Nivolumab Plus Axitinib in Patients With Anti-PD1 Refractory Advanced Melanoma

Study Overview
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Brief Summary
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This is Phase II trial of nivolumab plus axitinib for patients with unresectable stage III or IV melanoma who have progressed on prior anti-PD1 therapy with or without concomitant anti-CTLA4 therapy. Patients will receive treatment with nivolumab 480 mg intravenously every 4 weeks and axitinib 5 mg twice daily by mouth. Patients may continue both agents for up to two years if they do not experience disease progression or dose-limiting toxicities.

Detailed Description
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This trial hypothesizes that decreasing hypoxia in the TME will re-sensitize melanoma tumors to anti-PD1 therapy. Axitinib has already been safely combined with anti-PD1 therapy and was overall well-tolerated. With nivolumab plus axitinib taken together, based on previously published work and data from our laboratories, it is hypothesized that axitinib can metabolically remodel the TME to render it more sensitive to ICB, specifically by reducing intra-tumoral hypoxia, increasing T cell infiltration, and increasing polyfunctional T cells. It will determined if treatment with nivolumab plus axitinib will prolong both progression-free and overall survival.

Official Title
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A Phase II Trial of Nivolumab Plus Axitinib in Patients With Anti-PD1 Refractory Advanced Melanoma

Conditions
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Advanced Melanoma, Unresectable Melanoma

Intervention / Treatment
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* Drug: Nivolumab
* Drug: Axitinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Have unresectable (stage III) or advanced (stage IV) cutaneous or mucosal melanoma. Patients with uveal melanoma are not eligible. Progressed on prior anti-PD1 therapy with or without anti-CTLA4 therapy. Patients may have progressed in the adjuvant setting if treated within the last 6 months. Prior treatment with BRAF/MEK inhibitors permitted, however, not required. Progression must be radiographic, and progression of disease will be confirmed by a radiologist. Patients must have progressed during anti-PD-1 therapy, defined as unequivocal progression on or within 3 months of the last dose of anti-PD-1 therapy if treated in the metastatic setting, or within 6 months if treated in the adjuvant setting. Have measurable disease based on RECIST 1.1. Patients do not have to have biopsiable disease to be eligible. However, patients with biopsiable disease must undergo biopsy at study entry and at week 12. Have a performance status of 0 or 1 on the ECOG Performance Scale. Demonstrate adequate organ function, per protocol Patients with brain metastases are permitted if they are asymptomatic or previously treated with CNS directed therapy with stable CNS disease for at least 2 weeks. Stable is defined as asymptomatic or not progressing on imaging. Female patients of childbearing potential - negative pregnancy testing; use of birth control, surgically sterile or abstain from heterosexual activity during study and for 5 months after the last dose of study medication. Male subjects - agree to use an adequate contraception starting with the first dose of study therapy through 7 months after the last dose of study therapy; abstinence acceptable Exclusion Criteria: Prior history of Grade 3 or 4 immune-related adverse events or immune-related adverse events requiring discontinuation of prior therapies. History of hypertensive crisis or hypertensive encephalopathy. Significant thrombotic (e.g. deep vein thrombosis or pulmonary embolism) or hemorrhagic event within 6 months prior to enrollment. History of prior immune-related adverse event due to an anti-PD1 or anti-CTLA4 that has not resolved to grade 1 on a steroid dose of prednisone 10 mg or less at the time of study entry (excluding vitiligo and endocrine toxicity). Patients with prior myocarditis or other immune-mediated cardiac adverse events, prior Guillain-Barre syndrome, encephalitis, meningitis, or transverse myelitis, prior Stevens-Johnson syndrome or toxic epidermal necrolysis are excluded regardless of grade. Poorly controlled hypertension defined as systolic blood pressure (SBP) > 160 and/or diastolic blood pressure (DBP) > 100 despite antihypertensives. If subject is above this goal, treatment with anti-hypertensives to achieve better blood pressure control is permitted. Ambulatory blood pressure assessment is permitted if there is concern for discrepant blood pressure readings while patients are in clinic. Has Class III or IV heart failure based on the New York Heart Association. Has had major surgery within 4 weeks of randomization. This does not include outpatient surgeries that do not require post-operative admission. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy (greater than the equivalent of prednisone 10 mg daily, unless for prior endocrine toxicity) or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment (premedication with steroids for contrast imaging studies is permitted). Has a known history of active TB (Bacillus Tuberculosis). Hypersensitivity to nivolumab or axitinib, or any of their excipients. Has had prior chemotherapy or targeted small molecule therapy within 1 week prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to a previously administered agent. Has had radiation within 2 weeks of randomization. Has current use or anticipated need for treatment with drugs or foods that are known strong cytochrome P450 (CYP34A4/5) inhibitors including but not limited to atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, troleandomycin, voriconazole, and grapefruit or grapefruit juice. NOTE: The topical use of these medications, such as 2% ketoconazole cream is allowed. Has current use or anticipated need for treatment with drugs known to be strong CYP3A4/5 inducers, including but not limited to carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, and St. John's wort. Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy, in situ cervical cancer, in situ colon cancer, or nonmetastatic prostate cancer not on systemic therapy. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least 2 weeks prior to the first dose of trial treatment 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 7 days prior to trial treatment. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability. Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment. Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis. Has an active infection requiring systemic IV antibiotic therapy. Has had any of the following within the past 6 months Myocardial infarction or unstable angina Ventricular arrythmia Acute decompensated heart failure Cerebrovascular accident Hypertensive emergency requiring ICU admission Presence of a disorder that may impact absorption of axitinib, such as inability to take oral medication, requirement for IV alimentation, prior gastric resection, treatment for active peptic ulcer confirmed by endoscopy within the past 3 months, active GI bleed, malabsorption syndrome. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial. Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 5 months after the last dose of trial treatment for females and 7 months after the last dose of trial treatment for males. Has a known history of HIV (HIV 1/2 antibodies) if the CD4 count is less than 350 mm3 or serum HIV viral load is < 25,000 IU/mL. Has a known history of or is positive for hepatitis B (hepatitis B surface antigen [HBsAg] reactive) or hepatitis C (hepatitis C virus [HCV] RNA [qualitative] is detected). Note: Without known history, testing only needs to be performed if there is clinical suspicion for Hepatitis B or C. Is currently incarcerated or otherwise detained. Has received a live vaccine within 30 days of planned start of study therapy. (intranasal iNinfluenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed) Note: Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and may qualify for the study. Note: If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Nivolumab plus Axitinib<br>Nivolumab 480mg, IV, every 4 weeks, for up to two years. Axitinib 5mg, PO, BID, for up to two years. | Drug: Nivolumab<br>* Nivolumab is a human IgG4 monoclonal antibody that blocks PD-1. It is a type of Immunotherapy and works as a checkpoint inhibitor, blocking a signal that prevents activation of T cells from attacking the cancer.<br>* Other names: AG013736;Drug: Axitinib<br>* Axitinib (AG013736; trade name Inlyta) is a small molecule tyrosine kinase inhibitor.Its primary mechanism of action is thought to be vascular endothelial growth factor receptor 1-3, c-KIT and PDGFR inhibition, this, in turn, enables it to inhibit angiogenesis (the formation of new blood vessels by tumours)<br>* Other names: INLYTA;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) | Overall response rate (ORR) will be estimated by the percentage of patients who achieve Complete Response (CR) or Partial Response (PR) as best response by RECIST v1.1 criteria (with exact 95% CI). Per RECIST v1.1, Complete Response (CR) is defined as disappearance of all target lesions; disappearance of all non-target lesions and normalization of tumor marker level. Partial Response (PR) is defined as at least a 30% decrease in the sum of the LD of target lesions, taking as reference the baseline sum LD. | Up to 12 weeks from baseline (after treatment) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Serious Adverse Events Possibly, Probably or Definitely Related to Study Treatment | Frequency of patients experiencing Serious Adverse Events determined to be possibly, probably or definitely related to study treatment using a Bayesian monitoring scheme to continuously monitor the rate of severe adverse events (SAE). SAEs are defined as grade 3 and higher toxicity events that are attributable to the study combination therapy. Toxicity events will evaluated by NCI Common Terminology for Adverse Events (CTCAE v5.0). | Up to 28 days after discontinuation of study treatment | 
| Progression-free Survival (PFS) | Progression-free survival is the time measured from the initial date of treatment to the date of documented progression, or the date of death (in the absence of progression), whichever occurs first, with progression defined by RECIST v 1.1. Progressive disease (PD) is defined as at least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions; appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions | Up to 5 years | 
| Overall Survival (OS) | The length of time from the start of treatment that patients remain alive, until death from any cause. | Up to 5 years |