Ignite Creation Date:
2024-05-06 @ 7:40 AM
Last Modification Date:
2024-10-26 @ 11:50 AM
Study NCT ID:
NCT02571725
Status:
ACTIVE_NOT_RECRUITING
Last Update Posted:
2024-01-11
First Post:
2015-10-06
Brief Title:
PARP-inhibition and CTLA-4 Blockade in BRCA-deficient Ovarian Cancer
Sponsor:
New Mexico Cancer Care Alliance
Organization:
New Mexico Cancer Care Alliance
Study Overview
Official Title:
A Phase 1-2 Study of the Combination of Olaparib and Tremelimumab in BRCA1 and BRCA2 Mutation Carriers With Recurrent Ovarian Cancer
Status:
ACTIVE_NOT_RECRUITING
Status Verified Date:
2023-10
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Of the approximately 21000 cases of ovarian cancer diagnosed annually in the US 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 polyadenosine 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 Its 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
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
Detailed Description:
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 BRCA12 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
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 BRCA12 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 Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None