Clinical trial NCT03637491: A Study of Avelumab, Binimetinib and Talazoparib in Patients With Locally Advanced or Metastatic RAS-mutant Solid Tumors
Official title: 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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
PHASE2
Conditions: Pancreatic Cancer
Keywords: KRAS
NRAS
PDAC
Pancreatic Cancer
Lead sponsor: Pfizer
Sponsor class: INDUSTRY
First posted: 2018-08-20
Enrollment: 36
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: 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: 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.

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 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.

Primary outcomes:
measure: Number of Participants With Dose Limiting Toxicities (DLTs) During the Primary DLT Evaluation Period (Cycle 1) in Phase 1b
timeFrame: From date of first study treatment to day 28 of study treatment (Up to 28 days)
measure: Phase 2: Confirmed Objective Response (OR) Based on Investigator Assessment Per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.
timeFrame: 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 outcomes:
measure: Number of Participants With Adverse Events During the On-Treatment Period
timeFrame: 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
measure: Number of Participants With Hematology Laboratory Abnormalities During the On-Treatment Period Graded by National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI-CTCAE), Version 4.03
timeFrame: Prior to study drug administration on Days 1 and 15 of each treatment cycle, until 30 days after last dose (assessed for a maximum duration of up to 31 months)
measure: Number of Participants With Chemistry Laboratory Abnormalities During the On-Treatment Period Graded by National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI-CTCAE), Version 4.03
timeFrame: Prior to study drug administration on Days 1 and 15 of each treatment cycle, until 30 days after last dose (assessed for a maximum duration of up to 31 months)
measure: Predose Concentration During Multiple Dosing (Ctrough) for Avelumab
timeFrame: 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.
measure: Predose Concentration During Multiple Dosing (Ctrough) for Binimetinib
timeFrame: 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
measure: Predose Concentration During Multiple Dosing (Ctrough) for Talazoparib
timeFrame: 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
measure: Maximum Observed Plasma Concentration (Cmax) for Avelumab
timeFrame: Post 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
measure: Maximum Observed Plasma Concentration (Cmax) for Binimetinib
timeFrame: Post dose on Day 1 and Day 8 of Cycle 1
measure: Number of Participants With Anti-drug Antibody (ADA) Categories
timeFrame: from the first dose of study up to Day 1 of Cycle 12 for a maximum of 12 months
measure: Neutralizing Antibodies (nAb) Against Avelumab
timeFrame: from the first dose of study up to Day 1 of Cycle 12 for a maximum of 12 months
measure: Percentage of Participants With Confirmed Objective Response (OR) in Phase 1b Based on Investigator Assessment (RECIST v1.1)
timeFrame: 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).
measure: Progression-Free Survival (PFS) Based on Investigator Assessment (RECIST v1.1) in Phase 1b
timeFrame: 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).
measure: Overall Survival (OS) in Phase 1b
timeFrame: From date of first study treatment until the date of death due to any cause (assessed for a maximum duration of up to 31 months).
measure: Time-to-Tumor Response (TTR) in Phase 1b
timeFrame: 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).
measure: Duration of Response (DR) in Phase 1b
timeFrame: 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).
measure: Phase 2: Number of Participants With Programmed Death-Ligand 1 (PD-L1) Expression, DNA Damage Repair (DDR) Gene Alterations, and Tumor Mutational Burden (TMB) in Baseline Tumor Tissue.
timeFrame: Baseline
Other outcomes:
Locations:
city: Fayetteville
country: United States
facility: Highlands Oncology Group
state: Arkansas
city: Rogers
country: United States
facility: Highlands Oncology Group
state: Arkansas
city: Springdale
country: United States
facility: Highlands Oncology Group
state: Arkansas
city: Encinitas
country: United States
facility: California Cancer Associates for Research and Excellence, Inc (cCARE)
state: California
city: Aurora
country: United States
facility: University of Colorado Denver CTO (CTRC)
state: Colorado
city: Aurora
country: United States
facility: University of Colorado Hospital
state: Colorado
city: Lafayette
country: United States
facility: Horizon Oncology Research, LLC
state: Indiana
city: Pittsburgh
country: United States
facility: UPMC Hillman Cancer Center
state: Pennsylvania
city: Houston
country: United States
facility: The University of Texas MD Anderson Cancer Center
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah, Huntsman Cancer Hospital
state: Utah
city: Salt Lake City
country: United States
facility: University of Utah, Huntsman Cancer Institute
state: Utah
city: Brussels
country: Belgium
facility: Institut Jules Bordet
city: Gent
country: Belgium
facility: UZ Gent
city: Singapore
country: Singapore
facility: Singapore National Eye Centre
city: Singapore
country: Singapore
facility: Singapore General Hospital
city: Singapore
country: Singapore
facility: SingHealth Investigational Medicine Unit
city: Singapore
country: Singapore
facility: National Heart Centre Singapore
city: Singapore
country: Singapore
facility: National Cancer Centre Singapore
Study officials:
affiliation: Pfizer
name: Pfizer CT.gov Call Center
role: STUDY_DIRECTOR
References:
citation: Sun C, Fang Y, Labrie M, Li X, Mills GB. Systems approach to rational combination therapy: PARP inhibitors. Biochem Soc Trans. 2020 Jun 30;48(3):1101-1108. doi: 10.1042/BST20191092.