Nivolumab After Combined Modality Therapy in Treating Patients With High Risk Stage II-IIIB Anal Cancer

PRIMARY OBJECTIVES:

I. To evaluate whether therapy with nivolumab following combined modality therapy (CMT)
improves disease-free survival (DFS) compared with observation in patients with high risk
anal carcinoma.

SECONDARY OBJECTIVES:

I. To compare nivolumab following combined modality therapy (CMT) with observation in
patients with high risk anal carcinoma with regard to objective response rate (complete [CR]
and partial [PR]), stable disease and progression.

II. To compare nivolumab following combined modality therapy (CMT) with observation in
patients with high risk anal carcinoma with regard to severe toxicity interval.

III. To compare nivolumab following combined modality therapy (CMT) with observation in
patients with high risk anal carcinoma with regard to colostomy-free survival.

IV. To compare nivolumab following combined modality therapy (CMT) with observation in
patients with high risk anal carcinoma with regard to overall survival.

V. To compare nivolumab following combined modality therapy (CMT) with observation in
patients with high risk anal carcinoma with regard to toxicity.

OUTLINE: Patients who received standard CMT are randomized to 1 of 2 arms.

ARM A: Patients receive nivolumab intravenously (IV) over 30 minutes on day 1. Treatment
repeats every 14 days for up to 12 courses in the absence of disease progression or
unacceptable toxicity.

ARM B: Patients undergo observation.

After completion of study treatment, patients are followed up every 3 months for 2 years,
then every 6 months for 3 years.

Inclusion Criteria:

- REGISTRATION TO STEP 1 ELIGIBILITY CRITERIA

- Patients must have histologically proven stage II (T3N0 only), IIIA, or IIIB invasive
anal (anal margin) squamous cell carcinoma; this may include tumors of
non-keratinizing histology such as basaloid, transitional cell, or cloacogenic
histology

- Patients must have Eastern Cooperative Oncology Group (ECOG) performance status of 0-2

- Patients must have hemoglobin levels of > 10g/dL within 2 weeks prior to registration

- Patient must have a platelet count of > 100,000/mm^3 within 2 weeks prior to
registration

- Patient's absolute neutrophil count (ANC) level must be > 1500/mm^3 within 2 weeks
prior to registration

- Serum creatinine must be =< 2 X upper limit of normal (ULN) within 2 weeks prior to
registration

- Total bilirubin must be < 2 X ULN within 2 weeks prior to registration

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =<
2.5 X institutional upper limit of normal within 2 weeks prior to registration

- Albumin >= 3.0 g/dL within 2 weeks prior to registration

- Human immunodeficiency virus (HIV)+ patients with CD4 > 200 and serum HIV viral load
of < 200 copies/mm^3 are permitted

- Participants must be purified protein derivative (PPD) negative; alternatively,
the QuantiFERON-tuberculosis (TB) Gold In-Tube (QFT-GIT) assay (Cellestis
Limited, Carnegie, Australia) can be used; an individual is considered positive
for M. tuberculosis infection if the IFN-gamma response to TB antigens is above
the test cut-off (after subtracting the background IFN-gamma response in the
negative control); the result must be obtained within 12 weeks prior to
enrollment; PPD positive (or Quantiferon assay positive) participants are
permitted if prophylaxis has been completed prior to enrollment

- No history of acquired immune deficiency syndrome (AIDS)-related complications
within past year other than a history of low CD4+ T-cell count (> 200/mm^3) prior
to initiation of combination antiretroviral therapy; on study CD4+ T-cell count
may not be informative due to chemoradiotherapy should not be used as an
exclusion criterion if low

- Patient must be healthy on the basis of HIV disease with high likelihood of near
normal life span were it not for the anal cancer

- Participants MUST receive appropriate care and treatment for HIV infection,
including antiretroviral medications when clinically indicated, and should be
under the care of a physician experienced in HIV management; participants will be
eligible regardless of antiretroviral medication (including no antiretroviral
medication) provided there is no intention to initiate therapy or the regimen has
been stable for at least 4 weeks with no intention to change the regimen within
12 weeks following enrollment

- Patient must have =< grade 2 diarrhea (participants with grade 1 diarrhea are
eligible provided stool for ova/parasites and stool cryptosporidium studies are
negative

- For patients registering prior to start of chemoradiotherapy, baseline scans must have
been completed within 4 weeks prior to registration

- Patients with an allogenic bone marrow/stem, cell or solid organ transplant are
excluded

- Women of child-bearing potential must use an accepted and effective method of
contraception and/or abstain from sexual intercourse while on protocol treatment and
for at least 5 months after the last dose of nivolumab; sexually active males must use
an accepted and effective method of contraception and/or abstain from sexual
intercourse while on protocol treatment and for at least 7 months after the last dose
of nivolumab

- Women must not be pregnant or breast-feeding; all females of childbearing potential
must have a serum or urine pregnancy test to rule out pregnancy within 2 weeks prior
to registration

- Pregnant women are excluded from this study; breastfeeding should be discontinued

- Patients will be excluded if they have a T1, T2N0 or M1 cancer

- Patients must not have had prior potentially curative surgery (abdominal, peritoneal
resection) for carcinoma of the anus

- Participants may not be receiving any other standard anti-cancer therapy or
experimental agent concurrently with the study drugs

- Any surgery must have been completed >= 4 weeks prior to starting study treatment

- No uncontrolled intercurrent illness including, but not limited to ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements

- Individuals with a history of a different malignancy are ineligible except if they
have been disease-free for at least 2 years and are deemed by the investigator to be
at low risk for recurrence; individuals with the following cancers are eligible if
diagnosed and treated within the past 5 years: cervical cancer in situ, and basal cell
or squamous cell carcinoma of the skin

- Patient must not have active autoimmune disease that has required systemic treatment
in past 2 years

- No prior treatment with an immune checkpoint inhibitor (anti-PD-1, anti-PD-L1,
anti-PD-L2, anti-CTLA4 monoclonal antibody)

- No patients with immunodeficiency or receiving systemic steroid therapy equivalent to
> 10 mg prednisone per day or any other form of immunosuppressive therapy within 7
days prior to the first dose of study medication; topical corticosteroid or occasional
inhaled corticosteroids are allowed

- No live vaccines within 30 days prior to registration; examples of live vaccines
include, but are not limited to, the following: measles, mumps, rubella, chicken pox,
yellow fever, rabies, BCG, and typhoid (oral) vaccine; seasonal influenza vaccines for
injection are generally killed virus vaccines and are allowed; however, intranasal
influenza vaccines (e.g., Flu-Mist) are live attenuated vaccines and are not allowed;
NOTE: no live vaccines may be administered while participating in the trial

- Patients must not have known interstitial lung disease that is symptomatic or may
interfere with the detection or management of suspected drug-related pulmonary
toxicity

- Radiation therapy data are submitted to Imaging and Radiation Oncology Core (IROC)
Rhode Island for quality review

- REGISTRATION TO STEP 2 ELIGIBILITY CRITERIA: Patients will be registered no sooner
than 4 weeks following completion of standard chemoradiation for anal cancer; standard
chemoradiation therapy

- REGISTRATION TO STEP 2 ELIGIBILITY CRITERIA: Patients must have histologically proven
stage II (T3N0 only), IIIA, or IIIB invasive anal (anal margin) squamous cell
carcinoma; this may include tumors of non-keratinizing histology such as basaloid,
transitional cell, or cloacogenic histology

- REGISTRATION TO STEP 2 ELIGIBILITY CRITERIA: Patients must not have received less than
54 Gy of radiation for the treatment of the anal cancer

- REGISTRATION TO STEP 2 ELIGIBILITY CRITERIA: Patients must have ECOG performance
status of 0-2

- REGISTRATION TO STEP 2 ELIGIBILITY CRITERIA: Patients must have hemoglobin levels of >
10g/dL within 2 weeks prior to registration

- REGISTRATION TO STEP 2 ELIGIBILITY CRITERIA: Patient must have a platelet count of >
100,000/mm^3 within 2 weeks prior to registration

- REGISTRATION TO STEP 2 ELIGIBILITY CRITERIA: Patient's ANC level must be > 1500/mm^3
within 2 weeks prior to registration

- REGISTRATION TO STEP 2 ELIGIBILITY CRITERIA: Serum creatinine must be =< 2 X ULN
within 2 weeks prior to registration

- REGISTRATION TO STEP 2 ELIGIBILITY CRITERIA: Total bilirubin must be < 2 X ULN within
2 weeks prior to registration

- REGISTRATION TO STEP 2 ELIGIBILITY CRITERIA: AST (SGOT)/ALT (SGPT) =< 2.5 X
institutional upper limit of normal within 2 weeks prior to registration

- REGISTRATION TO STEP 2 ELIGIBILITY CRITERIA: Albumin >= 3.0 g/dL within 2 weeks prior
to registration

- REGISTRATION TO STEP 2 ELIGIBILITY CRITERIA: Human immunodeficiency virus (HIV)+
patients with CD4 > 200 and serum HIV viral load of < 200 copies/mm^3 are permitted

- Participants must be PPD negative; alternatively, the QuantiFERON-TB Gold In-Tube
(QFT-GIT) assay (Cellestis Limited, Carnegie, Australia) can be used; an
individual is considered positive for M. tuberculosis infection if the IFN-gamma
response to TB antigens is above the test cut-off (after subtracting the
background IFN-gamma response in the negative control); the result must be
obtained within 12 weeks prior to enrollment; PPD positive (or Quantiferon assay
positive) participants are permitted if prophylaxis has been completed prior to
enrollment

- No history of AIDS-related complications within past year other than a history of
low CD4+ T-cell count (> 200/mm^3) prior to initiation of combination
antiretroviral therapy; on study CD4+ T-cell count may not be informative due to
chemoradiotherapy should not be used as an exclusion criterion if low

- Patient must be healthy on the basis of HIV disease with high likelihood of near
normal life span were it not for the anal cancer

- Participants MUST receive appropriate care and treatment for HIV infection,
including antiretroviral medications when clinically indicated, and should be
under the care of a physician experienced in HIV management; participants will be
eligible regardless of antiretroviral medication (including no antiretroviral
medication) provided there is no intention to initiate therapy or the regimen has
been stable for at least 4 weeks with no intention to change the regimen within
12 weeks following enrollment

- Patient must have =< grade 2 diarrhea (participants with grade 1 diarrhea are
eligible provided stool for ova/parasites and stool cryptosporidium studies are
negative)

- REGISTRATION TO STEP 2 ELIGIBILITY CRITERIA: Scans done within 4 weeks of
randomization to Step 2

- REGISTRATION TO STEP 2 ELIGIBILITY CRITERIA: Patient must have recovered from all
toxicities associated with chemoradiotherapy for anal cancer, to grade =< 1 with the
exception of alopecia

- REGISTRATION TO STEP 2 ELIGIBILITY CRITERIA: Patient must start treatment within 12
weeks of completion of chemoradiotherapy

- REGISTRATION TO STEP 2 ELIGIBILITY CRITERIA: Patients with an allogenic bone
marrow/stem, cell or solid organ transplant are excluded

- REGISTRATION TO STEP 2 ELIGIBILITY CRITERIA: Women of child-bearing potential must use
an accepted and effective method of contraception and/or abstain from sexual
intercourse while on protocol treatment and for at least 5 months after the last dose
of nivolumab; sexually active males must use an accepted and effective method of
contraception and/or abstain from sexual intercourse while on protocol treatment and
for at least 7 months after the last dose of nivolumab

- REGISTRATION TO STEP 2 ELIGIBILITY CRITERIA: Women must not be pregnant or
breast-feeding; all females of childbearing potential must have a serum or urine
pregnancy test to rule out pregnancy within 2 weeks prior to registration

- REGISTRATION TO STEP 2 ELIGIBILITY CRITERIA: Pregnant women are excluded from this
study; breastfeeding should be discontinued

- REGISTRATION TO STEP 2 ELIGIBILITY CRITERIA: Patients must not have had prior
potentially curative surgery (abdominal, peritoneal resection) for carcinoma of the
anus

- REGISTRATION TO STEP 2 ELIGIBILITY CRITERIA: Participants may not be receiving any
other standard anti-cancer therapy or experimental agent concurrently with the study
drugs

- REGISTRATION TO STEP 2 ELIGIBILITY CRITERIA: No uncontrolled intercurrent illness
including, but not limited to ongoing or active infection, symptomatic congestive
heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric
illness/social situations that would limit compliance with study requirements

- REGISTRATION TO STEP 2 ELIGIBILITY CRITERIA: Individuals with a history of a different
malignancy are ineligible except if they have been disease-free for at least 2 years
and are deemed by the investigator to be at low risk for recurrence; individuals with
the following cancers are eligible if diagnosed and treated within the past 5 years:
cervical cancer in situ, and basal cell or squamous cell carcinoma of the skin

- REGISTRATION TO STEP 2 ELIGIBILITY CRITERIA: Patient must not have active autoimmune
disease that has required systemic treatment in past 2 years

- REGISTRATION TO STEP 2 ELIGIBILITY CRITERIA: No prior treatment with an immune
checkpoint inhibitor (anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA4 monoclonal
antibody)

- REGISTRATION TO STEP 2 ELIGIBILITY CRITERIA: No patients with immunodeficiency or
receiving systemic steroid therapy equivalent to > 10 mg prednisone per day or any
other form of immunosuppressive therapy within 7 days prior to the first dose of study
medication; topical corticosteroid or occasional inhaled corticosteroids are allowed

- REGISTRATION TO STEP 2 ELIGIBILITY CRITERIA: No live vaccines within 30 days prior to
the first dose of trial treatment and while participating in the trial; examples of
live vaccines include, but are not limited to, the following: measles, mumps, rubella,
chicken pox, yellow fever, rabies, BCG, and typhoid (oral) vaccine; seasonal influenza
vaccines for injection are generally killed virus vaccines and are allowed; however,
intranasal influenza vaccines (e.g., Flu-Mist) are live attenuated vaccines and are
not allowed

- REGISTRATION TO STEP 2 ELIGIBILITY CRITERIA: Patients must not have known interstitial
lung disease that is symptomatic or may interfere with the detection or management of
suspected drug-related pulmonary toxicity

- REGISTRATION TO STEP 2 ELIGIBILITY CRITERIA: Patients must not have a history of
allergic reactions attributed to compounds of similar chemical or biologic composition
to nivolumab