PRIMARY OBJECTIVE:
I. To demonstrate that anti-PD-1 therapy in combination with carboplatin/weekly paclitaxel
results in improved progression free survival (PFS) versus systemic chemotherapy alone.
SECONDARY OBJECTIVES:
I. To demonstrate that anti-PD-1 therapy in combination with carboplatin/weekly paclitaxel
results in improved overall survival (OS) versus systemic chemotherapy alone.
II. To demonstrate that anti-PD-1 therapy in combination with carboplatin/weekly paclitaxel
results in improved objective response using Response Evaluation Criteria in Solid Tumors
(RECIST) version (v)1.1 versus systemic chemotherapy alone.
III. To evaluate toxicity profiles of the two regimens.
OUTLINE: Patients are randomized to 1 of 2 arms.
ARM A: Patients receive carboplatin intravenously (IV) on day 1, and paclitaxel IV on days 1,
8 and 15. Treatment repeats every 28 days for up to 6 cycles in the absence of disease
progression or unacceptable toxicity.
ARM B: Patients receive carboplatin on day 1, paclitaxel IV on days 1, 8 and 15, and
nivolumab IV over 30 minutes on days 1 and 15 of cycle 1, and then on day 1 only of
subsequent cycles. Treatment repeats every 28 days for up to 6 cycles for carboplatin and
paclitaxel, and up to 2 years for nivolumab in the absence of disease progression or
unacceptable toxicity.
After completion of study treatment, patients are followed up at 1 month, then every 3 months
for 2 years.
Inclusion Criteria:
- Patient must have inoperable, recurrent, or metastatic disease (tumor resectability
should be assessed by a local surgeon or a multidisciplinary team) not amenable to
curative therapy
- Patient must have histological or cytological confirmation of anal squamous cell
carcinoma (includes basaloid and cloacogenic lesions) from the primary tumor or a
newly 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 in
Solid Tumors (RECIST) criteria version 1.1 and based on radiologic assessment
performed < 4 weeks prior to randomization
- Patient receiving palliative (limited-field) radiation therapy is allowed, as long as
the lesion treated for palliation is not a target lesion
- Patients with brain metastasis are eligible if patient is asymptomatic and if
treatment ended > 3 months prior to randomization. Patients with treated brain
metastases are eligible if follow-up brain imaging after central nervous system
(CNS)-directed therapy shows no evidence of progression within 4 weeks prior to
randomization
- Leukocytes >= 3,000/mcL (obtained < 14 days prior to randomization)
- Absolute neutrophil count >= 1,500/mcL (obtained < 14 days prior to randomization)
- Platelets >= 100,000/mcL (obtained < 14 days prior to randomization)
- Hemoglobin (Hb) >= 9 g/dL for males and >= 9 g/dL for females (obtained < 14 days
prior to randomization)
- Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (obtained < 14 days
prior to randomization)
- Aspartate transaminase (AST)(serum glutamic-oxaloacetic transaminase [SGOT]) /alanine
transferase (ALT)(serum glutamate pyruvate transaminase [SGPT]) =< 5 x institutional
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-retroviral
therapy (ART) with undetectable viral load are eligible
- All HIV+ patients should be under the care of an infectious diseases specialist.
If a relationship with an infectious diseases specialist is not established, an
infectious disease specialist should be consulted. Records of all viral counts
and peripheral T-cell counts should be documented in order to follow these values
over the course of treatment
- All patients must be willing to undergo testing for HIV testing if not tested
within the past 12 months
- For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral
load must be undetectable on suppressive therapy, if indicated
- Patients with a history of hepatitis C virus (HCV) infection must have been treated
and cured. For patients with HCV infection who are currently on treatment, they are
eligible if they have an undetectable HCV viral load
- Patients with known history or current symptoms of cardiac disease, should have a
clinical risk assessment of cardiac function using the New York Heart Association
Functional 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 are at
risk because of underlying cardiovascular disease or exposure to cardiotoxic drugs
must be willing to undergo evaluation of cardiac function including electrocardiogram
(EKG) and echocardiogram (ECHO) as clinically indicated
- Patient must have the ability to understand and the willingness to sign a written
informed consent document. Patients with impaired decision-making capacity (IDMC) who
have a legally authorized representative (LAR) or caregiver and/or family member
available will also be considered eligible
- Patients must agree to not receive live vaccines while on this study
Exclusion Criteria:
- Women must not be pregnant or breast-feeding due to the potential harm to an unborn
fetus and possible risk for adverse events in nursing infants with the treatment
regimens being used. All females of childbearing potential must have a blood test or
urine study with a minimum sensitivity of 25 IU/L or equivalent units of Bacille
Calmette-Guerin (BCG), within 14 days prior to randomization to rule out pregnancy. A
female of childbearing potential is defined as any woman, regardless of sexual
orientation or whether they have undergone tubal ligation, who meets the following
criteria: 1) has achieved menarche at some point, 2) has not undergone a hysterectomy
or bilateral oophorectomy; or 2) has not been naturally postmenopausal (amenorrhea
following cancer therapy does not rule out childbearing potential) for at least 24
consecutive months (i.e., has had menses at any time in the preceding 24 consecutive
months).
- Women of childbearing potential and sexually active males must not expect to conceive
or father children by using accepted and effective method(s) of contraception or to
abstain from sexual intercourse for at least one week prior to the start of treatment,
and continue for 5 months after the last dose of protocol treatment for women of
childbearing potential and 7 months after the last dose of protocol treatment for
males who are sexually active with women of childbearing potential (WOCBP)
- Patient must not have had previous use of systemic chemotherapy or other
investigational drugs for the treatment of inoperable recurrent or metastatic anal
cancer (previous use of radiotherapy or chemoradiotherapy in this setting is not an
exclusion criterion if: 1) non-irradiated target tumor lesions are present at
randomization for the purpose of tumor response assessment or 2) in the absence of
non-irradiated target tumor lesions, progression of the irradiated tumor lesions
according 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 another
investigational study
- Patient must not have had prior immunotherapy
- Patient must not have a history of known hypersensitivity reaction to any platinum or
taxane-based chemotherapy or monoclonal antibody
- Patient must not have active autoimmune disease or history of autoimmune disease that
might recur, which may affect vital organ function or require immune suppressive
treatment including chronic prolonged systemic corticosteroids (defined as
corticosteroid use of duration one month or greater). These include but are not
limited to patients with a history of immune related neurologic disease, multiple
sclerosis, 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 epidermal necrolysis (TEN),
Stevens-Johnson syndrome, or anti-phospholipid syndrome. Patients with any of these
are ineligible because of the risk of recurrence or exacerbation of disease
- Patient must not have a condition requiring systemic treatment with either
corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive
medications within 14 days of randomization. Inhaled or topical steroids and adrenal
replacement doses < 10 mg daily prednisone equivalents are permitted in the absence of
active autoimmune disease. Patients are permitted to use topical, ocular,
intra-articular, intranasal, and inhalational corticosteroids (with minimal systemic
absorption). Physiologic replacement doses of systemic corticosteroids are permitted,
even if < 10 mg/day prednisone equivalents. A brief course of corticosteroids for
prophylaxis (e.g., contrast dye allergy) or for treatment of non-autoimmune conditions
(e.g., delayed-type hypersensitivity reaction caused by contact 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 or
pulmonary fibrosis) or evidence of interstitial lung disease on baseline chest
computed tomography (CT) scan
- Patient must not have a serious active infection requiring IV antibiotics at time of
randomization
- Patient must not have other primary malignancy within the last 3 years, except for
adequately treated carcinoma in situ of the cervix or squamous carcinoma of the skin,
or adequately controlled limited basal cell skin cancer, or any other cancer from
which the patient has been disease-free for at least 3 years
- Patient must not have known peripheral neuropathy > grade 1 at the time of
randomization (absence of deep tendon reflexes as the sole neurological abnormality
does not render the patient ineligible)
