Clinical Trials /

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

NCT03233711

Description:

This randomized phase II clinical trial studies how well nivolumab after combined modality therapy works in treating patients with high risk stage II-IIIB anal cancer. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread.

Related Conditions:
  • Anal Canal Cloacogenic Carcinoma
  • Anal Squamous Cell Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Nivolumab After Combined Modality Therapy in Treating Patients With High Risk Stage II-IIIB Anal Cancer
  • Official Title: A Randomized Phase II Study of Nivolumab After Combined Modality Therapy (CMT) in High Risk Anal Cancer

Clinical Trial IDs

  • ORG STUDY ID: NCI-2017-01347
  • SECONDARY ID: NCI-2017-01347
  • SECONDARY ID: EA2165
  • SECONDARY ID: EA2165
  • SECONDARY ID: U10CA180820
  • NCT ID: NCT03233711

Conditions

  • Anal Basaloid Carcinoma
  • Anal Canal Cloacogenic Carcinoma
  • Anal Margin Squamous Cell Carcinoma
  • Stage IIB Anal Cancer AJCC v8
  • Stage IIIA Anal Cancer AJCC v8
  • Stage IIIB Anal Cancer AJCC v8
  • Stage IIIC Anal Cancer AJCC v8

Interventions

DrugSynonymsArms
NivolumabBMS-936558, MDX-1106, NIVO, ONO-4538, OpdivoArm A (nivolumab)

Purpose

This randomized phase II clinical trial studies how well nivolumab after combined modality therapy works in treating patients with high risk stage II-IIIB anal cancer. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread.

Detailed Description

      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:

      Ia. Objective response rate (complete [CR] and partial [PR]), stable disease and progression.

      Ib. Severe toxicity interval. Ic. Colostomy-free survival. Id. Overall survival. Ie.
      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 4 weeks for up to 6 cycles in the absence of disease progression or
      unacceptable toxicity.

      ARM B: Patients undergo observation for up to 6 months.

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

Trial Arms

NameTypeDescriptionInterventions
Arm A (nivolumab)ExperimentalPatients receive nivolumab IV over 30 minutes on day 1. Treatment repeats every 4 weeks for up to 6 cycles in the absence of disease progression or unacceptable toxicity.
  • Nivolumab
Arm B (clinical observation)OtherPatients undergo observation for up to 6 months.

    Eligibility Criteria

            Inclusion Criteria:
    
              -  REGISTRATION TO STEP 1 ELIGIBILITY CRITERIA
    
              -  Patients must have histologically proven stage IIB (T3N0M0 only), IIIA (T2N1M0), IIIB
                 (T4N0M0), or IIIC (T3N1M0, T4N1M0) invasive squamous cell carcinoma of the anus or
                 anorectum, according to the American Joint Committee on Cancer (AJCC) 8th edition;
                 this may include tumors of non-keratinizing histology such as basaloid, transitional
                 cell, or cloacogenic histology; individuals with squamous cell carcinoma of the anal
                 margin are eligible if there is evidence of extension of the primary tumor into the
                 anal canal
    
              -  For patients registering to Arm T, patients must not have received prior
                 chemoradiotherapy for anal cancer
    
              -  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 =< 1.5 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)
    
              -  Patients known to be human immunodeficiency virus (HIV)+ are permitted; patients with
                 CD4 > 200 and serum HIV viral load of < 200 copies/mm^3 are eligible, and in addition:
    
                   -  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 20 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 and 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;
    
                   -  NOTE: HIV testing is not required for eligibility
    
              -  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 because the study drugs administered may
                 cause harm to an unborn fetus or breastfeeding child; the effects of nivolumab on a
                 developing fetus are unknown and may cause harm; 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 because the study agents have the
                 potential for teratogenic or abortifacient effects; because there is an unknown but
                 potential risk of adverse events in nursing infants secondary to treatment of the
                 mother with the study agents, breastfeeding should be discontinued
    
              -  Patients will be excluded if they have a T1 or M1, and T2N0 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 the past 2 years
    
                   -  NOTE: This does not include patients with controlled hypothyroidism
    
              -  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
    
              -  Previously irradiated patients (Arm S) must have received radiation per National
                 Comprehensive Cancer Network guidelines; radiation therapy delivered on protocol (Arm
                 T) will be reviewed
    
              -  REGISTRATION TO STEP 2 ELIGIBILITY CRITERIA: Patients will be registered within 63
                 days following completion of standard chemoradiation for anal cancer; standard
                 chemoradiation therapy is as defined
    
              -  REGISTRATION TO STEP 2 ELIGIBILITY CRITERIA: Patients must have histologically proven
                 stage IIB (T3N0M0 only), IIIA (T2N1M0), IIIB (T4N0M0), or IIIC (T3N1M0, T4N1M0)
                 invasive squamous cell carcinoma of the anus or anorectum, according to the AJCC 8th
                 edition; this may include tumors of non-keratinizing histology such as basaloid,
                 transitional cell, or cloacogenic histology; individuals with squamous cell carcinoma
                 of the anal margin are eligible if there is evidence of extension of the primary tumor
                 into the anal canal
    
              -  REGISTRATION TO STEP 2 ELIGIBILITY CRITERIA: Patients must have received at least 54
                 gray (Gy) of radiation to the PTVp (primary) and 45 Gy to PTVn (elective nodal region)
                 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 =< 1.5 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: Patients known to be human
                 immunodeficiency virus (HIV)+ patients with CD4 > 200 and serum HIV viral load of <
                 200 copies/mm^3 are eligible; in addition:
    
                   -  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 20 weeks prior to enrollment; PPD positive (or Quantiferon assay
                      positive) participants are permitted if prophylaxis has been completed prior to
                      enrollment; NOTE: If patient completed chemoradiation on Step 1, PPD testing does
                      not need to be performed again
    
                   -  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)
    
                   -  NOTE: HIV testing is not required for eligibility
    
              -  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: 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 because the study drugs administered may cause harm to an unborn fetus
                 or breastfeeding child; the effects of nivolumab on a developing fetus are unknown and
                 may cause harm; 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 because the study agents have the potential for teratogenic or abortifacient
                 effects; because there is an unknown but potential risk of adverse events in nursing
                 infants secondary to treatment of the mother with the study agents, 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 3
          
    Maximum Eligible Age:N/A
    Minimum Eligible Age:18 Years
    Eligible Gender:All
    Healthy Volunteers:No

    Primary Outcome Measures

    Measure:Disease free survival
    Time Frame:Up to 5 years
    Safety Issue:
    Description:Will be defined as the occurrence of progression of local disease, distant metastases, second primary or death from the date of randomization.

    Secondary Outcome Measures

    Measure:Objective response rate
    Time Frame:Up to 5 years
    Safety Issue:
    Description:Will be defined by complete and partial response.
    Measure:Severe toxicity interval
    Time Frame:The time between randomization and the occurrence of late severe side effects (up to 5 years)
    Safety Issue:
    Description:The following late side effects are considered as severe: any anal/rectal damage (ulcer, fistula, or perforation), rectal stenosis that required colostomy, skin ulceration, and severe fibrosis. This parameter estimates the probability of being free of late side effects for patients under loco-regional control.
    Measure:Colostomy-free survival
    Time Frame:Up to 5 years
    Safety Issue:
    Description:
    Measure:Overall survival
    Time Frame:Up to 5 years
    Safety Issue:
    Description:
    Measure:Incidence of toxicities
    Time Frame:Up to 5 years
    Safety Issue:
    Description:Will be assessed by National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0.

    Details

    Phase:Phase 2
    Primary Purpose:Interventional
    Overall Status:Recruiting
    Lead Sponsor:National Cancer Institute (NCI)

    Last Updated