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

• ClinicalTrials.gov Identifier: NCT03637491
• Recruitment Status: Terminated
• First Posted: August 20, 2018
• Last Update Posted: July 23, 2021
• Sponsor: Pfizer
• Information provided by (Responsible Party): Pfizer

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Pancreatic Cancer	Drug: Avelumab; Drug: Binimetinib; Drug: Talazoparib	Phase 1; Phase 2

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 36 participants
• Allocation: Randomized
• Intervention Model: Sequential Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: August 15, 2018
• Actual Primary Completion Date: December 3, 2020
• Actual Study Completion Date: February 2, 2021

Arms and Interventions

Arm	Intervention/treatment
Experimental: Avelumab and binimetinib; Open label	Drug: Avelumab; IV treatment; Other Name: MSB0010718C; Drug: Binimetinib; Oral treatment; Other Names: MEK162; ARRY-438162
Experimental: Avelumab, binimetinib and talazoparib; Open label	Drug: Avelumab; IV treatment; Other Name: MSB0010718C; Drug: Binimetinib; Oral treatment; Other Names: MEK162; ARRY-438162; Drug: Talazoparib; Oral treatment; Other Name: MDV3800, BMN 673
Experimental: Binimetinib and talazoparib.; Open label.	Drug: Binimetinib; Oral treatment; Other Names: MEK162; ARRY-438162; Drug: Talazoparib; Oral treatment; Other Name: MDV3800, BMN 673

Outcome Measures

Primary Outcome Measures :

1. Dose Limiting Toxicity (DLT) [ Time Frame: Cycle 1 (days 1-28 of study treatment) ]
   Phase 1: DLT during the primary DLT evaluation period (Cycle 1)
2. Confirmed Objective Response (OR) [ Time Frame: From start date (date of randomization for randomized cohorts and first dose of study treatment for non-randomized cohorts) until the date of first documentation of progressive disease or death due to any cause assessed up to approximately 24 months. ]
   Phase 2: Confirmed OR, defined as a complete response (CR) or partial response (PR) per RECIST v1.1. Both CR and PR must be confirmed by repeat assessments performed no less than 4 weeks after the criteria for response are first met.

Secondary Outcome Measures :

1. Concentration of avelumab in blood [ Time Frame: Day 1, Day 8 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. ]
   Pharmacokinetic parameters: pre-dose/trough concentrations (Ctrough)
2. Concentration of avelumab in blood [ Time Frame: Day 1, Day 8 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. ]
   Pharmacokinetic parameters: post dose concentrations (Cmax)
3. Avelumab ADA levels [ Time Frame: Day 1, Day 8 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. ]
   Immunogenicity assessment of avelumab
4. Neutralizing antibodies (nAb) against avelumab. [ Time Frame: Day 1, Day 8 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. ]
   Immunogenicity assessment of avelumab
5. Concentration of binimetinib in plasma [ Time Frame: Pre-dose on Day 1, Day 8 and Day 15 of Cycle 1 (each cycle is 28 days). Day 1 of Cycle 2 and 3 ]
   Pharmacokinetic parameters: pre-dose/trough concentrations (Ctrough)
6. Concentration of binimetinib in plasma [ Time Frame: Day 1, Day 8 and Day 15 of Cycle 1 (each cycle is 28 days). Day 1 of Cycle 2 and Cycle 3. ]
   Pharmacokinetic parameters: post dose concentrations (Cmax).
7. Concentration of talazoparib in plasma [ Time Frame: Pre-dose on Day 1, 8 and Day 15 of Cycle 1 (each cycle is 28 days), and on Day 1 of Cycle 2 and 3 ]
   Pharmacokinetic parameters: pre-dose/trough concentrations (Ctrough)
8. Biomarker Tumor Mutational Burden [ Time Frame: Baseline ]
   Tumor mutational burden in baseline tumor tissue
9. Biomarker PD-L1 [ Time Frame: Baseline ]
   PD-L1 expression level in baseline tumor tissue.
10. Biomarker DNA Damage Repair [ Time Frame: Baseline ]
    DDR gene alterations in baseline tumor tissue.
11. Objective Response [ Time Frame: From the start of treatment until disease progression/recurrence up to approximately 24 months. ]
    Phase 1b: Confirmed OR based on Investigator assessment per RECIST v1.1.
12. Time to Tumor Response (TTR) [ Time Frame: Baseline up to approximately 24 months ]
    TTR is defined, for patients with an OR, as the time from the 'start date' to the first documentation of objective response (CR or PR) which is subsequently confirmed
13. Duration of Response (DR) [ Time Frame: Baseline up to approximately 24 months ]
    DR is defined, for patients with OR, as the time from the first documentation of objective response (CR or PR) to the date of first documentation of PD or death due to any cause
14. Overall Survival (OS) [ Time Frame: Baseline up to approximately 24 months ]
    OS is defined as the time from time from the 'start date' to the date of death due to any cause. Patients without an event (death) will be censored at the date of last contact
15. Progression Free Survival [ Time Frame: Baseline up to approximately 24 months ]
    PFS is defined as the time from 'start date' to the date of PD by RECIST v1.1 or death due to any cause, whichever occurs first

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

United States, Arkansas

Highlands Oncology Group

Fayetteville, Arkansas, United States, 72703

Highlands Oncology Group

Rogers, Arkansas, United States, 72758

Highlands Oncology Group

Springdale, Arkansas, United States, 72762

United States, California

California Cancer Associates for Research and Excellence, Inc (cCARE)

Encinitas, California, United States, 92024

United States, Colorado

University of Colorado Denver CTO (CTRC)

Aurora, Colorado, United States, 80045

University of Colorado Hospital

Aurora, Colorado, United States, 80045

United States, Indiana

Horizon Oncology Research, LLC

Lafayette, Indiana, United States, 47905

United States, Pennsylvania

UPMC Hillman Cancer Center

Pittsburgh, Pennsylvania, United States, 15232

United States, Texas

The University of Texas MD Anderson Cancer Center

Houston, Texas, United States, 77030

United States, Utah

University of Utah, Huntsman Cancer Hospital

Salt Lake City, Utah, United States, 84112

University of Utah, Huntsman Cancer Institute

Salt Lake City, Utah, United States, 84112

Belgium

Institut Jules Bordet

Brussels, Belgium, 1000

UZ Gent

Gent, Belgium, 9000

Singapore

Singapore National Eye Centre

Singapore, Singapore, 168751

Singapore General Hospital

Singapore, Singapore, 169608

SingHealth Investigational Medicine Unit

Singapore, Singapore, 169608

National Heart Centre Singapore

Singapore, Singapore, 169609

National Cancer Centre Singapore

Singapore, Singapore, 169610

Sponsors and Collaborators

Pfizer

Investigators

• Study Director: Pfizer CT.gov Call Center; Pfizer

More Information

Additional Information:

To obtain contact information for a study center near you, click here. 

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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. Review.

• Responsible Party: Pfizer
• ClinicalTrials.gov Identifier: NCT03637491
• Other Study ID Numbers: B9991033; 2018-000124-34 ( EudraCT Number )
• First Posted: August 20, 2018
• Last Update Posted: July 23, 2021
• Last Verified: July 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No
• Plan Description: Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/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:

KRAS; NRAS; PDAC; Pancreatic Cancer

Additional relevant MeSH terms:

Pancreatic Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Endocrine Gland Neoplasms; Digestive System Diseases; Pancreatic Diseases; Endocrine System Diseases; Talazoparib; Poly(ADP-ribose) Polymerase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents