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.
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.
