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

  • STATUS
    Recruiting
  • End date
    Aug 30, 2026
  • participants needed
    31
  • sponsor
    Yana Najjar
Updated on 30 April 2022

Summary

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.

Description

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.

Details
Condition Advanced Melanoma, Unresectable Melanoma
Treatment Nivolumab, Axitinib
Clinical Study IdentifierNCT04493203
SponsorYana Najjar
Last Modified on30 April 2022

Eligibility

Yes No Not Sure

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
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