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

NCT ID: NCT02648724

Last Updated: 2022-06-22

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 57 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2016-03-31
• Study Completion Date: 2020-12-31

Brief Summary

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 was evaluated for safety and tolerability. Additionally, the recommended Phase 2 dose (RP2D) was to be determined. Sym015 was given at different dose levels on an every second week (Q2W) dosing schedule. Each patient was given one single weight based dose level.

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

Conditions

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

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: SEQUENTIAL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Part 1: 6 mg/kg

Sym015 was tested in four dose titration cohorts. Patients in this cohort received 6 mg/kg. A substitute or an additional dose level could potentially be evaluated.

Group Type: EXPERIMENTAL

Sym015

Intervention Type: DRUG

Sym015 is a mixture of two monoclonal antibodies which specifically bind to non-overlapping epitopes in the extracellular domain of MET.

Part 1: 12 mg/kg

Sym015 was tested in four dose titration cohorts. Patients in this cohort received 12 mg/kg. A substitute or an additional dose level could potentially be evaluated.

Group Type: EXPERIMENTAL

Sym015

Intervention Type: DRUG

Sym015 is a mixture of two monoclonal antibodies which specifically bind to non-overlapping epitopes in the extracellular domain of MET.

Part 1: 18 mg/kg

Sym015 was tested in four dose titration cohorts. Patients in this cohort received 18 mg/kg. A substitute or an additional dose level could potentially be evaluated.

Group Type: EXPERIMENTAL

Sym015

Intervention Type: DRUG

Sym015 is a mixture of two monoclonal antibodies which specifically bind to non-overlapping epitopes in the extracellular domain of MET.

Part 1: 24 mg/kg

Sym015 was tested in four dose titration cohorts. Patients in this cohort received 24 mg/kg. A substitute or an additional dose level could potentially be evaluated.

Group Type: EXPERIMENTAL

Sym015

Intervention Type: DRUG

Sym015 is a mixture of two monoclonal antibodies which specifically bind to non-overlapping epitopes in the extracellular domain of MET.

Part 2: Basket Cohort

Patients with KRAS WT advanced solid tumor malignancies with MET-amplification were to receive Sym015 at the RP2D. Included in this group was a subset of patients who have received prior therapy with a MET-targeting TKI.

Group Type: EXPERIMENTAL

Sym015

Intervention Type: DRUG

Sym015 is a mixture of two monoclonal antibodies which specifically bind to non-overlapping epitopes in the extracellular domain of MET.

Part 2: NSCLC MET-Amplified Cohort

Patients with advanced NSCLC with MET-amplification were to receive Sym015 at the RP2D. Patients may have received prior therapy with MET-targeting and/or EGFR-targeting agents.

Group Type: EXPERIMENTAL

Sym015

Intervention Type: DRUG

Sym015 is a mixture of two monoclonal antibodies which specifically bind to non-overlapping epitopes in the extracellular domain of MET.

Part 2: NSCLC METex14del Cohort

Patients with advanced NSCLC with METex14del were to 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.

Group Type: EXPERIMENTAL

Sym015

Intervention Type: DRUG

Sym015 is a mixture of two monoclonal antibodies which specifically bind to non-overlapping epitopes in the extracellular domain of MET.

Interventions

Sym015

Sym015 is a mixture of two monoclonal antibodies which specifically bind to non-overlapping epitopes in the extracellular domain of MET.

Intervention Type: DRUG

Other Intervention Names

Anti-MET

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Symphogen A/S

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Amita Patnaik, MD, FRCP(C)

Role: PRINCIPAL_INVESTIGATOR

South Texas Accelerated Research Therapeutics, LLC

David Ross Camidge, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

University of Colorado, Denver

Locations

University of Colorado Cancer Center

Aurora, Colorado, United States

University of Chicago Medical Center

Chicago, Illinois, United States

Indiana University Health Melvin and Bren Simon Cancer Center

Indianapolis, Indiana, United States

Massachusetts General Hospital

Boston, Massachusetts, United States

Dana Farber Cancer Institute/D -1251

Boston, Massachusetts, United States

Comprehensive Cancer Centers of Nevada

Las Vegas, Nevada, United States

University Hospitals Cleveland Medical Center

Cleveland, Ohio, United States

University of Texas Southwestern Medical Center

Dallas, Texas, United States

The University of Texas M.D. Anderson Cancer Center

Houston, Texas, United States

South Texas Accelerated Research Therapeutics, LLC

San Antonio, Texas, United States

Rigshospitalet

Copenhagen, , Denmark

Queen Mary Hospital

Hong Kong, , Hong Kong

CHA Bundang Medical Center, CHA University

Seongnam-si, Gyeonggi-do, South Korea

Severance Hospital, Yonsei University Health System

Seoul, , South Korea

Asan Medical Center

Seoul, , South Korea

Gangnam Severance Hospital, Yonsei University Health System

Seoul, , South Korea

Samsung Medical Center

Seoul, , South Korea

Korea University Guro Hospital

Seoul, , South Korea

Hospital Universitario Quiron Dexeus

Barcelona, Barcelona/Cataluna, Spain

Hospital Universitario Vall d'Hebron

Barcelona, Barcelona/Cataluna, Spain

Hospital Clinic de Barcelona

Barcelona, Barcelona/Cataluna, Spain

Centro Oncologico MD Anderson

Madrid, , Spain

China Medical University Hospital

Taichung, , Taiwan

Taichung Veterans General Hospital

Taichung, , Taiwan

National Cheng Kung University Hospital

Tainan City, , Taiwan

Taipei Medical University Hospital

Taipei, , Taiwan

Tri-Service General Hospital

Taipei, , Taiwan

Countries

United States; Denmark; Hong Kong; South Korea; Spain; Taiwan

References

Grandal MM, Havrylov S, Poulsen TT, Koefoed K, Dahlman A, Galler GR, Conrotto P, Collins S, Eriksen KW, Kaufman D, Woude GFV, Jacobsen HJ, Horak ID, Kragh M, Lantto J, Bouquin T, Park M, Pedersen MW. Simultaneous Targeting of Two Distinct Epitopes on MET Effectively Inhibits MET- and HGF-Driven Tumor Growth by Multiple Mechanisms. Mol Cancer Ther. 2017 Dec;16(12):2780-2791. doi: 10.1158/1535-7163.MCT-17-0374. Epub 2017 Aug 11.

Reference Type: DERIVED

PMID: 28802255 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

2016-003912-11

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

Sym015-01

Identifier Type: -

Identifier Source: org_study_id