Clinical Trials /

Testing the Addition of an Immunotherapy Drug, Tremelimumab, to the PARP Inhibition Drug, Olaparib, for Recurrent Ovarian, Fallopian Tube or Peritoneal Cancer

NCT04034927

Description:

This phase II trial studies how well olaparib with or without tremelimumab works in treating patients with ovarian, fallopian tube, or peritoneal cancer that has come back (recurrent). Olaparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as tremelimumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving olaparib and tremelimumab together may work better than olaparib alone in treating patients with ovarian, fallopian tube, or peritoneal cancer.

Related Conditions:
  • Fallopian Tube Clear Cell Adenocarcinoma
  • Fallopian Tube Transitional Cell Carcinoma
  • Malignant Ovarian Clear Cell Tumor
  • Malignant Ovarian Mixed Epithelial Tumor
  • Ovarian Transitional Cell Carcinoma
  • Undifferentiated Ovarian Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Testing the Addition of an Immunotherapy Drug, Tremelimumab, to the PARP Inhibition Drug, Olaparib, for Recurrent Ovarian, Fallopian Tube or Peritoneal Cancer
  • Official Title: A Phase II Randomized Trial of Olaparib Versus Olaparib Plus Tremelimumab in Platinum-Sensitive Recurrent Ovarian Cancer

Clinical Trial IDs

  • ORG STUDY ID: NCI-2019-04829
  • SECONDARY ID: NCI-2019-04829
  • SECONDARY ID: NRG-GY021
  • SECONDARY ID: NRG-GY021
  • SECONDARY ID: U10CA180868
  • NCT ID: NCT04034927

Conditions

  • Fallopian Tube Carcinosarcoma
  • Fallopian Tube Clear Cell Adenocarcinoma
  • Fallopian Tube Transitional Cell Carcinoma
  • Fallopian Tube Undifferentiated Carcinoma
  • Germline BRCA1 Gene Mutation
  • Germline BRCA2 Gene Mutation
  • High Grade Fallopian Tube Serous Adenocarcinoma
  • High Grade Ovarian Serous Adenocarcinoma
  • Ovarian Clear Cell Tumor
  • Ovarian Seromucinous Carcinoma
  • Ovarian Undifferentiated Carcinoma
  • Platinum-Sensitive Fallopian Tube Carcinoma
  • Platinum-Sensitive Ovarian Carcinoma
  • Platinum-Sensitive Primary Peritoneal Carcinoma
  • Primary Peritoneal Carcinosarcoma
  • Primary Peritoneal Clear Cell Carcinoma
  • Primary Peritoneal High Grade Serous Adenocarcinoma
  • Primary Peritoneal Transitional Cell Carcinoma
  • Primary Peritoneal Undifferentiated Carcinoma
  • Recurrent Fallopian Tube Carcinoma
  • Recurrent Ovarian Endometrioid Adenocarcinoma
  • Recurrent Ovarian Serous Adenocarcinoma
  • Recurrent Ovarian Transitional Cell Carcinoma
  • Recurrent Primary Peritoneal Carcinoma

Interventions

DrugSynonymsArms
OlaparibAZD 2281, AZD-2281, AZD2281, KU-0059436, Lynparza, PARP Inhibitor AZD2281Arm I (olaparib)
TremelimumabAnti-CTLA4 Human Monoclonal Antibody CP-675,206, CP-675, CP-675,206, CP-675206, TicilimumabArm II (olaparib, tremelimumab)

Purpose

This phase II trial studies how well olaparib with or without tremelimumab works in treating patients with ovarian, fallopian tube, or peritoneal cancer that has come back (recurrent). Olaparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as tremelimumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving olaparib and tremelimumab together may work better than olaparib alone in treating patients with ovarian, fallopian tube, or peritoneal cancer.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine whether olaparib plus tremelimumab has adequate safety in the study
      population. (Safety Lead-in Trial Components) II. To compare the progression-free survival
      (PFS) duration of olaparib monotherapy versus olaparib plus tremelimumab in women with
      recurrent, platinum sensitive ovarian, primary peritoneal, or fallopian tube cancer. (Phase
      II Trial Component)

      SECONDARY OBJECTIVES:

      I. To compare the overall response rate (ORR) by Response Evaluation Criteria in Solid Tumors
      (RECIST) 1.1 in women with recurrent, platinum sensitive ovarian, primary peritoneal or
      fallopian tube cancer treated with either olaparib monotherapy or olaparib plus tremelimumab.

      II. To compare the overall survival (OS) of women with recurrent, platinum sensitive ovarian,
      primary peritoneal or fallopian tube cancer treated with either olaparib monotherapy or
      olaparib plus tremelimumab.

      EXPLORATORY OBJECTIVES:

      I. To explore whether conditions in the tumor microenvironment (as measured by gene
      expression signature in archived tumor samples) identify patients that benefit from combined
      olaparib and tremelimumab immunotherapy.

      II. To explore whether mutations in BRCA1/2 genes or other evidence of homologous repair
      deficiency (HRD+) is prognostic and/or predictive of response to combined olaparib and
      tremelimumab immunotherapy.

      III. To explore associations between PD1 expression in the tumor microenvironment and outcome
      and changes in circulating leukocyte populations.

      IV. To explore the correlation between tumor mutational burden and response to olaparib and
      tremelimumab immunotherapy.

      V. To explore the impact of olaparib and tremelimumab versus olaparib monotherapy on
      circulating leukocyte subsets via exploration of the immunomodulatory effects of PARP
      inhibition and the added impact of CTLA4 blockade in this patient population.

      VI. To explore cytokine/chemokine levels using a multiplex immunoassay (Olink) and correlate
      these levels with clinical endpoints.

      VII. To use cell-free deoxyribonucleic acid (DNA) to assess BRCA mutation status as a
      mechanism of acquired resistance to prior PARP inhibition and to compare with treatment
      efficacy.

      OUTLINE: Patients are randomized to 1 of 2 arms.

      ARM I: Patients receive olaparib orally (PO) twice daily (BID) in the absence of disease
      progression or unacceptable toxicity.

      ARM II: Patients receive olaparib as in Arm I. Patients also receive tremelimumab
      intravenously (IV) over 60 minutes on day 1. Cycles of tremelimumab repeat every 4 weeks for
      4 doses and then every 12 weeks for up to 2 years total in the absence of disease progression
      or unacceptable toxicity.

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

Trial Arms

NameTypeDescriptionInterventions
Arm I (olaparib)Active ComparatorPatients receive olaparib PO BID in the absence of disease progression or unacceptable toxicity.
  • Olaparib
Arm II (olaparib, tremelimumab)ExperimentalPatients receive olaparib as in Arm I. Patients also receive tremelimumab IV over 60 minutes on day 1. Cycles of tremelimumab repeat every 4 weeks for 4 doses and then every 12 weeks for up to 2 years total in the absence of disease progression or unacceptable toxicity.
  • Olaparib
  • Tremelimumab

Eligibility Criteria

        Inclusion Criteria:

          -  Patients must have platinum-sensitive, recurrent high-grade serous or high-grade
             endometrioid ovarian, primary peritoneal, or fallopian tube cancer. Submission of BRCA
             testing results is required for all patients. Patients with other (clear cell, mixed
             epithelial, undifferentiated carcinoma, or transitional cell carcinoma) high-grade
             histologies are also eligible, provided that the patient has a known deleterious
             germline BRCA1 or BRCA2 mutation identified through testing at a clinical laboratory.
             Due to the long acceptance of germline BRCA testing through Myriad, Myriad testing
             reports will be accepted without additional documentation. If testing for germline
             BRCA is done by other organizations, in addition to the testing report, documentation
             from a qualified medical professional (e.g., ovarian cancer specialty physician
             involved in the field, high risk genetics physician, genetics counselor) detailing the
             laboratory results is required. Please retain a copy of all reports (positive,
             variants of uncertain significance [VUS], or negative).

          -  Platinum-sensitive disease defined as no clinical or radiographic evidence of disease
             recurrence for > 6 months (or 182 days) after last receipt of platinum-based therapy.
             The date should be calculated from the last administered dose of platinum therapy.

          -  Patients must have had a complete clinical response to their prior line of platinum
             therapy and cannot have had progression through prior platinum-based therapy.

          -  Patients must have RECIST 1.1 measurable disease. Patients with biochemical recurrence
             based on CA125 levels alone are not eligible.

          -  Prior therapy:

               -  Prior chemotherapy must have included a first-line platinum-based regimen with or
                  without consolidation chemotherapy.

               -  Prior bevacizumab therapy as a component of frontline or recurrent treatment is
                  permitted.

               -  Patients may have received an unlimited number of platinum-based therapies in the
                  recurrent setting.

               -  Patients may have received up to one non-platinum-based line of therapy in the
                  recurrent setting. Prior hormonal therapy will not be counted as this
                  non-platinum-based line.

               -  Prior treatment with a PARP inhibitor:

                    -  Patients may not have had a prior PARP inhibitor in the recurrent setting.

                    -  Prior use of a PARP inhibitor in the upfront maintenance setting is allowed
                       for women with a confirmed BRCA1 or BRCA2 germline or somatic mutation.

                    -  Women who received a PARP inhibitor for maintenance therapy in the frontline
                       setting must have received at least one other chemotherapy regimen for
                       recurrence prior to enrolling on this trial.

                    -  Patients who demonstrated disease progression while on a PARP inhibitor are
                       excluded.

               -  Prior hormonal-based therapy for ovarian, primary peritoneal, or fallopian tube
                  cancer is acceptable.

          -  Body weight > 30 kg.

          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2

          -  Absolute neutrophil count (ANC) >= 1,500/mcl (within 14 days prior to enrollment)

          -  Platelets >= 100,000/mcl (within 14 days prior to enrollment)

          -  Hemoglobin >= 10 g/dL (within 14 days prior to enrollment)

          -  Leukocytes >= 3,000/mcl (within 14 days prior to enrollment)

               -  Note: blood transfusions are not permitted within 28 days prior to enrollment

          -  Glomerular filtration rate (GFR) >= 50 mL/min/1.73 m^2 (within 14 days prior to
             enrollment)

               -  GFR (estimated creatinine clearance or CLcr) will be estimated using the
                  Cockcroft and Gault equation for females

          -  Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (within 14 days
             prior to enrollment)

          -  Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3 times
             institutional ULN (within 14 days prior to enrollment)

          -  Adequately controlled thyroid function, with no symptoms of thyroid dysfunction and
             thyroid stimulating hormone (TSH) within normal limits. Thyroid replacement therapy is
             permitted to achieve a TSH within normal limits.

          -  Patients must be able to swallow and retain oral medications and not have
             gastrointestinal illnesses that would preclude absorption of olaparib as judged by the
             treating physician.

          -  Evidence of post-menopausal status or negative urinary or serum pregnancy test for
             pre-menopausal patients. Women will be considered post-menopausal if they have been
             amenorrheic for 12 months without an alternative medical cause. The following
             age-specific requirements apply:

               -  Women < 50 years of age would be considered post-menopausal if they have been
                  amenorrheic for 12 months or more following cessation of exogenous hormonal
                  treatments and if they have luteinizing hormone and follicle-stimulating hormone
                  levels in the post-menopausal range for the institution or underwent surgical
                  sterilization (bilateral oophorectomy or hysterectomy).

               -  Women >= 50 years of age would be considered post-menopausal if they have been
                  amenorrheic for 12 months or more following cessation of all exogenous hormonal
                  treatments, had radiation-induced menopause with last menses > 1 year ago, had
                  chemotherapy-induced menopause with last menses > 1 year ago, or underwent
                  surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or
                  hysterectomy).

               -  Administration of study drugs (olaparib, tremelimumab) may have an adverse effect
                  on pregnancy and poses a risk to the human fetus, including embryo-lethality.
                  Women of childbearing potential (WOCBP) must agree to use two (2) highly
                  effective forms of contraception from up to 14 days prior to enrollment (for oral
                  contraceptives), during treatment, and for 6 months after the last dose of study
                  medication.

          -  Life expectancy >= 12 weeks.

          -  Patients with brain metastases are eligible if follow-up brain imaging after central
             nervous system (CNS)-directed therapy shows no evidence of progression. Imaging
             studies must have been completed no later than 14 days prior to enrollment. In
             addition, patients must have been successfully weaned off steroid support. Patients
             should not have received steroids for the treatment of brain metastases within 14 days
             prior to enrollment.

          -  Human immunodeficiency virus (HIV) testing is not required by protocol unless
             clinically indicated. Known HIV positive patients are eligible if they meet the
             following criteria:

               -  They must be on an anti-retroviral regimen with evidence of at least two
                  undetectable viral loads within the past 6 months on this same regimen; the most
                  recent undetectable viral load must be within 12 weeks of study enrollment.

               -  They must have a CD4 count >= 250 cells/uL over the past 6 months on this same
                  anti-retroviral regimen and must not have had a CD4 count < 200 cells/ul over the
                  past 2 years, unless it was deemed related to THE CANCER AND/OR
                  chemotherapy-induced bone marrow suppression.

                    -  For patients who have received chemotherapy in the past 6 months, a CD4
                       count < 250 cells/ul during chemotherapy is permitted as long as viral loads
                       were undetectable during this same chemotherapy.

               -  They must have an undetectable viral load and a CD4 count >= 250 cells/uL within
                  7 days prior to enrollment.

               -  They must not be currently receiving prophylactic therapy for an opportunistic
                  infection and must not have had an opportunistic infection within the past 6
                  months.

          -  The patient or a legally authorized representative must provide study-specific
             informed consent prior to study entry and, for patients treated in the United States
             (U.S.), authorization permitting release of personal health information.

        Exclusion Criteria:

          -  Active infection requiring antibiotic therapy (except for uncomplicated urinary tract
             infections), including tuberculosis (clinical evaluation that includes clinical
             history, physical examination and radiographic findings, and tuberculosis (TB) testing
             in line with local practice), hepatitis B (known positive hepatitis B virus [HBV]
             surface antigen [HBsAg] result), or hepatitis C. Patients with a past or resolved HBV
             infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence
             of HBsAg) are eligible. Patients positive for hepatitis C virus (HCV) antibody are
             eligible only if polymerase chain reaction is negative for HCV ribonucleic acid (RNA).

          -  Hormonal therapy directed at treatment for the cancer must be discontinued at least 28
             days prior to enrollment. Hormone replacement therapy for symptom management is
             permitted.

          -  Any other therapy directed at treating the cancer including chemotherapy,
             biologic/targeted agents, and immunologic agents, unless discontinued at least 28 days
             prior to enrollment.

          -  Any radiation therapy unless discontinued at least 28 days prior to enrollment.

          -  Major surgical procedure (defined as any surgery requiring general anesthesia or
             inpatient care) within 28 days prior to enrollment.

          -  Current or prior use of immunosuppressive medication within 14 days before enrollment.
             The following are exceptions to this criterion:

               -  Intranasal, inhaled, topical steroids, or local steroid injections (i.e.
                  intra-articular injection)

               -  Systemic corticosteroids at physiologic doses not to exceed 10mg/day of
                  prednisone or its equivalent

               -  Steroids as premedication for hypersensitivity reactions (i.e. computed
                  tomography [CT] scan contrast allergy premedication).

          -  Patients with active autoimmune disease that has required systemic treatment in the
             past 2 years (i.e., with use of disease modifying agents, corticosteroids, or
             immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or
             physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency,
             etc.) is not considered a form of systemic treatment.

               -  Patients with autoimmune disease (e.g., psoriasis, extensive atopic dermatitis,
                  severe asthma, inflammatory bowel disease [IBD], multiple sclerosis [M.S.],
                  uveitis, vasculitis) requiring concurrent use of any systemic immunosuppressants
                  or steroids are excluded from the study. Patients with vitiligo, mild,
                  intermittent asthma requiring only occasional beta-agonist inhaler use, or mild
                  localized eczema are eligible.

               -  Any patient with an allogeneic (allo)-transplant of any kind is excluded,
                  including xenograft heart valve.

               -  Chronic use of immune-suppressive drugs (i.e. systemic corticosteroids) for the
                  management of cancer or non-cancer related illnesses (i.e. chronic obstructive
                  pulmonary disease [COPD]).

               -  Note: ongoing steroid use for the management of brain metastases is not
                  permitted.

          -  History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to olaparib or tremelimumab.

          -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active
             infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable
             angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic
             gastrointestinal conditions associated with diarrhea, or psychiatric illness/social
             situations that would limit compliance with study requirements, substantially increase
             risk of incurring adverse events (AEs) or compromise the ability of the patient to
             give written informed consent.

          -  Subjects must not have evidence of bowel obstruction on imaging or symptoms consistent
             with a bowel obstruction. Additional workup to rule this out is not required.

          -  Known potent CYP3A4 inhibitors or inducers must be discontinued prior to starting
             treatment.

          -  Symptoms associated with toxicities (> Common Terminology Criteria for Adverse Event
             [CTCAE version (v) 5.] grade 2) caused by prior cancer therapy, excluding alopecia,
             vitiligo, and the laboratory values defined in the inclusion criteria.

               -  Patients with grade >= 2 neuropathy will be evaluated on a case-by-case basis
                  after consultation with the Study Chair.

          -  Patients who are receiving any other investigational agent.

          -  Resting electrocardiogram (ECG) with corrected QT interval (QTc) > 470 msec on two or
             more time points within a 24-hour period, or a family history of long QT syndrome. If
             an initial ECG is within normal limits, a repeat ECG is not required.

          -  Patients who have previously received anti-CTLA-4 antibody therapy.

          -  Blood transfusions are not permitted within 28 days prior to study enrollment.

          -  Patients must not have signs or symptoms suggestive of myelodysplastic syndrome or
             acute myeloid leukemia.

          -  Pregnant or lactating patients

          -  Receipt of live attenuated vaccines within 30 days of enrollment. Note: patients, if
             enrolled, should not receive live vaccines while receiving study treatment and up to
             30 days after the last treatment dose. Inactivated vaccines are permitted.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:Progression free survival (PFS)
Time Frame:Duration of time from study entry to time of progression per Response Evaluation Criteria in Solid Tumors (RECIST) criteria or death due to any cause, whichever occurs first, assessed up to 5 years
Safety Issue:
Description:Descriptive statistics will be used to summarize adverse events (AEs). The primary summary of AEs will present counts and percentages, regardless of whether the AE was attributed to any of the study agents.

Secondary Outcome Measures

Measure:Objective response
Time Frame:Up to 5 years
Safety Issue:
Description:The objective response rate is the percentage of subjects with a best overall complete response (CR) or partial response (PR) among those with target lesions at the time of enrollment.
Measure:Overall survival (OS)
Time Frame:Time from enrollment and randomization to the date of death due to any cause, assessed up to 5 years
Safety Issue:
Description:Kaplan-Meier procedures will be used to estimate the cumulative distribution of survival times for each treatment in this population. A proportional hazards model stratified by BRCA status and prior PARPi treatment will be used to estimate the treatment hazard ratio and the corresponding confidence interval.
Measure:Incidence of adverse events
Time Frame:Up to 5 years
Safety Issue:
Description:Safety data will be summarized for all treated subjects. All adverse events, including severe adverse events (SAEs) and treatment-related adverse events, will be categorized and graded for severity according to National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:National Cancer Institute (NCI)

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