Cabozantinib and Pembrolizumab for Advanced Metastatic Melanoma

The study aims to evaluate the safety and preliminary efficacy of the combination of cabozantinib and pembrolizumab in advanced melanoma

This is an open-label, Phase 1b/2 trial for adults with advanced melanoma. The objective of the Phase 1b portion of the study is to establish the recommended Phase 2 dose of cabozantinib in combination with pembrolizumab in patients with unresectable melanoma and assess the safety and tolerability of the combined treatments. The objective of the Phase 2 portion of the study is to evaluate the preliminary efficacy of the established dose of cabozantinib in combination with pembrolizumab as measured by best overall response rate (ORR) (complete response [CR] + partial response [PR]) with the combination of agents in patients with unresectable stage III or stage IV melanoma.

Cabozantinib will be administered in the tablet form, at three dose levels: 40, 20 and 60 mg per day. Pembrolizumab will be administered as an intravenous infusion at a fixed dose of 200 mg once every 3 weeks.

Cabozantinib is an oral small molecule potent inhibitor of pro-invasive receptor tyrosine kinases (RTKs). Cabozantinib will be administered in the tablet form, at three dose levels: 40, 20 and 60 mg per day, in combination with pembrolizumab. The drug is taken continuously for 21 days or 3 weeks. This period of time is defined as one treatment cycle.

Pembrolizumab is a humanized antibody which will be administered as an intravenous infusion at a fixed dose of 200 mg once every 3 weeks in combination with cabozantinib.

All adverse events (AEs )will be considered in DLT assessment unless an event is clearly unrelated to trial treatment. The National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 will be used.

Phase 2: Best overall response rate (ORR) (complete response (CR) + partial response (PR)) per RECIST v1.1

PFS is defined as the time between the first dose of study therapy and the earliest date of progression or death (participants who have neither progressed nor died will be censored at the most recent last-known-alive date).

OS is defined as defined as the time between the first dose of study therapy and death (participants who have not died will be censored at the most recent last-known-alive date).

Inclusion Criteria: A patient must meet all of the following criteria to be eligible for enrollment (defined as receiving the first trial treatment) in the trial: Histologically or cytologically confirmed unresectable in-transit (stage IIIc) or metastatic (stage IV) melanoma. Must have at least 1 lesion that qualifies as a measurable (target) lesion per RECIST v1.1 Must have available and be willing to submit archival tissue as described in Section 11.9. The tumor tissue must be adequate for PD-L1 testing. Subjects must be willing to have blood draws for future biomarker testing as outlined in Section 11.9. The subject has an ECOG performance score of ≤2 However; the phase 1b part will include only ECOG performance of 0-1 and life expectancy of >12 weeks Aged 18 years and older. The subject should not have received any treatment for advanced melanoma, EXCEPT, BRAF and/or MEK inhibitor (2 week washout). The subjects who have received adjuvant therapy including anti- PD-1 can be included in the study, if the last dose of the adjuvant treatment was ≥ 6 months prior to developing metastatic relapse. The subject is capable of understanding and complying with the protocol requirements and has signed the informed consent document. Female patients of childbearing potential, must have a negative urine or serum pregnancy test within 72 hours prior to taking the first dose of study medication. If the urine test is positive or cannot be confirmed as negative then a serum test is required which must be negative for the patient to enroll. Able to swallow pills The subject must have recovered to baseline or < Grade 1 CTCAE v 4 from toxicities related to any prior treatments, unless AE(s) are clinically nonsignificant and /or stable on supportive therapy. Exclusion Criteria: A patient meeting any of the following criteria is not eligible to participate in this study: Subject had prior treatment with any anti-PD-1, anti-PD-L1, or anti- PD-L2 agent for the treatment of advanced melanoma (although prior use in adjuvant setting is allowed if the last dose >6 months prior developing metastatic disease). Subjects with diagnosis of ocular and mucosal melanoma Subject had prior cabozantinib for any indication. Subject who received any small molecule tyrosine kinase inhibitor within 2 weeks before first dose of study treatment. Subject who has had chemotherapy, radioactive, or biological cancer therapy within four weeks prior to the first dose of study drug, or who has not recovered to CTCAE Grade 1 or better from the AEs due to cancer therapeutics administered more than four weeks earlier. Radiation therapy for bone metastasis within 2 weeks, any other radiation therapy within 4 weeks before first dose of study treatment. Systemic treatment with radionuclides within 6 weeks before the first dose of study treatment. Subjects with clinically relevant ongoing complications from prior radiation therapy are not eligible. Patient is currently participating or has participated in a study of an investigational agent or using an investigational device within 30 days of the first dose of study drug. (A patient in the Survival Follow up phase of an investigational agent where no further treatment is expected is eligible).Patient is expected to require any other form of systemic or localized antineoplastic therapy while on study. Patient is on any systemic corticosteroid therapy (more than 10 mg daily of prednisone or equivalent) within one week before the planned date for first dose of randomized treatment or on any other form of immunosuppressive medication. Patient has a history of a malignancy (other than the disease under treatment in the study) within 2 years prior to first study drug administration. This should exclude adequately treated Stage 1 or Stage 2 basal/squamous cell carcinoma of the skin, carcinoma in situ of the cervix or breast, or other in situ cancers. Shorter intervals can be considered after discussion with Sponsor. Patient has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Patients with previously treated brain metastases may participate provided they are stable (without evidence of progression by MRI for at least four weeks prior to the first dose of study drug), have no evidence of new or enlarging brain metastases, neurologically asymptomatic and are off systemic steroids for at least two weeks. Patient previously had a severe hypersensitivity reaction to treatment with another monoclonal antibody or small molecule tyrosine kinase inhibitor. Patient has an active autoimmune disease or a documented history of autoimmune disease or syndrome that requires systemic steroids or immunosuppressive agents. Patients with vitiligo or resolved childhood asthma/atopy would be an exception to this rule. Patients that require intermittent use of bronchodilators or local steroid injections would not be excluded from the study. Patients with hypothyroidism stable on hormone replacement will not be excluded from the study. Patient has an active infection requiring systemic therapy. Patient has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). Patient has a known history of or is positive for Hepatitis B (HBsAg reactive) or Hepatitis C (HCV RNA [qualitative] is detected). Patients will be tested for hepatitis B or C infections during screening if they are considered by the investigator to be at higher risk for these infections and have not been previously tested. Patient has a 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. Patient has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial. Patient is, at the time of signing informed consent, a regular user (including "recreational use") of any illicit drugs or had a recent history (within the last year) of substance abuse (including alcohol). Patient is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the study. Patient has received a live vaccine within 30 days prior to first dose. Patient requires concomitant anticoagulation with oral anticoagulants (eg, warfarin, direct thrombin and Factor Xa inhibitors) or platelet inhibitors (eg, clopidogrel). Allowed anticoagulants are the following: Low-dose aspirin for cardioprotection (per local applicable guidelines) is permitted. Low-dose low molecular weight heparins (LMWH) are permitted. Anticoagulation with therapeutic doses of LMWH is allowed in subjects without known brain metastases who are on a stable dose of LMWH for at least 6 weeks before first dose of study treatment, and who have had no clinically significant hemorrhagic complications from the anticoagulation regimen or the tumor Patient has experienced any of the following within 3 months before the first dose of study treatment: clinically-significant hematemesis, hematuria or gastrointestinal bleeding Clinically-significant hemoptysis of ≥ 0.5 teaspoon (2.5ml) of red blood any other signs indicative of pulmonary hemorrhage Present use or anticipated need for strong CYP3A4 inducers or inhibitors. Patients may not have received a strong CYP3A4 inducer within 12 days prior to registration nor a strong CYP3A4 inhibitor within 7 days prior to registration. Because the lists of these agents are constantly changing, it is important to regularly consult a comprehensive list such as the one located at http://medicine.iupui.edu/clinpharm/ddis/. The subject has uncontrolled, significant intercurrent or recent illness including, but not limited to, the following conditions: Cardiovascular disorders including, Congestive heart failure (CHF): New York Heart Association (NYHA) Class 3 (moderate) or Class 4 (severe) at the time of screening. Concurrent uncontrolled hypertension defined as sustained BP ≥150 mm Hg systolic (grade 2), or ≥ 90 mm Hg diastolic (grade 2) despite optimal antihypertensive treatment. (Note: If there is any BP measurement that is performed within the screening period that is < 150 mm Hg systolic and < 90 mm Hg diastolic, then BP does not meet definition of sustained.) Any congenital history of long QT syndrome. Any of the following within 6 months before the first dose of study treatment: unstable angina pectoris clinically-significant cardiac arrhythmias stroke (including TIA, or other ischemic event) myocardial infarction thromboembolic event requiring therapeutic anticoagulation (Note: subjects with a venous filter (e.g. vena cava filter) are not eligible for this study Cavitating pulmonary lesions(s) or known endotracheal or endobronchial disease manifestation. Lesions invading or encasing any major blood vessels. Gastrointestinal disorders particularly those associated with a high risk of perforation or fistula formation including: Any of the following within 28 days before the first dose of study treatment: intra-abdominal tumor/metastases invading GI mucosa (malignant abdominal ascites does not constitute mucosal invasion) active peptic ulcer disease, inflammatory bowel disease (including ulcerative colitis and Crohn's disease), diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis malabsorption syndrome] Any of the following within 6 months before the first dose of study treatment: history of abdominal fistula gastrointestinal perforation bowel obstruction or gastric outlet obstruction intra-abdominal abscess. Note: Complete resolution of an intra-abdominal abscess must be confirmed prior to initiating treatment with cabozantinib even if the abscess occurred more than 6 months ago. GI surgery (particularly when associated with delayed or incomplete healing) within 28 days. Note: Complete healing following abdominal surgery must be confirmed prior to initiating treatment with cabozantinib even if surgery occurred more than 28 days ago. Other disorders associated with a high risk of fistula formation including PEG tube placement within 3 months before the first dose of study therapy or concurrent evidence of intraluminal tumor involving the trachea and esophagus. Moderate or severe hepatic impairment. Other clinically significant disorders such as: active infection requiring systemic treatment within 28 days before the first dose of study treatment serious non-healing wound/ulcer/bone fracture within 28 days before the first dose of study treatment history of organ transplant concurrent uncompensated hypothyroidism or thyroid dysfunction within 7 days before the first dose of study treatment Major surgery (eg, thoracotomy, removal or biopsy of brain metastasis) within 3 months before Week 1 Day 1. Complete wound healing from major surgery must have occurred 1 month before Week 1 Day 1 and from minor surgery (eg, simple excision, tooth extraction) at least 10 days before Week 1 Day 1. Subjects with clinically relevant ongoing complications from prior surgery are not eligible. The subject has organ and marrow function and laboratory values as follows: Table 2: Laboratory values for exclusion: System Laboratory Value Hematological Absolute neutrophil count (ANC) <1,500/mm3/mcL White blood cell count < 2,500/mm3. Platelets <100,000/mm3 / mcL Hemoglobin <9 g/dL- transfusion of packed red blood cells allowed up to 7 days prior to D1. Renal Serum creatinine >1.5 X upper limit of normal (ULN), GFR <30 ml/min Serum electrolytes Serum phosphorus, magnesium, and potassium < LLN supplementation allowed if necessary Hepatic Serum total bilirubin > 1.5 X ULN Patients with a total bilirubin > 1.5 X ULN will not be excluded if Direct bilirubin >/= ULN AST (SGOT) and ALT (SGPT) > 2.5 X ULN Albumin < 2.8 g/dl Coagulation International Normalized Ratio (INR) or Prothrombin Time (PT) Activated Partial Thromboplastin Time (aPTT) >1.3 ULN. Patients on oral anticoagulation are excluded Urine Urine protein/creatinine ratio (UPCR) > 1 (113.2 mg/mmol) creatinine or 24-hr urine protein of >/= 1 g * Cardiovascular: The subject has a corrected QT interval calculated by the Fridericia formula (QTcF) >/= 500ms within 14 days before Cycle 1 Day 1. Ejection fraction on Echo or MUGA </= 50%. NYHA class >/= 3. Note: If a single ECG show a QTcF with an absolute value </= 500 ms, two additional ECGs at intervals of approximately 2 min must be performed within 30 min after the initial ECG, and the average of these three consecutive results for QTcF will be used to determine eligibility.