EA2176: Phase 3 Clinical Trial of Carboplatin and Paclitaxel +/- Nivolumab in Metastatic Anal Cancer Patients

Inclusion Criteria:

• Patient must have inoperable, recurrent, or metastatic disease not amenable tocurative therapy

• Patient must have histological or cytological confirmation of anal squamous cellcarcinoma (includes basaloid and cloacogenic lesions) from the primary tumor or anewly diagnosed recurrent/metastatic lesion

• Patient must be >= 18 years of age

• Patient must have Eastern Cooperative Oncology Group (ECOG) performance status =< 0-1

• Patients must have measurable disease according to Response Evaluation Criteria inSolid Tumors (RECIST) criteria version 1.1 and based on radiologic assessmentperformed < 4 weeks prior to randomization

• Patient receiving palliative (limited-field) radiation therapy is allowed, as longas the lesion treated for palliation is not a target lesion and is > 7 days fromcompletion from palliative radiation

• Patients with brain metastasis are eligible if patient is asymptomatic and iftreatment ended > 3 months prior to randomization. Patients with treated brainmetastases are eligible if follow-up brain imaging after central nervous system (CNS)-directed therapy shows no evidence of progression within 4 weeks prior torandomization

• Absolute neutrophil count >= 1,500/mcL (obtained < 14 days prior to randomization)

• Platelets >= 100,000/mcL (obtained < 14 days prior to randomization)

• Hemoglobin (Hgb) >= 9 g/dL for males and >= 9 g/dL for females (obtained < 14 daysprior to randomization)

• Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (obtained < 14days prior to randomization)

• Aspartate transaminase (AST)(serum glutamic-oxaloacetic transaminase [SGOT]) /alanine transferase (ALT)(serum glutamate pyruvate transaminase [SGPT]) =< 5 xinstitutional ULN (obtained < 14 days prior to randomization)

• Creatinine =< 1.5 x institutional ULN OR creatinine clearance (CrCl) >= 50 mL/min (if using the Cockcroft-Gault formula) (obtained < 14 days prior to randomization)

• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviraltherapy (ART) with CD4 count >= 200 or have a CD4 count < 200 but an undetectableviral load are eligible

• All HIV+ patients should be under the care of an infectious diseasesspecialist. If a relationship with an infectious diseases specialist is notestablished, an infectious disease specialist should be consulted. Records ofall viral counts and peripheral T-cell counts should be documented in order tofollow these values over the course of treatment

• All patients must be willing to undergo testing for HIV testing if not testedwithin the past 12 months

• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBVviral load must be undetectable or on suppressive therapy (if indicated)

• Patients with a history of hepatitis C virus (HCV) infection must have been treatedand cured. For patients with HCV infection who are currently on treatment, they areeligible if they have an undetectable HCV viral load

• Patients with known history or current symptoms of cardiac disease, should have aclinical risk assessment of cardiac function using the New York Heart AssociationFunctional Classification. To be eligible for this trial, patients should be class 2B or better. Patients with a history of congestive heart failure (CHF) or who areat risk because of underlying cardiovascular disease or exposure to cardiotoxicdrugs must be willing to undergo evaluation of cardiac function includingelectrocardiogram (EKG) and echocardiogram (ECHO) as clinically indicated

• Patient must have the ability to understand and the willingness to sign a writteninformed consent document. Patients with impaired decision-making capacity (IDMC)who have a legally authorized representative (LAR) or caregiver and/or family memberavailable will also be considered eligible

• Patients must agree to not receive live vaccines while on this study

Exclusion Criteria:

• Patient must not be pregnant or breast-feeding due to the potential harm to anunborn fetus and possible risk for adverse events in nursing infants with thetreatment regimens being used. All patients of childbearing potential must have ablood test or urine study with a minimum sensitivity of 25 IU/L or equivalent unitsof Bacille Calmette-Guerin (BCG), within 14 days prior to randomization to rule outpregnancy. A patient of childbearing potential is defined as anyone, regardless ofwhether they have undergone tubal ligation, who meets the following criteria: 1) hasachieved menarche at some point, 2) has not undergone a hysterectomy or bilateraloophorectomy; or 2) has not been naturally postmenopausal (amenorrhea followingcancer therapy does not rule out childbearing potential) for at least 24 consecutivemonths (i.e., has had menses at any time in the preceding 24 consecutive months).

• Patients of childbearing potential must not expect to conceive children by usingaccepted and effective method(s) of contraception or to abstain from sexualintercourse for at least one week prior to the start of treatment, and continue for 5 months after the last dose of protocol treatment

• Patient must not have had previous use of systemic chemotherapy or otherinvestigational drugs for the treatment of inoperable recurrent or metastatic analcancer (previous use of radiotherapy or chemoradiotherapy in this setting is not anexclusion criterion if: 1) non-irradiated target tumor lesions are present atrandomization for the purpose of tumor response assessment or 2) in the absence ofnon-irradiated target tumor lesions, progression of the irradiated tumor lesionsaccording to the RECIST criteria version 1.1 is documented)

• Patient must not have current or recent (within 30 days prior to randomization)treatment with another investigational drug or participation in anotherinvestigational study

• Patient must not have had prior immunotherapy

• Patient must not have a history of known hypersensitivity reaction to any platinumor taxane-based chemotherapy or monoclonal antibody

• Patient must not have active autoimmune disease or history of autoimmune diseasethat might recur, which may affect vital organ function or require immunesuppressive treatment including chronic prolonged systemic corticosteroids (definedas corticosteroid use of duration one month or greater). These include but are notlimited to patients with a history of immune related neurologic disease, multiplesclerosis, autoimmune (demyelinating) neuropathy, Guillain-Barre syndrome,myasthenia gravis; systemic autoimmune disease such as systemic lupus erythematosus (SLE), connective tissue diseases, scleroderma, inflammatory bowel disease (IBD),Crohn's, ulcerative colitis, and patients with a history of toxic epidermalnecrolysis (TEN), Stevens-Johnson syndrome, or anti-phospholipid syndrome. Patientswith any of these are ineligible because of the risk of recurrence or exacerbationof autoimmune disease

• Patient must not have a condition requiring systemic treatment with eithercorticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressivemedications within 14 days of randomization. Inhaled or topical steroids and adrenalreplacement doses < 10 mg daily prednisone equivalents are permitted in the absenceof active autoimmune disease. Patients are permitted to use topical, ocular,intra-articular, intranasal, and inhalational corticosteroids (with minimal systemicabsorption). Physiologic replacement doses of systemic corticosteroids arepermitted, even if < 10 mg/day prednisone equivalents. A brief course ofcorticosteroids for prophylaxis (e.g., contrast dye allergy) or for treatment ofnon-autoimmune conditions (e.g., delayed-type hypersensitivity reaction caused bycontact allergen) is permitted

• Patient must not have had major surgery performed =< 28 days prior to randomization

• Patient must not have a history of interstitial lung disease (e.g., pneumonitis orpulmonary fibrosis) or evidence of interstitial lung disease on baseline chestcomputed tomography (CT) scan

• Patient must not have a serious active infection requiring IV antibiotics at time ofrandomization

• Patient must not have other primary malignancy within the last 3 years, except foradequately treated carcinoma in situ of the cervix or squamous carcinoma of theskin, or adequately controlled limited basal cell skin cancer, or any other cancerfrom which the patient has been disease-free for at least 3 years

• Patient must not have known peripheral neuropathy > grade 1 at the time ofrandomization (absence of deep tendon reflexes as the sole neurological abnormalitydoes not render the patient ineligible)