Clinical Trials /

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

NCT04493203

Description:

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.

Related Conditions:
  • Cutaneous Melanoma
  • Mucosal Melanoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: 20-101
  • NCT ID: NCT04493203

Conditions

  • Advanced Melanoma
  • Unresectable Melanoma

Interventions

DrugSynonymsArms
NivolumabOpdivo, AG013736Nivolumab plus Axitinib
AxitinibINLYTANivolumab plus Axitinib

Purpose

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

      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.
    

Trial Arms

NameTypeDescriptionInterventions
Nivolumab plus AxitinibExperimentalNivolumab 480mg, IV, every 4 weeks, for up to two years. Axitinib 5mg, PO, BID, for up to two years.
  • Nivolumab
  • Axitinib

Eligibility Criteria

        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.

          -  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:

          -  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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall Response Rate (ORR)
Time Frame:Up to 12 weeks from baseline (after treatment)
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure:Serious Adverse Events Possibly, Probably or Definitely Related to Study Treatment
Time Frame:Up to 28 days after discontinuation of study treatment
Safety Issue:
Description: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).
Measure:Progression-free Survival (PFS)
Time Frame:Up to 5 years
Safety Issue:
Description: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
Measure:Overall Survival (OS)
Time Frame:Up to 5 years
Safety Issue:
Description:The length of time from the start of treatment that patients remain alive, until death from any cause.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Yana Najjar

Last Updated

July 27, 2020