Javelin BRCA/ATM: Avelumab Plus Talazoparib in Patients With BRCA or ATM Mutant Solid Tumors
Keywords
Abstract
Description
Avelumab is a human immunoglobulin (Ig)G1 monoclonal antibody (mAb) directed against programmed death ligand 1 (PD-L1). Avelumab selectively binds to PD-L1 and competitively blocks its interaction with programmed death receptor 1 (PD-1), thereby interfering with this key immune checkpoint inhibition pathway. Avelumab is currently being investigated as single agent and in combination with other anti cancer therapies in patients with locally advanced or metastatic solid tumors and various hematological malignancies.
Talazoparib is a potent, orally bioavailable poly (adenosine diphosphate [ADP] ribose) polymerase (PARP) inhibitor, which is cytotoxic to human cancer cell lines harboring gene mutations that compromise deoxyribonucleic acid (DNA) repair, an effect referred to as synthetic lethality, and by trapping PARP protein on DNA thereby preventing DNA repair, replication, and transcription.
Avelumab in combination with talazoparib will be investigated in patients with locally advanced (primary or recurrent) or metastatic solid tumors with a BReast CAncer susceptibility gene (BRCA)1, or BRCA2, or ataxia telangiectasia mutated (ATM) gene defect.
Dates
| Last Verified: | 05/31/2020 |
| First Submitted: | 05/24/2018 |
| Estimated Enrollment Submitted: | 06/10/2018 |
| First Posted: | 06/20/2018 |
| Last Update Submitted: | 06/21/2020 |
| Last Update Posted: | 06/23/2020 |
| Actual Study Start Date: | 06/17/2018 |
| Estimated Primary Completion Date: | 03/07/2021 |
| Estimated Study Completion Date: | 12/01/2022 |
Condition or disease
Intervention/treatment
Drug: Combination of avelumab and talazoparib
Drug: Combination of avelumab and talazoparib
Phase
Arm Groups
| Arm | Intervention/treatment |
|---|---|
| Experimental: Combination of avelumab and talazoparib Single arm open label | Drug: Combination of avelumab and talazoparib IV treatment |
Eligibility Criteria
| Ages Eligible for Study | 18 Years To 18 Years |
| Sexes Eligible for Study | All |
| Accepts Healthy Volunteers | Yes |
| Criteria | Inclusion Criteria: - BRCA1, BRCA2 and/or ATM gene defect. - Histological diagnosis of locally advanced (primary or recurrent) or metastatic solid tumors that are not amenable for treatment with curative intent - Availability a tumor tissue sample from a diagnostic biopsy/surgery or a metastatic tumor biopsy. - Progressive disease at study enrollment. - Minimum age 18 years (in Japan, minimum age 20 years). - ECOG performance status 0 or 1. - Adequate bone marrow, renal and liver function. - For childbearing female patients, negative serum or urine pregnancy test at screening - Signed and dated informed consent document. Exclusion Criteria: - Prior anti-cancer therapy or radiation therapy within 2 weeks prior to enrolment. Palliative radiotherapy to metastatic lesion(s) permitted providing that it has been completed at least 2 days prior to enrolment and no significant toxicity are expected. - Major surgery within 4 weeks prior to study enrollment. - Current use of immunosuppressive medication at the time of study enrollment. - Known prior severe hypersensitivity to investigational products or any component in their formulations - Known history of immune-mediated colitis, inflammatory bowel disease, pneumonitis, pulmonary fibrosis. - Active or prior autoimmune disease that might deteriorate when receiving an immunostimulatory agent. - Prior organ transplantation including allogenic stem-cell transplantation. - Administration of live attenuated vaccines within 4 weeks of study enrollment. - Diagnosis of myelodysplastic syndrome. - Known symptomatic brain metastases requiring steroids. - Persisting toxicity related to prior therapy Grade >1. - Known history of HIV or AIDS. - Positive HBV or HCV test indicating acute or chronic infection. - Active infection requiring systemic therapy. - Clinically significant (active) cardiovascular disease: cerebral vascular accident/stroke or myocardial infarction within 6 months prior to study enrollment; unstable angina, congestive heart failure or a serious cardiac arrhythmia requiring medication. - Diagnosis of any other malignancy within 2 years prior to study enrollment, except for adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ of the breast, bladder, or cervix, or low-grade prostate cancer or other early-stage low-risk cancers. - Pregnant or breastfeeding female patients; female or male patients who are able to have children who are unable or unwilling to use contraception as outlined in the protocol. |
Outcome
Primary Outcome Measures
1. Confirmed Objective Response (OR) [From date of first dose of study treatment until the date of first documented disease progression or date of death from any cause, whichever comes first, assessed up to approximately 24 months]
Secondary Outcome Measures
1. Confirmed OR as assessed by the investigator [From the first dose of study treatment until the date of first documented disease progression or date of death from any cause, whichever comes first, assessed up to approximately 24 months]
2. Time to tumor response (TTR) [Baseline up to approximately 24 months]
3. Duration of response (DR) [Baseline up to approximately 24 months]
4. Progression free survival (PFS) [Baseline up to approximately 24 months]
5. Overall survival (OS) [Baseline up to approximately 24 months]
6. Time to prostate-specific antigen (PSA) progression for mCRPC patients [Baseline up to approximately 24 months]
7. CA-125 response for ovarian cancer patients [Baseline and Day 1 of each Cycle (1 cycle is 28 days)]
8. Prostate specific antigen (PSA) response [Baseline up to approximately 24 months]
9. Circulating Tumor Cells (CTC) count conversion for mCRPC patients [Day 1 Cycles 1-4]
10. Biomarker PD-L1 [Baseline]
11. Presence of defects in a panel of key oncogenes [Baseline.]
12. Plasma concentrations Ctrough talazoparib [Day 1, Day 15 Cycle 3]
13. Plasma concentrations post-dose talazoparib [Day 1, Day 15 Cycle 3]
14. Serum concentrations Ctrough avelumab [Day 1 Cycles 1, 3, 6, 12, 18, 24 and Day 15 Cycle 1]
15. Serum concentrations Cmax avelumab [Day 1 Cycles 1, 3, 6, 12, 18, 24 and Day 15 Cycle 1]
16. Anti-drug antibody (ADA) levels of avelumab [Day 1 Cycles 1, 3, 6, 12, 18, 24 and Day 15 Cycle 1]
17. Neurtralizing antibodies (Nab) levels against avelumab [Day 1 Cycles 1, 3, 6, 12, 18, 24 and Day 15 Cycle 1]
