Clinical Trials /

A Phase II Study Of Nivolumab/ Bevacizumab/Rucaparib

NCT02873962

Description:

This research study is evaluating three drugs called Nivolumab, Bevacizumab, and Rucaparib as a possible treatment for relapsed Relapsed Ovarian, Fallopian Tube Or Peritoneal Cancer.

Related Conditions:
  • Fallopian Tube Carcinoma
  • Ovarian Carcinoma
  • Ovarian Carcinosarcoma
  • Ovarian Epithelial Tumor
  • Primary Peritoneal Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: A Phase II Study Of Nivolumab/ Bevacizumab/Rucaparib
  • Official Title: A Phase II Study With a Safety lead-in of Nivolumab in Combination With Bevacizumab or in Combination With Bevacizumab and Rucaparib for the Treatment of Relapsed Epithelial Ovarian, Fallopian Tube or Peritoneal Cancer

Clinical Trial IDs

  • ORG STUDY ID: 16-263
  • NCT ID: NCT02873962

Conditions

  • Peritoneal Cancer
  • Ovarian Cancer
  • Fallopian Tube Cancer

Interventions

DrugSynonymsArms
BevacizumabAvastinNivolumab with Bevacizumab
NivolumabOpdivoNivolumab with Bevacizumab
RucaparibRubracaNivolumab with Bevacizumab and Rucaparib

Purpose

This research study is evaluating three drugs called Nivolumab, Bevacizumab, and Rucaparib as a possible treatment for relapsed Relapsed Ovarian, Fallopian Tube Or Peritoneal Cancer.

Detailed Description

      This research study is a Phase II clinical trial. Cancers are recognized by the immune
      system, and under some circumstances,the immune system may control or even eliminate tumors.
      An antibody is a natural protein made by our immune system that binds other proteins and
      molecules to fight infection and its ill effects.

      Nivolumab is an experimental antibody drug that may make the immune response more active
      against Cancer. Bevacizumab is an antibody that works by stopping the formation of blood
      vessels.Rucaparib is an oral pill that can block the ways cells repair their DNA, which can
      cause damage to certain cancer cells.

      The FDA (the U.S. Food and Drug Administration) has not approved Nivolumab for Relapsed
      Ovarian, Fallopian Tube Or Peritoneal Cancer but it has been approved for other uses.

      Bevacizumab has been FDA approved when used together with chemotherapy for the treatment of
      Ovarian, Fallopian Tube, Or Primary Peritoneal Cancer that has returned within 6 months of a
      chemotherapy that contains a platinum drug.

      Rucaparib has been FDA approved for the treatment of patients with BRCA-mutated ovarian
      cancer who have been treated with 2 or more prior chemotherapies or as maintenance therapy
      following for women with platinum-sensitive recurrent ovarian cancer.

      The combination of Nivolumab, Bevacizumab, and Rucaparib has not been approved by the FDA in
      any setting.
    

Trial Arms

NameTypeDescriptionInterventions
Nivolumab with BevacizumabExperimentalPatients will receive treatment every 14 days with Nivolumab and Bevacizumab administered on day 1 of each cycle.
  • Bevacizumab
  • Nivolumab
Nivolumab with Bevacizumab and RucaparibExperimentalPatients will receive treatment every 14 days with Nivolumab, Bevacizumab administered on day 1 of each cycle and Rucaparib will be taken orally twice daily on days 1-14 .
  • Bevacizumab
  • Nivolumab
  • Rucaparib

Eligibility Criteria

        Inclusion Criteria:

          -  Participants must have histologic or cytologic confirmation of epithelial ovarian
             cancer, fallopian tube or peritoneal cancer. All histologies (including serous,
             mucinous, endometrioid, clear cell, MMMTs, and mixed histologies) are eligible. All
             tumor grades are eligible.

          -  Participants must have received a first-line platinum-based chemotherapy regimen

          -  Participants must have relapsed disease despite standard therapy.

          -  Participants with platinum-resistant or platinum-sensitive disease (within 12 months)
             are eligible. Platinum-resistant disease is defined as relapse within 6 months after
             the last dose of platinum-based chemotherapy. Platinum-sensitive disease is defined as
             relapse greater than 6 months after the last dose of platinum-based chemotherapy.
             Participants with platinum-sensitive disease who have experienced relapse within 6 to
             12 months after the last dose of platinum-based chemotherapy are eligible.Participants
             with primary platinum-refractory disease (defined as progression during or relapsed
             within 2 months of their initial platinum-based chemotherapy) are not eligible.

          -  Participants must have received no more than 3 prior chemotherapy regimens. There is
             no limit to the number of prior hormonal therapies.

          -  Participants must have measurable disease by RECIST 1.1 criteria.

          -  Participants who have received prior bevacizumab are eligible unless there is evidence
             of unacceptable toxicity due to prior bevacizumab exposure.

          -  Participants may not have received any prior treatment with an anti-PD-1, anti PD-L1,
             anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or drug specifically targeting
             T-cell co-stimulation or immune checkpoint pathways.

          -  Participants must have stopped any hormonal therapy at least 1 week prior to treatment
             with nivolumab and bevacizumab.Participants may continue on hormone replacement
             therapy administered for post-menopausal symptoms.

          -  Age ≥ 18 years

          -  Estimated life expectancy of greater than 6 months.

          -  ECOG performance status of 0 or 1

          -  Screening laboratory values must meet the following criteria and should be obtained
             within 14 days prior to registration:

               -  WBC ≥ 2,000/µL

               -  Neutrophils ≥ 1,500/µL

               -  Platelets ≥ 100,000/mcL

               -  Hemoglobin > 9.0 g/dL

               -  Serum creatinine within the institutional ULN or creatinine clearance (CrCl) ≥ 60
                  mL/min (calculated using the Cockgroft-Gault formula) for participants with serum
                  creatinine levels above institutional ULN

               -  AST (SGOT) / ALT (SGPT) ≤ 3 × institutional ULN

               -  Total bilirubin ≤ 1.5 × institutional ULN (except participants with Gilbert
                  Syndrome, who can have total bilirubin ≤ 3.0 × institutional ULN with direct
                  bilirubin that is within institutional ULN)

               -  Coagulation parameters (INR, aPTT) ≤ 1.25 × institutional ULN

          -  Patients with treated limited stage basal cell or squamous cell carcinoma of the skin
             or carcinoma in situ of the breast or cervix are eligible. Patients with stage IA
             endometrial cancer are eligible if the following conditions are met: without vascular
             or lymphatic invasion AND no serous, clear cell or grade 3 histology. Patients with
             early stage I or II cancers treated with curative intent who have no evidence of
             recurrent cancer 3 years following diagnosis and judged by the investigator to be at
             low risk of recurrence are eligible.

          -  Participants must have biopsiable disease and be willing to undergo pre-treatment
             biopsy, or have an archival tumor sample obtained < 20 months prior to study entry.

          -  Women of childbearing potential (WOCBP) is defined as any female who has experienced
             menarche and who has not undergone surgical sterilization (hysterectomy or bilateral
             oophorectomy) or who is not postmenopausal. Menopause is defined clinically as 12
             months of amenorrhea in a woman over 45 in the absence of other biological or
             physiological causes. Additionally, women under the age of 62 who are not surgically
             sterile must have a documented serum follicle stimulating hormone (FSH) level less
             than 40 mIU/mL to document postmenopausal status.

          -  Nivolumab, bevacizumab, and rucaparib may each cause fetal harm or risk to human
             pregnancy. For this reason, WOCBP must agree to use appropriate method(s) of
             contraception for 6 months after the last dose of study treatment, per FDA
             recommendations on use of contraception following bevacizumab. Should a woman become
             pregnant or suspect she is pregnant while participating in this study, she should
             inform her treating physician immediately. Patients receiving rucaparib should
             immediately discontinue rucaparib if they should become pregnant or suspect they are
             pregnant.

          -  WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L
             or equivalent units of HCG) within 24 hours prior to the start of study treatments.

          -  Women must not be breastfeeding

          -  Participants 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, in the absence of active autoimmune disease. 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.

          -  Ability to understand and the willingness to sign a written informed consent document.

        Specific criteria for Cohort 2

        -Patients must have undergone germline BRCA testing and must not have a deleterious or
        suspected deleterious BRCA mutation. Where tumor testing has been performed, patients with
        a deleterious or suspected deleterious somatic BRCA mutation are also not eligible.

        Exclusion Criteria:

          -  Patients with platinum-refractory disease are ineligible. Platinum-refractory disease
             is defined as relapse less than 2 months after the last dose of platinum-based
             chemotherapy.

          -  Patients with platinum-sensitive disease with relapse greater than 12 months after the
             last dose of platinum-based chemotherapy are ineligible.

          -  Participants who have had chemotherapy or radiotherapy within 3 weeks prior to
             entering the study or those who have not recovered from adverse events due to agents
             administered more than 3 weeks earlier.

          -  Participants may not be receiving any other investigational agents nor have
             participated in an investigational trial within the past 4 weeks.

          -  Participants must agree not to use natural herbal products or other "folk remedies"
             while participating in this study.

          -  Patients with a history of allergic reactions attributed to bevacizumab or to
             compounds of similar chemical or biologic composition to nivolumab or bevacizumab are
             excluded.

          -  Patients are excluded if they have active brain metastases or leptomeningeal
             metastases. Subjects with brain metastases are eligible if metastases have been
             treated and there is no magnetic resonance imaging (MRI) evidence of progression for
             at least 6 months after treatment is complete and within 28 days prior to the first
             dose of nivolumab and bevacizumab administration. There must also be no requirement
             for immunosuppressive doses of systemic corticosteroids (> 10 mg/day prednisone
             equivalents) for at least 2 weeks prior to study drug administration.

          -  Patients with any of the following cardiovascular diseases are excluded:

               -  History of myocardial infarction within six months

               -  Unstable angina

               -  Angina pectoris that requires the use of anti-anginal medication

               -  History of documented congestive heart failure (NYHA classification of III or IV)
                  or documented cardiomyopathy

               -  Valvular disease with documented compromise in cardiac function

               -  If cardiac function assessment is clinically indicated or performed:

        LVEF less than normal per institutional guidelines, or < 55%, if threshold for normal not
        otherwise specified by institutional guidelines

          -  Any prior history of hypertensive crisis or hypertensive encephalopathy

          -  Patients may not have any evidence of pre-existing inadequately controlled
             hypertension (defined as a systolic BP of >140 mmHg or a diastolic BP of >90 mmHg),
             and must have a normal blood pressure (≤140/90 mmHg) taken in the clinic setting by a
             medical professional within 2 weeks prior to starting study.

          -  Clinically significant peripheral vascular disease

          -  Vascular disease including aortic aneurysm or dissection

          -  History of stroke, transient ischemic attack or subarachnoid hemorrhage

          -  Ventricular arrhythmias except for benign premature ventricular contractions

          -  Cardiac conduction abnormality requiring a pacemaker

          -  Known history of QT/QTc prolongation or torsades de pointes

          -  QTc prolongation > 470 msec or other significant ECG abnormality noted during
             screening

               -  Grade 2 or higher proteinuria (2+ or higher protein on urinalysis or urine
                  protein:creatinine (UPC) ratio ≥ 1.0; if both tests are performed, UPC should be
                  used to evaluate eligibility) or hematuria.

               -  Participants may not have evidence of a bowel obstruction, abdominal fistula, or
                  intra-abdominal abscess within 6 months of study entry. Participants with current
                  signs or symptoms suggestive of bowel obstruction including early or partial
                  obstruction are ineligible. Participants with a history of gastrointestinal
                  perforation at any time point are ineligible.

               -  Non-healing wound, ulcer or bone fracture.

               -  Serious active infection requiring intravenous antibiotics and/or hospitalization
                  at study entry.

               -  Current dependency on IV hydration or TPN.

               -  Any patient with a history of major depressive episode, bipolar disorder,
                  obsessive/compulsive disorder, schizophrenia, a history of suicide attempt or
                  ideation, or homicide/homicidal ideation as judged by the investigator and/or
                  based on recent psychiatric assessment may not participate in this study without
                  discussion with and agreement of the study PI.

               -  Uncontrolled current illness including, but not limited to, ongoing or active
                  infection or psychiatric illness/social situations that would limit compliance
                  with study requirements.

               -  Patients are excluded if they have an active, known or suspected autoimmune
                  disease other than the following: vitiligo, type I diabetes mellitus, residual
                  hypothyroidism due to autoimmune condition only requiring hormone replacement,
                  psoriasis not requiring systemic treatment, or conditions not expected to recur
                  in the absence of an external trigger.

               -  Patients are excluded if they have a condition requiring systemic treatment with
                  either corticosteroids (> 10 mg daily prednisone equivalents) or other
                  immunosuppressive medications within 14 days of study drug administration, with
                  the exception of 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). Participants
                  are permitted to use topical, ocular, intra-articular, intranasal, and
                  inhalational corticosteroids (with minimal systemic absorption).

               -  Patients are excluded if they test positive for hepatitis B virus surface antigen
                  (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute
                  or chronic infection.

               -  Patients are excluded if they have known history of testing positive for human
                  immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).

               -  Evidence of prior or current coagulopathy or bleeding diathesis.

               -  Major surgical procedure, open biopsy, or significant traumatic injury within 28
                  days prior to starting nivolumab and bevacizumab

               -  History of severe infusion reactions to monoclonal antibody therapy

        Specific criteria for Cohort 2

          -  Patients who have received a prior PARP inhibitor are not allowed to enroll to Cohort
             2 of the trial

          -  Patients are excluded from Cohort 2 should they have pre-existing duodenal stent
             and/or any gastrointestinal disorder or defect that would, in the opinion of the
             investigator, interfere with absorption of rucaparib.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:Cohort 1: Objective Response Rate
Time Frame:2 years
Safety Issue:
Description:Using RESIST 1.1 criteria or modified GCIG CA-125 criteria

Secondary Outcome Measures

Measure:Progression Free Survival
Time Frame:6 months
Safety Issue:
Description:The percentage of patients progression-free at 6 months
Measure:Best Overall Response Rate
Time Frame:2 years
Safety Issue:
Description:Using RESIST 1.1 criteria or modified GCIG CA-125 criteria
Measure:Duration Of Response
Time Frame:2 years
Safety Issue:
Description:It will be described using the method of Kaplan-Meier
Measure:The Association Of Baseline PD-L1 Expression With Anti-Tumor Activity
Time Frame:2 years
Safety Issue:
Description:It will be evaluated using a Wilcoxon rank sum test of marker levels in responders versus non-responders using a one-sided alpha = 0.05.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Dana-Farber Cancer Institute

Trial Keywords

  • Relapsed Ovarian Cancer

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