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Javelin BRCA/ATM: Avelumab Plus Talazoparib in Patients With BRCA or ATM Mutant Solid Tumors

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ClinicalTrials.gov Identifier: NCT03565991
Recruitment Status : Recruiting
First Posted : June 21, 2018
Last Update Posted : December 10, 2018
Sponsor:
Information provided by (Responsible Party):
Pfizer

Brief Summary:
Avelumab in combination with talazoparib will be investigated in patients with locally advanced or metastatic solid tumors with a BRCA or ATM defect.

Condition or disease Intervention/treatment Phase
Locally Advanced or Metastatic Solid Tumors Genes, BRCA 1 Drug: Avelumab Drug: Talazoparib Phase 2

Detailed 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.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 200 participants
Intervention Model: Single Group Assignment
Intervention Model Description:

Single arm study with two cohorts enrolled in parallel.

  • Cohort 1 will enroll patients with locally advanced or metastatic solid tumors with one or more defects in the BRCA1 or BRCA2 genes
  • Cohort 2 will enroll patients with locally advanced or metastatic solid tumors with one or more defects in the ATM gene
Masking: None (Open Label)
Masking Description: Open label
Primary Purpose: Treatment
Official Title: A Phase 2 Study To Evaluate Safety And Anti-tumor Activity Of Avelumab In Combination With Talazoparib In Patients With Brca Or Atm Mutant Tumors
Actual Study Start Date : June 18, 2018
Estimated Primary Completion Date : March 8, 2021
Estimated Study Completion Date : December 2, 2022

Resource links provided by the National Library of Medicine

Drug Information available for: Avelumab

Arm Intervention/treatment
Experimental: Combination of avelumab and talazoparib
Single arm open label
Drug: Avelumab
IV treatment
Other Name: Bavencio

Drug: Talazoparib
Oral treatment
Other Name: MDV3800, BMN 673




Primary Outcome Measures :
  1. Confirmed Objective Response (OR) [ Time Frame: 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 ]
    Confirmed OR in patients with locally advanced or metastatic solid tumors with BRCA 1/2 or ATM defect, as assessed by Blinded Independent Central Review using RECIST v1.1 and, in patients with mCRPC, RECIST v1.1. and PCWG3.


Secondary Outcome Measures :
  1. Confirmed OR as assessed by the investigator [ Time Frame: 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 ]
    Confirmed OR as assessed by the investigator, using RECIST v1.1 and, in patients with mCRPC, RECIST v1.1 and PCWG3.

  2. Time to tumor response (TTR) [ Time Frame: Baseline up to approximately 24 months ]
    TTR is defined for patients with confirmed objective response (CR or PR) as the time from the first dose of study treatment to the first documentation of objective tumor response.

  3. Duration of response (DR) [ Time Frame: Baseline up to approximately 24 months ]
    DR is defined for patients with confirmed objective response (CR or PR) as the time from the first documentation of objective tumor response to the first documentation of objective tumor progression or to death due to any cause, whichever occurs first.

  4. Progression free survival (PFS) [ Time Frame: Baseline up to approximately 24 months ]
    PFS is defined as the time from the first dose of study treatment to the date of disease progression by RECIST v1.1 or death due to any cause, whichever occurs first.

  5. Overall survival (OS) [ Time Frame: Baseline up to approximately 24 months ]
    OS is defined as the time from the first dose of study treatment to the date of death.

  6. Time to prostate-specific antigen (PSA) progression for mCRPC patients [ Time Frame: Baseline up to approximately 24 months ]
    Time to PSA progression is defined as the time from the first dose to the date that a greater than or equal to 25% increase in PSA from baseline.

  7. CA-125 response for ovarian cancer patients [ Time Frame: Baseline and Day 1 of each Cycle (1 cycle is 28 days) ]
    CA-125 response is defined as at least a 50% reduction in CA-125 levels from baseline.

  8. Prostate specific antigen (PSA) response [ Time Frame: Baseline up to approximately 24 months ]
    PSA response is defined as at least a 50% reduction in PSA levels from baseline

  9. Circulating Tumor Cells (CTC) count conversion for mCRPC patients [ Time Frame: Day 1 Cycles 1-4 ]
    CTC conversion for mCRPC patients

  10. Biomarker PD-L1 [ Time Frame: Baseline ]
    PD-L1 expression level in baseline tumor tissue.

  11. Presence of defects in a panel of key oncogenes [ Time Frame: Baseline. ]
    Presence of defects in a panel of key oncogenes.

  12. Plasma concentrations Ctrough talazoparib [ Time Frame: Day 1, Day 15 Cycle 3 ]
    Pharmacokinetic parameter for talazoparib.

  13. Plasma concentrations post-dose talazoparib [ Time Frame: Day 1, Day 15 Cycle 3 ]
    Pharmacokinetic parameter for talazoparib.

  14. Serum concentrations Ctrough avelumab [ Time Frame: Day 1 Cycles 1, 3, 6, 12, 18, 24 and Day 15 Cycle 1 ]
    Pharmacokinetic parameter for avelumab.

  15. Serum concentrations Cmax avelumab [ Time Frame: Day 1 Cycles 1, 3, 6, 12, 18, 24 and Day 15 Cycle 1 ]
    Pharmacokinetic parameter for avelumab.

  16. Anti-drug antibody (ADA) levels of avelumab [ Time Frame: Day 1 Cycles 1, 3, 6, 12, 18, 24 and Day 15 Cycle 1 ]
    Immunogenicity assessment of avelumab.

  17. Neurtralizing antibodies (Nab) levels against avelumab [ Time Frame: Day 1 Cycles 1, 3, 6, 12, 18, 24 and Day 15 Cycle 1 ]
    Immunogenicity assessment of avelumab.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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 female patients; breastfeeding female patients; fertile male patients and female patients of childbearing potential who are unwilling or unable to use 2 methods of contraception.

Information from the National Library of Medicine

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): NCT03565991


Contacts
Contact: Pfizer CT.gov Call Center 1-800-718-1021 ClinicalTrials.gov_Inquiries@pfizer.com

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Sponsors and Collaborators
Pfizer
Investigators
Study Director: Pfizer CT.gov Call Center Pfizer

Additional Information:
Responsible Party: Pfizer
ClinicalTrials.gov Identifier: NCT03565991     History of Changes
Other Study ID Numbers: B9991032
2018-000345-39 ( EudraCT Number )
First Posted: June 21, 2018    Key Record Dates
Last Update Posted: December 10, 2018
Last Verified: December 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Information relating to our policy on data sharing and the process for requesting data can be found at the following link: http://www.pfizer.com/research/clinical_trials/trial_data_and_results/data_requests

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Pfizer:
BRCA, ATM

Additional relevant MeSH terms:
Antibodies, Monoclonal
Talazoparib
Immunologic Factors
Physiological Effects of Drugs
Poly(ADP-ribose) Polymerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents