| Eligibility |
Inclusion Criteria:
- Histologic diagnosis of unresectable or advanced mucosal melanoma arising from the
head/neck (e.g. sinonasal, oral cavity, conjunctival), gastrointestinal (e.g.
anorectal, esophageal), or genitourinary (e.g. vulvovaginal, urethral) sites.
- Measurable disease
1. Initial study entry: Subjects must have at least 1 extracranial, unresectable,
non-bony lesion that is measurable radiographically (based on RECIST 1.1).
2. Triplet arms: assessable disease required. RECIST 1.1 measurable disease is not
required.
- Prior therapy
1. Initial study entry: No prior systemic therapy (adjuvant or metastatic).
2. Triplet arms: Only prior systemic therapy is nivolumab + axitinib on this trial.
- ECOG performance status of 0-2.
- Asymptomatic untreated brain metastases are allowed. Symptomatic brain metastases that
have undergone local therapy with RT or surgery and have not required an increase in
steroid dose in prior 2 weeks are allowed.
- Screening laboratory parameters:
1. White blood cell (WBC) count = 2000/µL;
2. Absolute neutrophil count (ANC) = 1500/µL;
3. Platelets = 100,000/µL;
4. Hemoglobin (Hgb) = 9 g/dL;
5. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) = 3 × upper
limit of normal (ULN);
6. Total bilirubin = 1.5 × ULN (< 3 mg/dL for subjects with Gilbert's disease);
7. Estimated glomerular filtration rate (GFR) = 30 mL/min;either Cockcroft Gault or
a cancer-specific GFR Model such as the camGFR version 2 can be used;
- Age = 18 years.
- Females of childbearing potential who are sexually active with a nonsterilized male
partner must use 2 methods of effective contraception from screening, and must agree
to continue using such precautions for 23 weeks after the final dose of
investigational product; cessation of birth control after this point should be
discussed with a responsible physician. Periodic abstinence, the rhythm method, and
the withdrawal method are not acceptable methods of birth control. [Females of
childbearing potential are defined as those who are not surgically sterile (i.e.,
bilateral tubal ligation, bilateral oophorectomy, or complete hysterectomy) or
postmenopausal (defined as 12 months with no menses without an alternative medical
cause).] Nonsterilized males who are sexually active with a female partner of
childbearing potential must use 2 acceptable methods of effective contraception from
Day 1 and for 31 weeks after receipt of the final dose of investigational product.
Acceptable methods of effective contraception are described in the following:
- Barrier Methods (Male condom plus spermicide, cap plus spermicide, or diaphragm plus
spermicide).
- Intrauterine Device Methods (Copper T, or Levonorgestrelreleasing intrauterine system
(e.g., Mirena®), also considered a hormonal method).
- Hormonal Methods (Implants, hormone shot or injection, combined pill, mini pill, or
Patch).
Exclusion Criteria:
- Active autoimmune disease or any condition requiring systemic treatment with either
corticosteroids (>10 mg daily of prednisone equivalents) or other immunosuppressive
medications within 14 days of study drug administration. Inhaled or topical steroids
and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in
the absence of active autoimmune disease.
- History of motor neuropathy considered to be of autoimmune origin (e.g., Guillain-
Barre Syndrome, Myasthenia Gravis).
- History of myocarditis.
- History of, or any active evidence of non-infectious pneumonitis
- Other active, concurrent malignancy that requires ongoing systemic treatment or
interferes with radiographic assessment of melanoma response as determined by the
investigator.
- Cardiovascular disease, including:
- History of acute coronary syndromes (including myocardial infarction and unstable
angina), coronary artery bypass graft (CABG) coronary angioplasty, or stenting
within 6 months prior to study entry.
- Current Class II or higher congestive heart failure as defined by the New York
Heart Association (NYHA) functional classification system.
- Treatment-refractory hypertension defined as a blood pressure of systolic >150
mmHg and/or diastolic >90 mmHg despite adequate attempts at antihypertensive
therapy.
- Underlying hematologic issues including:
- Congenital bleeding diathesis
- GI bleeding requiring intervention within the past 6 months
- Active hemoptysis within 42 days prior to study enrollment
- Pulmonary emboli or deep vein thromboses (DVT) that are not stable on
anticoagulation regimen.
- History of severe allergic reactions to an unknown allergen or any components of the
study drugs.
- Other serious infectious illnesses (e.g., active symptoms of COVID-19 infection or a
post-infectious symptomatic autoimmune syndrome, serious bacterial infections
requiring antibiotics).
- Women who are breastfeeding or who are pregnant as evidenced by a positive serum
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) performed
within 14 days of the first dose of study drug and by a urine pregnancy test (minimum
sensitivity 25 IU/L or equivalent units of HCG) within 24 hours of the first dose of
study drug(s).
- Genetic or autoimmune condition causing heightened radio sensitivity.
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