Study Evaluating the Efficacy of a Double Immunotherapy Combined With Olaparib in Patients With Solid Cancers and Carriers of Homologous Recombination Repair Genes After Olaparib Treatment (GUIDE2REPAIR)
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|ClinicalTrials.gov Identifier: NCT04169841|
Recruitment Status : Not yet recruiting
First Posted : November 20, 2019
Last Update Posted : November 22, 2019
|Condition or disease||Intervention/treatment||Phase|
|Immunotherapy||Drug: olaparib, durvalumab, tremelimumab||Phase 2|
With the development of cost effective and rapid technology of genome sequencing, precision medicine becomes a new way to think oncology. Current targets involve mainly tyrosine kinase, but DNA repair machinery could also be targetable. Some of DNA repair aberrations have been associated with sensitivity to platinum and poly (adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitors like Olaparib, suggesting that treatment with a PARP inhibitor may exploit a synthetic lethal interaction when the presence of alteration of the homologous repair pathway was observed. PARP is involved in multiple aspects of DNA repair, and the PARP inhibitor Olaparib has recently been approved for treating ovarian cancers with BRCA1/2 mutations. In addition, it showed that using a high-throughput, next-generation sequencing assay in prostate cancer, detection of genomic alteration in genes involved in homologous repair pathway BRCA2, ATM, BRCA1, PALB2, CHEK2, FANCA, and HDAC2, is associated with response to olaparib. Thus demonstrating the clinical validation of the usage of precision medicine to position PARP inhibitor like olaparib in different cancer types based on molecular analysis.
Preclinical studies showed DNA damage promotes neoantigen expression. It is possible that increased DNA damage by PARPi would yield greater mutational burden and expand neoantigen expression, leading to greater immune recognition of the tumor. PARPi is also associated with immunomodulation. The PARPi talazoparib increases the number of peritoneal CD8+ T cells and natural killer cells and increases production of interferon (IFN)-γ and tumor necrosis factor-α in a BRCA1-mutated ovarian cancer xenograft model. Hence, addition of PARPi to immune checkpoint blockade could complement the clinical benefit of immune checkpoint inhibition.
Such high level of mutation results in high number of neoantigen and antitumor immune response thus given the rational to use immunotherapy to target such type. A recent paper validate this strategy using the anti PD-1 pembrolizumab Some case reports suggest also that other mutations that induce hypermutated tumor (POLD, POLE, or MYH) could gain benefit from anti PD-1 therapy. Additional DNA repair machinery dysfunction may lead to accumulation of mutations. And such level of mutations could induce better response to immunotherapy. In the lung non-small cell setting high mutation rate were associated with better efficacy of both nivolumab and pembrolizumab.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||270 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||Precision Medicine Phase II Study Evaluating the Efficacy of a Double Immunotherapy by Durvalumab and Tremelimumab Combined With Olaparib in Patients With Solid Cancers and Carriers of Homologous Recombination Repair Genes Mutation in Response or Stable After Olaparib Treatment|
|Estimated Study Start Date :||January 1, 2020|
|Estimated Primary Completion Date :||January 1, 2020|
|Estimated Study Completion Date :||January 1, 2023|
Experimental: GUIDE2REPAIR patients
olaparib + immunotherapy (durvalumab + tremelimumab) during 4 months followed by durvalumab alone as maintenance in patients with solid cancer and in response or stable after prior molecular target therapy by olaparib based on molecular sequencing.
Drug: olaparib, durvalumab, tremelimumab
Olaparib 300 mg BID during 8 weeks. Olaparib tablets should be taken at the same time each day, approximately 12 hours apart with one glass of water. The tablets should be swallowed whole and not chewed, crushed, dissolved or divided. Olaparib tablets can be taken with or without food
Olaparib 300 mg during 4 months as per same requirement as below. Durvalumab 1500 mg plus tremelimumab 75 mg via IV infusion Q4W, starting on Week 0, for up to a maximum of 4 doses followed by durvalumab monotherapy 1500 mg via IV infusion Q4W, starting 4 weeks after the last infusion of the combination and in response or stable after prior molecular target therapy by olaparib based on molecular sequencing.
- Safety Assessments: progression free survival [ Time Frame: 6 months after the initiation of immunotherapy for all cohorts excepted for ovarian cohort where PFS will be evaluated at 12 months. ]progression free survival
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): NCT04169841
|Contact: Emilie REDERSTORFF||03 45 34 81 email@example.com|
|CHRU Jean Minjoz||Not yet recruiting|
|Contact: Laura MANSI 03 70 63 24 03 firstname.lastname@example.org|
|CHU François Mitterrand||Not yet recruiting|
|Contact: Antoine DROUILLARD 03 80 29 37 50 email@example.com|
|Institut Hospitalier Franco-Britannique||Not yet recruiting|
|Contact: Benoist CHIBAUDEL 01 47 59 18 73 firstname.lastname@example.org|
|Centre Oscar Lambret||Not yet recruiting|
|Contact: Nicolas PENEL 03 20 29 59 59 email@example.com|
|Centre Leon Berard||Not yet recruiting|
|Contact: Olivier TREDAN 04 78 78 26 44 firstname.lastname@example.org|
|Principal Investigator:||François GHIRINGHELLI||Centre Georges Francois Leclerc|