Clinical trialPhase 1 / Phase 2Terminated

A Study of Avelumab, Binimetinib and Talazoparib in Patients With Locally Advanced or Metastatic RAS-mutant Solid Tumors

A PHASE 1B/2 STUDY TO EVALUATE SAFETY AND CLINICAL ACTIVITY OF COMBINATIONS OF AVELUMAB, BINIMETINIB AND TALAZOPARIB IN PATIENTS WITH LOCALLY ADVANCED OR METASTATIC RAS-MUTANT SOLID TUMORS

NCT03637491 ↗ ClinicalTrials.gov, retrieved 6 November 2026

Outcome: Stopped earlyAvailable clinical data has shown limited anti-tumor activity and reaching target study drug dose levels may not be feasible. (Other)
Phase: Phase 1 / Phase 2
Status: Terminated
Study type: Interventional
Start: 15 August 2018
Expected end: 2 February 2021
Enrollment: 36 participants
Sites: 18
Primary outcomes: Number of Participants With Dose Limiting Toxicities (DLTs) During the Primary DLT Evaluation Period (Cycle 1) in Phase 1b; Phase 2: Confirmed Objective Response (OR) Based on Investigator Assessment Per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.
Sponsor: Industry
Results posted: 2022-01-26
Last update: 26 January 2022

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Brief summary public domain (ClinicalTrials.gov)

This Phase 1b/2 study will examine the effects of the study drugs, avelumab, binimetinib and talazoparib when given in a 2 (doublet) or 3 (triplet) drug combination, in patients with locally advanced or metastatic RAS-mutant solid tumors. The Phase 1b part of the study will assess if the different study drugs can be given together safely and which doses to use for further research. Phase 2 will test if the study treatments have an effect on tumor size and growth, and gather more information about potential side effects.

Detailed description public domain (ClinicalTrials.gov)

This is a Phase 1b/2, open label, multi-center, safety, clinical activity, pharmacokinetic (PK), and pharmacodynamics (PD) study of combinations of avelumab, binimetinib and talazoparib in adult patients with metastatic pancreatic ductal adenocarcinoma and other locally advanced or metastatic KRAS- or NRAS-mutant solid tumors. The Phase 1b part of this study will initially assess doublet drug combinations to determine a recommended dose for further investigation. Following this, the recommended dose for the combination of avelumab, binimetinib and talazoparib (triplet) will be determined. The recommended doses for the doublet and triplet combinations will be used in the Phase 2 part of the study, which will assess the safety and preliminary anti-tumor activity of the study treatments.

Intervention public domain (ClinicalTrials.gov)

Drug: Avelumab. IV treatment

Intervention public domain (ClinicalTrials.gov)

Drug: Binimetinib. Oral treatment

Intervention public domain (ClinicalTrials.gov)

Drug: Talazoparib. Oral treatment

Arm public domain (ClinicalTrials.gov)

Avelumab and binimetinib (experimental): Open label

Arm public domain (ClinicalTrials.gov)

Avelumab, binimetinib and talazoparib (experimental): Open label

Arm public domain (ClinicalTrials.gov)

Binimetinib and talazoparib. (experimental): Open label.

Primary outcome public domain (ClinicalTrials.gov)

Number of Participants With Dose Limiting Toxicities (DLTs) During the Primary DLT Evaluation Period (Cycle 1) in Phase 1b. Any adverse events (AEs) occurring in the first cycle of treatment (28 days) which were attributable to study drugs and met DLT criteria. DLT was defined as hematologic: Grade 4 neutropenia lasting\>5 days; febrile neutropenia; neutropenic infection; Grade \>=3 thrombocytopenia with bleed; Grade 4 thrombocytopenia; Grade 4 anemia; non-hematologic: Grade ≥3 toxicities (with some exceptions) ; Grade≥3 creatinine phosphokinase (CPK) with creatinine \>= 1.5xbaseline; Grade 3 troponin increase with cardiac toxicity; potential Hy's Law cases; eye disorders: retinopathy or retinal detachment Grade≥3; retinal vascular disorder; Grade≥3 uveitis, blurred vision, flashing lights, floaters or others for \>21 consecutive days; other Grade 4; cardiac disorders: absolute LVEF decrease \>10% and the LVEF was below LLN; other Grade≥3; respiratory disorders: interstitial lung disease Grade≥2; bronchospasm Grade 3; skin and subcutaneous tissue disorders; non-adherence to treatment schedule; dose reductions. Time frame: From date of first study treatment to day 28 of study treatment (Up to 28 days).

Primary outcome public domain (ClinicalTrials.gov)

Phase 2: Confirmed Objective Response (OR) Based on Investigator Assessment Per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.. Confirmed OR, defined as a complete response (CR) or partial response (PR) per RECIST v1.1. CR was defined as complete disappearance of all target and non-target lesions, with the exception of nodal disease and sustained for at least 4 weeks. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to less than (\<) 10 mm. PR was defined as at least 30% decrease in the sum of the longest dimensions of target lesions taking as reference the baseline sum longest dimensions. Both CR and PR must be confirmed by repeated assessments performed no less than 4 weeks after the criteria for response were first met. Time frame: From date of first study treatment until the date of first documentation of progressive disease or death due to any cause (assessed for a maximum duration of up to 31 months)..

Secondary outcome public domain (ClinicalTrials.gov)

Number of Participants With Adverse Events During the On-Treatment Period. Time frame: From the first dose of study treatment through minimum (30 days + last dose of study treatment, start day of new anti-cancer drug therapy - 1 day) assessed for a maximum duration of up to 31 months.

Secondary outcome public domain (ClinicalTrials.gov)

Predose Concentration During Multiple Dosing (Ctrough) for Avelumab. Time frame: Pre-dose on Day 1, and Day 15 of Cycle 1 (each cycle is 28 days); Day 1 and Day 15 of Cycle 2; and Day 1 of Cycles 3, 5, 9 and 12..

Secondary outcome public domain (ClinicalTrials.gov)

Predose Concentration During Multiple Dosing (Ctrough) for Binimetinib. Time frame: Predose on Day 15 of Cycle 1 (each cycle is 28 days), Day 1 and Day 15 of Cycle 2, Day 1 of Cycle 3 for avelumab+binimetinib groups, and on Day 8 and Day 15 of Cycle 1, Day 1 of Cycle 2, Day 1 of Cycle 3 for binimetinib+talazoparib groups.

Secondary outcome public domain (ClinicalTrials.gov)

Predose Concentration During Multiple Dosing (Ctrough) for Talazoparib. Time frame: Pre-dose on Days 1, 8 and Day 15 of Cycle 1 (each cycle is 28 days), and on Day 1 of Cycle 2 and Cycle 3.

Eligibility public domain (ClinicalTrials.gov)

Inclusion Criteria: * Histological diagnosis of locally advanced (primary or recurrent) or metastatic solid tumors that are not amenable for treatment with curative intent as follows: 1. Metastatic pancreatic ductal adenocarcinoma; or 2. Phase 2 only: Stage IIIb/IV NSCLC or other advanced solid tumors with documented positive KRAS or NRAS mutation as determined using a validated test performed in a CAP/CLIA-certified laboratory (or other comparable local or regional certification). * Have had disease progression during or following at least 1 and not more than 2 prior lines of treatment for advanced or metastatic disease. * Patients with NSCLC must have previously received treatment with an anti-PD-1 or anti-PD-L1 agent for advanced disease. * Measurable disease as per RECIST v1.1 criteria. * Provision of a baseline tumor sample. * Age ≥18 years (Japanese patients must be ≥20 years old) * Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0 or 1. * Adequate bone marrow, renal and liver functions. * Adequate cardiac function. * Informed consent provided. Exclusion Criteria: * Prior treatment with avelumab, a PARP inhibitor or MEK inhibitor. * Prior systemic anti-cancer therapy within 2 weeks prior to study enrollment. * Persisting toxicity related to prior therapy. * Current use of immunosuppressive medication. * Known history of immune-mediated colitis, inflammatory bowel disease, pneumonitis, pulmonary fibrosis, uveitis or iritis. * Active or prior autoimmune disease that might deteriorate when receiving an immunostimulatory agent. * Diagnosis of myelodysplastic syndrome (MDS). * Known symptomatic brain metastases requiring steroids. * Known history of testing positive for HIV or hepatitis. * Clinically significant (ie, active) cardiovascular disease. * History of thromboembolic or cerebrovascular events. * Current or anticipated use of a P-gp inhibitor, inducer, or inhibitor of breast cancer resistance protein (BCRP) * Uncontrolled hypertension. * Concurrent neuromuscular disorder that is associated with the potential of elevated creatinine kinase. * Known history of Gilbert's syndrome. * History or current evidence of retinal degenerative disease, retinal vein occlusion (RVO) or current risk factors for RVO. * Other acute or chronic medical or psychiatric condition.

Enrollment public domain (ClinicalTrials.gov)

Enrollment: 36 participants (actual).

Why stopped public domain (ClinicalTrials.gov)

Available clinical data has shown limited anti-tumor activity and reaching target study drug dose levels may not be feasible.

Posted results (ClinicalTrials.gov registry) · primary outcome public domain (ClinicalTrials.gov)

Number of Participants With Dose Limiting Toxicities (DLTs) During the Primary DLT Evaluation Period (Cycle 1) in Phase 1b [From date of first study treatment to day 28 of study treatment (Up to 28 days)]. Count Of Participants, Participants. Avelumab+Binimetinib 30mg (Phase 1b) (n=10): 3; Avelumab+Binimetinib 45mg (Phase 1b) (n=11): 5; Binimetinib 30mg+Talazoparib 0.75mg (Phase 1b) (n=6): 2; Binimetinib 45mg+Talazoparib 0.75mg (Phase 1b) (n=5): 2.

Posted results (ClinicalTrials.gov registry) · primary outcome public domain (ClinicalTrials.gov)

Phase 2: Confirmed Objective Response (OR) Based on Investigator Assessment Per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. [From date of first study treatment until the date of first documentation of progressive disease or death due to any cause (assessed for a maximum duration of up to 31 months).].