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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04034927
Recruitment Status : Suspended (Scheduled Interim Monitoring)
First Posted : July 29, 2019
Last Update Posted : October 22, 2020
Sponsor:
Collaborator:
NRG Oncology
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Tracking Information
First Submitted Date  ICMJE July 25, 2019
First Posted Date  ICMJE July 29, 2019
Last Update Posted Date October 22, 2020
Actual Study Start Date  ICMJE October 11, 2019
Estimated Primary Completion Date December 31, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 25, 2019)
  • 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 ]
  • Dose-limiting toxicity (DLT) (Safety Lead-In) [ Time Frame: Up to 4 weeks ]
    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.
  • RECIST 1.1 response (Efficacy Lead-In) [ Time Frame: Up to 5 years ]
    A logistic model will be used to estimate the relative odds of responding (CR+PR) to olaparib + tremelimumab relative to olaparib after adjusting for BRCA mutation status and prior PARP inhibitor (PARPi) usage.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: July 25, 2019)
  • Objective response [ Time Frame: Up to 5 years ]
    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.
  • Overall survival (OS) [ Time Frame: Time from enrollment and randomization to the date of death due to any cause, assessed up to 5 years ]
    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.
  • Incidence of adverse events [ Time Frame: Up to 5 years ]
    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.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Testing the Addition of an Immunotherapy Drug, Tremelimumab, to the PARP Inhibition Drug, Olaparib, for Recurrent Ovarian, Fallopian Tube or Peritoneal Cancer
Official Title  ICMJE A Phase II Randomized Trial of Olaparib Versus Olaparib Plus Tremelimumab in Platinum-Sensitive Recurrent Ovarian Cancer
Brief Summary 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). PARPs are proteins that help repair DNA mutations. PARP inhibitors, such as olaparib, can keep PARP from working, so tumor cells can't repair themselves, and they may stop growing. 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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Fallopian Tube Endometrioid Tumor
  • High Grade Fallopian Tube Serous Adenocarcinoma
  • High Grade Ovarian Serous Adenocarcinoma
  • Malignant Ovarian Endometrioid Tumor
  • Platinum-Sensitive Fallopian Tube Carcinoma
  • Platinum-Sensitive Ovarian Carcinoma
  • Platinum-Sensitive Primary Peritoneal Carcinoma
  • Primary Peritoneal High Grade Serous Adenocarcinoma
  • Recurrent Fallopian Tube Carcinoma
  • Recurrent Fallopian Tube Endometrioid Adenocarcinoma
  • Recurrent Ovarian Endometrioid Adenocarcinoma
  • Recurrent Ovarian Serous Adenocarcinoma
  • Recurrent Primary Peritoneal Carcinoma
  • Recurrent Primary Peritoneal Endometrioid Adenocarcinoma
Intervention  ICMJE
  • Drug: Olaparib
    Given PO
    Other Names:
    • AZD 2281
    • AZD-2281
    • AZD2281
    • KU-0059436
    • Lynparza
    • PARP Inhibitor AZD2281
  • Biological: Tremelimumab
    Given IV
    Other Names:
    • Anti-CTLA4 Human Monoclonal Antibody CP-675,206
    • CP-675
    • CP-675,206
    • CP-675206
    • Ticilimumab
Study Arms  ICMJE
  • Active Comparator: Arm I (olaparib)
    Patients receive olaparib PO BID in the absence of disease progression or unacceptable toxicity.
    Intervention: Drug: Olaparib
  • Experimental: Arm II (olaparib, tremelimumab)
    Patients 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.
    Interventions:
    • Drug: Olaparib
    • Biological: Tremelimumab
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Suspended
Estimated Enrollment  ICMJE
 (submitted: July 25, 2019)
170
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 31, 2022
Estimated Primary Completion Date December 31, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Patients must have platinum-sensitive, recurrent high-grade serous or high-grade endometrioid (grade 3) ovarian, primary peritoneal, or fallopian tube cancer. Patients with other histologies are also eligible, provided that the patient has a known deleterious germline or somatic BRCA1 or BRCA2 mutation identified through testing at a clinical laboratory. Submission of BRCA testing results (germline and/or somatic) is required for all patients.
  • 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 response (complete or partial) 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)

    • Note: blood transfusions are not permitted within 28 days prior to enrollment
  • Creatinine =< 1.5 x institutional/laboratory upper limit of normal (ULN) (within 14 days prior to enrollment)
  • 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, bilateral salpingectomy 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)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
  • 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.
  • Known clinically significant liver disease, including active viral, alcoholic, or other hepatitis; and cirrhosis. 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.
  • 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 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.
Sex/Gender  ICMJE
Sexes Eligible for Study: Female
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04034927
Other Study ID Numbers  ICMJE NCI-2019-04829
NCI-2019-04829 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
NRG-GY021 ( Other Identifier: NRG Oncology )
NRG-GY021 ( Other Identifier: CTEP )
U10CA180868 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page.
URL: https://grants.nih.gov/policy/sharing.htm
Responsible Party National Cancer Institute (NCI)
Study Sponsor  ICMJE National Cancer Institute (NCI)
Collaborators  ICMJE NRG Oncology
Investigators  ICMJE
Principal Investigator: Sarah F Adams NRG Oncology
PRS Account National Cancer Institute (NCI)
Verification Date October 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP