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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03637491
Recruitment Status : Recruiting
First Posted : August 20, 2018
Last Update Posted : February 28, 2020
Sponsor:
Information provided by (Responsible Party):
Pfizer

Tracking Information
First Submitted Date  ICMJE August 10, 2018
First Posted Date  ICMJE August 20, 2018
Last Update Posted Date February 28, 2020
Actual Study Start Date  ICMJE August 15, 2018
Estimated Primary Completion Date April 19, 2023   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 16, 2018)
  • 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)
  • 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.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: December 9, 2019)
  • 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)
  • 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)
  • 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
  • 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
  • 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)
  • 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).
  • 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)
  • Biomarker Tumor Mutational Burden [ Time Frame: Baseline ]
    Tumor mutational burden in baseline tumor tissue
  • Biomarker PD-L1 [ Time Frame: Baseline ]
    PD-L1 expression level in baseline tumor tissue.
  • Biomarker DNA Damage Repair [ Time Frame: Baseline ]
    DDR gene alterations in baseline tumor tissue.
  • 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.
  • 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
  • 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
  • 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
  • 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
Original Secondary Outcome Measures  ICMJE
 (submitted: August 16, 2018)
  • 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)
  • 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)
  • 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
  • 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
  • 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.
  • Biomarker Tumor Mutational Burden [ Time Frame: Baseline ]
    Tumor mutational burden in baseline tumor tissue
  • Biomarker PD-L1 [ Time Frame: Baseline ]
    PD-L1 expression level in baseline tumor tissue.
  • Biomarker DNA Damage Repair [ Time Frame: Baseline ]
    DDR gene alterations in baseline tumor tissue.
  • 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)
  • 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)
  • 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
  • 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
  • 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
  • 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
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Study of Avelumab, Binimetinib and Talazoparib in Patients With Locally Advanced or Metastatic RAS-mutant Solid Tumors
Official Title  ICMJE 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
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Pancreatic Cancer
Intervention  ICMJE
  • 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
Study Arms  ICMJE
  • Experimental: Avelumab and binimetinib
    Open label
    Interventions:
    • Drug: Avelumab
    • Drug: Binimetinib
  • Experimental: Avelumab, binimetinib and talazoparib
    Open label
    Interventions:
    • Drug: Avelumab
    • Drug: Binimetinib
    • Drug: Talazoparib
  • Experimental: Binimetinib and talazoparib.
    Open label.
    Interventions:
    • Drug: Binimetinib
    • Drug: Talazoparib
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: December 9, 2019)
122
Original Estimated Enrollment  ICMJE
 (submitted: August 16, 2018)
127
Estimated Study Completion Date  ICMJE October 16, 2023
Estimated Primary Completion Date April 19, 2023   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Pfizer CT.gov Call Center 1-800-718-1021 ClinicalTrials.gov_Inquiries@pfizer.com
Listed Location Countries  ICMJE Belgium,   Singapore,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03637491
Other Study ID Numbers  ICMJE B9991033
2018-000124-34 ( EudraCT Number )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
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
Responsible Party Pfizer
Study Sponsor  ICMJE Pfizer
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Pfizer CT.gov Call Center Pfizer
PRS Account Pfizer
Verification Date February 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP