Clinical trial NCT03565991: Javelin BRCA/ATM: Avelumab Plus Talazoparib in Patients With BRCA or ATM Mutant Solid Tumors
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 JAVELIN BRCA/ATM
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Locally Advanced or Metastatic Solid Tumors
Genes, BRCA 1
Keywords: BRCA, ATM
Lead sponsor: Pfizer
Sponsor class: INDUSTRY
First posted: 2018-06-21
Enrollment: 202
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
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
Primary purpose: TREATMENT

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.

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.

Eligibility 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.

Primary outcomes:
measure: Percentage of Participants With Confirmed Objective Response (OR) as Assessed by Blinded Independent Central Review (BICR)
timeFrame: From the first dose of study treatment until the date of first documented disease progression or date of death from any cause, whichever came first, assessed up to approximately 24 months
Secondary outcomes:
measure: Number of Participants With Treatment-Emergent Adverse Events (TEAEs)
timeFrame: From baseline up to 30 days after last dose of study treatment, maximum up to 4.3 years approximately
measure: Number of Participants With New or Worsening Hematology Laboratory Test Results During the On-Treatment Period
timeFrame: From baseline up to 30 days after last dose of study treatment, maximum up to 4.3 years approximately
measure: Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period
timeFrame: From baseline up to 30 days after last dose of study treatment, maximum up to 4.3 years approximately
measure: Serum Lowest (Trough) Concentration (Ctrough) of Avelumab
timeFrame: Predose on Day 1 of Cycles 1, 3, 6, 12, 18, 24 and Day 15 of Cycle 1
measure: Serum Maximum Concentration (Cmax) for Avelumab
timeFrame: One hour post-dose on Day 1 of Cycles 1, 3, 6, 12, 18, 24 and Day 15 of Cycle 1
measure: Plasma Ctrough for Talazoparib
timeFrame: Predose on Cycle 1 Days 1, 15 and Cycle 3 Day 1
measure: Plasma Post-dose Concentrations for Talazoparib
timeFrame: Postdose (samples collected within 2 hours post dose plus/minus 12 minutes) on Days 1,15 of Cycle 1, and Day 1 of Cycle 3
measure: Number of Participants by Avelumab Anti-drug Antibody (ADA) Categories
timeFrame: Predose (within 2 hours before start of avelumab infusion) on Day 1 of Cycles 1, 3, 6, 12, 18, 24 and Day 15 of Cycle 1
measure: Number of Participants With Neutralizing Antibodies (Nab) Levels Against Avelumab Ever-Positive
timeFrame: Predose (within 2 hours before start of avelumab infusion) on Day 1 of Cycles 1, 3, 6, 12, 18, 24 and Day 15 of Cycle 1
measure: Percentage of Participants With Confirmed OR as Assessed by The Investigator
timeFrame: 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
measure: Time to Tumor Response (TTR) as Assessed by BICR
timeFrame: Baseline up to approximately 24 months
measure: TTR as Assessed by Investigator
timeFrame: Baseline up to approximately 24 months
measure: Duration of Response (DoR) as Assessed by BICR
timeFrame: Baseline up to approximately 24 months
measure: DoR as Assessed by Investigator
timeFrame: Baseline up to approximately 24 months
measure: Progression Free Survival (PFS) as Assessed by BICR
timeFrame: Baseline up to approximately 24 months
measure: PFS as Assessed by Investigator
timeFrame: Baseline up to approximately 24 months
measure: Overall Survival (OS) for All Participants
timeFrame: Baseline up to approximately 24 months
measure: Time to Prostate-Specific Antigen (PSA) Progression for Participants With mCRPC
timeFrame: Baseline up to approximately 24 months
measure: Number of Participants With Confirmed PSA Response
timeFrame: Baseline up to approximately 24 months
measure: Number of Participants With Circulating Tumor Cell (CTC) Count Conversion
timeFrame: Day 1 of Cycle 1 to Cycle 4
measure: Number of Participants With Cancer Antigen 125 (CA-125) Response
timeFrame: Baseline, Day 1 of each treatment Cycle, maximum up to 4.3 years approximately
measure: Number of Participants With Positive Programmed Death Ligand 1 (PD-L1) Expression in Baseline Tumor Tissue
timeFrame: Baseline
measure: Number of Participants With Different Status for Defects in BRCA1, BRCA2 and ATM
timeFrame: Baseline
measure: Number of Participants by Status of Tumor Mutational Burden (TMB) at Baseline
timeFrame: Baseline
Other outcomes:
Locations:
city: Palo Alto
country: United States
facility: Stanford Cancer Center
state: California
city: Palo Alto
country: United States
facility: Stanford Women's Cancer Center
state: California
city: Stanford
country: United States
facility: Stanford Healthcare
state: California
city: Stanford
country: United States
facility: Stanford University School of Medicine
state: California
city: Alpharetta
country: United States
facility: Atlanta Cancer Care -Alpharetta
state: Georgia
city: Athens
country: United States
facility: Northside Hospital, Inc. - GCS/Athens
state: Georgia
city: Atlanta
country: United States
facility: Northside Hospital, Inc. - GCS/Annex
state: Georgia
city: Atlanta
country: United States
facility: Atlanta Cancer Care - Atlanta
state: Georgia
city: Atlanta
country: United States
facility: Northside Hospital, Inc. - Central Research Department
state: Georgia
city: Atlanta
country: United States
facility: Northside Hospital, Inc. - GCS/Northside
state: Georgia
city: Canton
country: United States
facility: Northside Hospital, Inc. - GCS/Canton
state: Georgia
city: Cumming
country: United States
facility: Atlanta Cancer Care - Cumming
state: Georgia
city: Decatur
country: United States
facility: Atlanta Cancer Care - Decatur
state: Georgia
city: Decatur
country: United States
facility: Northside Hospital, Inc.-GCS/Stemmer
state: Georgia
city: Jonesboro
country: United States
facility: Atlanta Cancer Care - Stockbridge
state: Georgia
city: Macon
country: United States
facility: Northside Hospital, Inc.-GCS/Macon
state: Georgia
city: Marietta
country: United States
facility: Northside Hospital, Inc.-GCS/Kennestone
state: Georgia
city: New Orleans
country: United States
facility: Ochsner Clinic Foundation
state: Louisiana
city: Boston
country: United States
facility: Brigham and Women's Hospital
state: Massachusetts
city: Boston
country: United States
facility: Dana Farber Cancer institute
state: Massachusetts
city: Creve Coeur
country: United States
facility: Siteman Cancer Center - West County
state: Missouri
city: Saint Louis
country: United States
facility: Barnes-Jewish Hospital
state: Missouri
city: Saint Louis
country: United States
facility: Washington University Infusion Center Pharmacy
state: Missouri
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Saint Louis
country: United States
facility: Siteman Cancer Center - South County
state: Missouri
city: Saint Louis
country: United States
facility: Siteman Cancer Center - North County
state: Missouri
city: Saint Peters
country: United States
facility: Siteman Cancer Center - St.Peters
state: Missouri
city: Middletown
country: United States
facility: Memorial Sloan Kettering Cancer Center- Monmouth
state: New Jersey
city: Harrison
country: United States
facility: Memorial Sloan Kettering Cancer Center- Westchester
state: New York
city: Long Island City
country: United States
facility: Memorial Sloan Kettering Cancer Center - Investigational Drug Service Pharmacy
state: New York
city: New York
country: United States
facility: Laura and Isaac Perlmutter Cancer Center at NYU Langone
state: New York
city: New York
country: United States
facility: Laura and Isaac Perlmutter Cancer Center
state: New York
city: New York
country: United States
facility: NY Investigational Pharmacy
state: New York
city: New York
country: United States
facility: NYU Langone Medical Center
state: New York
city: New York
country: United States
facility: NYU Langone Radiology - 32nd Street
state: New York
city: New York
country: United States
facility: NYU Langone Radiology Ambulatory Care Center East 41st Street
state: New York
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center - David H. Koch Center for Cancer Care (74th Street).
state: New York
city: New York
country: United States
facility: Rockefeller Outpatient Center
state: New York
city: New York
country: United States
facility: Rockefeller Outpatient Pavilion (53rd Street)
state: New York
city: New York
country: United States
facility: Evelyn H. Lauder Breast and Imaging Center
state: New York
city: New York
country: United States
facility: Memorial Hospital
state: New York
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: White Plains
country: United States
facility: White Plains Hospital
state: New York
city: Columbus
country: United States
facility: The Ohio State University Wexner Medical Center
state: Ohio
city: Columbus
country: United States
facility: The Ohio State University
state: Ohio
city: Columbus
country: United States
facility: Stephanie Spielman Comprehensive Breast Cancer
state: Ohio
city: Columbus
country: United States
facility: Martha Morehouse Medical Plaza
state: Ohio
city: Hilliard
country: United States
facility: OSU Gynecologic Oncology at Mill Run
state: Ohio
city: Oklahoma City
country: United States
facility: Stephenson Cancer Center
state: Oklahoma
city: Philadelphia
country: United States
facility: Hospital of the University of Pennsylvania/Penn Investigational Drug Services
state: Pennsylvania
city: Philadelphia
country: United States
facility: Hospital of the University of Pennsylvania
state: Pennsylvania
city: Philadelphia
country: United States
facility: Penn IDS Central
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Magee-Women's Hospital Women's Cancer Center
state: Pennsylvania
city: Pittsburgh
country: United States
facility: UPMC Hillman Cancer Center Investigational Drug Service
state: Pennsylvania
city: Pittsburgh
country: United States
facility: UPMC Hillman Cancer Center
state: Pennsylvania
city: Chattanooga
country: United States
facility: Tennessee Oncology, PLLC
state: Tennessee
city: Chattanooga
country: United States
facility: The Sarah Cannon Research Institute
state: Tennessee
city: Cleveland
country: United States
facility: Tennessee Oncology, PLLC
state: Tennessee
city: Dickson
country: United States
facility: Tennessee Oncology, PLLC
state: Tennessee
city: Franklin
country: United States
facility: Tennessee Oncology, PLLC
state: Tennessee
city: Gallatin
country: United States
facility: Tennessee Oncology, PLLC
state: Tennessee
city: Hermitage
country: United States
facility: Tennessee Oncology, PLLC
state: Tennessee
city: Lebanon
country: United States
facility: Tennessee Oncology, PLLC
state: Tennessee
city: Murfreesboro
country: United States
facility: Tennessee Oncology, PLLC
state: Tennessee
city: Nashville
country: United States
facility: Tennessee Oncology, PLLC
state: Tennessee
city: Nashville
country: United States
facility: The Sarah Cannon Research Institute
state: Tennessee
city: Nashville
country: United States
facility: Tennessee Oncology, PLLC
state: Tennessee
city: Nashville
country: United States
facility: Tennessee Oncology, PLLC
state: Tennessee
city: Nashville
country: United States
facility: Tennessee Oncology, PLLC
state: Tennessee
city: Shelbyville
country: United States
facility: Tennessee Oncology, PLLC
state: Tennessee
city: Smyrna
country: United States
facility: Tennessee Oncology, PLLC
state: Tennessee
city: Houston
country: United States
facility: The University of Texas
state: Texas
city: Brussels
country: Belgium
facility: Institut Jules Bordet
city: Brussel
country: Belgium
facility: UZ Brussel
city: Edegem
country: Belgium
facility: Universitair Ziekenhuis Antwerpen
city: Copenhagen
country: Denmark
facility: Rigshospitalet
city: Odense C
country: Denmark
facility: Odense University Hospital
city: Clermont Ferrand
country: France
facility: Centre Jean Perrin
city: La Rochelle
country: France
facility: Groupe Hospitalier La Rochelle-Ré-Aunis
city: Montpellier Cedex 5
country: France
facility: Institut Regional du Cancer de Montpellier - ICM Val d'Aurelle
city: Torette Di Ancona
country: Italy
facility: Presidio AO-U, Ospedali Riuniti Umberto I - G.M. Lancisi - G. Salesi
state: AN
city: Meldola
country: Italy
facility: IRCCS-Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST)
state: FC
city: Monza
country: Italy
facility: Azienda Socio-Sanitaria Territoriale Monza, Ospedale San Gerardo
state: MB
city: Milano
country: Italy
facility: Fondazione IRCCS, Istituto Nazionale dei Tumori
state: MI
city: Milano
country: Italy
facility: Istituto Europeo di Oncologia, Istituto di Ricovero e Cura a Carattere Scientifico
state: MI
city: Napoli
country: Italy
facility: Fondazione Pascale, IRCCS, Istituto Nazionale dei Tumori
city: Roma
country: Italy
facility: Azienda Policlinico Umberto I, Universita La Sapienza, Oncologia B
city: Roma
country: Italy
facility: Fondazione Policlinico Universitario Agostino Gemelli Unità di Farmacologia Clinica
city: Kashiwa
country: Japan
facility: National Cancer Center Hospital East
state: Chiba
city: Osaka-shi
country: Japan
facility: Osaka International Cancer Institute
state: Osaka
city: Chuo-ku
country: Japan
facility: National Cancer Center Hospital
state: Tokyo
city: Amsterdam
country: Netherlands
facility: Amsterdam University Medical Centre, location VUmc
state: Noord Holland
city: Rotterdam
country: Netherlands
facility: Erasmus Universitair Medisch Centrum
state: Zuid-holland
city: Barcelona
country: Spain
facility: Hospital Universitario Vall d'Hebron
city: Madrid
country: Spain
facility: H.G.U. Gregorio Maranon
city: Madrid
country: Spain
facility: Clinica Universidad de Navarra
city: Madrid
country: Spain
facility: H.U. Fundación Jiménez Díaz
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen de Valme
city: London
country: United Kingdom
facility: Barts Health NHS Trust, St Bartholomew's Hospital
city: London
country: United Kingdom
facility: Sarah Cannon Research Institute UK
Study officials:
affiliation: Pfizer
name: Pfizer CT.gov Call Center
role: STUDY_DIRECTOR
References:
citation: Schram AM, Colombo N, Arrowsmith E, Narayan V, Yonemori K, Scambia G, Zelnak A, Bauer TM, Jin N, Ulahannan SV, Colleoni M, Aftimos P, Donoghue MTA, Rosen E, Rudneva VA, Telli ML, Domchek SM, Galsky MD, Hoyle M, Chappey C, Stewart R, Blake-Haskins JA, Yap TA. Avelumab Plus Talazoparib in Patients With BRCA1/2- or ATM-Altered Advanced Solid Tumors: Results From JAVELIN BRCA/ATM, an Open-Label, Multicenter, Phase 2b, Tumor-Agnostic Trial. JAMA Oncol. 2023 Jan 1;9(1):29-39. doi: 10.1001/jamaoncol.2022.5218.