Clinical Trials /

Balstilimab Versus Investigator Choice Chemotherapy in Patients With Recurrent Cervical Cancer (BRAVA)

NCT04943627

Description:

This Phase 3 trial is an open-label, randomized study with single-agent Balstilimab (BAL) or Investigator Choice (IC) chemotherapy (single-agent gemcitabine, irinotecan, pemetrexed, vinorelbine, or topotecan) in patients with recurrent, persistent, or metastatic cervical cancer who have progressed after receiving platinum based chemotherapy.

Related Conditions:
  • Cervical Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: Balstilimab Versus Investigator Choice Chemotherapy in Patients With Recurrent Cervical Cancer (BRAVA)
  • Official Title: A Phase 3 Trial of Balstilimab Versus Investigator Choice Chemotherapy in Patients With Recurrent Cervical Cancer After Platinum-Based Chemotherapy (BRAVA)

Clinical Trial IDs

  • ORG STUDY ID: C-700-03
  • NCT ID: NCT04943627

Conditions

  • Advanced Cancer
  • Metastatic Cervical Cancer

Interventions

DrugSynonymsArms
Balstilimab (BAL)AGEN2034, Anti-PD-1Monotherapy with Balstilimab (BAL)
TopotecanMonotherapy with Investigator Choice (IC) Chemotherapy per Institutional guidelines
VinorelbineMonotherapy with Investigator Choice (IC) Chemotherapy per Institutional guidelines
GemcitabineMonotherapy with Investigator Choice (IC) Chemotherapy per Institutional guidelines
IrinotecanMonotherapy with Investigator Choice (IC) Chemotherapy per Institutional guidelines
PemetrexedMonotherapy with Investigator Choice (IC) Chemotherapy per Institutional guidelines

Purpose

This Phase 3 trial is an open-label, randomized study with single-agent Balstilimab (BAL) or Investigator Choice (IC) chemotherapy (single-agent gemcitabine, irinotecan, pemetrexed, vinorelbine, or topotecan) in patients with recurrent, persistent, or metastatic cervical cancer who have progressed after receiving platinum based chemotherapy.

Detailed Description

      The purpose of this Phase 3 trial is to demonstrate prolongation of OS in patients treated
      with BAL as compared to IC chemotherapy.

      This Phase 3 trial is an open-label, randomized study with single-agent BAL or IC
      chemotherapy (single-agent gemcitabine, irinotecan, pemetrexed, vinorelbine, or topotecan) in
      patients with recurrent, persistent, or metastatic cervical cancer who have progressed after
      receiving platinum based chemotherapy.

      Population:

      Patients with recurrent, unresectable, or metastatic cervical cancer who have progressed
      after receiving at least 1 prior line of platinum-containing chemotherapy with or without
      bevacizumab.

      In this study, > 50% of patients will have received prior treatment with bevacizumab, which
      will be determined prior to enrollment.

      Stratification

        -  Histology (squamous cell carcinoma [SCC] vs adenocarcinoma [AC] or adenosquamous
           carcinoma [ASC])

        -  Region of the world (United States or Europe Union or Australia vs other countries)

        -  Eastern Cooperative Oncology Group (ECOG) status 0 vs 1

      Randomization

      • 2:1, BAL: IC chemotherapy

      Approximately 486 patients will be enrolled and randomized with 2:1 allocation between the
      BAL and IC chemotherapy arms.
    

Trial Arms

NameTypeDescriptionInterventions
Monotherapy with Balstilimab (BAL)Experimental300 mg IV once every 3 weeks for up to 24 months
  • Balstilimab (BAL)
Monotherapy with Investigator Choice (IC) Chemotherapy per Institutional guidelinesActive ComparatorTopotecan: 1 or 1.25 mg/m^2 IV on Days 1 to 5, every 21 days or Vinorelbine: 30 mg/m^2 IV on Days 1 and 8, every 21 days or Gemcitabine: 1000 mg/m^2 IV on Days 1 and 8, every 21 days or Irinotecan: 100 or 125 mg/m^2 IV weekly for 28 days, every 42 days or Pemetrexed: 500 mg/m^2 IV on Day 1, every 21 days
  • Topotecan
  • Vinorelbine
  • Gemcitabine
  • Irinotecan
  • Pemetrexed

Eligibility Criteria

        Inclusion Criteria:

          1. Voluntarily agree to participate by giving written informed consent.

          2. ≥ 18 years of age.

          3. Diagnosis and prior systemic treatment:

               1. Has recurrent or metastatic cervical cancer (SCC, AC, or ASC histology) and has
                  experienced disease progression during or after treatment with a standard
                  platinum based therapy with or without bevacizumab.

               2. Has received at least 1 prior systemic therapy regimen for recurrent, persistent,
                  and/or metastatic cervical cancer.

             Note: Chemotherapy administered in the adjuvant or neoadjuvant setting, or in
             combination with radiation therapy, should not be counted as a prior systemic therapy
             regimen for recurrent, persistent, and/or metastatic cervical cancer.

          4. Measurable disease - based on Investigator assessment.

             a. Radiological evidence of measurable disease on imaging based on RECIST v1.1 Note:
             Patients must have at least 1 "target lesion" to be used to assess response, as
             defined by RECIST v1.1. Tumors within a previously irradiated field will be designated
             as "non target" lesions unless progression is documented, or a biopsy is obtained to
             confirm persistence at least 90 days following completion of radiation therapy.

          5. Has a life expectancy of at least 3 months and an ECOG performance status of 0 or 1.

          6. Patients must have sufficient and adequate formalin-fixed tumor tissue sample
             available that is not older than 3 years; otherwise, a fresh biopsy is required.
             Archival tissue or fresh biopsy must be from a site not previously irradiated.

          7. Has adequate organ function as indicated by the following laboratory values:

               1. Adequate hematological function defined by absolute neutrophil count ≥ 1.5 ×
                  109/L, platelet count ≥ 100 × 109/L, and stable hemoglobin ≥ 8 g/dL (without
                  transfusions within 1 week before first dose).

               2. Adequate hepatic function based by a total bilirubin level ≤ 1.5 × the upper
                  limit of normal (ULN), aspartate aminotransferase (AST) level ≤ 2.5 × ULN,
                  alanine aminotransferase (ALT) level ≤ 2.5 × ULN, alkaline phosphatase (ALP) ≤
                  2.5 × ULN, and albumin ≥ 3.0 mg/dL. In the case of hepatic metastases, < 5 × ULN
                  for AST/ALT and ALP.

               3. Adequate renal function defined as calculated creatinine clearance > 40 mL/min or
                  a serum creatinine < 1.5 × ULN, per institutional standards (creatinine clearance
                  should be calculated per institutional standards).

               4. Adequate coagulation defined by international normalized ratio or prothrombin
                  time ≤ 1.5 × institutional upper limit of normal IULN unless the patient is
                  receiving anticoagulant therapy) and activated partial thromboplastin time ≤ 1.5
                  × IULN (unless the patient is receiving anticoagulant therapy).

               5. Normal thyroid function (thyroid stimulating hormone) whether or not the patient
                  is on supplemental thyroid hormone.

          8. Has no history of another primary malignancy except:

               1. Malignancy treated with curative intent and with no known active disease ≥ 5
                  years before the first dose of study drug and of low potential risk for
                  recurrence.

               2. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence
                  of disease.

               3. Adequately treated carcinoma in situ without evidence of disease.

          9. Women of childbearing potential (WOCP) must have a negative serum pregnancy test at
             Screening (within 72 hours before first dose of study drug). Non-childbearing
             potential is defined as (by other than medical reasons):

               1. ≥ 45 years of age and has not menstruated for greater than 1 year.

               2. Definitive pelvic radiation for the treatment of cervical cancer.

               3. Whose status is post hysterectomy, bilateral oophorectomy, or tubal ligation.

               4. WOCP must be willing to use 2 highly effective methods of contraception (defined
                  in the informed consent form) throughout the trial, starting with the Screening
                  Visit through 90 days after the last dose of study drug Note: Abstinence is
                  acceptable if this is the established and preferred contraception for the
                  patient.

         10. Is willing and able to comply with the requirements of the protocol.

        Exclusion Criteria:

          1. Is currently participating and receiving study therapy or has participated in a trial
             of an investigational agent and received study therapy or used an investigational
             device within 4 weeks before the first dose of treatment.

          2. Has an inadequate period of time prior to first dose of study treatment that is
             defined as:

               1. Received systemic cytotoxic chemotherapy or biological therapy within 28 days
                  before initiation of study treatment

               2. Received radiation therapy within 28 days before initiation of study treatment,
                  except for palliative bone therapy, which can be received 2 weeks prior to
                  initiation of study treatment

               3. Had major surgery within 4 weeks before initiation of study treatment

          3. Has received prior therapy with:

             a. Any antibody/drug targeting T-cell co-regulatory proteins (immune checkpoints) such
             as anti-programmed cell death protein 1 and anti-PD-L1 antibodies.

          4. Has persisting toxicity related to prior therapy of NCI-CTCAE v5.0 Grade ≥ 1 severity,
             with the exceptions noted below:

               1. Peripheral neuropathy Grade ≤ 2.

               2. Alopecia Grade ≤ 2.

          5. Is expected to require any other form of systemic or localized antineoplastic therapy
             while on trial (including maintenance therapy with another agent, radiation therapy,
             and/or surgical resection).

          6. Has known severe hypersensitivity reactions to fully human monoclonal antibodies (NCI
             CTCAE v5.0 Grade ≥ 3), any history of anaphylaxis, or uncontrolled asthma.

          7. Is receiving systemic corticosteroids ≤ 7 days prior to the first dose of trial
             treatment or receiving any other form of systemic immunosuppressive medication
             (corticosteroid use on trial for management of immune-related adverse events and/or as
             a premedication for intravenous [IV] contrast allergies/reactions is allowed).
             Patients who are receiving daily corticosteroid replacement therapy are an exception
             to this rule. Examples of permitted therapy are daily prednisone at doses of 5 to 7.5
             mg or equivalent hydrocortisone dose and steroid therapy administered by topical,
             intraocular, intranasal, and/or inhalation routes.

          8. History of central nervous system tumor, metastasis(es), and/or carcinomatous
             meningitis identified either on the baseline brain imaging obtained during the
             Screening period or identified prior to consent.

             Note: Patients with a history of brain metastases that have been treated may
             participate provided they show evidence of stable supra-tentorial lesions at screening
             (based on 2 sets of brain images, performed ≥ 4 weeks apart, and obtained after the
             brain metastases treatment). In addition, any neurologic symptoms that developed
             either as a result of the brain metastases or their treatment must have resolved or be
             minimal and be expected as sequelae from treated lesions. For individuals who received
             steroids as part of brain metastases treatment, steroids must be discontinued ≥ 7 days
             prior to the first dose of study drug.

          9. Has active or history of autoimmune disease that requires systemic treatment within 2
             years of the start of study drug (ie, with use of disease-modifying agents,
             corticosteroids, or immunosuppressive drugs) Note: Patients with autoimmune conditions
             requiring hormone replacement therapy or topical treatments are eligible.

         10. Has had an allogeneic tissue/solid organ transplant requiring ongoing
             immunosuppressive treatment.

         11. Has or had known drug-induced interstitial lung disease, not fully resolved, or has
             had a history of pneumonitis that has required oral or IV corticosteroids.

         12. Has an active infection requiring IV systemic treatment.

         13. Has known history of HIV (HIV 1/2 antibodies).

         14. Has known untreated hepatitis B/hepatitis C virus (HBV/HCV) or tuberculosis. Active
             HBV is defined as a known positive hepatitis B surface antigen result. Active HCV is
             defined as a known positive hepatitis C antibody result and known quantitative HCV RNA
             results greater than the lower limits of detection of the assay.

         15. Has clinically significant (ie, active) cardiovascular disease: cerebral vascular
             accident/stroke or myocardial infarction within 6 months before enrollment, unstable
             angina, congestive heart failure (New York Heart Association Class ≥ II), or serious
             uncontrolled cardiac arrhythmia requiring medication.

         16. Has other systemic conditions or organ abnormalities that in the opinion of the
             Investigator may interfere with the conduct and/or interpretation of the current
             trial.

         17. Has known psychiatric or substance use disorders that would interfere with cooperation
             or compromise participation with the requirements of the trial.

         18. Is legally incapacitated or has limited legal capacity.

         19. Is pregnant or breastfeeding.

         20. Has received a live/attenuated vaccine within 14 days of first dose of study treatment
             and other vaccines within 48 hours of first dose of study treatment.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall survival in patients with PD-L1 positive tumors randomized to BAL vs Investigator's Choice chemotherapy
Time Frame:time until observing 234 OS events but no later than 36 months after enrollment of the last patient
Safety Issue:
Description:Hazard Ratio for Overall Survival (OS) by treatment assignement, stratified by histology, region of the world, ECOG PS in all patients with PD-L1 positive tumors

Secondary Outcome Measures

Measure:Progression-free survival in patients with PD-L1 positive tumors randomized to BAL vs Investigator's Choice chemotherapy
Time Frame:time until observing 234 OS events but no later than 36 months after enrollment of the last patient
Safety Issue:
Description:Hazard Ratio for PFS by treatment assignment, stratified by histology, region of the world, ECOG PS in all patients with PD-L1 positive tumors
Measure:Progression-free survival in all patients randomized to BAL vs Investigator's Choice chemotherapy
Time Frame:time until observing 234 OS events but no later than 36 months after enrollment of the last patient
Safety Issue:
Description:Hazard Ratio for PFS by treatment assignment, stratified by histology, region of the world, ECOG PS in all patients
Measure:Objective response rate (ORR) to BAL and to IC chemotherapy in patients with PD-L1 positive tumors
Time Frame:time until observing 234 OS events but no later than 36 months after enrollment of the last patient
Safety Issue:
Description:Proportion, with Wilson confidence intervals, of patients with best overall response (by RECIST 1.1) of PR or CR, among all patients with PD-L1 positive tumors randomized to BAL and to IC chemotherapy.
Measure:Objective response rate (ORR) to BAL and to IC chemotherapy in all patients tumors
Time Frame:time until observing 234 OS events but no later than 36 months after enrollment of the last patient
Safety Issue:
Description:Proportion, with Wilson confidence intervals, of patients with best overall response (by RECIST 1.1) of PR or CR, among all patients randomized to BAL and to IC chemotherapy.

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Agenus Inc.

Trial Keywords

  • Advanced Cancer
  • Metastatic Cervical Cancer
  • Open-Label
  • Randomized
  • Monotherapy
  • Anti-PD-1

Last Updated

July 9, 2021