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Clinical Trial 19479

Cancer Type: Gynecological Tumor
Interventions:CP-675,206 (tremelimumab); Olaparib (Lynparza); tremelimumab

Study Type: Treatment
Phase of Study: Phase II
Investigators:

  • Robert Wenham

Call 813-745-6100
or 1-800-679-0775
Overview

Study Title

A Phase 1-2 Study of the Combination of Olaparib and Tremelimumab in BRCA1 and BRCA2 Mutation Carriers with Recurrent Ovarian Cancer

Summary

The purpose of this study is to evaluate the safety and efficacy of a combination of a PARP inhibitor (Olaparib) with a T cell checkpoint inhibitor (the anti-CTLA-4 antibody Tremelimumab) in women with recurrent BRCA mutation-associated ovarian cancer.

Objective

1.0 STUDY OBJECTIVES 1.1 Primary Objectives: Phase 1 Component Primary Objective: To define the safety profile of Tremelimumab and Olaparib in women with BRCA1 or BRCA2 mutation-associated ovarian, tubal, or primary peritoneal cancer who are refractory to standard therapy. Phase 2 Component Primary Objective: 
 To determine the preliminary efficacy of the combination of Tremelimumab and Olaparib as measured by objective response (partial plus complete remission) according to the new immune-related response criteria in solid tumors (irRC). 2.2 Secondary Objectives Phase 2 Component: -To determine overall survival (OS), and progression free survival (PFS) according to the new immune-related response criteria in solid tumors (irRC). -To determine the adverse event profile and tolerability of the combination of Tremelimumab and Olaparib in patients with BRCA1 or BRCA2 mutation-associated ovarian cancer. 2.3 Translational Objectives: -To evaluate immunologic correlates of response to combination therapy (absolute lymphocyte count, myeloid derived suppressor cell numbers, T cell subsets, T cell function and specificity) in both peripheral blood and tumor (when possible). -To identify biomarkers of response to combined targeted and immune therapy through genomic analysis and cytokine profiling of peripheral blood samples. -To explore whether resistance mechanisms to PARP-inhibitors can be overcome with the addition of immune checkpoint blockade. -The exploratory analyses may not be reported in the clinical study report (CSR), if not, they will be reported separately.

Inclusion Criteria

  • Participants must have recurrent epithelial ovarian, fallopian tube, or primary peritoneal carcinoma for which standard curative measures do not exist.
  • 18 years of age or older.
  • Must have a confirmed germline mutation in the BRCA1 or BRCA2 gene.
  • Must have measurable disease as defined by World Health Organization (WHO) criteria.
  • Patients with platinum-sensitive or platinum-resistant disease are eligible.
  • Must have received at least 1 prior course of platinum-based chemotherapy for the management of primary disease including carboplatin, cisplatin, or another platinum compound.
  • There are no restrictions on the total number of prior regimens participants may have received.
  • Gynecologic Oncology Group (GOG) performance status of 0, 1, or 2
  • Adequate organ and marrow function.
  • Women of child-bearing potential must have a negative pregnancy test prior to study entry and agree to use adequate contraception prior to study entry, for the duration of study participation, and for 180 days following completion of therapy.
  • Ability to understand and the willingness to sign a written informed consent document.

  • Exclusion Criteria

  • Recovery from effects of recent surgery, radiotherapy, or chemotherapy have not been demonstrated.
  • Not free of active infection requiring antibiotic therapy (except for uncomplicated urinary tract infections).
  • Hormonal therapy directed at treatment for the cancer must be discontinued at least 1 week 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, must be discontinued at least 3 weeks prior to enrollment.
  • Any prior radiation therapy must be discontinued at least 4 weeks prior to enrollment.
  • A history of autoimmune disorders other than vitiligo (e.g., psoriasis, extensive atopic dermatitis, asthma, inflammatory bowel disease, multiple sclerosis, uveitis, vasculitis), chronic inflammatory condition, or any condition requiring concurrent use of any systemic immunosuppressants or steroids for any reason are excluded from the study. Any patient with an allo-transplant of any kind would be excluded as well, including xenograft heart valve. Mild, intermittent asthma requiring only occasional beta-agonist inhaler use or mild localized eczema will not be excluded.
  • Chronic use of immune-suppressive drugs (i.e., systemic corticosteroids used in the management of cancer or non-cancer related illnesses, e.g., COPD).
  • Known HIV-positive patients and those with other acquired/inherited immunodeficiencies.
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to olaparib or tremelimumab, or other agents used in study.
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
  • Concomitant use of known potent cytochrome P450 isoform 3A4 (CYP3A4) inhibitors.
  • Persistent toxicities (> Common Terminology Criteria for Adverse Event (CTCAE) grade 2) caused by prior cancer therapy, excluding alopecia.
  • Pregnant or nursing.
  • Receiving any other investigational agent.
  • For Phase 2, the inclusion/exclusion criteria above apply. In addition, the following exclusion criteria apply: A.) Resting electrocardiogram with corrected QT interval (QTc) >470msec on two or more time points within a 24hr period, or a family history of long QT syndrome. B.) Have previously received anti-CTLA-4 antibody therapy.