Clinical trial NCT03330405: Javelin Parp Medley: Avelumab Plus Talazoparib In Locally Advanced Or Metastatic Solid Tumors
Official title: A PHASE 1B/2 STUDY TO EVALUATE SAFETY AND ANTI TUMOR ACTIVITY OF AVELUMAB IN COMBINATION WITH THE POLY(ADENOSINE DIPHOSPHATE [ADP]-RIBOSE) POLYMERASE (PARP) INHIBITOR TALAZOPARIB IN PATIENTS WITH LOCALLY ADVANCED OR METASTATIC SOLID TUMORS
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
PHASE2
Conditions: Avelumab in Combination With Talazoparib Will be Investigated in Patients With Locally Advanced (Primary or Recurrent) or Metastatic Solid Tumors
Keywords: NSCLC, TNBC, hormone receptor positive (HR+) breast cancer, recurrent epithelial ovarian cancer, UC, and castration resistant prostate cancer (CRPC).
Lead sponsor: Pfizer
Sponsor class: INDUSTRY
First posted: 2017-11-06
Enrollment: 223
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: Avelumab in combination with talazoparib will be investigated in patients with locally advanced (primary or recurrent) or metastatic solid tumors, including non-small cell lung cancer (NSCLC), triple negative breast cancer (TNBC), hormone receptor positive (HR+) breast cancer, recurrent platinum sensitive ovarian cancer, urothelial cancer (UC), and castration resistant prostate cancer (CRPC).

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, including non-small cell lung cancer (NSCLC), triple negative breast cancer (TNBC), hormone receptor positive (HR+) breast cancer, recurrent platinum sensitive ovarian cancer, urothelial cancer (UC), and castration resistant prostate cancer (CRPC).

Eligibility criteria: Inclusion Criteria:

* Histological diagnosis of locally advanced (primary or recurrent) or metastatic solid tumors that are not amenable for treatment with curative intent in adult patients with: NSCLC, TNBC, HR+ breast cancer, recurrent platinum sensitive ovarian cancer, UC, CRPC, and other advanced solid tumors with a BRCA or ATM gene defect
* Mandatory primary or metastatic tumor biopsy. If archival tumor tissue is available from a biopsy/surgery the tumor tissue may be submitted without repeating a tumor biopsy during the screening period.
* Minimum age in Japan is 20 years.
* ECOG performance status 0 or 1.
* Resolved acute effects of prior therapy
* Adequate bone marrow, renal, and liver function.
* Negative serum pregnancy test at screening.
* Pregnant, breastfeeding females or female patients able to have children must agree to use highly effective method of contraception throughout the study and for at least 30 days after the last dose of avelumab and for at least 7 months after the last dose of talazoparib; fertile male patients must use a condom during treatment and for at least 4 months after the last dose of talazoparib.
* Signed and dated informed consent.

Exclusion Criteria:

* Prior treatment with a PARP inhibitor.
* Prior immunotherapy with IL-2, IFN-α, or an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, OX 40, GITR, LAG 3, IDO, TDO,TIM 3, CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways. Prior treatment with Sipuleucel-T for patients with mCRPC is allowed. For cohort A2 NSCLC patients prior treatment with anti-PD-1/L1 is allowed
* Prior anti-cancer therapy within 2 weeks prior to study enrollment. Prior radiation therapy within 2 weeks prior to enrollment. Prior palliative radiotherapy to metastatic lesion(s) is permitted, provided it has been completed 2 days prior to study enrollment and no clinically significant toxicities are expected (eg, mucositis, esophagitis).
* Major surgery within 4 weeks prior to study enrollment.
* Current use of immunosuppressive medication at the time of study enrollment.
* Known prior or suspected hypersensitivity to investigational products.
* 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.
* Vaccination within 4 weeks of study enrollment and while on trial is prohibited except for administration of inactivated vaccines.
* Diagnosis of Myelodysplastic Syndrome.
* Patients with known brain metastases requiring steroids.
* Participation in other studies involving investigational drug(s) within 4 weeks prior to study participation and/or during study participation.
* Persisting toxicity related to prior therapy \>Grade 1
* Known HIV or AIDs-related illness.
* Positive HBV or HCV test indicating acute or chronic infection.
* Active infection requiring systemic therapy.
* Clinically significant cardiovascular disease: cerebral vascular accident/stroke or myocardial infarction within 6 months prior to study entry; unstable angina, congestive heart failure or a serious cardiac arrhythmia requiring medication.
* Current or anticipated use within 7 days prior to first dose of study drug, or anticipated use during the study of a strong P-gp inhibitor.
* Other acute or chronic medical or psychiatric conditions.

Primary outcomes:
measure: Phase 1b: Number of Participants With Dose Limiting Toxicities (DLTs)
timeFrame: Cycle 1; 28 days
measure: Phase 2: Percentage of Participants With Confirmed Objective Response (OR) as Per Response Evaluation Criteria in Solid Tumors (RECIST) Version (v) 1.1 by Investigator Assessment
timeFrame: From start of the treatment until disease progression or death due to any cause, whichever occurred first (maximum up to 4.3 years approximately)
measure: Phase 2: Percentage of Participants With Confirmed Objective Response (OR) as Per RECIST v1.1 and Prostate Cancer Working Group 3 (PCWG3) by Investigator Assessment
timeFrame: From start of the treatment until disease progression or death due to any cause, whichever occurred first (maximum up to 4.3 years approximately)
Secondary outcomes:
measure: Number of Participants With Treatment-Emergent Adverse Events (TEAEs)
timeFrame: From start of the treatment up to 30 days after last dose or start of new anticancer therapy minus 1 day, whichever occurred first (maximum up to 5.2 years approximately)
measure: Number of Participants With Grade >=3 TEAEs
timeFrame: From start of the treatment up to 30 days after last dose or start of new anticancer therapy minus 1 day, whichever occurred first (maximum up to 5.2 years approximately)
measure: Number of Participants With Serious TEAEs
timeFrame: From start of the treatment up to 30 days after last dose or start of new anticancer therapy minus 1 day, whichever occurred first (maximum up to 5.2 years approximately)
measure: Number of Participants With TEAEs Leading to Discontinuation of Either Study Drug
timeFrame: From start of the treatment up to 30 days after last dose or start of new anticancer therapy minus 1 day, whichever occurred first (maximum up to 5.2 years approximately)
measure: Number of Participants With TEAEs Leading to Discontinuation of All Study Drugs
timeFrame: From start of the treatment up to 30 days after last dose or start of new anticancer therapy minus 1 day, whichever occurred first (maximum up to 5.2 years approximately)
measure: Number of Participants With TEAEs Leading to Death
timeFrame: From start of the treatment up to 30 days after last dose or start of new anticancer therapy minus 1 day, whichever occurred first (maximum up to 5.2 years approximately)
measure: Number of Participants With New or Worsening Hematology Laboratory Test Results to Grade >=1 During the On-Treatment Period
timeFrame: From start of the treatment up to 30 days after last dose or start of new anticancer therapy minus 1 day, whichever occurred first (maximum up to 5.2 years approximately)
measure: Number of Participants With New or Worsening Hematology Laboratory Test Results to Grade >=3 During the On-Treatment Period
timeFrame: From start of the treatment up to 30 days after last dose or start of new anticancer therapy minus 1 day, whichever occurred first (maximum up to 5.2 years approximately)
measure: Number of Participants With New or Worsening Chemistry Laboratory Test Results to Grade >=1 During the On-Treatment Period
timeFrame: From start of the treatment up to 30 days after last dose or start of new anticancer therapy minus 1 day, whichever occurred first (maximum up to 5.2 years approximately)
measure: Number of Participants With New or Worsening Chemistry Laboratory Test Results to Grade >=3 During the On-Treatment Period
timeFrame: From start of the treatment up to 30 days after last dose or start of new anticancer therapy minus 1 day, whichever occurred first (maximum up to 5.2 years approximately)
measure: Trough Concentrations (Ctrough)/Predose and Maximum Concentrations (Cmax) of Serum Avelumab Concentrations (μg/mL) by Visit (Excluding Site 1055)
timeFrame: Predose/0 Hour (H) and 1 H on Days 1 and 15 of Cycle 1 and on Day 1 of Cycles 2-4, and additionally on Day 1 of Cycles 6, 9, 12, 18, and 24.
measure: Predose and Postdose Plasma Talazoparib Concentrations (pg/mL) by Visit (Excluding Site 1055)
timeFrame: Pre-dose and post-dose (at the end of the avelumab infusion) on Days 1 and 15 of Cycle 1 and on Day 1 of Cycles 2-4.
measure: Number of Participants With at Least 1 Valid Anti-drug Antibody (ADA) Result at: Any Time Point (N0), Baseline (N1), Baseline and Post-Baseline (N2), and Post-Baseline and Without Positive Baseline ADA Result (N3)
timeFrame: Pre-dose (within 2 hours of talazoparib dose) on Day 1 and Day 15 of Cycle 1, on Day 1 of Cycle 2-4 and then on Day 1 of Cycles 6, 9, 12, 18, 24, and at the end of treatment (EOT)
measure: Number of Participants by ADA Categories
timeFrame: Pre-dose (within 2 hours of talazoparib dose) on Day 1 and Day 15 of Cycles 1, on Day 1 of Cycle 2-4 and then on Day 1 of Cycles 6, 9, 12, 18, 24, and at the end of treatment (EOT)
measure: Phase 1b: Percentage of Participants With Confirmed OR as Per RECIST v1.1 and PCWG3 by Investigator Assessment
timeFrame: From start of the treatment until disease progression or death due to any cause, whichever occurred first (maximum up to 5.2 years approximately)
measure: Phase 1b: Time to Response (TTR) in Participants With Confirmed CR or PR
timeFrame: From the first dose of study treatment to the first documentation of objective tumor response/the first objective evidence of soft tissue response with no evidence of confirmed bone disease progression (<=5.2 years approximately)
measure: Phase 2: TTR in Participants With Confirmed CR or PR
timeFrame: From the first dose of study treatment to the first documentation of objective tumor response/the first objective evidence of soft tissue response with no evidence of confirmed bone disease progression (<= 5.2 years approximately)
measure: Phase 2: Duration of Response (DR) in Participants With Confirmed CR or PR
timeFrame: From the first objective tumor response/soft tissue response to the first objective tumor progression/subsequent objective evidence of radiographic progression or death due to any cause, whichever occurred first (<=5.2 years approximately)
measure: Phase 1b: Progression-Free Survival (PFS) in Participants With Confirmed CR or PR
timeFrame: From the first dose of study treatment to the date of disease progression/radiographic progression in soft tissue or bone, or death due to any cause, whichever occurred first (maximum up to 5.2 years approximately)
measure: Phase 2: PFS in Participants With Confirmed CR or PR (RECIST v1.1)
timeFrame: From the first dose of study treatment to the date of disease progression/radiographic progression in soft tissue or bone, or death due to any cause, whichever occurred first (maximum up to 5.2 years approximately)
measure: Phase 2: PFS in Participants With Confirmed CR or PR (RECIST v1.1 and PCWG3)
timeFrame: From the first dose of study treatment to the date of disease progression/radiographic progression in soft tissue or bone, or death due to any cause, whichever occurred first (maximum up to 5.2 years approximately)
measure: Phase 2: Time to Prostate-Specific Antigen (PSA) Progression for Participants With mCRPC
timeFrame: From the first dose to the date that a >=25% increase in PSA with an absolute increase of >=2 μg/L (2 ng/mL) above the nadir (or baseline for participants with no PSA decline) was documented (maximum up to 5.2 years approximately)
measure: Phase 1b: Overall Survival
timeFrame: From the first dose of study treatment to the date of death (maximum up to 5.2 years approximately)
measure: Phase 2: Overall Survival
timeFrame: From the first dose of study treatment to the date of death (maximum up to 5.2 years approximately)
measure: Phase 2: Percentage of Participants With PSA Response
timeFrame: From baseline PSA (ng/mL) to the maximal PSA response with a threshold of 50% (maximum up to 5.2 years approximately)
measure: Phase 1b: Percentage of Participants With CA-125 Response
timeFrame: From baseline to at least a 50% reduction in CA-125 level (maximum up to 5.2 years approximately)
measure: Phase 2: Percentage of Participants With CA-125 Response
timeFrame: From baseline to at least a 50% reduction in CA-125 level (maximum up to 5.2 years approximately)
measure: Number of Participants With Different Programmed Death-Ligand 1 (PD-L1) Status at Baseline
timeFrame: At baseline (the last available assessment prior to the start of study treatment was defined as 'baseline' value or 'baseline' assessment)
measure: Number of Participants With Different Tumor Mutational Burden (TMB) at Baseline
timeFrame: At baseline (the last available assessment prior to the start of study treatment was defined as 'baseline' value or 'baseline' assessment)
measure: Number of Participants With Different DNA Damage Repair (DDR) Status at Baseline
timeFrame: At baseline (the last available assessment prior to the start of study treatment was defined as 'baseline' value or 'baseline' assessment)
Other outcomes:
Locations:
city: Fayetteville
country: United States
facility: Highlands Oncology Group
state: Arkansas
city: Fayetteville
country: United States
facility: Highlands Oncology
state: Arkansas
city: Rogers
country: United States
facility: Highlands Oncology Group
state: Arkansas
city: Rogers
country: United States
facility: Highlands Oncology
state: Arkansas
city: Springdale
country: United States
facility: Highlands Oncology Group
state: Arkansas
city: Springdale
country: United States
facility: Highlands Oncology
state: Arkansas
city: Beverly Hills
country: United States
facility: Tower Hematology Oncology Medical Group
state: California
city: Los Angeles
country: United States
facility: Keck Hospital of USC
state: California
city: Los Angeles
country: United States
facility: LAC+USC Medical Center
state: California
city: Los Angeles
country: United States
facility: USC/Norris Comprehensive Cancer Center/Investigational Drug Services
state: California
city: Los Angeles
country: United States
facility: USC/Norris Comprehensive Cancer Center
state: California
city: Los Angeles
country: United States
facility: Cedars-Sinai Medical Center
state: California
city: Newport Beach
country: United States
facility: Hoag Memorial Hospital Presbyterian
state: California
city: Palo Alto
country: United States
facility: Freidenrich Center for Translational Research (CTRU)
state: California
city: Stanford
country: United States
facility: Stanford Cancer Institute
state: California
city: Stanford
country: United States
facility: Stanford Hospital and Clinics
state: California
city: Stanford
country: United States
facility: Stanford Women's Cancer Center
state: California
city: Washington
country: United States
facility: Georgetown University Medical Center
state: District of Columbia
city: Boston
country: United States
facility: Massachusetts General Hospital (MGH)
state: Massachusetts
city: Boston
country: United States
facility: Massachusetts General Hospital Attn: Lalit Joshi
state: Massachusetts
city: Boston
country: United States
facility: Massachusetts General Hospital Attn: Svetlana Rashkova
state: Massachusetts
city: Boston
country: United States
facility: Brigham & Women's Hospital
state: Massachusetts
city: Boston
country: United States
facility: Dana Farber Cancer Institute, Attn: Vasilika Koci, PharmD
state: Massachusetts
city: Boston
country: United States
facility: Dana-Farber Cancer Institute
state: Massachusetts
city: Minneapolis
country: United States
facility: University Of Minesota Health: Clinics And Surgery Center
state: Minnesota
city: Minneapolis
country: United States
facility: University of Minesota Medical Center, Fairview IDS Pharmacy
state: Minnesota
city: Minneapolis
country: United States
facility: University of Minnesota Medical Center, Fairview
state: Minnesota
city: Buffalo
country: United States
facility: Roswell Park Cancer Center Institute
state: New York
city: New York
country: United States
facility: NYU 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
state: New York
city: New York
country: United States
facility: NYU Laura and Isaac Perlmutter Cancer Center
state: New York
city: New York
country: United States
facility: NYU Langone Radiology - Ambulatory Care Center
state: New York
city: New York
country: United States
facility: Icahn School of Medicine at Mount Sinai
state: New York
city: New York
country: United States
facility: Mount Sinai Hospital- Pharmacy department
state: New York
city: Cleveland
country: United States
facility: Cleveland Clinic Taussig Cancer Center Investigational Pharmacy
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Houston
country: United States
facility: The University of Texas MD Anderson Cancer Center
state: Texas
city: North Ryde
country: Australia
facility: Macquarie University
state: New South Wales
city: St. Leonards
country: Australia
facility: Northern Cancer Institute
state: New South Wales
city: Sydney
country: Australia
facility: Northern Cancer Institute
state: New South Wales
city: Brisbane
country: Australia
facility: Mater Misericordiae Ltd
state: Queensland
city: Murdoch
country: Australia
facility: Fiona Stanley Hospital
state: Western Australia
city: Brussels
country: Belgium
facility: Institut Jules Bordet
city: Bruxelles
country: Belgium
facility: Cliniques Universitaires Saint-Luc
city: Charleroi
country: Belgium
facility: Grand Hôpital de Charleroi - Site Notre-Dame
city: Edmonton
country: Canada
facility: Cross Cancer Institute
state: Alberta
city: Toronto
country: Canada
facility: Princess Margaret Cancer Centre
state: Ontario
city: Copenhagen
country: Denmark
facility: Phase 1 Unit, Department of Oncology, Section 5073.
city: Herlev
country: Denmark
facility: Herlev og Gentofte Hospital
city: Herlev
country: Denmark
facility: The Experimental Cancer Therapy Unit
city: Budapest
country: Hungary
facility: Orszagos Onkologiai Intezet
city: Miskolc
country: Hungary
facility: CRU Hungary Kft.
city: Pecs
country: Hungary
facility: Pecsi Tudomanyegyetem
city: Incheon
country: Korea, Republic of
facility: Gachon University Gil Medical Center
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center
city: Obninsk
country: Russian Federation
facility: Medical Radiological Research Center n.a. A.F. Tsyba -
state: Kaluga Region
city: Obninsk
country: Russian Federation
facility: Medical Radiological Research Center n.a. A.F. Tsyba
state: Kaluga Region
city: Chelyabinsk
country: Russian Federation
facility: GBUZ
city: Moscow
country: Russian Federation
facility: FSBI "National Medical Research Centre of Oncology n.a.
city: Omsk
country: Russian Federation
facility: Budget Healthcare Institution of Omsk Region "Clinical Oncology Dispensary"
city: Yaroslavl
country: Russian Federation
facility: State budgetary institution of healthcare of Yaroslavl region "Clinical oncology hospital"
city: London
country: United Kingdom
facility: University College London Hospitals NHS Foundation Trust
state: Other
city: Leicester
country: United Kingdom
facility: University Hospitals of Leicester NHS Trust
city: Newcastle Upon Tyne
country: United Kingdom
facility: Freeman Hospital, The Sir Bobby Robson Cancer Trials
Study officials:
affiliation: Pfizer
name: Pfizer CT.gov Call Center
role: STUDY_DIRECTOR
References:
citation: Yap TA, Bardia A, Dvorkin M, Galsky MD, Beck JT, Wise DR, Karyakin O, Rubovszky G, Kislov N, Rohrberg K, Joy AA, Telli ML, Schram AM, Conte U, Chappey C, Stewart R, Stypinski D, Michelon E, Cesari R, Konstantinopoulos PA. Avelumab Plus Talazoparib in Patients With Advanced Solid Tumors: The JAVELIN PARP Medley Nonrandomized Controlled Trial. JAMA Oncol. 2023 Jan 1;9(1):40-50. doi: 10.1001/jamaoncol.2022.5228.