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

• Sponsor: Pfizer
• Collaborator: Array BioPharma
• Information provided by (Responsible Party): Pfizer

Study Description

Brief Summary:

This Phase 1b/2 study will examine the effects of the study drugs, avelumab and binimetinib given together (doublet) and in combination with talazoparib (triplet), 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; Non-Small Cell Lung Cancer; Cancer	Drug: Avelumab; Drug: Binimetinib; Drug: Talazoparib	Phase 2

Detailed Description:

This is a Phase 1b/2, open label, multi-center, safety, clinical activity, pharmacokinetic (PK), and pharmacodynamics (PD) study of avelumab in combination with binimetinib with or without talazoparib in adult patients with locally advanced or metastatic KRAS- or NRAS-mutant non-small cell lung cancer, pancreatic ductal adenocarcinoma, or other KRAS- or NRAS-mutant solid tumors.

The Phase 1b part of this study will initially assess the combination of avelumab and binimetinib (doublet) 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

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	127 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 Avelumab in Combination With Binimetinib With or Without Talazoparib in Patients With Locally Advanced or Metastatic RAS-Mutant Solid Tumors
Actual Study Start Date :	August 15, 2018
Estimated Primary Completion Date :	July 26, 2022
Estimated Study Completion Date :	February 1, 2023

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

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 7 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 7 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 7 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 7 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. 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.
6. Biomarker Tumor Mutational Burden [ Time Frame: Baseline ]
   Tumor mutational burden in baseline tumor tissue
7. Biomarker PD-L1 [ Time Frame: Baseline ]
   PD-L1 expression level in baseline tumor tissue.
8. Biomarker DNA Damage Repair [ Time Frame: Baseline ]
   DDR gene alterations in baseline tumor tissue.
9. Concentration of talazoparib in plasma [ Time Frame: Pre-dose on Day 1 and Day 15 of Cycle 1 and Cycle 2 (each cycle is 28 days), and on Day 1 of Cycle 3 ]
   Pharmacokinetic parameters: pre-dose/trough concentrations (Ctrough)
10. Concentration of binimetinib in plasma [ Time Frame: Pre-dose on Day 1 and Day 15 of Cycle 1 and Cycle 2 (each cycle is 28 days), and on Day 1 of Cycle 3 ]
    Pharmacokinetic parameters: pre-dose/trough concentrations (Ctrough)
11. 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
12. 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
13. 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
14. 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

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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. Stage IIIb/IV NSCLC with documented positive KRAS or NRAS mutation status as determined using a validated test performed in a College of American Pathologists (CAP)/Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory (or other comparable local or regional certification); or
  2. Metastatic pancreatic ductal adenocarcinoma; or
  3. Phase 2 only: 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

Contacts

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Contact: Pfizer CT.gov Call Center	1-800-718-1021	ClinicalTrials.gov_Inquiries@pfizer.com

Locations

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United States, Arkansas
Highlands Oncology Group	Recruiting
Fayetteville, Arkansas, United States, 72703
Highlands Oncology Group	Recruiting
Rogers, Arkansas, United States, 72758
United States, California
California Cancer Associates for Research and Excellence, Inc (cCARE)	Not yet recruiting
Encinitas, California, United States, 92024
California Cancer Associates for Research and Excellence, Inc (cCARE)	Not yet recruiting
San Marcos, California, United States, 92069
United States, Colorado
University of Colorado Denver CTO (CTRC)	Recruiting
Aurora, Colorado, United States, 80045
University of Colorado Hospital	Recruiting
Aurora, Colorado, United States, 80045
United States, Indiana
Horizon Oncology Research, LLC	Recruiting
Lafayette, Indiana, United States, 47905
United States, Pennsylvania
UPMC Hillman Cancer Center Investigational Drug Service	Recruiting
Pittsburgh, Pennsylvania, United States, 15232
UPMC Hillman Cancer Center	Recruiting
Pittsburgh, Pennsylvania, United States, 15232
United States, Texas
The University of Texas MD Anderson Cancer Center	Recruiting
Houston, Texas, United States, 77030
United States, Utah
University of Utah, Huntsman Cancer Hospital	Recruiting
Salt Lake City, Utah, United States, 84112
University of Utah, Huntsman Cancer Institute	Recruiting
Salt Lake City, Utah, United States, 84112
Belgium
Institut Jules Bordet	Recruiting
Brussels, Belgium, 1000
UZ Gent	Recruiting
Gent, Belgium, 9000
Singapore
Singapore National Eye Centre	Recruiting
Singapore, Singapore, 168751
Singapore General Hospital	Recruiting
Singapore, Singapore, 169608
SingHealth Investigational Medicine Unit	Recruiting
Singapore, Singapore, 169608
National Heart Centre Singapore	Recruiting
Singapore, Singapore, 169609
National Cancer Centre	Recruiting
Singapore, Singapore, 169610

Sponsors and Collaborators

Pfizer

Array BioPharma

Investigators

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Study Director:	Pfizer CT.gov Call Center	Pfizer

More Information

Additional Information:

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

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Responsible Party:	Pfizer
ClinicalTrials.gov Identifier:	NCT03637491 History of Changes
Other Study ID Numbers:	B9991033; 2018-000124-34 ( EudraCT Number )
First Posted:	August 20, 2018
Last Update Posted:	June 5, 2019
Last Verified:	June 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	Yes
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.
URL:	https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests

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Studies a U.S. FDA-regulated Drug Product:		Yes
Studies a U.S. FDA-regulated Device Product:		No

Keywords provided by Pfizer:

Lung Cancer; NSCLC; KRAS	NRAS; PDAC; Pancreatic Cancer

Additional relevant MeSH terms:

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Carcinoma, Non-Small-Cell Lung; Pancreatic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases; Digestive System Neoplasms	Endocrine Gland Neoplasms; Digestive System Diseases; Pancreatic Diseases; Endocrine System Diseases; Antibodies, Monoclonal; Talazoparib; Immunologic Factors; Physiological Effects of Drugs; Poly(ADP-ribose) Polymerase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents