Clinical Trials /

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

NCT03637491

Description:

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.

Related Conditions:
  • Malignant Solid Tumor
  • Pancreatic Ductal Adenocarcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: B9991033
  • SECONDARY ID: 2018-000124-34
  • NCT ID: NCT03637491

Conditions

  • Pancreatic Cancer
  • Non-Small Cell Lung Cancer
  • Cancer

Interventions

DrugSynonymsArms
AvelumabMSB0010718CAvelumab and binimetinib
BinimetinibMEK162, ARRY-438162Avelumab and binimetinib
TalazoparibMDV3800, BMN 673Avelumab, binimetinib and talazoparib

Purpose

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.

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.
    

Trial Arms

NameTypeDescriptionInterventions
Avelumab and binimetinibExperimentalOpen label
  • Avelumab
  • Binimetinib
Avelumab, binimetinib and talazoparibExperimentalOpen label
  • Avelumab
  • Binimetinib
  • Talazoparib

Eligibility 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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Dose Limiting Toxicity (DLT)
Time Frame:Cycle 1 (days 1-28 of study treatment)
Safety Issue:
Description:Phase 1: DLT during the primary DLT evaluation period (Cycle 1)

Secondary Outcome Measures

Measure: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.
Safety Issue:
Description:Pharmacokinetic parameters: pre-dose/trough concentrations (Ctrough)
Measure: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.
Safety Issue:
Description:Pharmacokinetic parameters: post dose concentrations (Cmax)
Measure: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.
Safety Issue:
Description:Immunogenicity assessment of avelumab
Measure: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.
Safety Issue:
Description:Immunogenicity assessment of avelumab
Measure:Objective Response
Time Frame:From the start of treatment until disease progression/recurrence up to approximately 24 months.
Safety Issue:
Description:Phase 1b: Confirmed OR based on Investigator assessment per RECIST v1.1.
Measure:Biomarker Tumor Mutational Burden
Time Frame:Baseline
Safety Issue:
Description:Tumor mutational burden in baseline tumor tissue
Measure:Biomarker PD-L1
Time Frame:Baseline
Safety Issue:
Description:PD-L1 expression level in baseline tumor tissue.
Measure:Biomarker DNA Damage Repair
Time Frame:Baseline
Safety Issue:
Description:DDR gene alterations in baseline tumor tissue.
Measure: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
Safety Issue:
Description:Pharmacokinetic parameters: pre-dose/trough concentrations (Ctrough)
Measure: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
Safety Issue:
Description:Pharmacokinetic parameters: pre-dose/trough concentrations (Ctrough)
Measure:Time to Tumor Response (TTR)
Time Frame:Baseline up to approximately 24 months
Safety Issue:
Description: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
Measure:Duration of Response (DR)
Time Frame:Baseline up to approximately 24 months
Safety Issue:
Description: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
Measure:Overall Survival (OS)
Time Frame:Baseline up to approximately 24 months
Safety Issue:
Description: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
Measure:Progression Free Survival
Time Frame:Baseline up to approximately 24 months
Safety Issue:
Description: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

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Pfizer

Trial Keywords

  • Lung Cancer
  • NSCLC
  • KRAS
  • NRAS
  • PDAC
  • Pancreatic Cancer

Last Updated

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