN, OCN, CCRP
    484-503-4152

    Robyn.Rex@sluhn.org
  • Treatment Agent: PV-10

    Synopsis: Researchers want to find out if an investigational drug called PV-10 given in combination with another drug called pembrolizumab (also called Keytruda®) can help people with metastatic melanoma. PV-10 consists of a red dye (stain with the color red) called rose bengal that is dissolved in a sterile salt solution. Previous laboratory studies have shown that PV-10 gets into tumor cells without getting into normal cells and causes tumor cells to die. In earlier studies of people with melanoma, some melanoma tumors that were injected with PV-10 got smaller or went away. PV-10 has been tested in approximately 200 people with melanoma.

    • Age 18 years or older, male or female.
    • Histologically or cytologically confirmed diagnosis of melanoma.
    • Stage IV melanoma for which surgery is not recommended.
    • At least 1 cutaneous or subcutaneous Injectable Lesion with longest diameter at least 5 mm.
    • A minimum of 1 measurable Target Lesion (i.e., ≥ 10 mm longest diameter).
    • Performance Status: ECOG 0-1.
    • Clinical Laboratories:
      • Absolute neutrophil count (ANC) ≥ 1.5 x 109/L and platelet count ≥100 x 109/L.
      • Estimated creatinine clearance (CrCl, by Cockroft-Gault formula) or estimated glomerular filtration rate (eGFR) ≥ 30 mL/min/1.73 m2.
      • Total bilirubin ≤ 3 times the upper limit of normal (ULN).
      • Aspartate transaminase (AST), alanine transaminase (ALT) and alkaline phosphatase (ALP) ≤ 5 times the upper limit of normal (ULN).
    • Thyroid function abnormality ≤ CTCAE Grade 2.
    • Untreated or clinically active melanoma brain metastases.
      • Subjects with ≤ 3 brain metastases and each ≤ 1 cm size that were treated with either surgical resection and/or radiation therapy are eligible for study participation provided (a) there is no evidence of progressive CNS disease on brain imaging at least 30 days after definitive treatment and (b) the subject is not taking prednisone at >10 mg or equivalent daily.
      • Subjects with > 1 cm or > 3 in number treated brain metastases are eligible for study participation provided (a) there is no evidence of progressive CNS disease on brain imaging at least 90 days after treatment with surgery and/or radiation therapy and (b) if the subject is not taking prednisone at >10 mg or equivalent daily.
    • Prior treatment with PV-10 or any anti-PD-1 antibody.
      • Subjects previously treated with any anti-PD-L1 antibody are eligible for study participation.
    • Prior cancer therapy or anti-cancer vaccine within 4 weeks of initial study treatment.
    • Known sensitivity to any of the products or components to be administered during dosing.
    • Concurrent or Intercurrent Illness:
      • History or evidence of symptomatic autoimmune pneumonitis, glomerulonephritis, vasculitis, or other systemic autoimmune disease.
      • Evidence of clinically significant immunosuppression.
      • Impaired wound healing or other extremity complications due to severe or uncontrolled diabetes mellitus in subjects whose Injectable Lesions are located in an extremity.
      • Severe peripheral vascular disease (i.e., severe claudication [pain occurring after less than 200 meters of walking], rest pain, ischemic ulceration or gangrene) in subjects Significant concurrent or intercurrent illness, psychiatric disorders, or alcohol or chemical dependence that would, in the opinion of the Investigator, compromise the subject’s safety or compliance or interfere with interpretation of study results.
      • Uncontrolled thyroid disease or cystic fibrosis.
      • Clinically significant acute or unstable cardiovascular, cerebrovascular (stroke), renal, gastrointestinal, pulmonary, immunological, endocrine, or central nervous system disorders.
      • Malignancy other than melanoma within 2 years of enrollment except for: adequately treated (i.e., with curative intent) basal or squamous cell carcinoma, in situ carcinoma of the cervix, in situ ductal adenocarcinoma of the breast, in situ prostate cancer, or limited stage bladder cancer.
    • Pregnancy:
      • Female subjects who are pregnant or lactating.
      • Female subjects who have positive serum pregnancy test taken within 14 days of initiation of study treatment.
      • Female subjects of childbearing potential (defined as having a menstrual cycle within the past 12 months and not having had a surgical procedure to accomplish sterilization) who are not using highly effective contraception (e.g., oral contraceptives, intrauterine devices, double barrier methods such as condoms and diaphragms, abstinence or equivalent measures).
      • Male subjects who are unwilling to use acceptable method of effective

SLUHN 2016-33

An Open-Label, Phase 1b, Multi-Arm Study to Evaluate the Safety, Tolerability, and Pharmacodynamics of Investigational Treatments in Combination With Standard of Care Immune Checkpoint Inhibitors in Patients With Advanced Melanoma

  • Physician & Study Coordinator
  • Synopsis
  • Inclusion Criteria
  • Exclusion Criteria
  • Study Coordinator

    Robyn Rex, RN, OCN, CCRP
    484-503-4152

    Robyn.Rex@sluhn.org
  • Treatment Agent: TAK-580, TAK-202 (Plozalizumab), and Vedolizumab

    Synopsis:  The drugs being tested in this study are called TAK-580, TAK-202 (plozalizumab), and vedolizumab. These investigational drugs are given to patients along with standard of care checkpoint inhibitors ([nivolumab in Arms 1 and 2] or nivolumab + ipilimumab in Arm 3). This study will look at the safety profile of the combination treatments in each arm when administered to participants with advanced melanoma.

    Participants will be assigned to one of the 3 treatment groups:
    TAK-580 + Nivolumab
    TAK-202 (Plozalizumab) +Nivolumab
    Vedolizumab + Nivolumab + Ipilimumab

    • Is a male or female participant of 18 years or older.
    • Has histologically confirmed, unresectable Stage III or Stage IV melanoma per the American Joint Committee on Cancer (AJCC) staging system.
    • Has an eastern cooperative oncology group (ECOG) performance status of 0-1.
    • Adequate bone marrow reserve and renal and hepatic function within 28 days before the first dose of study drug on the basis of the defined laboratory parameters.
    • Had disease accessible for repeat biopsy and willingness to undergo serial tumor biopsies.
    • Additional Inclusion Requirements for arm 1 only (nivolumab + TAK-580)
      • BRAF (gene) V600 mutation-positive or NRAS (gene) mutation-positive disease previously untreated with RAF, MEK, or other inhibitors of the mitogen-activated protein kinase (MAPK) pathway. Participants who have progressed on these agents can still be enrolled in Arms 2 or 3.
    • Additional Inclusion Requirements for expansion cohorts only a) Measurable disease per RECIST guidelines (v 1.1) and at least 1 non-target lesion accessible for biopsy per the guidelines above.
    • Has active brain metastases or leptomeningeal metastases. Participants with brain metastases are eligible if these have been treated and there is no magnetic resonance imaging (MRI) evidence of progression for at least 4 weeks after treatment is complete and within 28 days prior to first dose of study drug administration. There must also be no requirement for high doses of systemic corticosteroids that could result in immunosuppression (greater than [>] 10 mg/day prednisone equivalents) for at least 2 weeks prior to study drug administration.
    • Has ocular melanoma.
    • Had prior treatment with an anti-programmed cell death 1 (PD-1) , anti-PD-L1 (ligands for PD-1), anti-PD-L2 (ligands for PD-1).
    • Has active, known or suspected autoimmune disease.
    • Has a condition requiring systemic treatment with either corticosteroids or other immunosuppressive medications within 14 days of study drug administration.
    • Has a history of pneumonitis requiring treatment with steroids; history of idiopathic pulmonary fibrosis (including pneumonitis), interstitial lung disease, drug-induced pneumonitis, organizing pneumonia, or evidence of active pneumonitis on screening chest CT scan; history of radiation pneumonitis in the radiation field (fibrosis) is permitted.
    • Is previously diagnosed HIV infection or active hepatitis B or C.
    • Additional Exclusion Requirements for arm 1 only (nivolumab Plus TAK-580)
      • Concomitant use or administration of clinically significant enzyme inducers less than equal to (<=) 14 days before the first dose of TAK-580.
      • Treatment with gemfibrozil (or other strong CYP2C8 inhibitor) within 14 days before the first dose of TAK-580.
      • Left ventricular ejection fraction (LVEF) less than (<)50 percent (%) as measured by echocardiogram (ECHO) or multiple gated acquisition scan (MUGA) within 4 weeks before receiving the first dose of study drug.
      • Known GI disease or prior GI procedure that could interfere with the oral absorption or tolerance of the TAK-580.
    • Additional Exclusion Requirements for arm 3 only (vedolizumab Plus nivolumab Plus ipilimumab)
      • Had prior exposure to rituximab, natalizumab, vedolizumab, or alemtuzumab.
      • Has a history of any major neurological disorders, including stroke, multiple sclerosis, brain tumor, or neurodegenerative disease.
      • Has taken any live vaccinations within 30 days before study drug administration except for the influenza vaccine.
      • Has previous anti- cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) therapies. 

SLUHN 2016-40

A Phase 1b/2, Open-label, Dose Escalation Study of Entinostat in Combination with Pembrolizumab in Patients with Non-small Cell Lung Cancer, with Expansion Cohorts in Patients with Non-small Cell Lung Cancer and Melanoma

  • Physician & Study Coordinator
  • Synopsis
  • Inclusion Criteria
  • Exclusion Criteria
  • Study Coordinator

    Robyn Rex, RN, OCN, CCRP
    484-503-4152

    Robyn.Rex@sluhn.org
  • Treatment Agent: Pembrolizumab and Entinostat

    Synopsis:  The purpose of this study is to find out what the best dose of entinostat is when taking both entinostat and pembrolizumab together, as well as to see if there are side effects when the two drugs are combined. This study will also look at whether the combination of these two drugs may slow the progression of cancer. It will also study whether there is something in the blood that can be measured to assess how the therapy works with the patient’s immune system and/or in being able to predict how well future patients may respond to the therapy.

  • Patients with NSCLC:

    • Has histologically- or pathologically-confirmed recurrent/metastatic NSCLC.
    • If has adenocarcinoma, required to have previously been tested for anaplastic lymphoma kinase (ALK) rearrangements and epidermal growth factor receptor (EGFR) mutations, with results available for collection in this study, and, if positive, has been treated with prior EGFR or ALK therapy.
    • Received at least 1 chemotherapeutic regimen in the advanced/metastatic setting and experienced documented, unequivocal progressive disease by either RECIST 1.1 or clinical assessment.
    • Patients with NSCLC enrolled in Cohort 1 of the Expansion Phase should not have been previously treated with a PD-1/PD-L1-blocking antibody

    Patients in Expansion Phase, Cohorts 2 and 3:

    • Previously treated with a PD-1/PD-L1-blocking antibody and experienced experienced documented, unequivocal progressive disease by irRECIST during or after such treatment.

    Patients with Melanoma:

    • Has a histologically- or cytologically-confirmed diagnosis of unresectable or metastatic melanoma and experienced unequivocal progressive disease following a PD-1 or PD-L1-blocking antibody and, if BRAF V600 mutation-positive, a BRAF inhibitor.

    All Patients :

    • Aged 18 years or older on the day written informed consent is given.
    • If has brain metastases, must have stable neurologic status following local therapy for at least 4 weeks without the use of steroids or on stable or decreasing dose of ≤10 mg daily prednisone (or equivalent), and must be without neurologic dysfunction that would confound the evaluation of neurologic and other AEs.
    • Evidence of locally recurrent or metastatic disease based on imaging studies within 28 days before the first study drug dose:
      • At least 1 measurable lesion ≥20 mm by conventional techniques or ≥10 mm by spiral CT scan or MRI, with the last imaging performed within 28 days before the first study drug dose. If there is only 1 measurable lesion and it is located in previously irradiated field, it must have demonstrated unequivocal progression according to RECIST, version 1.1.
    • If receiving radiation therapy, has a 2-week washout period following completion of the treatment prior to receiving the first study drug dose and continues to have at least 1 measureable lesion, per above criterion.
    • ECOG performance status of 0 or 1.
    • Has acceptable, applicable laboratory parameters.
    • Female subjects must not be pregnant.
    • If male, agrees to use an adequate method of contraception
    • Experienced resolution of toxic effect(s) of the most recent prior chemotherapy to Grade 1 or less (except alopecia). If patient underwent major surgery or radiation therapy of >30 Gy, they must have recovered from the toxicity and/or complications from the intervention.
    • Willing to have fresh tumor samples collected during screening and at other time points designated as mandatory, per the Schedule of Study Assessments.
    • Able to understand and give written informed consent and comply with study procedures.
  • Patients meeting any of the following criteria are not eligible for study participation:

    • Diagnosis of immunodeficiency or receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug. The use of physiologic doses of corticosteroids may be approved after consultation with the Sponsor.
    • Active autoimmune disease that has required systemic treatment in past 2 years (i.e., with disease modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment.
    • History of interstitial lung disease (ILD).
    • Allergy to benzamide or inactive components of entinostat.
    • History of allergies to any active or inactive ingredients of pembrolizumab.
    • History or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the patient's participation for the full duration of the study, or is not in the best interest of the patient to participate, in the opinion of the treating Investigator, including, but not limited to:
      • Myocardial infarction or arterial thromboembolic events within 6 months prior to baseline or severe or unstable angina, New York Heart Association (NYHA) Class III or IV disease, or a QTc interval > 470 msec.
      • Uncontrolled heart failure or hypertension, uncontrolled diabetes mellitus, or uncontrolled systemic infection.
      • Another known additional malignancy that is progressing or requires active treatment (excluding adequately treated basal cell carcinoma or cervical intraepithelial neoplasia [CIN]/cervical carcinoma in situ or melanoma in situ). Prior history of other cancer is allowed, as long as there is no active disease within the prior 5 years.
      • Evidence of pneumonitis or history of pneumonitis.
      • Active infection requiring systemic therapy.
      • Known active central nervous system (CNS) metastases and/or carcinomatous meningitis.

    Note: Patients with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging [using the identical imaging modality for each assessment, either MRI or CT scan] for at least 4 weeks prior to the first dose of study drug and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 2 weeks prior to the first dose of study drug or are on stable or decreasing dose of ≤10 mg daily prednisone (or equivalent). This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability.

    • Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the study.
    • Currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment.
    • Received a live virus vaccination within 30 days of the first dose of treatment.
    • Prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to baseline or who has not recovered (i.e., ≤Grade 1 or at baseline) from AEs due to agents administered more than 4 weeks earlier.
    • Prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study baseline or who has not recovered (i.e., ≤Grade 1 or at baseline) from AEs due to a previously administered agent.

    Note: Patients with ≤Grade 2 neuropathy or ≤Grade 2 alopecia are an exception to this criterion and may qualify for the study.

    Note: If patient underwent major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.

    • Received transfusion of blood products (including platelets or red blood cells) or administration of colony stimulating factors (including granulocyte-colony stimulating factor [G-CSF], granulocyte macrophage-colony stimulating factor [GM-CSF], or recombinant erythropoietin) within 4 weeks prior to the first dose of study drug.
    • Currently receiving treatment with any other agent listed on the prohibited medication list such as valproic acid, or other systemic cancer agents within 14 days of the first dose of treatment.
    • If female, is pregnant, breastfeeding, or expecting to conceive, or if male, expect to father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of study drug.
    • Known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies).
    • Known active hepatitis B (e.g., hepatitis B surface antigen-reactive) or hepatitis C (e.g., hepatitis C virus ribonucleic acid [qualitative]).
    • Is or has an immediate family member (e.g., spouse, parent/legal guardian, sibling, or child) who is investigational site or sponsor staff directly involved with this study, unless prospective Institutional Review Board (IRB)/Ethics Committee (EC) approval (by chair or designee) is given allowing exception to this criterion for a specific patient.

SLUHN 2016-43

A US Multi-Site Observational Study in Patients with Unresectable and Metastatic Melanoma: The Optimize Study

  • Physician & Study Coordinator
  • Synopsis
  • Inclusion Criteria
  • Exclusion Criteria
  • Study Coordinator

    Carolyn Seith, MSPH
    484-503-4702

    carolyn.seith@sluhn.org

     

  • Treatment Agent: N/A

    Synopsis:  The purpose of this study is to collect information about post-approval or “real world” experience on the treatment and management of unresectable or metastatic melanoma.
    This observational study will follow the regulator medical care of patients who have unresectable or metastatic melanoma and related conditions, the treatments given for this disease, and document the burden of disease on those who provide care to those patients. The data will be collected from both past (e.g. medical history of unresectable or metastatic melanoma) and future medical records.

  • Prospective cohort patients:

    • Diagnosis date must occur on or after March 24, 2011 (date of ipilimumab approval in US)
    • Diagnosis of stage III (unresectable) or stage IV melanoma (includes mucosal, uveal acrallentiginous, leptomeningeal disease)
    • Age ≥ 18 years at time of entry into study
    • Patients must be actively receiving or scheduled to receive systemic treatment (any line, eg, first, second, third line [including investigational drugs]).
    • For patients initiating new treatment, treatment must be started within 28 days after signing informed consent.
    • For patients currently receiving treatment, patients must enroll within the first 21 days of starting new treatment

    Retrospective cohort patients:

    • Patients with diagnosis of confirmed unresectable stage III or stage IV melanoma (including mucosal, uveal, acral-lentiginous, leptomeningeal disease)
    • Age ≥ 18 years at time of unresectable or metastatic melanoma diagnosis
    • Initiated therapy for unresectable or metastatic melanoma within 4 years prior to approval of ipilimumab (first immune checkpoint inhibitor therapy approved in US) - March 25, 2007 – March 24, 2011
    • One year of follow-up data is required from date of therapy initiation, if a patient passed away within the one year of follow-up; such patients are still eligible and the date of death will be collected.
    • If retrospective patients have at least one year of follow-up data and are then treated with immuno-oncology, immune checkpoint inhibitor therapy, or targeted therapy, these patients will be analyzed separately.
  • Prospective patients:

    • Patients participating in a clinical study that does not allow enrollment into a non-interventional study or clinical studies in which the investigational treatment is blinded
    • Patients who started new treatment > 21 days
    • Patients who enrolled in study but did not initiate treatment before 28 days
    • Patients with current malignancies (except non-melanoma skin cancer and the following in situ cancers: bladder, gastric, colon, endometrial, cervical/dysplasia, melanoma, or breast) that requires additional systemic therapy

SLUHN 2016-60

Pattern of Use and Safety/Effectiveness of Nivolumab in Routine Oncology Practice 

  • Physician & Study Coordinator
  • Synopsis
  • Inclusion Criteria
  • Exclusion Criteria
  • Study Coordinator

    Carolyn Seith, MSPH
    484-503-4702

    carolyn.seith@sluhn.org

     

  • Treatment Agent: N/A

    Synopsis:  The purpose of this study is to understand how nivolumab is used to treat patients who are diagnosed with advanced melanoma or lung cancer; and patients’ health-related experiences overall. Patients invited to participate are planning to start on nivolumab, either on its own or in combination with Ipilimumab as per routine care. The study will collect information about the patient’s health condition, how the patient is being treated with nivolumab and if there are any side effects from the treatment, and how the side effects are managed by the patient’s doctor. This study involves the collecting of information only and will not affect the treatment decision made by the patient’s physician. The data will be collected from the information previously recorded by the patient’s physician in the medical records, and future data that is collected by the patient’s doctor as part of routine care and treatment until the patient completes the study or withdraws consent. Participation in this study, the collected information and study results will help to understand how nivolumab is used and how best its side effects can be managed.

  • Individuals must meet all of the following inclusion criteria to be eligible for the study:

    • Age >= 18
    • Histologically or cytologically confirmed diagnosis of melanoma (including uveal
      melanoma) or lung cancer
    • Treatment with commercial nivolumab for the first time, alone or in combination with ipilimumab, for the approved indications of nivolumab within 14 days before informed consent for this study OR in the case where treatment has not yet been initiated, documentation that the treatment strategy is determined before an informed consent to study participation, and treatment is initiated within 28 days after informed consent.
  • Individuals will not be enrolled if 1 of the following exclusion criteria is met:

    • Prior participation in a clinical trial within the past 4 weeks.
    • Previously treated with anti-PD-1, anti-PD-L1, or anti-PD-L2 antibodies.
    • Previously treated with anti-CTLA-4 for lung cancer.
    • Current or pending participation in a clinical trial.
    • Current or pending systemic treatment for cancer other than melanoma and lung cancer.
    • Inability to comply with the study protocol.

SLUHN 2016-83

A Phase 2 Study of REGN2810, a Fully Human Monoclonal Antibody to Programmed Death-1 (PD-1), in Patients with Advanced Cutaneous Squamous Cell Carcinoma

  • Physician & Study Coordinator
  • Synopsis
  • Inclusion Criteria
  • Exclusion Criteria
  • Study Coordinator

    Carolyn Seith, MSPH
    484-503-4702

    carolyn.seith@sluhn.org

     

  • Treatment Agent: REGN2810

    Synopsis:  This study is being done to test effects of REGN2810 (''study drug") in patients with advanced CSCC. These effects could be good (for example, shrinking of tumors) or bad (called side effects). Researchers will study the effects and how long they last to understand if REGN2810 could be used for treatment of advanced cutaneous squamous cell carcinoma (CSCC). This drug is not approved by the US Food and Drug Administration (FDA).

    There are two groups of patients in this study. Group 1 is for patients in whom the skin cancer has spread to other parts of the body (such as lung, liver, bone or lymph nodes). Group 2 is for patients in which the cancer remains localized in the skin. Patients in both groups will receive the same study treatment. 

  • Individuals will not be enrolled if 1 of the following exclusion criteria is met:

    • At least 1 measurable lesion.
    • Eastern Cooperative Oncology Group (ECOG) performance status ≤1.
    • Adequate bone marrow function.
    • Adequate renal function.
    • Adequate hepatic function.
    • Archived or newly obtained tumor material.
    • Patients must consent to undergo biopsies of externally visible CSCC lesions (Group 2 only).
    • Surgical or radiological treatment of lesions contraindicated.
  • Individuals will not be enrolled if 1 of the following exclusion criteria is met:

    • Ongoing or recent (within 5 years) evidence of significant autoimmune disease that required treatment with systemic immunosuppressive treatments, which may suggest risk for immune-related adverse events.
    • Prior treatment with an agent that blocks the PD-1/PD-L1pathway.
    • Prior treatment with a BRAF inhibitor.
    • Prior treatment with other immune modulating agents within fewer than 4 weeks prior to the first dose of REGN2810. Examples of immune modulating include therapeutic vaccines, cytokine treatments, or agents that target cytotoxic T-lymphocyte antigen 4 (CTLA-4), 4-1BB (CD137), or OX-40.
    • Untreated brain metastasis(es) that may be considered active.
    • Immunosuppressive corticosteroid doses (>10 mg prednisone daily or equivalent) within 4 weeks prior to the first dose of REGN2810.
    • Infection with human immunodeficiency virus (HIV) and/or chronic/active infection with hepatitis B virus or hepatitis C virus.
    • History of pneumonitis within the last 5 years.
    • Allergic reactions or acute hypersensitivity reaction attributed to antibody treatments.
    • Known allergy to doxycycline or tetracycline.
    • Patients with a history of solid organ transplant.
    • Any medical co-morbidity, physical examination finding, or metabolic dysfunction, or clinical laboratory abnormality that renders the patient unsuitable.
    • Other protocol-defined inclusion/exclusion criteria may apply.

SLUHN 2015-93

A Phase 1b, Open-label, Multicenter, Dose Escalation Trial of Intratumoral Injections of SD-101 in Combination with Pembrolizumab in Patients with Metastatic Melanoma

  • Physician & Study Coordinator
  • Synopsis
  • Inclusion Criteria
  • Exclusion Criteria
  • Study Coordinator

    Robyn Rex, RN, OCN, CCRP
    484-503-4152

    Robyn.Rex@sluhn.org
  • Treatment Agent: Pembrolizumab and SD-101

    Synopsis: The purpose of this study is to learn about the safety of SD-101 and to find out what effects (both good and bad) it has on you and your Melanoma when given along with another drug developed by Merck called Keytruda® (pembrolizumab).

    Dynavax is developing an investigational drug, SD-101, which is being studied in combination with another drug developed by Merck, Keytruda® (Pembrolizumab), as a treatment for Metastatic Melanoma. SD-101 is an investigational drug being developed by Dynavax. In this study, SD-101 is injected directly into a tumor and causes the release of immune signals which attract immune cells into the area. SD-101 stimulates the body’s immune response by increasing the ability of immune cells to recognize and kill tumor cells and may work not only at the site of the injection, but also at tumors at other sites in the body.

    • Histologically or cytologically confirmed unresectable in-transit (stage IIIc) or metastatic (stage IV) melanoma:
      • At least 1 site of disease which must be palpable and easily accessible for intratumoral injection. A second site of disease that can be assessed is desirable. Patients must have measurable disease as defined per immune-related response criteria (irRC):
      • Clinical lesions will only be considered measurable when they are superficial, such as skin, subcutaneous tissues, or palpable lymph node.
      • Tumor mass: Must be accurately measurable in 2 perpendicular diameters by scan or physical examination.
      • Malignant lymph nodes: Must be measurable in 2 perpendicular diameters, with both its longest diameter and its longest perpendicular.
    • Aged 18 years and older
    • Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 or 1.
    • Patient must have adequate organ function as indicated by the following laboratory values:
      Hematological
      Absolute neutrophil count (ANC) ≥ 1,500 /mL
      Platelet count ≥ 100,000 /mL
      Hemoglobin ≥ 9 g/dL or ≥ 5.6 mmol/L– without qualifications
      Renal
      Serum creatinine ≤ 1.5 X upper limit of normal (ULN)
      Hepatic
      Serum total bilirubin:
      • ≤ 1.5 X ULN OR
      • < 3 X ULN for persons with Gilbert’s syndrome OR Direct bilirubin ≤ ULN for patients with total bilirubin levels > 1.5 ULN
      • Aspartate transaminase (AST) and alanine transaminase (ALT) (also known as serum glutamic oxaloacetic transaminase [SGOT] and serum glutamic pyruvic transaminase [SGPT]):
      • ≤ 2.5 X ULN OR
      • ≤ 5 X ULN for patients with liver metastases
    • Life expectancy of at least 6 months.
    • Women of childbearing potential (WOCBP), as defined in this protocol, must be willing to use a medically acceptable method of contraceptive from Day 1 through 16 weeks after the last dose of trial treatment. Acceptable birth control methods include oral contraceptive medication, an intrauterine device (IUD), an injectable contraceptive (such as Depo-Provera®), a birth control patch, or a barrier method (such as condom or diaphragm with spermicide).
    • Male patients must agree to use an adequate method of contraception from Day 1 through 16 weeks after the last dose of trial treatment.
    • Ability to understand and sign informed consent form and comply with treatment protocol.
    • Patients with surgically resectable Stage IIIc melanoma.
    • Patient who has had chemotherapy, radiotherapy, or biological cancer therapy (see Criterion 14) within 4 weeks prior to the first dose of trial treatment, or who has not recovered to CTCAE Grade 1 or better from the AEs due to cancer therapeutics administered more than 4 weeks earlier.
    • Patient is expected to require any other form of anti-cancer therapy while in the trial.
    • Patient is positive for hepatitis B (HBsAg reactive), hepatitis C (HCV RNA qualitative), or human immunodeficiency virus (HIV) (HIV ½ antibodies)
    • Uveal or ocular melanoma.
    • Active infection including cytomegalovirus.
    • Patient is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial.
    • Active autoimmune disease requiring systemic treatment in the past 12 weeks or a disease that requires immunosuppressive medication including systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, Sjogren’s syndrome, or autoimmune thrombocytopenia.
    • Known active central nervous system (CNS) metastases or carcinomatous meningitis. Patients with prior history of CNS metastases are eligible if deemed not active for at least 1 month and cannot be receiving steroids.
    • Use of any investigational agent other than an anti-PD-1 antibody within the last 28 days.
    • Clinically significant cardiovascular disease (eg, uncontrolled hypertension, myocardial infarction, unstable angina), New York Heart Association (NYHA) Grade II or greater congestive heart failure, serious cardiac arrhythmia requiring medication within 1 year prior to Day 1; or Grade II or greater peripheral vascular disease at trial entry.
    • Any other significant medical or psychiatric condition, laboratory abnormality, or difficulty complying with protocol requirements that may increase the risk associated with trial participation or trial drug administration that may interfere with the interpretation of trial results and, in the judgment of the investigator, would make the patient inappropriate for this trial.
    • History of sensitivity to any component of SD-101 or hypersensitivity reaction to treatment with a monoclonal antibody.
    • Has had a diagnosis of cancer within the last 3 years other than melanoma, except curatively treated early stage carcinomas with no evidence of recurrence.
    • Patient had prior therapy with an investigational antibody targeting immunoregulatory receptors or mechanisms (with exception of ipilimumab, anti-PD-1 antibody, or anti-PD-L1 antibody).
    • Is taking systemic corticosteroids (more than 3 consecutive days) or other immunomodulators or immune suppressive medication.

SLUHN 2014-117

PV-10 Intralesional Injection vs Systemic Chemotherapy for Treatment of Locally Advanced Cutaneous Melanoma without Distant Metastases

  • Physician & Study Coordinator
  • Synopsis
  • Inclusion Criteria
  • Exclusion Criteria
  • Study Coordinator

    Robyn Rex, RN, OCN, CCRP
    484-503-4152

    Robyn.Rex@sluhn.org
  • Treatment Agent: PV-10

    Synopsis: This is an international multicenter, open-label, randomized controlled trial (RCT) of single-agent intralesional PV-10 versus systemic chemotherapy with dacarbazine (DTIC) or temozolomide (TMZ) to assess treatment of locally advanced cutaneous melanoma in patients who are BRAF V600 wild-type and have failed or are not otherwise candidates for at least one immune checkpoint inhibitor. Subjects in the comparator arm will receive the Investigator's choice of dacarbazine or temozolomide as determined by Investigator preference and/or local availability of the agent. Effectiveness will be assessed by comparison of progression-free survival (PFS) between all intent-to-treat (ITT) subjects in the two study treatment arms.

    • Age 18 years or older, male or female
    • Histologically or cytologically confirmed melanoma
    • Stage IIIB or IIIC recurrent, satellite or in-transit cutaneous or subcutaneous melanoma
    • At least 1 cutaneous Target Lesion > =10 mm in longest diameter. Target Lesions should be at least 10 mm from any other lesion
    • No lesion > 30 mm in longest diameter; and no more than 20 lesions
    • Calculated required PV-10 dose ≤ 15 mL (based on total tumor burden)
    • Performance Status: Eastern Cooperative Oncology Group (ECOG) 0-2
    • Failed, did not tolerate, or not a candidate for (due to co-morbidities, pre-existing autoimmune disease or drug unavailability) treatment with ipilimumab or another immune checkpoint inhibitor
    • Not a candidate for treatment with vemurafenib, dabrafenib or trametinib (i.e., BRAF V600 wild-type)
    • Life Expectancy: At least 6 months.
    • Clinical Laboratories:
      • Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L and platelet count ≥100 x 10^9/L
      • Creatinine ≤ 3 times the upper limit of normal (ULN)
      • Estimated creatinine clearance (CrCl) or estimated glomerular filtration rate (eGFR) ≥ 30 mL/min/1.73 m2
      • Total bilirubin ≤ 3 times the upper limit of normal (ULN)
      • Aspartate transaminase (AST), alanine transaminase (ALT) and alkaline phosphatase (ALP) ≤ 5 times the upper limit of normal (ULN)
      • Lactate dehydrogenase (LDH) ≤ 2 times the upper limit of normal (ULN).
    • Thyroid function abnormality ≤ Grade 2
    • Presence or history of visceral or distant cutaneous or subcutaneous melanoma metastasis
    • Presence of active nodal metastasis
    • Presence of more than 20 melanoma lesions
    • Radiation therapy to any Study Lesion within 4 weeks of initial study treatment.
    • Chemotherapy or other systemic cancer therapy within 4 weeks of initial study treatment (6 weeks for nitrosoureas or mitomycin), or regional chemotherapy (limb infusion or perfusion) within 12 weeks of initial study treatment
    • Immunotherapy for cancer within 4 weeks of initial study treatment
    • Local treatment (e.g., surgery, cryotherapy, laser ablation) to any Study Lesion within 4 weeks of initial study treatment
    • Anti-tumor vaccine therapy within 6 weeks of initial study treatment.
    • Investigational agents within 4 weeks (or 5 half-lives) of initial study treatment.
    • Concurrent or Intercurrent Illness:
      • Impaired wound healing or other extremity complications due to diabetes mellitus in subjects whose Study Lesions are located in an extremity
      • Severe peripheral vascular disease in subjects whose Study Lesions are located in an extremity
      • Significant concurrent or intercurrent illness, psychiatric disorders, or alcohol or chemical dependence that would, in the opinion of the Investigator, compromise the subject's safety or compliance or interfere with interpretation of study results.
      • Uncontrolled thyroid disease or cystic fibrosis
      • Clinically significant acute or unstable cardiovascular, cerebrovascular (stroke), renal, gastrointestinal, pulmonary, immunological, endocrine, or central nervous system disorders
    • Pregnancy:
      • Female subjects who are pregnant or lactating
      • Female subjects who have positive serum pregnancy test taken within 14 days of study treatment
      • Female subjects of child-bearing potential who are not using effective contraception (e.g., oral contraceptives, intrauterine devices, double barrier methods such as condoms and diaphragms, abstinence or equivalent measures)

SLUHN 2014-104

A Multi-Center Phase 2 Open-Label Study to Evaluate Safety and Efficacy in Subjects with Melanoma Metastatic to the Brain treated with Nivolumab in Combination with Ipilimumab followed by Nivolumab Monotherapy

  • Physician & Study Coordinator
  • Synopsis
  • Inclusion Criteria
  • Exclusion Criteria
  • Study Coordinator

    Robyn Rex, RN, OCN, CCRP
    484-503-4152

    Robyn.Rex@sluhn.org
  • Treatment Agent: Nivolumab and Ipilimumab

    Synopsis: The purpose of this study is to provide you access to receive treatment with an investigational drug called nivolumab (also known as BMS-936558) in combination with ipilimumab (Yervoy™) followed by nivolumab alone (monotherapy) for melanoma brain metastases.

    Nivolumab is an antibody (a type of human protein) that is being tested to see if it will allow the body’s immune system to work against tumor cells. Ipilimumab (Yervoy™) is an approved therapy for metastatic melanoma and has demonstrated improved overall survival.

    In this study, the combination treatment of nivolumab and ipilimumab followed by nivolumab monotherapy in the treatment of melanoma brain metastases looks to see how anti-body therapy works in people with your condition.

    • Target Population
      • Histologically confirmed malignant melanoma with measurable metastases in both brain and extracranial compartments
      • At least 1 measurable brain metastasis ≥ 0.5 cm in longest diameter and ≤ 3 cm in longest diameter that has not been previously irradiated. No clinical requirement for local intervention (surgery, radiosurgery, corticosteroid therapy) or other systemic therapy
      • Prior therapy, if given, limited to stereotactic radiotherapy and prior excision of a single melanoma brain metastasis if there has been complete recovery and there are no neurologic sequelae. Growth or change in a lesion previously irradiated will not be considered measurable. Regrowth in cavity of previously excised lesion will not be considered measurable
      • Must have tissue available from a prior biopsy of an extracranial metastasis for biomarker analysis. Biopsy should be excisional, incisional, (these are prioritized sample types), punch, or core needle. Fine needle aspirates or other cytology samples are not allowable. The prior biopsy material provided should be obtained after the most recent prior systemic therapy, when available, so that the biopsy is representative of the baseline state prior to entry into the present study
      • Subjects must be free of neurologic signs and symptoms related to metastatic brain lesions and must not have required or received systemic corticosteroid therapy in the 10 days prior to beginning protocol therapy
      • Allowable prior therapy: Approved adjuvant regimen, which may include molecularly-targeted agent(s) and Interferon (IFN-α). For advanced disease, only prior cytokine therapy, defined as interleukin-2 at any dose and/or IFN-α (any formulation) within 6 months prior to study enrollment. Patients must have recovered fully from the sequelae of any prior therapy and be at least 3 weeks past the last exposure to any prior radiotherapy or allowable systemic therapy. Treatment with prior ipilimumab and any PD-1/pharmacodynamics (PD-L1) inhibitor is not allowed
      • ECOG performance status 0 or 1
    • Target Disease Exceptions
      • History of known leptomeningeal involvement (lumbar puncture not required)
      • Previous stereotactic or highly conformal radiotherapy within 3 weeks before the start of dosing for this study. Note the stereotactic radiotherapy field must not have included the brain index lesion/s
      • Number of Central nervous system (CNS) lesions previously treated with stereotactic radiotherapy (SRT) is >3
    • Medical History and Concurrent Diseases
      • History of whole brain irradiation
      • Autoimmune disease: subjects with a documented history of inflammatory bowel disease, including ulcerative colitis and Crohn's disease are excluded from study treatment as are subjects with a history of symptomatic disease (eg, rheumatoid arthritis, systemic progressive sclerosis [scleroderma], Systemic Lupus Erythematosus, autoimmune vasculitis [e.g., Granulomatosis with polyangiitis (formerly Wegener's)], and sarcoidosis including interferon-induced sarcoidosis. Subjects with motor neuropathy considered of autoimmune origin (e.g., Guillain-Barre Syndrome and Myasthenia Gravis) are excluded from study treatment
      • Subjects with major medical, neurologic or psychiatric condition who are judged as unable to fully comply with study therapy or assessments should not be enrolled
      • Any concurrent malignancy other than non-melanoma skin cancer or carcinoma in situ of the cervix. For any prior invasive malignancy, at least 5 years must have elapsed since curative therapy and patients must have no residual sequelae of prior therapy
      • The use of corticosteroids is not allowed for 10 days prior to initiation of therapy (based upon 5 times the expected half life of dexamethasone). If alternative corticosteroid therapy has been used, consultation with the sponsor Medical Monitor is required to determine the washout period prior to initiating study treatment
    • Physical and Laboratory Test Findings
      • Positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection
      • Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS) even if fully immunocompetent on ART—due to the unknown effects of HIV on the immune response to combined nivolumab plus ipilimumab or the unique toxicity spectrum of these drugs in patients with HIV
    • Allergies and Adverse Drug Reaction
      • History of allergy to study drug components
      • History of severe hypersensitivity reaction to any monoclonal antibody
    • Other Exclusion Criteria
      • Prisoners or subjects who are involuntarily incarcerated
      • Subjects who are compulsorily detained for treatment of either a psychiatric or physical (e.g., infectious disease) illness Eligibility criteria for this study have been carefully considered to ensure the safety of the study subjects and that the results of the study can be used. It is imperative that subjects fully meet all eligibility criteria

SLUHN 2014-47

An Open-Label, Phase 1, Dose Escalation Study of MLN2480 in Patients With Relapsed or Refractory Solid Tumors Followed by a Dose Expansion Phase in Patients With Metastatic Melanoma

  • Physician & Study Coordinator
  • Synopsis
  • Inclusion Criteria
  • Exclusion Criteria
  • Study Coordinator

    Robyn Rex, RN, OCN, CCRP
    484-503-4152

    Robyn.Rex@sluhn.org
  • Treatment Agent: MLN2480

    Synopsis: The main purposes of this study are to determine If MLN2480 is safe, tolerable and potentially effective in melanoma. The other purpose of this study is to determine how much MLN2480 can be given to patients once a week without causing side effects and risks that are too severe.

    This study also wants to know how MLN2480 may affect proteins that are involved in how the drug works in the body. Lastly, the study wants to evaluate the efficacy of MLN2480 in Melanoma

    • Informed consent
    • Male or female patients 18 years or older
    • Dose Escalation phase: Patients with solid tumors (including melanoma) who have failed or are not candidates for standard therapies of for whom no approved therapy is available
    • Dose Expansion phase: Metastatic melanoma (locally advanced or metastatic melanoma)
    • Dose Expansion phase: At least 1 measurable lesion which has not been treated previously with radiotherapy. A newly arising lesion in a previously irradiated field is acceptable
    • For patients undergoing biopsy procedures: Prothrombin time (PT) and activated partial thromboplastin time (aPTT) must be within the normal range
    • Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1
    • Adequate tissue sample from either archival formalin-fixed paraffin-embedded (FFPE) tumor tissue or new biopsy of tumor
    • Previous chemotherapy, immunotherapy, and hormone therapy must be completed at least 4 weeks prior to the administration of MLN2480 and radiation must be completed at least 3 weeks prior to the administration of MLN2480; all associated toxicity must be resolved to ≤ Grade 1
    • Expected survival time of at least 3 months in the opinion of the investigator
    • Patients who do not have hypo- or hyperthyroidism
    • Ability to swallow and retain oral medication
    • Female patients who are post menopausal for at least 1 year, surgically sterile, or agree to practice 2 effective methods of contraception through 3 months after the last dose of study drug or agree to practice true abstinence
    • Male patients who, even if surgically sterilized, agree to practice effective barrier contraception through 3 months after the last dose of alisertib or agree to practice true abstinence
    • History of any major disease that might interfere with safe protocol participation
    • Dose Expansion phase: Previous treatment with RAF or MEK inhibitors
    • Laboratory values as specified in study protocol
    • Current enrollment in any other investigational treatment study
    • Evidence of current uncontrolled cardiovascular conditions within the past 6 months
    • Prior investigational agents for malignant or non-malignant disease within 4 weeks prior to Day 1
    • Active hepatitis or human immunodeficiency virus (HIV) infection
    • Active bacterial or viral infection
    • Female patients who are pregnant or currently breastfeeding
    • Major surgery within 28 days of Day 1
    • Refractory nausea and vomiting, malabsorption, or significant bowel or stomach resection
    • Inability to comply with study requirements
    • Other unspecified reasons that, in the opinion of the investigator or Millennium, make the patient unsuitable for enrollment

SLUHN 2013-85

An Observational Pilot Study to Compare the Compliance with and Health Related Quality of Life during Therapy with Standard High-Dose Interferon Alfa (Intron&174; A, HDI) versus Pegylated Alfa-Interferon 2b (Sylatron&8482;, PEG IFN) in Patients with Surgically Resected Melanoma

  • Physician & Study Coordinator
  • Synopsis
  • Inclusion Criteria
  • Exclusion Criteria
  • Study Coordinator

    Robyn Rex, RN, OCN, CCRP
    484-503-4152

    Robyn.Rex@sluhn.org
  • Treatment Agent: N/A

    Synopsis: The purpose of this study is to evaluate patient cooperation and impression of treatment, as well as access the health–related quality of life (HRQOL) in surgically resected melanoma patients undergoing standard High-Dose Interferon Alfa (Intron® A, HDI) versus Pegylated Alfa-Interferon 2b (Sylatron™, PEG IFN) therapy.

    • Patient is male or female at least 18 years of age
    • Patient has had surgically resected melanoma and plans to receive adjuvant therapy with HDI or PEG IFN
    • Patient is willing and able to give written informed consent
    • Patient is willing to comply with all study requirements
    • Patient is unable or unwilling to complete QoL questionaire or compliance diary
    • Patient has a history of anaphylaxis due to any interferon alpha product
    • Patient has autoimmune hepatitis
    • Patient has decompensated liver disease (Child-Pugh score>6 ( Class B and C)
    • Patient has a history of neuropsychiatric disorder (including depression) that, in the judgment of the investigator, may impair the patient's ability to successfully complete treatment or protocol-related requirements

ECOG-ACRIN EA6134

A Randomized Phase III Trial of Dabrafenib + Trametinib Followed by Ipilimumab + Nivolumab at Progression vs. Ipilimumab + Nivolumab Followed by Dabrafenib + Trametinib at Progression in Patients with Advanced BRAFV600 Mutant Melanoma

  • Physician & Study Coordinator
  • Synopsis
  • Inclusion Criteria
  • Exclusion Criteria
  • Study Coordinator

    Robyn Rex, RN, OCN, CCRP
    484-503-4152

    Robyn.Rex@sluhn.org
  • Treatment Agent: Ipilumumab and Nivolumab

    Synopsis: This randomized phase III trial studies how well initial treatment with ipilimumab and nivolumab followed by dabrafenib and trametinib works and compares it to initial treatment with dabrafenib and trametinib followed by ipilimumab and nivolumab in treating patients with stage III-IV melanoma that contains a mutation known as v-raf murine sarcoma viral oncogene homolog B V600 (BRAFV600) and cannot be removed by surgery. Ipilimumab and nivolumab may block tumor growth by targeting certain cells. Dabrafenib and trametinib may block tumor growth by targeting the BRAFV600 gene. It is not yet known whether treating patients with ipilimumab and nivolumab followed by dabrafenib and trametinib is more effective than treatment with dabrafenib and trametinib followed by ipilimumab and nivolumab.

  • STEP 1

    • Eastern Cooperative Oncology Group (ECOG) performance status: 0 or 1
    • Women must not be pregnant or breast-feeding
      • All females of childbearing potential must have a blood test or urine study within 2 weeks prior to registration to rule out pregnancy
      • A female of childbearing potential is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months)
    • Women of child-bearing potential and sexually active males must be strongly advised to use an accepted and effective method of contraception or to abstain from sexual intercourse for the duration of their participation in the study, and for at least 2 weeks after treatment with dabrafenib or for 4 months after dabrafenib in combination with trametinib; should a woman become pregnant or suspect she is pregnant while she is participating in this study, she should inform her treating physician immediately
    • Patients must have measurable disease; all sites of disease must be evaluated within 4 weeks prior to randomization
    • Patients must have histological or cytological confirmation of melanoma that is metastatic or unresectable and clearly progressive
    • Patients must have BRAFV600E or BRAFV600K mutations, identified by a Food and Drug Administration (FDA)-approved test at a Clinical Laboratory Improvement Amendments (CLIA)-certified lab; if test at CLIA-certified lab used a non-FDA approved method, information about the assay must be provided (FDA approved tests for BRAF V600 mutations in melanoma include: THxID BRAF Detection Kit and Cobas 4800 BRAF V600 Mutation Test)
    • Patients may have had prior systemic therapy in the adjuvant setting; however, patients may not have had any prior treatment for advanced (measurable metastatic) disease or have had prior treatment with a BRAF or MEK inhibitor or a cytotoxic T-lymphocyte-associated protein 4 (CTLA4) or programmed cell death 1 (PD1) pathway blocker; patients may not have had any prior ipilimumab or BRAF inhibitors in the adjuvant setting
    • Patients must have discontinued chemotherapy, immunotherapy or other investigational agents used in the adjuvant setting >= 4 weeks prior to entering the study and recovered from adverse events due to those agents; patients must have discontinued radiation therapy >= 2 weeks prior to entering the study and recovered from any adverse events associated with treatment; prior surgery must be >= 4 weeks from registration and patients must be fully recovered from post-surgical complications
    • Patients must not receive any other investigational agents while on study or within four weeks prior to registration
    • Patients are ineligible if they have any currently active central nervous system (CNS) metastases; patients who have treated brain metastases (with either surgical resection or stereotactic radiosurgery [SRS]) that have been stable on head magnetic resonance imaging (MRI) or contrast computed tomography (CT) scan for at least 4 weeks following treatment and within 4 weeks of randomization are eligible; patients must not have taken any steroids =< 14 days prior to randomization for the purpose of managing their brain metastases; patients with only whole brain irradiation for treatment of CNS metastases will be ineligible
    • Patients must not have other current malignancies, other than basal cell skin cancer, squamous cell skin cancer, in situ cervical cancer, ductal or lobular carcinoma in situ of the breast; patients with other malignancies are eligible if they have been continuously disease-free for > 3 years prior to the time of registration; patients with history of rat sarcoma (RAS) mutation-positive tumors are not eligible regardless of interval from the current study; Note: prospective RAS testing is not required; however, if the results of previous RAS testing are known, they must be used in assessing eligibility
    • White blood count >= 3,000/uL
    • Absolute neutrophil count (ANC) >= 1,500/uL
    • Platelet count >= 100,000/uL
    • Hemoglobin > 9 g/dL
    • Serum creatinine =< 1.5 x upper limit of normal (ULN) or serum creatinine clearance (CrCl) >= 40 ml/min
    • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3 x ULN (=< 5 x ULN for patients with documented liver metastases)
    • Alkaline phosphatase =< 2 x ULN (=< 5 x ULN for patients with known liver involvement and =< 7 x ULN for patients with known bone involvement)
    • Total bilirubin =< 1.5 x ULN except subjects with normal direct bilirubin or those with known Gilbert's syndrome
    • Serum lactate dehydrogenase (LDH) < 10 X ULN (patients with LDH > 10 X ULN are felt to have aggressive disease and should be considered for BRAF inhibitor therapy off protocol)
    • Patients must not have any serious or unstable pre-existing medical conditions (aside from malignancy exceptions specified above), including but not limited to, ongoing or active infection requiring parenteral antibiotics on day 1, history of bleeding diathesis or need for concurrent anticoagulation (international normalized ratio [INR] =< 1.5 and partial thromboplastin time [PTT] within 1.1 x ULN), or psychiatric illness/social situations that would limit compliance with study requirements, interfere with subject's safety, or obtaining informed consent; therapeutic level dosing of warfarin can be used with close monitoring of prothrombin time (PT)/INR by the site; exposure may be decreased due to enzyme induction when on treatment, thus warfarin dosing may need to be adjusted based upon PT/INR; consequently, when discontinuing dabrafenib, warfarin exposure may be increased and thus close monitoring via PT/INR and warfarin dose adjustments must be made as clinically appropriate; prophylactic low dose warfarin may be given to maintain central catheter patency
    • Patients must not have a history of or evidence of cardiovascular risks including any of the following:
      • QT interval corrected for heart rate using the Bazett's formula (QTcB) >= 480 msec. at baseline
      • History of acute coronary syndromes (including myocardial infarction or unstable angina), coronary angioplasty, or stenting within the past 24 weeks prior to registration
      • History within the past 24 weeks prior to registration or evidence of current class II, III, or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system
      • Left ventricular ejection fraction (LVEF) =< lower limit of normal on cardiac echo or multi gated acquisition scan (MUGA)
      • Intra-cardiac defibrillator
      • Abnormal cardiac valve morphology (>= grade 2) documented by echocardiogram (ECHO) (subjects with grade 1 abnormalities [i.e., mild regurgitation/stenosis] can be entered on study); subjects with moderate valvular thickening should not be entered on study
      • History or evidence of current clinically significant uncontrolled cardiac arrhythmias; Clarification: subjects with atrial fibrillation controlled for > 30 days prior to dosing are eligible
      • Treatment refractory hypertension defined as a blood pressure of systolic > 140 mmHg and/or diastolic > 90 mm Hg which cannot be controlled by anti-hypertensive therapy
    • Individuals who are human immunodeficiency virus (HIV) infected are eligible
    • No known or anticipated interaction between the agents being used in the study, (including supporting medications for protocol specified therapy), and any anti-HIV therapy, (including agents used for prophylaxis) being used by the individual
    • Patients with evidence of active hepatitis B virus (HBV) or hepatitis C Virus (HCV) infection are not eligible; patients with cleared HBV and HCV infection will be allowed
    • Patients with active autoimmune disease or history of autoimmune disease that might recur, which may affect vital organ function or require immune suppressive treatment including systemic corticosteroids, should be excluded; these include but are not limited to patients with a history of immune related neurologic disease, multiple sclerosis, autoimmune (demyelinating) neuropathy, Guillain-Barre syndrome, myasthenia gravis; systemic autoimmune disease such as systemic lupus erythematosus (SLE), connective tissue diseases, scleroderma, inflammatory bowel disease (IBD), Crohn's, ulcerative colitis, hepatitis; and patients with a history of toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome, or phospholipid syndrome should be excluded; patients with vitiligo, endocrine deficiencies including thyroiditis managed with replacement hormones including physiologic corticosteroids are eligible; patients with rheumatoid arthritis and other arthropathies, Sjögren's syndrome and psoriasis controlled with topical medication and patients with positive serology, such as antinuclear antibodies (ANA), should be evaluated for the presence of target organ involvement and potential need for systemic treatment. If no systemic immune suppression is deemed necessary they can be eligible
    • The following medications or non-drug therapies are also prohibited while on treatment in this study:
      • Other anti-cancer therapies
      • Other investigational drugs
      • Patients taking any medications or substances that are strong inhibitors or inducers of cytochrome P450 family 3, subfamily A (CYP3A) or cytochrome P450 family 2, subfamily C, polypeptide 8 (CYP2C8) are ineligible
    • Patients must not have history of retinal vein occlusion (RVO)
    • Patients must not have evidence of interstitial lung disease or pneumonitis
    • Patients must not have malabsorption, swallowing difficulty, or other conditions that would interfere with the ingestion or absorption of dabrafenib or trametinib
    • Patients must not have any serious or unstable pre-existing medical conditions (aside from malignancy exceptions specified above), psychiatric disorders, or other conditions that could interfere with the subject's safety, obtaining informed consent, or compliance with study procedures

    STEP 2 (CROSSOVER ARM FOR PATIENTS WITH PROGRESSIVE DISEASE)

    • The patient must have met all eligibility criteria (except as detailed below) at the time of crossover
      • RECIST defined measurable disease is not required
      • Only prior systemic therapy as part of step 1 is allowed
      • Malabsorption, swallowing difficulty, or other conditions that would interfere with the ingestion or absorption of dabrafenib or trametinib, or history of retinal vein occlusion are acceptable for patients crossing over to ipilimumab + nivolumab treatment
      • History of autoimmune disease, excluding interstitial lung disease or pneumonitis, is allowed in patients crossing over to dabrafenib/trametinib therapy
      • Patients can be less than 4 weeks from surgery or SRS to CNS metastases
      • There is no restriction on serum LDH at crossover
      • Patients with a history of cardiovascular risks that developed during step 1 of therapy should be discussed with study principal investigator (PI) at time of crossover
    • Patients must have melanoma that is metastatic and clearly progressive on prior therapy
    • Patients must be at least 2 weeks and within 12 weeks from documented progressive disease (PD) on Step 1 of current study; all sites of disease must be evaluated within 4 weeks prior to registration
    • Patients must have recovered from adverse events (toxicities resolved to grade 1 or less) of prior therapy; patients with immune related toxicities from ipilimumab/nivolumab may continue onto Step 2 even if still on steroids to control side effects, so long as toxicity has resolved to grade 1 or less
    • Patients must have discontinued radiation therapy >= 2 weeks prior to registering to Step 2 of the study and recovered from any adverse events associated with treatment; prior surgery must be >= 2 weeks from registration to Step 2 and patients must be fully recovered from post-surgical complications
    • Patients are ineligible if they have any currently active CNS metastases; patients who have treated brain metastases (with either surgical resection or SRS) that have been stable on head MRI or contrast CT scan for at least 4 weeks following treatment and within 4 weeks prior to Step 2 registration are eligible; patients crossing over to ipilimumab + nivolumab must not have taken any steroids =< 14 days prior to registration for the purpose of managing their brain metastases; this exclusion does not apply for patients crossing over to dabrafenib + trametinib; patients with only whole brain irradiation for treatment of CNS metastases are ineligible
    • Patients must not have other current malignancies, other than basal cell skin cancer, squamous cell skin cancer, in situ cervical cancer, ductal or lobular carcinoma in situ of the breast

SWOG 1404

High-Dose Recombinant Interferon Alfa-2B or Pembrolizumab in Treating Patients With Stage III-IV High Risk Melanoma That Has Been Removed by Surgery

  • Physician & Study Coordinator
  • Synopsis
  • Inclusion Criteria
  • Exclusion Criteria
  • Study Coordinator

    Robyn Rex, RN, OCN, CCRP
    484-503-4152

    Robyn.Rex@sluhn.org
  • Treatment Agent: NA

    Synopsis: The purpose of this study is to compare the effects, good and/or bad, of the experimental drug MK-3475 (also called pembrolizumab) to the usual treatment with interferon alfa-2b. This study will allow the researchers to know whether treatment with MK-3475 (pembrolizumab) is better, the same, or worse than treatment with interferon alfa-2b. In this study, you will get either MK-3475 or interferon alfa-2b. There will be about 1,378 people taking part in this study.

  • Disease Related Criteria

    • Patients must have completely resected melanoma of cutaneous origin or of unknown primary in order to be eligible for this study. Patients must be classified as Stage IIIA (N2a), IIIB, IIIC, or Stage IV melanoma. Patients with melanoma of mucosal or other non-cutaneous origin are eligible. Patients with melanoma of ocular origin are not eligible. Patients with a history of brain metastases are ineligible.
    • Patients are eligible for this trial either at initial presentation of their melanoma or at the time of the first detected nodal, satellite/in-transit, distant metastases, or recurrent disease in prior lymphadenectomy basin or distant site. Nodal, satellite/in-transit metastasis, distant metastases or disease in a prior complete lymphadenectomy basin must have been confirmed histologically by H & E stained slides.
    • Patients with multiple regional nodal basin involvement are eligible. Gross or microscopic extracapsular nodal extension is permitted.
    • Patients at initial presentation of melanoma must undergo an adequate wide excision of the primary lesion, if present. (See Section 18.1 for guidelines on surgical management.) Patients with previously diagnosed melanoma must have had all current disease resected with pathologically negative margins and must have no evidence of disease at the primary site or must undergo re-resection of the primary site. A full lymphadenectomy meeting the criteria outlined in Section 18.1 is required for all patients including those with positive sentinel nodes. Patients with recurrent disease who have had a prior complete lymphadenectomy fulfill this requirement as long as all recurrent disease has been resected. For all patients, all disease must have been resected with negative pathological margins and no clinical, radiologic, or pathological evidence of any incompletely resected melanoma. Patients must be registered within 98 days of the last surgery performed to render the patient free of disease.

    Specimen Submission Criteria

    • Patients must have available and be willing to submit a minimum of five unstained slides from primary, lymph node, or metastatic site to determine PD-L1 expression as described in Section 15.2. The tumor tissue must be adequate for PD-L1 testing (defined as ≥ 100 tumor cells as confirmed by the treating institution’s local pathologist).
    • Patients must be offered the opportunity to participate in specimen banking as outlined in Section 15.3.
    • Patients must be willing to have blood draws for PK/ADA analysis as outlined in Section 15.4, should the patient be randomized to the MK-3475 arm.

    Prior/Concurrent Therapy Criteria

    • Patients may have received prior radiation therapy, including after the surgical resection. All adverse events associated with prior surgery and radiation therapy must have resolved to ≤ Grade 1 prior to registration.
    • Patients must not have had prior immunotherapy including, but not limited to interferon alfa-2b, high dose IL-2, PEG-IFN, anti-PD-1, anti-PD-L1 intra-tumoral or vaccine therapies. Patients must not be planning to receive any of the prohibited therapies listed in Section 7.2 during the screening or treatment phases of the study.
    • Patients must not be planning to receive concomitant other biologic therapy, radiation therapy, hormonal therapy, other chemotherapy, surgery or other therapy while on this protocol.

    Clinical/Laboratory Criteria

    • Patients must be ≥ 18 years of age.
      • All patients must have disease-free status documented by a complete physical examination and imaging studies within 42 days prior to registration. Imaging studies must include a total body PET-CT scan (with or without brain) or a CT of the chest, abdomen and pelvis plus a CT of the neck if patient has a primary melanoma of the head and neck. (CT should be done with intravenous contrast if there are no contraindications for it).
      • All patients must have a CT or MRI of the brain. The brain CT or MRI should be performed with intravenous contrast (unless contraindicated). Any other clinically-indicated imaging studies if performed (e.g. bone scan) must show no evidence of disease.
    • Patients must have adequate bone marrow function as evidenced by all of the following: ANC ≥ 1,500 microliter (mcL); platelets ≥ 100,000/mcL; Hemoglobin ≥ 10 g/dL. These results must be obtained within 42 days prior to registration.
    • Patients must have adequate hepatic function as evidenced by the following: total bilirubin ≤ 1.5 x institutional upper limit of normal ( IULN ) (except Gilbert’s Syndrome, who must have a total bilirubin < 3.0 mg/dL), and SGOT (AST) or SGPT (ALT) and alkaline phosphatase ≤ 2 x IULN. These results must be obtained within 42 days prior to registration following:
      • serum creatinine ≤ IULN OR measured or calculated creatinine clearance ≥ 60 mL/min. This result must have been obtained within 42 days prior to registration.
      • Calculated creatinine clearance = (140 - age) x wt (kg) x 0.85 (if female)
      • 72 x creatinine (mg/dl)
    • Patients must have LDH performed within 42 days prior to registration.
    • Patients must have Zubrod Performance Status ≤ 1 (see Section 10.4).
    • Patients must have a baseline ECG performed within 42 days of registration that is normal or considered not clinically significant by the site investigator.
    • Patients must not have evidence of active, non-infectious pneumonitis.
    • Patients must not have an active infection requiring systemic therapy.
    • Patients must not have active autoimmune disease that has required systemic treatment in past 2 years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
    • Patients must not have received live vaccines within 42 days prior to registration. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, chicken pox, shingles, yellow fever, rabies, BCG, and typhoid (oral) vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed.
    • Patients known to be HIV positive are eligible if they meet the following criteria within 30 days prior to registration: stable and adequate CD4 counts (≥ 350 mm3), and serum HIV viral load of < 25,000 IU/ml. Patients may be on or off anti-viral therapy so long as they meet the CD4 count criteria.
    • Patients must not have known active Hepatitis B Virus (HBV) or Hepatitis C Virus (HCV) infection prior to registration.
    • Patients must not have a history or current evidence of any condition, therapy or laboratory abnormality that might confound the trial results, interfere with the patient's participation for the full duration of the trial, or indicate that participation in the trial is not in the patient's best interests, in the opinion of the treating investigator.
    • No other prior malignancy is allowed except for the following: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, lobular carcinoma of the breast in situ, atypical melanocytic hyperplasia or melanoma in situ, adequately treated Stage I or II cancer (including multiple primary melanomas) from which the patient is currently in complete remission, or any other cancer from which the patient has been disease free for three years.
    • Women of childbearing potential must have a negative urine or serum pregnancy test within 28 days prior to registration. Women/men of reproductive potential must have agreed to use an effective contraceptive method for the course of the study through 120 days after the last dose of study medication. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. A woman is considered to be of "reproductive potential" if she has had menses at any time in the preceding 12 consecutive months. In addition to routine contraceptive methods, "effective contraception" also includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy, or bilateral tubal ligation. However, if at any point a previously celibate patient chooses to become heterosexually active during the time period for use of contraceptive measures outlined in the protocol, he/she is responsible for beginning contraceptive measures. Patients must not be pregnant or nursing due to unknown teratogenic side effects.
    • Patients who are able to complete questionnaires in English, Spanish or French must participate in the quality of life assessments. (Those patients who cannot complete the quality of life questionnaires in English, Spanish or French can be registered to S1404 without contributing to the quality of life studies.)

    Regulation Criteria

    • Patients must be informed of the investigational nature of this study and must sign and give written informed consent for this protocol in accordance with institutional and federal guidelines.
    • As a part of the OPEN registration process (see Section 13.4 for OPEN access instructions) the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system.
  • Disease Related Criteria

    • Patients must have completely resected melanoma of cutaneous origin or of unknown primary in order to be eligible for this study. Patients must be classified as Stage IIIA (N2a), IIIB, IIIC, or Stage IV melanoma. Patients with melanoma of mucosal or other non-cutaneous origin are eligible. Patients with melanoma of ocular origin are not eligible. Patients with a history of brain metastases are ineligible.
    • Patients are eligible for this trial either at initial presentation of their melanoma or at the time of the first detected nodal, satellite/in-transit, distant metastases, or recurrent disease in prior lymphadenectomy basin or distant site. Nodal, satellite/in-transit metastasis, distant metastases or disease in a prior complete lymphadenectomy basin must have been confirmed histologically by H & E stained slides.
    • Patients with multiple regional nodal basin involvement are eligible. Gross or microscopic extracapsular nodal extension is permitted.
    • Patients at initial presentation of melanoma must undergo an adequate wide excision of the primary lesion, if present. (See Section 18.1 for guidelines on surgical management.) Patients with previously diagnosed melanoma must have had all current disease resected with pathologically negative margins and must have no evidence of disease at the primary site or must undergo re-resection of the primary site. A full lymphadenectomy meeting the criteria outlined in Section 18.1 is required for all patients including those with positive sentinel nodes. Patients with recurrent disease who have had a prior complete lymphadenectomy fulfill this requirement as long as all recurrent disease has been resected. For all patients, all disease must have been resected with negative pathological margins and no clinical, radiologic, or pathological evidence of any incompletely resected melanoma. Patients must be registered within 98 days of the last surgery performed to render the patient free of disease.

    Specimen Submission Criteria

    • Patients must have available and be willing to submit a minimum of five unstained slides from primary, lymph node, or metastatic site to determine PD-L1 expression as described in Section 15.2. The tumor tissue must be adequate for PD-L1 testing (defined as ≥ 100 tumor cells as confirmed by the treating institution’s local pathologist).
    • Patients must be offered the opportunity to participate in specimen banking as outlined in Section 15.3.
    • Patients must be willing to have blood draws for PK/ADA analysis as outlined in Section 15.4, should the patient be randomized to the MK-3475 arm.

    Prior/Concurrent Therapy Criteria

    • Patients may have received prior radiation therapy, including after the surgical resection. All adverse events associated with prior surgery and radiation therapy must have resolved to ≤ Grade 1 prior to registration.
    • Patients must not have had prior immunotherapy including, but not limited to interferon alfa-2b, high dose IL-2, PEG-IFN, anti-PD-1, anti-PD-L1 intra-tumoral or vaccine therapies. Patients must not be planning to receive any of the prohibited therapies listed in Section 7.2 during the screening or treatment phases of the study.
    • Patients must not be planning to receive concomitant other biologic therapy, radiation therapy, hormonal therapy, other chemotherapy, surgery or other therapy while on this protocol.

    Clinical/Laboratory Criteria

    • Patients must be ≥ 18 years of age.
      • All patients must have disease-free status documented by a complete physical examination and imaging studies within 42 days prior to registration. Imaging studies must include a total body PET-CT scan (with or without brain) or a CT of the chest, abdomen and pelvis plus a CT of the neck if patient has a primary melanoma of the head and neck. (CT should be done with intravenous contrast if there are no contraindications for it).
      • All patients must have a CT or MRI of the brain. The brain CT or MRI should be performed with intravenous contrast (unless contraindicated). Any other clinically-indicated imaging studies if performed (e.g. bone scan) must show no evidence of disease.
    • Patients must have adequate bone marrow function as evidenced by all of the following: ANC ≥ 1,500 microliter (mcL); platelets ≥ 100,000/mcL; Hemoglobin ≥ 10 g/dL. These results must be obtained within 42 days prior to registration.
    • Patients must have adequate hepatic function as evidenced by the following: total bilirubin ≤ 1.5 x institutional upper limit of normal ( IULN ) (except Gilbert’s Syndrome, who must have a total bilirubin < 3.0 mg/dL), and SGOT (AST) or SGPT (ALT) and alkaline phosphatase ≤ 2 x IULN. These results must be obtained within 42 days prior to registration following:
      • serum creatinine ≤ IULN OR measured or calculated creatinine clearance ≥ 60 mL/min. This result must have been obtained within 42 days prior to registration.
      • Calculated creatinine clearance = (140 - age) x wt (kg) x 0.85 (if female)
      • 72 x creatinine (mg/dl)
    • Patients must have LDH performed within 42 days prior to registration.
    • Patients must have Zubrod Performance Status ≤ 1 (see Section 10.4).
    • Patients must have a baseline ECG performed within 42 days of registration that is normal or considered not clinically significant by the site investigator.
    • Patients must not have evidence of active, non-infectious pneumonitis.
    • Patients must not have an active infection requiring systemic therapy.
    • Patients must not have active autoimmune disease that has required systemic treatment in past 2 years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
    • Patients must not have received live vaccines within 42 days prior to registration. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, chicken pox, shingles, yellow fever, rabies, BCG, and typhoid (oral) vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed.
    • Patients known to be HIV positive are eligible if they meet the following criteria within 30 days prior to registration: stable and adequate CD4 counts (≥ 350 mm3), and serum HIV viral load of < 25,000 IU/ml. Patients may be on or off anti-viral therapy so long as they meet the CD4 count criteria.
    • Patients must not have known active Hepatitis B Virus (HBV) or Hepatitis C Virus (HCV) infection prior to registration.
    • Patients must not have a history or current evidence of any condition, therapy or laboratory abnormality that might confound the trial results, interfere with the patient's participation for the full duration of the trial, or indicate that participation in the trial is not in the patient's best interests, in the opinion of the treating investigator.
    • No other prior malignancy is allowed except for the following: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, lobular carcinoma of the breast in situ, atypical melanocytic hyperplasia or melanoma in situ, adequately treated Stage I or II cancer (including multiple primary melanomas) from which the patient is currently in complete remission, or any other cancer from which the patient has been disease free for three years.
    • Women of childbearing potential must have a negative urine or serum pregnancy test within 28 days prior to registration. Women/men of reproductive potential must have agreed to use an effective contraceptive method for the course of the study through 120 days after the last dose of study medication. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. A woman is considered to be of "reproductive potential" if she has had menses at any time in the preceding 12 consecutive months. In addition to routine contraceptive methods, "effective contraception" also includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy, or bilateral tubal ligation. However, if at any point a previously celibate patient chooses to become heterosexually active during the time period for use of contraceptive measures outlined in the protocol, he/she is responsible for beginning contraceptive measures. Patients must not be pregnant or nursing due to unknown teratogenic side effects.
    • Patients who are able to complete questionnaires in English, Spanish or French must participate in the quality of life assessments. (Those patients who cannot complete the quality of life questionnaires in English, Spanish or French can be registered to S1404 without contributing to the quality of life studies.)

    Regulation Criteria

    • Patients must be informed of the investigational nature of this study and must sign and give written informed consent for this protocol in accordance with institutional and federal guidelines.
    • As a part of the OPEN registration process (see Section 13.4 for OPEN access instructions) the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system.