Clinical Trials /

Sym015 (Anti-MET) in Patients With Advanced Solid Tumor Malignancies

NCT02648724

Description:

This is the first study to test Sym015 in humans. The primary purpose of this study is to see if Sym015 is safe and effective for patients with advanced solid tumor malignancies without available therapeutic options.

Related Conditions:
  • Malignant Solid Tumor
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Sym015 (Anti-MET) in Patients With Advanced Solid Tumor Malignancies
  • Official Title: An Open-Label, Multicenter Phase 1a/2a Trial Investigating the Safety, Tolerability and Antitumor Activity of Multiple Doses of Sym015, a Monoclonal Antibody Mixture Targeting MET, in Patients With Advanced Solid Tumor Malignancies

Clinical Trial IDs

  • ORG STUDY ID: Sym015-01
  • SECONDARY ID: 2016-003912-11
  • NCT ID: NCT02648724

Conditions

  • Oncology
  • MET Gene Amplification
  • NSCLC
  • MET Gene Mutation
  • Non Small Cell Lung Cancer

Interventions

DrugSynonymsArms
Sym015Anti-METPart 1: Dose-Escalation

Purpose

This is the first study to test Sym015 in humans. The primary purpose of this study is to see if Sym015 is safe and effective for patients with advanced solid tumor malignancies without available therapeutic options.

Detailed Description

      In the first part of the study (Part 1, dose-escalation), Sym015 will be evaluated for safety
      and tolerability. Additionally, the recommended Phase 2 dose (RP2D) will be determined.
      Sym015 will be given at different dose levels on an every second week (Q2W) dosing schedule.
      Each patient will be given one fixed dose level.

      In the second part of the study (Part 2, dose-expansion), dosing will be at the RP2D on a Q2W
      dosing schedule. Three cohorts will be included:

        -  Basket Cohort: Patients with KRAS wild-type (WT) advanced solid tumor malignancies with
           MET-amplification and without therapeutic options. Patients must have no prior therapy
           with MET-targeting agents, except a subset of patients having received prior therapy
           with a MET-targeting tyrosine kinase inhibitor (TKI). As of December 2018, accrual to
           this cohort is suspended.

        -  Non-Small Cell Lung Carcinoma (NSCLC) MET-Amplified Cohort: Patients with advanced NSCLC
           with MET-amplification, and without available therapeutic options. Patients may have
           received prior therapy with MET-targeting and/or epidermal growth factor receptor
           (EGFR)-targeting agents.

        -  NSCLC with MET exon 14 skipping alteration (METex14del) Cohort: Patients with advanced
           NSCLC METex14del, and without therapeutic options. Tumors need not be MET-amplified, and
           patients may have received prior therapy with MET-targeting and/or EGFR-targeting
           agents.
    

Trial Arms

NameTypeDescriptionInterventions
Part 1: Dose-EscalationExperimentalSym015 will be tested in four dose titration cohorts. A substitute or an additional dose level could potentially be evaluated.
  • Sym015
Part 2: Basket CohortExperimentalPatients with KRAS WT advanced solid tumor malignancies with MET-amplification will receive Sym015 at the RP2D. Included in this group will be a subset of patients who have received prior therapy with a MET-targeting TKI.
  • Sym015
Part 2: NSCLC MET-Amplified CohortExperimentalPatients with advanced NSCLC with MET-amplification will receive Sym015 at the RP2D. Patients may have received prior therapy with MET-targeting and/or EGFR-targeting agents.
  • Sym015
Part 2: NSCLC METex14del CohortExperimentalPatients with advanced NSCLC with METex14del will receive Sym015 at the RP2D. Tumors need not be MET-amplified, and patients may have received prior therapy with MET-targeting and/or EGFR-targeting agents. mutation.
  • Sym015

Eligibility Criteria

        Inclusion Criteria:

          -  Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1.

          -  Life expectancy >3 months assessed during Screening.

          -  Documented (histologically- or cytologically-proven) solid tumor malignancy that is
             locally advanced or metastatic, and that is refractory to standard therapy or for
             which no standard therapy is available or accessible.

          -  If female and of childbearing potential: a negative pregnancy test.

          -  Male or female: either not of childbearing potential or agreeing to use a medically
             effective method of contraception as per institutional standards during the trial and
             for 4 months after the last dose of trial drug.

          -  Part 1 ONLY: Tumor documented to be KRAS WT by local assessment.

          -  Part 2 ONLY:

               -  Measurable disease according to RECIST v1.1 that has been confirmed by computed
                  tomography (CT) or magnetic resonance imaging (MRI) within 4 weeks prior to Cycle
                  1/Day 1 (C1/D1).

               -  Basket Cohort ONLY:

                    -  Tumor documented to be KRAS WT by local assessment according to
                       institutional standards. If KRAS WT is not previously documented and if
                       archival tissue is not available for pretrial assessment, patient must be
                       willing to undergo a tumor biopsy to confirm eligibility.

                    -  Confirmed MET-amplification by local assessment.

                    -  No prior therapy with MET-targeting agents (except a subset of patients
                       having received prior therapy with a MET-targeting TKI).

                    -  Willingness to undergo a pre- and post-dosing biopsy (maximum of 2 biopsies)
                       from primary or metastatic tumor site(s) considered safely accessible for
                       biopsy

               -  NSCLC MET-Amplified Cohort ONLY:

                    -  Documented NSCLC meeting disease criteria as defined per protocol.

                    -  Documented MET-amplification.

                    -  May have received prior therapy with MET-targeting and/or EGFR-targeting
                       agents (antibodies or TKIs).

                    -  Willingness to undergo a pre-dosing biopsy (mandatory unless a recent tumor
                       biopsy is available), and potentially a biopsy at the End of Cycle 2 (EOC2)
                       (optional), from a primary or metastatic tumor site considered safely
                       accessible for biopsy.

               -  NSCLC METex14del Cohort ONLY:

                    -  Documented NSCLC meeting disease criteria as defined per protocol.

                    -  Documented METex14del (tumors need not be MET-amplified).

                    -  May have received prior therapy with MET-targeting and/or EGFR-targeting
                       agents (antibodies or TKIs).

                    -  Willingness to undergo a pre-dosing biopsy (mandatory unless a recent tumor
                       biopsy is available), and potentially a biopsy at the EOC2 (optional), from
                       a primary or metastatic tumor site considered safely accessible for biopsy.

        Exclusion Criteria:

          -  Any antineoplastic agent for the primary malignancy (standard or investigational)
             without delayed toxicity within 4 weeks or 5 plasma half-lives, whichever is shortest,
             prior to C1/D1, except nitrosoureas and mitomycin C within 6 weeks prior to C1/D1.

          -  Immunosuppressive or systemic hormonal therapy within 2 weeks prior to C1/D1, with
             exceptions.

          -  Use of hematopoietic growth factors within 2 weeks prior to C1/D1.

          -  Active second malignancy or history of another malignancy within the last 3 years,
             with exceptions.

          -  Central nervous system (CNS) malignancy including primary malignancies of the CNS and
             known, untreated CNS or leptomeningeal metastases, or spinal cord compression;
             patients with any of these not controlled by prior surgery or radiotherapy, or
             symptoms suggesting CNS involvement for which treatment is required.

          -  Inadequate recovery from an acute toxicity associated with any prior antineoplastic
             therapy.

          -  Major surgical procedure within 4 weeks prior to C1/D1 or inadequate recovery from any
             prior surgical procedure.

          -  Active thrombosis, or a history of deep vein thrombosis or pulmonary embolism, within
             1 month prior to C1/D1, unless adequately treated and stable.

          -  Active uncontrolled bleeding or a known bleeding diathesis.

          -  Significant cardiovascular disease or condition.

          -  Abnormal hematologic, renal or hepatic function.

          -  Part 2 ONLY:

               -  Radiotherapy against target lesions within 4 weeks prior to C1/D1, unless there
                  is documented progression of the lesion following the radiotherapy.

               -  Basket Cohort ONLY:

                    -  Prior therapy with MET-inhibiting agents (exceptions will be a subset of
                       patients that will be entered to the Basket Cohort after having received
                       prior therapy with a MET-targeting TKI).

                    -  Prior therapy with antibody to hepatocyte growth factor (HGF).

               -  Basket Cohort and NSCLC MET-Amplified Cohort ONLY:

                    -  Tumor status demonstrating MET-polysomy in the absence of MET-amplification,
                       as specified per protocol. Patients in the NSCLC METex14del Cohort with
                       polysomy are eligible.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Part 1: Assess the safety and tolerability of Sym015 on a Q2W schedule.
Time Frame:12 months
Safety Issue:
Description:Assess the occurrence of dose-limiting toxicities (DLTs) during Cycle 1 of Sym015 administration.

Secondary Outcome Measures

Measure:Part 1: Determine a Q2W RP2D of Sym015.
Time Frame:12 Months
Safety Issue:
Description:Determination based on an evaluation of the patient data for DLTs from Part 1.
Measure:Parts 1 and 2: Evaluate the immunogenicity of Sym015.
Time Frame:36 Months
Safety Issue:
Description:Serum sampling to assess the potential for anti-drug antibody (ADA) formation. For Part 2, this applies to both the Basket Cohort and the NSCLC Cohort.
Measure:Parts 1 and 2: Evaluate potential biomarkers of Sym015 action, and estimate, if feasible, the magnitude of biological activity.
Time Frame:36 Months
Safety Issue:
Description:Potential biomarkers of interest include genes, gene transcripts and proteins of the receptor tyrosine kinases (RTKs) and molecules of the MET signaling pathway. For Part 2, this applies to both the Basket Cohort and the NSCLC Cohort.
Measure:Parts 1 and 2: Area under the concentration-time curve in a dosing interval (AUC)
Time Frame:36 Months
Safety Issue:
Description:Will be estimated using non-compartmental methods and actual time points. For Part 2, this applies to both the Basket Cohort and the NSCLC Cohort.
Measure:Parts 1 and 2: Maximum concentration (Cmax)
Time Frame:36 months
Safety Issue:
Description:Will be derived from observed data. For Part 2, this applies to both the Basket Cohort and the NSCLC Cohort.
Measure:Parts 1 and 2: Time to reach maximum concentration (Tmax)
Time Frame:36 Months
Safety Issue:
Description:Will be derived from observed data. For Part 2, this applies to both the Basket Cohort and the NSCLC Cohort.
Measure:Parts 1 and 2: Trough concentration (Ctrough)
Time Frame:36 Months
Safety Issue:
Description:Will be derived from observed data. For Part 2, this applies to both the Basket Cohort and the NSCLC Cohort.
Measure:Parts 1 and 2: Elimination half-life (T½)
Time Frame:36 Months
Safety Issue:
Description:Will be estimated using non-compartmental methods and actual time points. For Part 2, this applies to both the Basket Cohort and the NSCLC Cohort.
Measure:Parts 1 and 2: Clearance (CL)
Time Frame:36 Months
Safety Issue:
Description:Will be estimated using non-compartmental methods and actual time points. For Part 2, this applies to both the Basket Cohort and the NSCLC Cohort.
Measure:Part 2: Additional preliminary evaluation of the antitumor activity of Sym015 when administered at the Q2W RP2D in a subset of patients.
Time Frame:24 Months
Safety Issue:
Description:This applies to the subset of patients in the Basket Cohort who received prior therapy with a MET-targeting TKI. Documented OR (defined as PR or CR), assessed by RECIST v1.1 at any time during trial participation by Investigator assessment.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Symphogen A/S

Trial Keywords

  • Advanced Solid Tumor Malignancies
  • MET Gene Amplification
  • MET Amplification
  • Wild-type
  • NSCLC
  • METex14del
  • Non-Small Cell Lung Carcinoma

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