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
• Results First Posted: January 26, 2022
• Last Update Posted: January 26, 2022
• 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. Number of Participants With Dose Limiting Toxicities (DLTs) During the Primary DLT Evaluation Period (Cycle 1) in Phase 1b [ Time Frame: From date of first study treatment to day 28 of study treatment (Up to 28 days) ]
   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.
2. Phase 2: Confirmed Objective Response (OR) Based on Investigator Assessment Per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. [ Time Frame: 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). ]
   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.

Secondary Outcome Measures :

1. Number of Participants With Adverse Events During the On-Treatment Period [ Time Frame: 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 ]
   An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Treatment-emergent adverse event (TEAE) means event between first dose of study treatment and up to 30 days after last dose that were absent before treatment or that worsened relative to pretreatment state. An SAE was an AE resulting in any of death; inpatient hospitalization; life-threatening experience; disability; congenital anomaly or deemed significant for any other reason. Symptoms of infusion-related reactions (IRRs) may include, but were not limited to, fever, chills, flushing, hypotension, dyspnea, wheezing, back pain, abdominal pain, and urticaria. Grade 3: severe or medically significant but not immediately life-threatening, hospitalization or prolongation of existing hospitalization indicated, disabling, limiting self-care ADL; Grade 4: life-threatening consequence, urgent intervention indicated; Grade 5: death related to AE.
2. 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 [ Time Frame: 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) ]
   Laboratory abnormalities were graded by NCI CTCAE version 4.03. Anemia, hemoglobin increased, lymphocyte count decreased, lymphocyte count increased, neutrophil count decreased, platelet count decreased, white blood cell decreased were evaluated. This outcome measure calculated the number of participants with laboratory abnormalities whose maximum on-treatment CTCAE Grade were 1-4.
3. 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 [ Time Frame: 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) ]
   Laboratory abnormalities were graded by NCI CTCAE version 4.03. Alanine aminotransferase increased, alkaline phosphatase increased, aspartate aminotransferase increased, blood bilirubin increased, creatine phosphokinase (cpk) increased, creatinine increased, gamma-glutamyl transferase (ggt) increased, hypercalcemia, hyperglycemia, hyperkalemia, hypermagnesemia, hypernatremia, hypoalbuminemia, hypocalcemia, hypoglycemia, hypokalemia, hypomagnesemia, hyponatremia, hypophosphatemia, lipase increased, serum amylase increased were evaluated. This outcome measure calculated the number of participants with laboratory abnormalities whose maximum on-treatment CTCAE Grade were 1-4.
4. Predose Concentration During Multiple Dosing (Ctrough) for Avelumab [ Time Frame: 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. ]
   Ctrough was the pre-dose concentration during multiple dosing and was directly observed from data. The lower limit of quantification (LLQ) was 0.20 microgram per milliliter. Concentration values below the LLQ were set to zero. Geometric Mean analysis was on the log scale. Zero values were not included in geometric mean and geometric coefficient of variation calculation. The geometric coefficient of variation is expressed in percentage.
5. Predose Concentration During Multiple Dosing (Ctrough) for Binimetinib [ Time Frame: 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 ]
   Ctrough was directly observed from data. Ctrough = concentration prior to study drug administration. The LLQ was 1.00 ng/mL. Concentration values below the LLQ were set to zero. Geometric Mean analysis was on the log scale. Zero values were not included in geometric mean and geometric coefficient of variation calculation. The geometric coefficient of variation is expressed in percentage.
6. Predose Concentration During Multiple Dosing (Ctrough) for Talazoparib [ Time Frame: 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 ]
   Ctrough was directly observed from data. Ctrough = concentration prior to study drug administration. The LLQ was 25 pg/mL. Concentration values below the LLQ were set to zero. Geometric Mean analysis was on the log scale. Zero values were not included in geometric mean and geometric coefficient of variation calculation. The geometric coefficient of variation is expressed in percentage.
7. Maximum Observed Plasma Concentration (Cmax) for Avelumab [ Time Frame: 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 ]
   Cmax was the maximum observed plasma concentration and was directly observed from data. The LLQ was 0.20 microgram per milliliter. Concentration values below the LLQ were set to zero. Geometric Mean analysis was on the log scale. Zero values were not included in geometric mean and geometric coefficient of variation calculation. The geometric coefficient of variation is expressed in percentage.
8. Maximum Observed Plasma Concentration (Cmax) for Binimetinib [ Time Frame: Post dose on Day 1 and Day 8 of Cycle 1 ]
   Cmax was the maximum observed plasma concentration and was directly observed from data. The LLQ was 1.00 ng/mL. Concentration values below the LLQ were set to zero. Geometric Mean analysis was on the log scale. Zero values were not included in geometric mean and geometric coefficient of variation calculation. The geometric coefficient of variation is expressed in percentage.
9. Number of Participants With Anti-drug Antibody (ADA) Categories [ Time Frame: from the first dose of study up to Day 1 of Cycle 12 for a maximum of 12 months ]
   Samples positive for ADA were analyzed for titer. Blood samples were collected for avelumab immunogenicity testing. Treatment-boosted ADA was defined as a positive ADA result at baseline and the titer ≥ 8×baseline titer at least once after treatment with avelumab. Treatment-induced ADA was defined as participants with ADA-negative at baseline and had at least one positive post-baseline ADA result; or if participant did not have a baseline sample, the participant had at least one positive post-baseline ADA result.
10. Neutralizing Antibodies (nAb) Against Avelumab [ Time Frame: from the first dose of study up to Day 1 of Cycle 12 for a maximum of 12 months ]
    The category of nAb included nAb never-positive, nAb ever-positive, baseline nAb positive, treatment-induced nAb, transient nAb response, persistent nAb response.
11. Percentage of Participants With Confirmed Objective Response (OR) in Phase 1b Based on Investigator Assessment (RECIST v1.1) [ Time Frame: 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). ]
    OR is defined as complete response (CR) or partial response (PR) according to RECIST v1.1 from the 'start date' (date of first study treatment) until the date of the first documentation of progressive disease (PD). 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. 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. PD was defined as unequivocal progression of pre-existing lesions and if overall tumor burden increased sufficiently to merit discontinuation of therapy. Both CR and PR must be confirmed by repeat assessments performed no less than 4 weeks after the criteria for response are first met. Clopper-Pearson method was used.
12. Progression-Free Survival (PFS) Based on Investigator Assessment (RECIST v1.1) in Phase 1b [ Time Frame: 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). ]
    PFS is defined as the time from the 'start date' (date of first study treatment) to the date of the first documentation of PD or death due to any cause, whichever occurs first. PD was defined as unequivocal progression of pre-existing lesions and if overall tumor burden increased sufficiently to merit discontinuation of therapy. CIs were calculated using Brookmeyer and Crowley method.
13. Overall Survival (OS) in Phase 1b [ Time Frame: 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). ]
    OS is defined as the time from the 'start date' (date of first study treatment) to the date of death due to any cause. CIs were calculated using Brookmeyer and Crowley method.
14. Time-to-Tumor Response (TTR) in Phase 1b [ Time Frame: 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). ]
    TTR is defined, for patients with an OR, as the time from the 'start date' (date of first study treatment) to the first documentation of objective response (CR or PR) which was subsequently confirmed. OR is defined as complete response (CR) or partial response (PR) according to RECIST v1.1 from the 'start date' until the date of the first documentation of progressive disease (PD). 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. 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. PD was defined as unequivocal progression of pre-existing lesions and if overall tumor burden increased sufficiently to merit discontinuation of therapy.
15. Duration of Response (DR) in Phase 1b [ Time Frame: 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). ]
    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. OR is defined as complete response (CR) or partial response (PR) according to RECIST v1.1 from the 'start date' until the date of the first documentation of progressive disease (PD). 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. 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. PD was defined as unequivocal progression of pre-existing lesions and if overall tumor burden increased sufficiently to merit discontinuation of therapy.
16. 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. [ Time Frame: Baseline ]
    PD-L1 expression was defined as the number of PD-L1 positive cells and/or qualitative assessment of PD-L1 staining on tumor and inflammatory cells in regions of interest. DDR gene alterations was defined as the number of somatic and germline mutations present in a panel of genes associated with DDR in baseline tumor derived nucleic acid, in germline nucleic acid and in circulating tumor DNA. TMB was defined as determination/estimation of the frequency of mutations (total and non-synonymous) present in baseline tumor derived nucleic acid samples and in baseline circulating tumor DNA.

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

  Study Documents (Full-Text)

Documents provided by Pfizer:

Study Protocol  [PDF] September 24, 2019

Statistical Analysis Plan  [PDF] November 13, 2019

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.

• Responsible Party: Pfizer
• ClinicalTrials.gov Identifier: NCT03637491
• Other Study ID Numbers: B9991033; 2018-000124-34 ( EudraCT Number )
• First Posted: August 20, 2018
• Results First Posted: January 26, 2022
• Last Update Posted: January 26, 2022
• Last Verified: December 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; Avelumab; Talazoparib; Antineoplastic Agents, Immunological; Antineoplastic Agents; Poly(ADP-ribose) Polymerase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action