PARP-inhibition and CTLA-4 Blockade in BRCA-deficient Ovarian 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. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.|
|ClinicalTrials.gov Identifier: NCT02571725|
Recruitment Status : Recruiting
First Posted : October 8, 2015
Last Update Posted : June 17, 2019
Of the approximately 21,000 cases of ovarian cancer diagnosed annually in the U.S, ten percent are attributed to hereditary syndromes, most commonly the result of mutations in the breast cancer susceptibility genes 1 or 2 (BRCA1 or BRCA2). Mutation in these genes results in the inability to repair double-stranded breaks in DNA. Treating these tumors with poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitors results in the specific killing of BRCA negative cells by blocking a second DNA-repair mechanism. Treatment of ovarian cancer patients with PARP inhibitors has resulted in improved progression free survival (PFS), but not overall survival (OS). It's not completely understood why this is the case, but some preclinical studies using ovarian cancer models in mice have suggested that combining PARP inhibitors with immune system modulators like T cell checkpoint inhibitors improves long-term survival.
Therefore, 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.
|Condition or disease||Intervention/treatment||Phase|
|Ovarian Cancer Fallopian Tube Cancer Peritoneal Neoplasms||Drug: Olaparib Drug: Tremelimumab||Phase 1 Phase 2|
The mechanism of action of Olaparib, a potent inhibitor of mammalian PARP-1, PARP-2, and PARP-3, has been proposed to involve the trapping of inactivated PARP onto single-stranded breaks preventing their repair and generating a potential block for cellular DNA replication. In tumors with homologous recombination deficiency, such as those with BRCA mutations, single agent treatment with Olaparib can lead to cell death and tumor regressions by a process known as synthetic lethality.
Tremelimumab is a human monoclonal immunoglobulin G2 (IgG2) antibody specific for human cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), a co-inhibitory receptor expressed on activated T cells. Tremelimumab has been shown to block the inhibitory signal mediated by interaction of human CTLA-4 on activated T cells with B7-1 and B7-2 on antigen-presenting cells. This is thought to maintain T cell activation in the tumor microenvironment and promote the establishment of tumor-specific immune responses.
Like melanoma, ovarian cancer is associated with significant tumor heterogeneity, and is also a rational target for immune therapy. Although antitumor effects have been observed in patients with epithelial ovarian cancer in response to anti-CTLA-4 antibody treatment, evidence of clinical disease regression has not been demonstrated. Based on data indicating that a subset of ovarian cancers associated with germline mutations in BRCA1/2 genes may be more immunogenic, we hypothesized that BRCA-negative tumors would be particularly vulnerable to checkpoint blockade, and that immune priming with targeted cytotoxic therapy using a PARP-inhibitor would sensitize ovarian tumors to immune therapy and optimize patient survival. We have demonstrated this in pre-clinical models of high grade BRCA1-negative ovarian cancer.
Based on significant therapeutic benefit demonstrated in pre-clinical models, this clinical trial evaluates the combination of Olaparib and Tremelimumab in women with recurrent BRCA-deficient ovarian cancers.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||50 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||A Phase 1-2 Study of the Combination of Olaparib and Tremelimumab, in BRCA1 and BRCA2 Mutation Carriers With Recurrent Ovarian Cancer|
|Study Start Date :||February 2016|
|Estimated Primary Completion Date :||February 2020|
|Estimated Study Completion Date :||February 2022|
Experimental: Olaparib and Tremelimumab
Each cycle is 28 days:
Olaparib at 300 mg, orally, twice daily + Tremelimumab at 10 mg/kg, intravenously, every 4 weeks for the first 6 doses, then every 12 weeks until disease progression or unacceptable toxicity.
In Phase 2, patients will receive doses of Olaparib and Tremelimumab determined in the Phase 1 portion as described above, based on tolerability.
Olaparib starts concomitantly with the first dose of Tremelimumab
3 to 6 patients will be treated at 10 mg/kg depending on RLT observed in the first 3 patients. If 0 out of 3 or 1 out of 6 patients experienced a RLT at 10 mg/kg, then this dose will be considered at the recommended phase 2 dose (RP2D). If 2 out of 6 patients experience RLT at this dose within 56 days, then dose reductions as detailed in the Arm description will be carried out.
Other Name: CP-675,206
- Phase 1: Recommended Phase 2 Dose (RP2D) [ Time Frame: Within 56 days of first treatment (up to 2 years) ]
The RP2D will be based on determination of the regimen-limiting toxicity (RLT), i.e., toxicity induced by the immunological agent that limits the administration of the backbone therapy (Olaparib).
RLT is defined as the following toxicities occurring during the first two cycles (56 days) of treatment (with the combination of Olaparib and Tremelimumab):
- Any grade 4 non-hematological toxicity that is treatment-related with the exception of alopecia, nausea and vomiting or lymphopenia.
- Any grade 3 non hematological toxicity that is treatment related that results in delay of Olaparib by greater than 4 weeks.
- Delay in starting the second cycle by more than 2 weeks due to toxicity attributable to Tremelimumab.
The RP2D of Tremelimumab is one that does not induce RLT in more than 1 of 6 patients.
- Phase 2: Objective response rate (ORR) [ Time Frame: 2 years ]Patients will be followed both clinically and radiographically every 12 weeks. Responses will be assessed using immune-related response criteria (irRC) (Wolchock et al 2009) in which tumor volume measurements are assessed along with the emergence of new measurable lesions. Each net percentage change in tumor burden accounts for the size and growth kinetics of both old and new lesions as they appear. The sum of the product of the diameters for all index lesions identified prior to enrollment is the immune-related sum of products of diameters (irSPD). Complete Response (CR), Disappearance of all tumor lesions; Partial Response (PR), >=50% decrease relative to the baseline irSPD. ORR = proportion of patients whose best overall response is either CR or PR.
- Phase 2: Progression free survival (PFS) [ Time Frame: 5 years ]PFS is defined as the time between the first dose of study therapy and the earliest of progression or death. Patients will be followed both clinically and radiographically every 12 weeks. Responses will be assessed using immune-related response criteria (irRC) (Wolchock et al 2009) in which tumor volume measurements are assessed along with the emergence of new measurable lesions. Each net percentage change in tumor burden accounts for the size and growth kinetics of both old and new lesions as they appear. The sum of the product of the diameters for all index lesions identified prior to enrollment is the immune-related sum of products of diameters (irSPD). New lesions alone do not qualify as progressive disease. Progressive disease is >= 25% increase in the irSPD (based on irSPD of all index lesions and any measurable new lesions) over the nadir irSPD, or the occurrence of any new measurable lesions if the SPD nadir is "0."
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02571725
|Contact: Valerie Parks, RN OCN, CCRPemail@example.com|
|United States, Florida|
|Moffitt Cancer Center||Recruiting|
|Tampa, Florida, United States, 33612|
|Contact: Eleni Rokakis, BSN, RN 813-745-3593 Eleni.Rokakis@moffitt.org|
|United States, New Mexico|
|Southwest Gynecologic Oncology Associates||Recruiting|
|Albuquerque, New Mexico, United States, 87106|
|Contact: Karen Finkelstein, MD 505-843-7813|
|University of New Mexico Comprehensive Cancer Center||Recruiting|
|Albuquerque, New Mexico, United States, 87131|
|Contact: Valerie Parks, RN 505-925-0390 firstname.lastname@example.org|
|Principal Investigator: Sarah F Adams, MD|
|United States, Ohio|
|The Ohio State University||Recruiting|
|Columbus, Ohio, United States, 43210|
|Contact: David M O'Malley, MD 614-685-6411|
|Contact: Molly Myers 614-685-6411 email@example.com|
|United States, Virginia|
|University of Virginia Cancer Center||Recruiting|
|Charlottesville, Virginia, United States, 22903|
|Contact: Anne Gabel 434-982-6657 firstname.lastname@example.org|
|Principal Investigator:||Sarah F Adams, MD||University of New Mexico Comprehensive Cancer Center|