Clinical Trials /

Testing the Addition of Nivolumab to Chemotherapy for Patients With Metastatic Anal Cancer

NCT04444921

Description:

This phase III trial compares the addition of nivolumab to chemotherapy (carboplatin and paclitaxel) versus usual treatment (chemotherapy alone) for the treatment of anal cancer that has spread to other places in the body (metastatic). 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. Chemotherapy drugs, such as carboplatin and paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving nivolumab together with carboplatin and paclitaxel may help doctors find out if the treatment is better or the same as the usual approach.

Related Conditions:
  • Anal Squamous Cell Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: Testing the Addition of Nivolumab to Chemotherapy for Patients With Metastatic Anal Cancer
  • Official Title: A Randomized Phase III Study of Immune Checkpoint Inhibition With Chemotherapy in Treatment-Naive Metastatic Anal Cancer Patients

Clinical Trial IDs

  • ORG STUDY ID: NCI-2020-04334
  • SECONDARY ID: NCI-2020-04334
  • SECONDARY ID: EA2176
  • SECONDARY ID: EA2176
  • SECONDARY ID: U10CA180820
  • NCT ID: NCT04444921

Conditions

  • Anal Basaloid Carcinoma
  • Anal Canal Cloacogenic Carcinoma
  • Metastatic Anal Squamous Cell Carcinoma
  • Recurrent Anal Squamous Cell Carcinoma
  • Stage III Anal Cancer AJCC v8
  • Stage IIIA Anal Cancer AJCC v8
  • Stage IIIB Anal Cancer AJCC v8
  • Stage IIIC Anal Cancer AJCC v8
  • Stage IV Anal Cancer AJCC v8
  • Unresectable Anal Squamous Cell Carcinoma

Interventions

DrugSynonymsArms
CarboplatinBlastocarb, Carboplat, Carboplatin Hexal, Carboplatino, Carboplatinum, Carbosin, Carbosol, Carbotec, CBDCA, Displata, Ercar, JM-8, Nealorin, Novoplatinum, Paraplatin, Paraplatin AQ, Paraplatine, Platinwas, RibocarboArm A (carboplatin, paclitaxel)
NivolumabBMS-936558, MDX-1106, NIVO, ONO-4538, OpdivoArm B (carboplatin, paclitaxel, nivolumab)
PaclitaxelAnzatax, Asotax, Bristaxol, Praxel, Taxol, Taxol KonzentratArm A (carboplatin, paclitaxel)

Purpose

This phase III trial compares the addition of nivolumab to chemotherapy (carboplatin and paclitaxel) versus usual treatment (chemotherapy alone) for the treatment of anal cancer that has spread to other places in the body (metastatic). 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. Chemotherapy drugs, such as carboplatin and paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving nivolumab together with carboplatin and paclitaxel may help doctors find out if the treatment is better or the same as the usual approach.

Detailed Description

      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.
    

Trial Arms

NameTypeDescriptionInterventions
Arm A (carboplatin, paclitaxel)Active ComparatorPatients receive carboplatin 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.
  • Carboplatin
  • Paclitaxel
Arm B (carboplatin, paclitaxel, nivolumab)ExperimentalPatients 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.
  • Carboplatin
  • Nivolumab
  • Paclitaxel

Eligibility Criteria

        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 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)
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Progression-free survival
Time Frame:Up to 2 years
Safety Issue:
Description:Defined as the first of progressive disease or death due to any cause. Analyzed using a stratified two-sided overall 0.05 level log-rank test. Will utilize standard Eastern Cooperative Oncology Group -American College of Radiology Imaging Network interim monitoring for efficacy evaluation.

Secondary Outcome Measures

Measure:Objective response rate (ORR)
Time Frame:Up to 2 years
Safety Issue:
Description:ORR is the ratio of the number of patients with a complete response or partial response, as defined by Response Evaluation Criteria in Solid Tumors version 1.1, to the total number of treated patients.
Measure:Overall survival
Time Frame:Time between treatment randomization and death by any cause, assessed up to 2 years
Safety Issue:
Description:Evaluated by a stratified log-rank test, and using a two-sided 0.05 level Cochran Mantel-Haenzel.
Measure:Incidence of adverse events
Time Frame:Up to 2 years
Safety Issue:
Description:Analyses of toxicity will be via frequency tabulations and percentages by worst degree of toxicity and comparisons will be done via chi-square or Fisher's exact tests as appropriate.

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:National Cancer Institute (NCI)

Last Updated

October 6, 2020