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BMS CA209-234

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.

BMS CA209-915

A Phase 3, Randomized Study of Adjuvant Immunotherapy with Nivolumab Combined with Ipilimumab versus Ipilimumab or Nivolumab Monotherapy after Complete Resection of Stage IIIb/c/d or Stage IV 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: Nivolumab, BMS-986214, Ipilimumab

    Synopsis: The purpose of this study is to test the effectiveness (how well the drug works), safety, and tolerability of two investigational drugs called nivolumab and ipilimumab in subjects with late stage skin cancer that have had their tumors completely removed, but are likely to have their cancer return.

    Nivolumab and ipilimumab are types of immunotherapy. Immunotherapy works by encouraging the body's own immune system to attack the cancer cells. OPDIVO® (nivolumab) is approved for the treatment of certain types of cancer, including skin, kidney, blood, and lung, in multiple countries including the United States (US, Dec-2014), the European Union (EU, Jun-2015), and Japan (Jul-2014). Ipilimumab (Yervoy™) is approved by the FDA, EMA and other health authorities for the treatment of metastatic melanoma. The combination of nivolumab (Opdivo™) and ipilimumab (Yervoy™) is also approved by the US FDA and the EMA for the treatment of metastatic melanoma. 
     

    • Completely surgically resected stage IIIb/c/d or stage IV melanoma within 12 weeks of participation in study.
    • Must have full activity or, if limited, must be able to walk and carry out activities such as light house work or office work
    • No prior anti-cancer treatment for melanoma (except surgery for the melanoma lesion(s) and/or except for adjuvant radiation therapy (RT) after neurosurgical resection for central nervous system (CNS) lesions)
    • History of uveal melanoma
    • Weight less than or equal to 40 kg
    • Patients with active, known or suspected autoimmune disease
    • Prior treatment with interferon (if complete < 6 months prior to participation in study), anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways

Delcath PHP-OCM-301

A Randomized, Controlled, Phase 3 Study to Evaluate the Efficacy, Safety and Pharmacokinetics of Melphalan/HDS Treatment in Patients with Hepatic-Dominant Ocular 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: Melphalan Hydrochloride for Injection for use with the Hepatic Delivery System

    Synopsis:  This study will evaluate two groups of patients who have melanoma that has spread from the eye to the liver: one group (50%) will get high-dose chemotherapy delivered specifically to the liver, while the other group (50%) will get one of 4 standard best alternative care treatments. Patients in each group will get repeating cycles of treatment until the cancer in the liver advances and will be followed until death. This study will evaluate the effect of the treatments on how long patients live and how long it takes for the cancer to advance or respond to the treatment.

    1. Male or female patients ≥ 18 years of age.
    2. Patients must weigh ≥ 35 kg (due to possible size limitations with respect to percutaneous catheterization of the femoral artery and vein using the Delcath Hepatic Delivery System).
    3. 50% or less histologically or cytologically-proven ocular melanoma metastases in the parenchyma of the liver.
    4. Disease in the liver must be measurable by computed tomography (CT) and/or magnetic resonance imaging (MRI).
    5. Evidence of limited extrahepatic disease on preoperative radiological studies is acceptable if the life threatening component of PD is in the liver. Limited extrahepatic disease is defined in this protocol as follows: metastasis in up to one other organ (bone, subcutaneous, or pulmonary), limited to up to 2 nodules and amenable to resection or radiation. The extrahepatic lesions should be no larger than 2 cm in diameter each. The rationale for permitting this limited extrahepatic disease is that these types of lesions are amenable to surgical resection or radiation.
    6. Scans used to determine eligibility (CT scan of the chest/abdomen/pelvis and MRI of the liver) must be performed within 28 days prior to randomization. An MRI of the liver is required at screening to validate that CT accurately reflects the extent of disease in the liver.
    7. Patients must not have chemotherapy, radiotherapy, chemoembolization, radioembolization, or immunoembolization for their malignancy in the month prior to treatment and must have recovered from all side effects of therapeutic and diagnostic interventions except those listed in Appendix B of the study protocol. Patients receiving anti programmed cell death protein 1 (PD-1) immunotherapy such as pembrolizumab or nivolumab, or human cytotoxic T-lymphocyte antigen 4 blocking antibody such as ipilimumab should wait 8 weeks before Melphalan/HDS treatment.
    8. Patients must have an ECOG PS of 0-1 at screening and on the day prior to treatment.
    9. Patients must have adequate hepatic function as evidenced by total serum bilirubin ≤ 1.5 x the upper limit of normal (ULN) and a prothrombin time (PT) within 2 seconds of the upper normal limit. Aspartate aminotransferase/alanine aminotransferase (AST/ALT) must be ≤ 2.5 x ULN.
    10. Patients must have a platelet count > 100,000/µL, hemoglobin ≥ 10.0 gm/dL, white blood cell count (WBC) > 2,000/uL, absolute neutrophil count (ANC) ≥ 1.5 x 109/L, and a serum creatinine ≤ 1.5 mg/dL unless the measured creatinine clearance is > 40 mL/min/1.73 m2.
    11. Provided signed informed consent.
    1. Patients with Child-Pugh Class B or C cirrhosis or with evidence of portal hypertension by history, endoscopy, or radiologic studies.
    2. Those with New York Heart Association functional classification II, III or IV active cardiac conditions, including unstable coronary syndromes (unstable or severe angina, recent myocardial infarction), worsening or new-onset congestive heart failure, significant arrhythmias and severe valvular disease must be evaluated for risks of undergoing general anesthesia.
    3. History or evidence of clinically significant pulmonary disease that precludes the use of general anesthesia.
    4. For female patients of childbearing potential (i.e., have had a menstrual period within the past 12 months): unwilling or unable to undergo hormonal suppression to avoid menstruation during treatment.
    5. For female patients of childbearing potential (i.e. have had a menstrual period within the past 12 months): a positive serum pregnancy test (β-human chorionic gonadotropin) within 7 days prior to enrollment.
    6. Sexually active females of childbearing potential and sexually active males with partners of reproductive potential: unwilling or unable to use appropriate contraception from screening until at least 6 months after last administration of study treatment.
    7. Lactating women are excluded from study participation.
    8. Patients taking immunosuppressive drugs or who are unable to be temporarily removed from chronic anti-coagulation therapy.
    9. Patients with active bacterial infections with systemic manifestations (malaise, fever, leucocytosis) are not eligible until completion of appropriate therapy.
    10. Patients with severe allergic reaction to iodine contrast, which cannot be controlled by premedication with antihistamines and steroids (because a hepatic angiogram is needed for the Delcath system procedure).
    11. Patients with a history of or known hypersensitivity to melphalan or the components of the Melphalan/HDS system.
    12. Patients with latex allergy.
    13. Patients with a history of hypersensitivity to heparin or the presence of heparin-induced thrombocytopenia.
    14. Patients with a history of bleeding disorders or evidence of intracranial abnormalities which would put them at risk for bleeding with anti-coagulation (e.g., strokes, active metastases).
    15. Patients with a history of gastrinoma, hepatic vasculature incompatible with perfusion, hepatofugal flow in the portal vein or known unresolved venous shunting.
    16. Known varices at risk of bleeding, including medium or large esophageal or gastric varices, or active peptic ulcer.
    17. Patients with prior Whipple's procedure.
    18. Patients with brain metastases or presence of other intracranial lesions at risk for bleeding by history or baseline radiologic imaging. Active infection, including Hepatitis B and Hepatitis C infection. Patients with anti-hepatitis B core antibody (HBc) positive, or hepatitis B surface antigen (HBsAg) but DNA negative are exception(s).
    19. Uncontrolled endocrine disorders including diabetes mellitus, hypothyroidism, or hyperthyroidism.
    20. Received any investigational agent for any indication within 30 days prior to first treatment.
    21. Not recovered from side effects of prior therapy to ≤ Grade 1 (according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE v. 4.03). Certain side effects that are unlikely to develop into serious or life-threatening events (e.g. alopecia) are allowed at > Grade 1.

Genentech CO39262

A Phase III, Double-Blinded, Randomized, Placebo Controlled Study of Atezolizumab Plus Cobimetinib and Vemurafenib versus Placebo Plus Cobimetinib and Vemurafenib in Previously Untreated Braf V600 Mutation Positive Patients with Unresectable Locally Advanced or 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: Vemurafenib, Cobimetinib, Atezolizumab

    Synopsis:  This is a Phase III, double-blinded, placebo-controlled, randomized, multicenter study designed to evaluate the efficacy, safety, and pharmacokinetics of combination of atezolizumab (ATZ), cobimetinib and vemurafenib compared with combination of ATZ placebo, cobimetinib and vemurafenib in participants with previously untreated BRAFv600 mutation-positive metastatic or unresectable locally advanced melanoma.

    • Age greater than or equal to (>/=) 18 years
    • Females of child bearing potential and males with female partners must and use of contraceptive methods with a failure rate of less than or equal to (</=)1% per year is required during treatment and for 6 months post treatment. Males should not expose pregnant partners to sperm and refrain from donating sperm for 6 months post treatment
    • Histologically confirmed Stage IV (metastatic) or unresectable Stage IIIc (locally advanced) melanoma
    • Naive to prior systemic anti-cancer therapy for melanoma (example: chemotherapy, hormonal therapy, targeted therapy, immunotherapy, or other biologic therapies) except adjuvant treatment with interferon (IFN), interleukin (IL)-2, or vaccine therapies or herbal therapies
    • Documentation of BRAFv600 mutation-positive status in melanoma tumor tissue (archival or newly obtained) through use of a clinical mutation test approved by the local health authority
    • Eastern Cooperative Oncology Group Performance (ECOG) Status of 0 or 1
    • Measurable disease according to RECIST v1.1
    • Life expectancy >/=18 weeks
    • For participants not receiving therapeutic anticoagulation: International normalized ratio (INR) or activated partial thromboplastin time (aPTT) less than or equal to (</=) 1.5*upper limit of normal (ULN) within 28 days prior to initiation of study treatment
    • For participants receiving therapeutic anticoagulation: stable anticoagulant regimen and stable INR during the 28 days immediately preceding initiation of study treatment
  • Cancer-Related Exclusion Criteria:

    • Major surgical procedure within 4 weeks prior study treatment initiation
    • Traumatic injury or palliative radiotherapy within 2 weeks prior study treatment initiation
    • Active malignancy (other than BRAFv600 mutation-positive melanoma) or malignancy within 3 years prior to screening, with the exception of resected melanoma, resected basal cell carcinoma (BCC), resected cutaneous squamous cell carcinoma (SCC), resected carcinoma in situ of the cervix, resected carcinoma in situ of the breast, in situ prostate cancer, limited-stage bladder cancer, or other curatively treated malignancies from which the participant has been disease-free for at least 3 years

    Ocular Exclusion Criteria:

    • History of or evidence of retinal pathology on ophthalmologic examination that is considered a risk factor for neurosensory retinal detachment, central serous chorioretinopathy, retinal vein occlusion (RVO), or neovascular macular degeneration

    Cardiac Exclusion Criteria:

    • History of clinically significant cardiac dysfunction
    • Left ventricular ejection fraction (LVEF) below the institutional lower limit of normal or below 50%

    Central Nervous System (CNS) Exclusion Criteria:

    • Untreated or actively progressing CNS lesions (carcinomatous meningitis)
    • History of metastases to brain stem, midbrain, pons, or medulla, or within 10 millimeter (mm) of the optic apparatus (optic nerves and chiasm); or leptomeningeal metastatic disease; or intracranial hemorrhage

    Additional Exclusion Criteria:

    • Current severe, uncontrolled systemic disease (including, but not limited to, clinically significant cardiovascular, pulmonary, or renal disease) other than cancer
    • History of malabsorption or other clinically significant metabolic dysfunction
    • Pregnant or breastfeeding, or intending to become pregnant during the study
    • Prior allogeneic stem cell or solid organ transplantation
    • History of idiopathic pulmonary fibrosis, organizing pneumonia (example: bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography (CT) scan
    • History of autoimmune disease
    • Known clinically significant liver disease, inherited liver disease and active viral disease
    • Active tuberculosis
    • Treatment with therapeutic oral or intravenous (IV) antibiotics; or with a live, attenuated vaccine; or systemic immunosuppressive medication
    • Known hypersensitivity to biopharmaceutical agents produced in Chinese hamster ovary cells or any component of the atezolizumab, cobimetinib, or vemurafenib formulations

Millennium C28003

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. 

Oncolys TL03001

Open-label, Multi-center Phase IIa Study to Evaluate the Efficacy, Safety, and Immunological Response of OBP-301, Telomerase Specific Replication-competent Oncolytic Adenovirus in Patients with Unresectable 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: OBP-301

    Synopsis:  You have been diagnosed with malignant melanoma, a form of skin cancer, which is unable to be treated by surgery. You are invited to take part in the testing of a new treatment that may shrink your tumors, and stop new ones from developing. OBP-301 is not approved for use and is considered experimental. In this study, your tumor (s) will be injected (using a needle and syringe) with an experimental virus called OBP-301. OBP-301 is a virus (an organism that can cause infection) known as an adenovirus. Adenoviruses are common in nature and when they multiply in normal human cells they may cause infections which result in symptoms like those you could get when you have a cold or the flu. However, OBP-301 has been genetically changed from the original virus to only reproduce in target cancer cells that are omitting a certain signal. As a result of this reproduction, OBP-301 is believed to burst and kill tumor cells.

    The purpose of this study is to see if OBP-301 will cause the tumors to shrink, while causing as few side effects as possible.

    • Histologically or cytologically confirmed malignant melanoma that is unresectable Stage IIIb, IIIc, or IV (M1a and M1b).
    • Patients must have received and failed or refused available therapy for Stage IIIb, IIIc, or IV melanoma (e.g., Imlygic™)
    • Patients must be ≥18 years of age.
    • At least 1 injectable tumor of ≥1 cm2 at Screening.
    • Measurable disease based on RECIST version 1.1 (other than a single injected lesion).
    • Patients with Stage IV, M1b melanoma must have less than 4 visceral lesions.
    • Willing to have biopsy specimens taken at Screening and at Cycle 6.
    • Life expectancy of ≥6 months from the date of enrollment.
    • Karnofsky Performance Status Scale (KPS) score of ≥70%.
    • Adequate organ function, hematologic status, coagulation status, kidney function, and liver function as follows:
      • Absolute neutrophils >1,500/µL
      • Hemoglobin >9 g/dL, without transfusion or hematopoietic growth factor
      • Platelets >100,000/µL,
      • International normalized ratio (INR) <2.0 and prothrombin time (PTT) within normal limits
      • Serum creatinine <2 × upper limit of normal (ULN)
      • Aspartate transaminase (AST) and alanine transaminase (ALT) <2 × ULN
      • Total bilirubin <2.0 mg/dL
      • Serum lactate dehydrogenase (LDH) levels <1.5 × ULN
    • Understand the study requirements and the treatment procedures, and is willing to comply with all specified follow-up evaluations, and provides written informed consent before any study-specific tests or procedures are performed.
    • Patients of reproductive potential must use effective contraception for the duration of the study and for 3 months (90 days) after the last administered dose with IP. Effective contraception includes oral contraceptives, implantable hormonal contraception, double-barrier method or intrauterine device.
    • Patients who have had administration of chemotherapy, target therapy, and/or immunotherapy within the last 4 weeks before enrollment.
    • Patients who have received other investigational medication within the last 4 weeks or a period of its 5 half-lives (whichever is shorter) before enrollment.
    • Patients who have had radiotherapy within the 4 weeks before Cycle 1, Day must have recovered from toxicities related to radiotherapy [to ≤Grade 1]) before administration of OBP 301.
    • Effects of any other prior therapies not reverted to ≤Grade 1 (or ≤Grade 2 for alopecia and peripheral neuropathy).
    • Patients with clinically active brain metastases.
    • Active or chronic infection, including human immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV), except for asymptomatic bacterial colonization.
    • Patients diagnosed with additional malignancy within 5 years before enrollment with the exception of curatively treated basal cell carcinoma of the skin, squamous cell carcinoma of the skin and/or curatively resected in situ cervical and/or breast cancers.
    • Current requirement for chronic systemic immunosuppressive medication including pharmacologic dose of glucocorticoids (>10 mg prednisone) or cyclosporine, or chronic use of any such medication within the last 4 weeks before study enrollment.
    • Uncontrolled intercurrent illness including, but not limited to, uncontrolled diabetes, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/psychological incompetence, whereby in the opinion of the Investigator the patient is assessed as being unable to provide information, consent, or comply with the study requirements and procedures.
    • Patients who are pregnant or breastfeeding, or expecting to conceive or father children within the projected timeframe of the study, starting from the time of the Screening Visit through 3 months (90 days) after administration of the last dose of IP. Females of childbearing potential must have a negative serum pregnancy test at Screening and a negative urine pregnancy test at each visit before administration of the IP. A female not of childbearing potential is one who has undergone bilateral oophorectomy or who has had no menses for 12 consecutive months.

Provectus PV10-MM-1201

A Phase 1b/2 Study of PV-10 Intralesional Injection in Combination with Immune Checkpoint Inhibition for Treatment of 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: 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

Regeneron R2810-ONC-1540

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, or associated with immune-mediated adverse events that were >/= grade 1 within 90 days prior to the first dose of REGN2810, or associated with toxicity that resulted in discontinuation of the immune-modulating agent. Examples of immune modulating agents 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.

Syndax SNDX-275-0601

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.

Provectus PV10-MM-31

PV-10 Intralesional Injection vs Systemic Chemotherapy or Intralesional Oncolytic Viral Therapy for Treatment of Locally Advanced Cutaneous 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: 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.

  • 1. Age 18 years or older, male or female.
    2. Histologically or cytologically confirmed melanoma.
    3. Recurrent, satellite or in-transit locally advanced cutaneous or subcutaneous melanoma metastases (i.e. AJCC Stage IIIB, IIIC or Stage IV M1a with no active nodal or distant
    cutaneous or subcutaneous metastases). Subjects whose Stage IV M1a disease has been treated must be free of disease at distant cutaneous, subcutaneous and nodal sites for at
    least 30 days prior to randomization.
    4. At least 1 cutaneous Target Lesion (each Target Lesion ≥ 10 mm in longest diameter). Target Lesions should be at least 10 mm from any other lesion.
    5. No lesion > 30 mm in longest diameter; and no more than 20 lesions.
    6. Calculated required PV-10 dose ≤ 15 mL (based on total tumor burden).
    7. Performance Status: ECOG 0-2.
    8. Failed, did not tolerate, or not a candidate for treatment with at least one immune checkpoint inhibitor (due to co-morbidities, pre-existing autoimmune disease, drug
    unavailability or standard of care).
    9. Failed or not a candidate for targeted therapy with BRAF or combined BRAF/MEK inhibitors (i.e., BRAF V600 wild-type or due to drug unavailability or standard of care).
    10. Clinical Laboratories: 
        • Absolute neutrophil count (ANC) ≥ 1.5 x 109/L and platelet count ≥100 x 109/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). 
        • LDH ≤ 2 times the upper limit of normal (ULN).
    11. Thyroid function abnormality ≤ CTCAE Grade 2.
    12. Candidate for at least one comparator drug: 
        • Subjects must be candidates for at least one of the designated comparator drugs.

  • 1. Presence or history of visceral metastasis.
    2. Presence of active nodal or distant cutaneous or subcutaneous metastases (e.g., radiologic or clinical evidence of current nodal or distant cutaneous or subcutaneous disease).
    3. Presence of more than 20 melanoma lesions.
    4. Radiation therapy to any Study Lesion within 6 weeks of initial study treatment.
    5. 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.
    6. Immunotherapy for cancer within 4 weeks of initial study treatment.
    7. Local treatment (e.g., surgery, cryotherapy, laser ablation) to any Study Lesion within 4 weeks of initial study treatment.
    8. Anti-tumor vaccine therapy within 6 weeks of initial study treatment.
    9. Investigational agents within 4 weeks of initial study treatment.
    10. 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.
    11. Pregnancy:
    • Female subjects who are pregnant or lactating.
    • Female subjects who have positive serum pregnancy test taken within 21 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).
    12. Contraindication for all comparators:
    • Subjects with contraindications to all of the designated comparator drugs.

BMS CA209-204

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 the brain. Both asymptomatic and symptomatic patients.
      • Cohort A (asymptomatic patients): At least 1 measurable brain metastasis ≥ 0.5 cm in 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. Cohort B (symptomatic patients): Subjects with neurologic signs and symptoms related to metastatic brain lesions are eligibile. Subjects must have at least 1 measurable brain metastasis ≥ 0.5 cm in and ≤ 3 cm in longest diameter that has not been previously irradiated. No immediate requirement (within 3 weeks prior to first treatment) for local intervention (surgery, radiosurgery, corticosteroid therapy). Steroid use is permitted as defined in the protocol.
      • Prior stereotactic radiotherapy (SRT) and prior excision of up to 3 melanoma brain metastases is permitted if there has been complete recovery, with no neurologic sequelae, and measurable lesions remain. 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. lesions or prior excision must have occurred ≥ 3 weeks before the start of dosing for this study
      • Must have tumor tissue available for biomarker analysis. Biopsy should be excisional, incisional, punch, or core needle
      • Cohort A (asymptomatic): Subjects must be free of neurologic signs and symptoms related to metastatic brain lesions and must not have required or received systemic corticosteroid therapy within 10 days prior to first treatment. Cohort B (symptomatic): Subjects with neurologic signs and symptoms related to metastatic brain lesions are eligible per Amendment 02. Subjects with neurologic signs and symptoms may be treated with a total daily dose of no more than 4 mg of dexamethasone that is stable or tapering for 10 days prior to first treatment. Subjects with neurologic signs and symptoms who are not being treated with steroids are eligible for Cohort B and should have no experience of seizure within 10 days prior to first treatment.
      • Allowable prior therapy:
        • Approved adjuvant therapies, which may include molecularly-targeted agents, IFN α, and ipilimumab. Patients who received ipilimumab as adjuvant therapy must have a 6 month washout before receiving any dosing on this study
        • For advanced disease, interleukin-2 at any dose and/or IFN-α (any formulation, no washout required); MEK and BRAF inhibitors: washout for at least 4 weeks prior to the start of dosing in this study
        • Steroids for physiological replacement are allowed.
      • Cohort A (asymptomatic): ECOG performance status ≤1 Cohort B (symptomatic): ECOG performance status ≤2
    • 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
      • Cohort A (asymptomatic): 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
      • Cohort B (symptomatic): Subjects with neurologic signs and symptoms related to brain metastases who are being treated with a daily dose of higher than 4 mg dexamethasone or equivalent within 10 prior to the start of treatment with study drug are excluded. 
    • 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

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