Physician

Sanjiv Agarwala, MD

Study Coordinator

Linda Hosler, BA, BSN, RN
484-526-6038

Linda.Hosler@sluhn.org

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Treatment Agent: Nivolumab, NKTR-214

Synopsis: The purpose of the study is to test the effectiveness (how well the drug works), safety, and tolerability of the investigational drug called NKTR-214 , when combined with nivolumab versus nivolumab given alone in participants with previously untreated melanoma skin cancer that is either unable to be surgically removed or has spread. NKTR-214 and nivolumab in this informed consent may also be referred to as study medication(s) or treatment.

The study has other objectives as well.  Blood and tissue samples will be obtained for research purposes.  This is to explore how the study drugs behave in your body and the possible association between proteins and genetic markers in your blood or tumor tissue and how well the study drugs work.   In the future, this might help to determine which people respond best to these study drugs.    For this reason the results of these tests will not be sent to you or your doctor, will not be used in planning your care, and will not become part of your medical record.

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• Eastern Cooperative Oncology Group (ECOG) performance status of ≤1 (adults 18 years or older)/Lansky Performance Score ≥ 80% (minors ages 12-17 only)
• Histologically confirmed stage III (unresectable) or stage IV melanoma
• Treatment-naive participants (ie, no prior systemic anticancer therapy for unresectable or metastatic melanoma) with the exception of prior adjuvant treatment

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• Active brain metastases or leptomeningeal metastases
• Uveal melanoma
• Participants with an active, known or suspected autoimmune disease

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Physician

Sanjiv Agarwala, MD

Study Coordinator

Carolyn Seith, MSPH
484-503-4702

carolyn.seith@sluhn.org

 

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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.

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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.

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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.

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Physician

Sanjiv Agarwala, MD

Study Coordinator

Carolyn Seith, MSPH
484-503-4702

carolyn.seith@sluhn.org

 

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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.

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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="" whole="" brain="" irradiation="" for="" treatment="" of="" cns="" metastases="" will="" be="" />
• 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="" />
• Alkaline phosphatase =< 2="" x="" uln="" (="" />< 5="" x="" uln="" for="" patients="" with="" known="" liver="" involvement="" and="" />< 7="" x="" uln="" for="" patients="" with="" known="" bone="" />
• Total bilirubin =< 1.5="" x="" uln="" except="" subjects="" with="" normal="" direct="" bilirubin="" or="" those="" with="" known="" gilbert's="" />
• 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="" 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="" />
• 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="" cardiac="" echo="" or="" multi="" gated="" acquisition="" scan="" />
  • 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="" whole="" brain="" irradiation="" for="" treatment="" of="" cns="" metastases="" are="" />
• 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

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Physician

Sanjiv Agarwala, MD

Study Coordinator

Carolyn Seith, MSPH
484-503-4702

carolyn.seith@sluhn.org

 

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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.

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• 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

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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

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Physician

Sanjiv Agarwala, MD

Study Coordinator

Carolyn Seith, MSPH
484-503-4702

carolyn.seith@sluhn.org

 

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Treatment Agent: Cobimetinib and Atezolizumab

Synopsis:The purpose of this study is to compare the efficacy and safety of cobimetinib plus atezolizumab with the efficacy and safety of pembrolizumab in patients with a type of skin cancer called melanoma that has spread to other parts of the body (metastatic), cannot be removed by surgery (unresectable), and have not received any prior treatment.

Cobimetinib is a type of drug called a MEK inhibitor. Cobimetinib (Cotellic®) is approved in the United States and European Union and in other countries for the treatment of metastatic melanoma when used together with Zelboraf® (vemurafenib). For melanoma without a BRAF mutation, cobimetinib is considered an experimental drug. This means that health authorities have not approved cobimetinib either alone or in combination with any drug for the treatment of BRAFV600 wild-type melanoma.

Atezolizumab is a type of drug called a programmed death-ligand 1 (PD-L1) blocker. Atezolizumab is an experimental drug for skin cancer. Atezolizumab (Tecentriq®) has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of metastatic urothelial bladder cancer and metastatic non-small cell lung cancer.

Pembrolizumab is a type of drug called a programmed death-1 (PD-1) receptor blocker. Pembrolizumab (Keytruda®) is approved for the treatment of patients with unresectable metastatic melanoma.

The purpose of this study is to compare the effects, good or bad, of cobimetinib plus atezolizumab versus pembrolizumab on you and your melanoma to find out which is better. In this study, you will receive treatment with either cobimetinib plus atezolizumab or pembrolizumab.

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• Histologically confirmed Stage IV (metastatic) or unresectable Stage IIIc (locally advanced) melanoma
• Naive to prior systemic anti-cancer therapy for melanoma
• Documentation of BRAFV600 wild-type status in melanoma tumor tissue through use of a clinical mutation test approved by the local health authority
• A representative, formalin-fixed, paraffin-embedded (FFPE) tumor specimen in a paraffin block (preferred) or 20 slides containing unstained, freshly cut, serial sections must be submitted along with an associated pathology report prior to study entry. If 20 slides are not available or the tissue block is not of sufficient size, the patient may still be eligible for the study, after discussion with and approval by the Medical Monitor
• Measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1
• Age >=18 years at time of signing Informed Consent Form
• Ability to comply with the study protocol, in the investigator's judgment
• Histologically or cytologically confirmed BRAFV600 wild-type melanoma
• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1
• Life expectancy >=3 months
• Adequate hematologic and end-organ function
• For women of childbearing potential: agreement to remain abstinent or use at least two forms of effective contraceptive with a failure rate of < 1% per year during the treatment period and for at least 3 months after the last dose of cobimetinib and at least 5 months after the last dose of atezolizumab or pembrolizumab
• For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures (e.g. condom), and agreement to refrain from donating sperm, for at least 3 months after the last dose of cobimetinib
• Willingness and ability of participants to use an electronic device to report selected study outcomes

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• Inability to swallow medications
• Malabsorption condition that would alter the absorption of orally administered medications
• Pregnancy, breastfeeding, or intention of becoming pregnant during the study
• History of severe hypersensitivity reactions to components of the cobimetinib, atezolizumab, or pembrolizumab formulations
• Current or recent treatment with therapeutic antibiotics, live attenuated vaccines or systemic immunostimulatory/immunosuppresive medication
• Any serious medical condition or abnormality in clinical laboratory tests that, in the investigator's judgment, precludes the patient's safe participation in and completion of the study Cancer-Related Exclusion Criteria
• Ocular melanoma
• Major surgery or radiotherapy within 21 days prior to Day 1 of Cycle 1 or anticipation of needing such procedure while receiving study treatment
• Uncontrolled tumor-related pain
• Uncontrolled pleural effusion, pericardial effusion, or ascites requiring repeated drainage more than once every 28 days
• Active or untreated central nervous system (CNS) metastases Exclusions Related to Cardiovascular Disease
• Unstable angina, new-onset angina within last 3 months, myocardial infarction within the last 6 months prior to Day 1 of Cycle 1, or current congestive heart failure classified as New York Heart Association Class II or higher
• Left ventricular ejection fraction (LVEF) below institutional lower limit of normal or <50%, whichever is lower
• Poorly controlled hypertension, defined as sustained, uncontrolled, non-episodic baseline hypertension consistently above 159/99 mmHg despite optimal medical management
• History or presence of an abnormal electrocardiogram (ECG) that is clinically significant in the investigator's opinion, including complete left bundle branch block, second- or third degree heart block, or evidence of prior myocardial infarction Exclusions Related to Infections
• HIV infection
• Active tuberculosis infection
• Severe infections within 4 weeks prior to Day 1 of Cycle 1, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia
• Signs or symptoms of clinically relevant infection within 2 weeks prior to Day 1 of Cycle 1
• Treatment with oral or IV antibiotics within 2 weeks prior to Day 1 of Cycle 1
• Active or chronic viral hepatitis B or C infection Exclusions Related to Ocular Disease
• Known risk factors for ocular toxicity Exclusions Related to Autoimmune Conditions and Immunomodulatory Drugs
• Active or history of autoimmune disease or immune deficiency
• Prior allogeneic stem cell or solid organ transplantation
• History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan
• Treatment with systemic immunosuppressive medications within 2 weeks prior to Day 1, Cycle 1 Exclusions Related to Other Medical Conditions or Medications
• Active malignancy (other than melanoma) or a prior malignancy within the past 3 years
• Any Grade >=3 hemorrhage or bleeding event within 28 days of Day 1 of Cycle 1
• History of stroke, reversible ischemic neurological defect, or transient ischemic attack within 6 months prior to Day 1
• Proteinuria >3.5 gm/24 hr
• Consumption of foods, supplements, or drugs that are strong or moderate CYP3A4 enzyme inducers or inhibitors at least 7 days prior to Day 1 of Cycle 1 and during study treatment

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Physician

Sanjiv Agarwala, MD

Study Coordinator

Linda Hosler, BA, BSN, RN
484-526-6038

Linda.Hosler@sluhn.org

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Treatment Agent: IMO-2125

Synopsis:You are being asked to participate in this study because you have been diagnosed with refractory melanoma. Refractory melanoma is a type of cancer mainly found on the skin, which may not be responding to available treatments. Researchers have developed a drug called IMO-2125 (sometimes referred to as “study drug”), which may be used to treat refractory melanoma. This is an investigational study, which means the study drug is experimental and is not approved by the U.S. Food and Drug Administration (FDA).

The study is being done to compare the effectiveness of the study drug given in combination with ipilimumab compared to ipilimumab given alone.

Ipilimumab is a drug currently approved by the US Food and Drug Administration, Health Canada, the European Medicines Agency, and the Australian Therapeutic Goods Administration for the treatment of advanced melanoma.

Idera is the manufacturer of IMO-2125.

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• Subjects must be willing and able to sign the informed consent and comply with the study protocol.
• Subjects must be ≥18 years of age.
• Subjects must have histologically confirmed metastatic melanoma with measurable (by RECIST v1.1), stage III (lymph node or in transit lesions) or stage IVA, IVB, or IVC disease that is accessible for injection.
  • Patients must have confirmed progression during or after treatment with either nivolumab or pembrolizumab. Confirmed progression is defined as:
• Radiological progression (confirmed at least 4 weeks after the initial scan showing PD); or
• (For progression based solely on worsening of non-target or new, non-measurable disease) confirmation by an additional scan at least 4 weeks after the initial scan unless it is accompanied by correlative symptoms.
  • In addition, all the following must hold:
• No intervening anti-cancer therapy between the last course of nivolumab or pembrolizumab and the first dose of study treatment is allowed except for local measures (e.g., surgical excision or biopsy, focal radiation therapy).
• The interval between last nivolumab or pembrolizumab and start of study treatment should be at least 21 days with no residual anti-PD-1-related immune toxicities in excess of Grade 1 severity.
• If BRAF mutation status is unknown, before randomization the subject must have BRAF testing performed using an approved assay method.
• Patients with BRAF-positive tumor(s) are eligible for the study if they received prior treatment with a BRAF inhibitor (alone of in combination with a MEK inhibitor) or declined targeted therapy.
• Patients must have Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 1.
• Patients must meet the following laboratory criteria:
  • Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L (1500/mm3)
  • Platelet count ≥ 75 x 10^9/L (75,000/mm3)
  • Hemoglobin ≥ 8.0 g/dL (4.96 mmol/L)
  • Serum creatinine ≤ 1.5 x upper limit of normal (ULN) or calculated creatinine clearance ≥ 60 mL/minute
  • Aspartate aminotransferase (AST) ≤ 2.5 x ULN; alanine aminotransferase (ALT) ≤ 2.5 x ULN; AST/ALT < 5 x ULN if liver involvement
  • Serum bilirubin ≤ 1.5 x ULN, except in subjects with Gilbert's Syndrome who must have a total bilirubin < 3 mg/dL
• Women of childbearing potential (WOCBP) and men must agree to use effective contraceptive methods from Screening throughout the study treatment period and until at least 90 days after the last dose of either ipilimumab or IMO-2125, whichever is later.
• WOCBP must have a negative pregnancy test (serum or urine).

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• Ocular melanoma.
• Prior therapy with a toll-like receptor (TLR) agonist, excluding topical agents.
• Prior ipilimumab treatment with the exception of adjuvant treatment completed ≥6 months prior to enrollment
• Systemic treatment with interferon (IFN)-α within the previous 6 months.
• Known hypersensitivity to any oligodeoxynucleotide.
• Active autoimmune disease requiring disease-modifying therapy at the time of Screening.
• Subjects requiring systemic steroid therapy should be receiving ≤ 10 mg/day of prednisone (or equivalent) for the 2 weeks preceding start of study.
• Subjects with another primary malignancy that has not been in remission for at least 3 years, with the exception of non-melanoma skin cancer, curatively treated localized prostate cancer with non-detectable prostate-specific antigen, cervical carcinoma in situ on biopsy or a squamous intraepithelial lesion on Papanicolaou (Pap) smear, and thyroid cancer (except anaplastic).
• Active systemic infections requiring antibiotics
• Active hepatitis A, B, or C infection.
• Known diagnosis of human immunodeficiency virus (HIV) infection.
• Women who are pregnant or breastfeeding.
• Prior severe reaction to treatment with a human antibody that cannot be managed with standard supportive measures.
• Known central nervous system, meningeal, or epidural disease. However, subjects with known brain metastases are allowed if the brain metastases are stable for ≥4 weeks before the first dose of study treatment.
• Impaired cardiac function or clinically significant cardiac disease.

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Physician

Sanjiv Agarwala, MD

Study Coordinator

Linda Hosler, BA, BSN, RN
484-526-6038

Linda.Hosler@sluhn.org

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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.

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• 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.

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• 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.

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Physician

Sanjiv Agarwala, MD

Study Coordinator

Linda Hosler, BA, BSN, RN
484-526-6038

Linda.Hosler@sluhn.org

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Treatment Agent: Pembrolizumab, ImmunoPulse tavo

Synopsis: The purpose of this study is to find out what effects, good and/or bad, the combination of a type of gene therapy treatment called plasmid electroporation and pembrolizumab has on your cancer. 

For the gene therapy treatment, we will inject a human gene into some of your tumor cells and, in order to make sure that the gene stays in the cells, we will send 6 bursts of electricity (“electroporation”) into the cells. The gene that will be injected into your tumor cells is called pIL-12 (plasmid interleukin-12) and is engineered with genetic material (DNA) to force the tumor to make the IL-12 protein. The number of tumors that you will have treated will be determined by your physician. The combination of pIL-12 injection and electroporation is being tested in other studies but has not been approved by the FDA (Food and Drug Administration).

Pembrolizumab binds to specific marker (PD-1) on immune cells and limits the tumor’s ability to exploit a “natural brake” that can suppress immune responses directed against tumor cells. Pembrolizumab has been approved for use in certain types of a cancers, including melanoma.

This study is being paid for by OncoSec Medical Inc., the company that makes the electroporation device, and is the sponsor of this study.  Merck, the company that manufactures Pembrolizumab, will provide the study drug at no cost to study participants.

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• Pathologically documented unresectable melanoma, AJCC Stage III or IV. Patients must have histological or cytological confirmed diagnosis of unresectable melanoma with progressive locally advanced or metastatic disease.
• Patients must be refractory to anti-PD-1 monoclonal antibodies (mAb) defined as pembrolizumab or nivolumab as either as monotherapy or in combination with other approved checkpoint inhibitors or targeted therapies according to their approved label, defined as (patients must meet all of the following criteria):
  • Received at least 4 doses of anti-PD1 mAb for pembrolizumab; minimum dose of 240 mg given every two weeks for nivolumab in monotherapy; minimum dose of 1 mg/kg given Q3W for nivolumab in combination with ipilimumab
  • Progressive disease after anti-PD1 mAb will be defined according to RECIST v1.1.
  • Documented disease progression within 24 weeks of the last dose of anti-PD1 mAb.

• Resolution/improvement of anti-PD1 mAb-related AEs

  • No history of common toxicity criteria adverse events (CTCAE) Grade 4 irAEs from anti-PD1 mAb.
  • No history of CTCAE Grade 3 requiring steroid treatment (>10 mg/day prednisone or equivalent dose) for >12 weeks or CTCAE Grade 2 pneumonitis regardless of steroid treatment.
  • Minimum of 4 weeks (washout period) from the last dose of anti PD1 mAb.
• Prior treatment with an approved BRAF inhibitor if BRAF V600 mutation-positive.
• Age ≥ 18 years of age on day of signing informed consent.
• Has a performance status of 0 or 1 on the ECOG Performance Scale.

• Have measurable disease based on RECIST v1.1, with at least one anatomically distinct lesion. Lesion or lesions must meet all the following baseline criteria:

  • Accessible for electroporation,
  • Must be accurately measured in at least one dimension (longest diameter in the plane of measurement is to be recorded)

• Demonstrate adequate organ function as defined below. All screening laboratories should be performed within 10 days of treatment initiation.

  System Laboratory Value Hematological Absolute neutrophil count (ANC) ≥1.5 × 109/L Platelets ≥100 × 109/L Hemoglobin ≥9 g/dL or ≥5.6 mmol/L Renal Creatinine* OR ≤1.5 × the upper limit of normal (ULN) OR Measured or calculated creatinine clearance (CrCl) Glomerular filtration rate (GFR) can also be used instead of creatinine or CrCl ≥ 60 mL/min for patient with creatinine levels >1.5 × institutional ULN Hepatic Total bilirubin ≤1.5 × ULN OR direct bilirubin ≤ULN for patients with total bilirubin levels > 1.5× ULN Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 × ULN OR ≤5 × ULN for patients with liver metastases Coagulation International Normalized Ratio (INR) or Prothrombin Time (PT) ≤1.5 × ULN unless patient is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants Activated Partial Thromboplastin Time (aPTT)

  * Creatinine clearance should be calculated per institutional standard.

• Women of childbearing potential must have negative serum or urine pregnancy test within 72 hours prior to receiving the first study drug administration.
• For women of childbearing potential, must be willing to use an adequate method of contraception from 30 days prior to the first study drug administration and 120 days following last day study drug administration
• Male patients of childbearing potential must be surgically sterile, or must agree to use adequate method of contraception during the study and at least 120 days following the last day of study drug administration.
• Able and willing to provide written informed consent and to follow study instructions.

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• Patient has disease that is suitable for local therapy administered with curative intent.
• Patient with a diagnosis of uveal melanoma.
• Patient has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer.
• Clinically active cerebral or non-measurable bone-only metastases. Patients with up to 3 (neurological performance status of 0) cerebral metastases may be enrolled, provided that all lesions have been adequately treated with stereotactic radiation therapy or gamma-knife therapy with no evidence of progression, and have not required steroids, for at least two months prior to enrolment.
• Greater than 3 sites of visceral metastases. For patients with less than or equal to 3 visceral metastases and liver lesions must meet RECIST v1.1 criteria for SD for at least 1 month prior to enrolment.
• Patients with electronic pacemakers or defibrillators.
• Patients who have a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
• Patients who have known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected); Note: Patients who have been vaccinated against Hepatitis B and who are positive only for the Hepatitis B surface antibody are permitted to participate in the study.
• Patient has a diagnosis of immunodeficiency or is 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.
• Patients who have received a live-virus vaccination within 30 days of the first dose of treatment. Seasonal flu vaccines that do not contain live virus are permitted.
• Patient has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients.
• Patients who have received transfusion of blood products (including platelets or red blood cells) or administration of colony stimulating factors (including G-CSF, GM-CSF or recombinant erythropoietin) within 4 weeks prior to study Cycle 1, Day 1 (baseline).
• Patient has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis.
• Patient has a history of interstitial lung disease.
• Patient has an active infection requiring systemic therapy.
• Patient has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the patient's participation for the full duration of the trial, or is not in the best interest of the patient to participate, in the opinion of the treating investigator.
• Patient has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events 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 or radiation therapy of >30 Gy, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting study combination therapy.
• Participation in another clinical trial within 30 days of screening. Note: Patients participating in an observational study are an exception to this criterion and may qualify for the study with Sponsor approval
• Patients who have had any targeted small molecule therapy or any immunotherapeutic after their confirmed progression on anti-PD-1 therapy.
• Patient has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
• Patients who are pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the screening visit through 120 days after the last dose of trial treatment.

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Physician

Sanjiv Agarwala, MD

Study Coordinator

Linda Hosler, BA, BSN, RN
484-526-6038

Linda.Hosler@sluhn.org

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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.

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• 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.

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• 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

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Physician

Sanjiv Agarwala, MD

Study Coordinator

Linda Hosler, BA, BSN, RN
484-526-6038

Linda.Hosler@sluhn.org

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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.

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• Age 18 years or older, male or female.
• Histologically or cytologically confirmed melanoma.
• 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.
• 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.
• 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: ECOG 0-2.
• 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).
• 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).
• 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).
• Thyroid function abnormality ≤ CTCAE Grade 2.
• Candidate for at least one comparator drug:
  • Subjects must be candidates for at least one of the designated comparator drugs.

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• Presence or history of visceral metastasis.
• 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).
• Presence of more than 20 melanoma lesions.
• Radiation therapy to any Study Lesion within 6 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 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 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).
• Contraindication for all comparators:
  • Subjects with contraindications to all of the designated comparator drugs.

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Physician

Sanjiv Agarwala, MD

Study Coordinator

Carolyn Seith, MSPH
484-503-4702

carolyn.seith@sluhn.org

 

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Treatment Agent: REGN2810

Synopsis:  The objective of this program is to provide access to CEMIPLIMAB to patients with metastatic (mCSCC) or locally advanced cutaneous squamous cell carcinoma (laCSCC) who are not candidates for surgery prior to CEMIPLIMAB being commercially available. CEMIPLIMAB is an investigational drug, which means that it is not approved for sale in the United States by the U.S. Food and Drug Administration (FDA).

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Key Inclusion Criteria:

1. Histologically confirmed diagnosis of invasive Cutaneous Squamous Cell Carcinoma (CSCC)
2. Hepatic function:
   1. Total bilirubin ≤1.5 x upper limit of normal (ULN; if liver metastases ≤3 x ULN).
   2. Transaminases ≤3 x ULN (or ≤5.0 x ULN, if liver metastases)
   3. Alkaline phosphatase ≤2.5 x ULN (or ≤5.0 x ULN, if liver or bone metastases) Patients with hepatic metastases: If transaminase levels (AST and/or ALT) are >3 x but ≤5 x ULN, total bilirubin must be ≤1.5 x ULN. If total bilirubin is >1.5 x but ≤3 x ULN, both transaminases (AST and ALT) must be ≤3 x ULN
3. Renal function: serum creatinine ≤1.5 x ULN or estimated creatinine clearance (CrCl) >30 mL/min
4. Bone marrow function:
   1. Hemoglobin ≥9.0 g/dL
   2. Absolute neutrophil count (ANC) ≥1.5 x 10^9/L
   3. Platelet count ≥75 x 10^9/L
5. Patients not candidates for surgery include the examples below, but are not limited to:
   • Metastatic disease (distant or nodal)
   • Recurrence in the same location and curative resection is unlikely
   • Significant local invasion that precludes complete resection
   • Surgery may result in severe disfiguration or dysfunction
   • Other conditions deemed to be contraindicating for surgery

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Key Exclusion Criteria:

1. 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 (irAEs). The following are not exclusionary: vitiligo, childhood asthma that has resolved, type 1 diabetes, residual hypothyroidism that required only hormone replacement, or psoriasis that does not require systemic treatment
2. Prior treatment with other immune modulating agents that was (a) within fewer than 4 weeks (28 days) prior to the first dose of cemiplimab (REGN2810), or (b) associated with immune-mediated adverse events (AEs) that were ≥ Grade 1 within 90 days prior to the first dose of cemiplimab (REGN2810), or (c) associated with toxicity that resulted in discontinuation of the immune-modulating agent
3. Continuous immunosuppressive corticosteroid treatment (doses >10 mg prednisone daily or equivalent) within 2 weeks prior to the first dose of cemiplimab (REGN2810)Note: Patients who require brief course of steroids (eg, as prophylaxis for imaging studies) are not excluded
4. Active uncontrolled infection requiring therapy, including infection with human immunodeficiency virus, or active infection with hepatitis B virus (HBV) or hepatitis C virus (HCV)
5. History of pneumonitis within the last 5 years

Note: Other protocol defined Inclusion/Exclusion criteria may apply

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Physician

Sanjiv Agarwala, MD

Study Coordinator

Linda Hosler, BA, BSN, RN
484-526-6038

Linda.Hosler@sluhn.org

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Treatment Agent: UV1

Synopsis: You are being asked to take part in this study because you have advanced melanoma and you are planned for treatment with pembrolizumab.

This is a clinical study involving an investigational drug, UV1. An investigational drug is a drug which has not yet been approved by the U.S. Food and Drug Administration (FDA).

The purpose of this study is to investigate the safety and tolerability of administering UV1 when given in combination with pembrolizumab, an FDA-approved cancer drug (immunotherapy) for melanoma. This is the first study of this drug combination.

UV1 has previously been tested in humans in clinical studies for prostate and non-small cell lung cancers. UV1 has also been investigated in combination with ipilimumab in a clinical study for melanoma patients.

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• Stage IIIB, IIIC or IV melanoma
• Previously untreated and eligible for pembrolizumab treatment (prior treatment with BRAF and MEK inhibitors permitted) 3) Adequate blood, liver and kidney function 4) Consent to undergo tumor biopsies during the study

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• Uveal or ocular malignant melanoma
• History of hematologic or primary solid tumor malignancy with the exception of patients in remission for at least 5 years, as judged by the investigator are allowed
• Prior systemic treatment for unresectable or metastatic melanoma. Exception: Prior treatment with BRAF and MEK inhibitors permitted. A washout period of at least 3-half-lives (median terminal half-life) prior to the first dose of trial treatment must have elapsed.
• Prior therapy with an anti-CTLA4, anti-PD-1, anti-PD-L1, anti-PD-L2 agent or oncolytic virus.
• Known hypersensitivity to GM-CSF
• Women who are breastfeeding, pregnant or expect to be pregnant during the study through 6 months after the last dose
• Men who plan to become a father during the study through 4 months after the last dose of study medication
• Known history of, or any evidence of active, non-infectious pneumonitis
• History of cardiac disease

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Physician

Sanjiv Agarwala, MD

Study Coordinator

Linda Hosler, BA, BSN-RN

484-503-4152

 

Linda.Hosler@sluhn.org

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Treatment Agent: L19IL2 and L19TNF

Synopsis: Efficacy of Daromun neoadjuvant treatment followed by surgery to improve in a statistically significant manner the recurrence-free survival (RES) of Stage IIIB/C melanoma patients with respect to the standard of care (surgery alone).

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• Diagnosis of clinical stage IIIB and IIIC metastatic melanoma, eligible for complete surgical resection of all metastases (surgically resectable).
• Eligible subjects must have measurable disease and must be candidate for intralesional therapy with at least one injectable cutaneous, subcutaneous, or nodal melanoma lesion (≥ 10 mm in longest diameter) or with multiple injectable lesions that in aggregate have a longest diameter of ≥ 10 mm.
• Males or females, age ≥ 18 years
• ECOG Performance Status/WHO Performance Status ≤ 1
• Life expectancy of > 24 months
• Absolute neutrophil count > 1.5 x 109/L
• Hemoglobin > 9.0 g/dL
• Platelets > 100 x 109/L
• Total bilirubin ≤ 30 μmol/L (or ≤ 2.0 mg/dl)
• ALT and AST ≤ 2.5 x the upper limit of normal (ULN)
• Serum creatinine < 1.5 x ULN and 24 h creatinine clearance > 60 mL/min
• LDH serum level ≤ 1.5 x ULN
• Documented negative test for HIV, HBV and HCV. For HBV serology, the determination of HBsAg, anti-HBsAg Ab and anti-HBcAg Ab is required. In patients with serology documenting previous exposure to HBV (e.g. anti-HBs Ab with no history of vaccination and/or anti-HBc Ab) negative serum HBV-DNA is also required.
• All acute toxic effects (excluding alopecia) of any prior therapy must have resolved to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) (v4.03) Grade ≤ 1 unless otherwise specified above
• All women of childbearing potential (WOCBP) must have negative pregnancy test results at the screening. WOCBP must be using, from the screening to three months following the last study drug administration, highly effective contraception methods. WOCBP and effective contraception methods are defined by the "Recommendations for contraception and pregnancy testing in clinical trials" issued by the Head of Medicine Agencies' Clinical Trial Facilitation Group and which include, for instance, progesterone-only or combined (estrogen- and progesterone-containing) hormonal contraception associated with inhibition of ovulation, intrauterine devices, intrauterine hormone-releasing systems, bilateral tubal occlusion, vasectomized partner or sexual abstinence. Pregnancy test will be repeated at the safety visit (only WOCBP and only for patients in Arm 1).
• Male patients with WOCBP partners must agree to use simultaneously two acceptable methods of contraception (i.e. spermicidal gel plus condom) from the screening to three months following the last study drug administration.
• Evidence of a personally signed and dated informed consent document indicating that the subject has been informed of all pertinent aspects of the study.
• Willingness and ability to comply with the scheduled visits, treatment plan, laboratory tests and other study procedures.

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• Uveal melanoma or mucosal melanoma
• Evidence of distant metastases at screening
• Previous or concurrent cancer that is distinct in primary site or histology from the cancer being evaluated in this study except cervical carcinoma in situ, treated basal cell carcinoma, superficial bladder tumors (Ta, Tis & T1), second primary melanoma in situ or any cancer curatively treated ≥ 5 years prior to study entry
• Presence of active infections (e.g. requiring antimicrobial therapy) or other severe concurrent disease, which, in the opinion of the investigator, would place the patient at undue risk or interfere with the study.
• History within the last year of acute or subacute coronary syndromes including myocardial infarction, unstable or severe stable angina pectoris.
• Inadequately controlled cardiac arrhythmias including atrial fibrillation
• Heart insufficiency (> Grade II, New York Heart Association (NYHA) criteria)
• LVEF ≤ 50% and/or abnormalities observed during baseline ECG and Echocardiogram investigations that are considered as clinically significant by the investigator.
• Uncontrolled hypertension
• Ischemic peripheral vascular disease (Grade IIb-IV)
• Severe diabetic retinopathy
• Active autoimmune disease
• History of organ allograft or stem cell transplantation
• Recovery from major trauma including surgery within 4 weeks prior to enrollment.
• Known history of allergy to IL2, TNF, or other human proteins/peptides/antibodies or any other constituent of the product.
• Breast feeding female
• Anti-tumor therapy (except small surgery) within 4 weeks before enrollment
• Previous in vivo exposure to monoclonal antibodies for biological therapy in the 6 weeks before enrollment
• Planned administration of growth factors or immunomodulatory agents within 7 days before enrollment
• Patient requires or is taking corticosteroids or other immunosuppressant drugs on a long-term basis. Limited use of corticosteroids to treat or prevent acute hypersensitivity reactions is not considered an exclusion criterion.
• Any conditions that in the opinion of the investigator could hamper compliance with the study protocol

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