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

NCT03637491 | Terminated Phase 1 Results FDA Drug

• 2 other identifiers: B99910332018-000124-34
• Study Type: interventional
• Target: 36
• Locations: 3 countries
• Sites: 18

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.

Conditions

Pancreatic Cancer

Keywords

KRAS; NRAS; PDAC; Pancreatic Cancer

Outcome Measures

Primary Outcomes (2)

• 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.

  From date of first study treatment to day 28 of study treatment (Up to 28 days)

• 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.

  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 (16)

• Number of Participants With Adverse Events During the On-Treatment Period

  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

• 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

  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)

• 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

  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)

• Predose Concentration During Multiple Dosing (Ctrough) for Avelumab

  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.

• Predose Concentration During Multiple Dosing (Ctrough) for Binimetinib

  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

Study Arms (3)

Avelumab and binimetinib

EXPERIMENTAL

Open label

Drug: Avelumab; Drug: Binimetinib

Avelumab, binimetinib and talazoparib

EXPERIMENTAL

Open label

Drug: Avelumab; Drug: Binimetinib; Drug: Talazoparib

Binimetinib and talazoparib.

EXPERIMENTAL

Open label.

Drug: Binimetinib; Drug: Talazoparib

Interventions

Avelumab DRUG

IV treatment

Also known as: MSB0010718C

Avelumab and binimetinib; Avelumab, binimetinib and talazoparib

Binimetinib DRUG

Oral treatment

Also known as: MEK162, ARRY-438162

Avelumab and binimetinib; Avelumab, binimetinib and talazoparib; Binimetinib and talazoparib.

Talazoparib DRUG

Oral treatment

Also known as: MDV3800, BMN 673

Avelumab, binimetinib and talazoparib; Binimetinib and talazoparib.

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Histological diagnosis of locally advanced (primary or recurrent) or metastatic solid tumors that are not amenable for treatment with curative intent as follows:
• Metastatic pancreatic ductal adenocarcinoma; or
• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Pfizer: lead

Study Sites (18)

Highlands Oncology Group

Fayetteville, Arkansas, 72703, United States

Location

Highlands Oncology Group

Rogers, Arkansas, 72758, United States

Location

Highlands Oncology Group

Springdale, Arkansas, 72762, United States

Location

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

Encinitas, California, 92024, United States

Location

University of Colorado Denver CTO (CTRC)

Aurora, Colorado, 80045, United States

Location

University of Colorado Hospital

Aurora, Colorado, 80045, United States

Location

Horizon Oncology Research, LLC

Lafayette, Indiana, 47905, United States

Location

UPMC Hillman Cancer Center

Pittsburgh, Pennsylvania, 15232, United States

Location

The University of Texas MD Anderson Cancer Center

Houston, Texas, 77030, United States

Location

University of Utah, Huntsman Cancer Hospital

Salt Lake City, Utah, 84112, United States

Location

University of Utah, Huntsman Cancer Institute

Salt Lake City, Utah, 84112, United States

Location

Institut Jules Bordet

Brussels, 1000, Belgium

Location

UZ Gent

Ghent, 9000, Belgium

Location

Singapore National Eye Centre

Singapore, 168751, Singapore

Location

Singapore General Hospital

Singapore, 169608, Singapore

Location

SingHealth Investigational Medicine Unit

Singapore, 169608, Singapore

Location

National Heart Centre Singapore

Singapore, 169609, Singapore

Location

National Cancer Centre Singapore

Singapore, 169610, Singapore

Location

Related Publications (2)

• Rodon Ahnert J, Tan DS, Garrido-Laguna I, Harb W, Bessudo A, Beck JT, Rottey S, Bahary N, Kotecki N, Zhu Z, Deng S, Kowalski K, Wei C, Pathan N, Laliberte RJ, Messersmith WA. Avelumab or talazoparib in combination with binimetinib in metastatic pancreatic ductal adenocarcinoma: dose-finding results from phase Ib of the JAVELIN PARP MEKi trial. ESMO Open. 2023 Aug;8(4):101584. doi: 10.1016/j.esmoop.2023.101584. Epub 2023 Jun 26.

  PMID: 37379764 DERIVED

• 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.

  PMID: 32379297 DERIVED

Related Links

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

MeSH Terms

Conditions

Pancreatic Neoplasms

Interventions

avelumab; binimetinib; talazoparib

Condition Hierarchy (Ancestors)

Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Endocrine Gland Neoplasms; Digestive System Diseases; Pancreatic Diseases; Endocrine System Diseases

Limitations and Caveats

Because there was a low probability of technical success for achieving target dose levels of the triplet combination while maintaining acceptable tolerability, and only limited anti-tumor activity was observed in this study of participants with mPDAC, a decision on the early termination was made on 14 December 2020. Phase 2 was not initiated, so PD-L1 Expression, DDR Gene Alterations, TMB and OR were not analyzed. Due to the low observed immunogenicity rate, nAb analysis was not conducted.

Results Point of Contact

• Title: Pfizer ClinicalTrials.gov Call Center
• Organization: Pfizer, Inc.

ClinicalTrials.gov_Inquiries@pfizer.com

1-800-718-1021

Study Officials

• Pfizer CT.gov Call Center

  Pfizer

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 10, 2018
• First Posted: August 20, 2018
• Study Start: August 15, 2018
• Primary Completion: December 3, 2020
• Study Completion: February 2, 2021
• Last Updated: January 26, 2022
• Results First Posted: January 26, 2022

Record last verified: 2021-12

Data Sharing

• IPD Sharing: Will not share

Locations

BE (2); SG (5); US (11)