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

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ClinicalTrials.gov Identifier: NCT02648724
Recruitment Status : Completed
First Posted : January 7, 2016
Last Update Posted : January 13, 2021
Sponsor:
Information provided by (Responsible Party):
Symphogen A/S

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.

Condition or disease Intervention/treatment Phase
Oncology MET Gene Amplification NSCLC MET Gene Mutation Non Small Cell Lung Cancer Drug: Sym015 Phase 1 Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 57 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : March 2016
Actual Primary Completion Date : December 2020
Actual Study Completion Date : December 2020

Arm Intervention/treatment
Experimental: Part 1: Dose-Escalation
Sym015 will be tested in four dose titration cohorts. A substitute or an additional dose level could potentially be evaluated.
Drug: Sym015
Sym015 is a mixture of two monoclonal antibodies which specifically bind to non-overlapping epitopes in the extracellular domain of MET.
Other Name: Anti-MET

Experimental: Part 2: Basket Cohort
Patients 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.
Drug: Sym015
Sym015 is a mixture of two monoclonal antibodies which specifically bind to non-overlapping epitopes in the extracellular domain of MET.
Other Name: Anti-MET

Experimental: Part 2: NSCLC MET-Amplified Cohort
Patients 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.
Drug: Sym015
Sym015 is a mixture of two monoclonal antibodies which specifically bind to non-overlapping epitopes in the extracellular domain of MET.
Other Name: Anti-MET

Experimental: Part 2: NSCLC METex14del Cohort
Patients 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.
Drug: Sym015
Sym015 is a mixture of two monoclonal antibodies which specifically bind to non-overlapping epitopes in the extracellular domain of MET.
Other Name: Anti-MET




Primary Outcome Measures :
  1. Part 1: Assess the safety and tolerability of Sym015 on a Q2W schedule. [ Time Frame: 12 months ]
    Assess the occurrence of dose-limiting toxicities (DLTs) during Cycle 1 of Sym015 administration.

  2. Part 2: Evaluate the antitumor activity of Sym015 when administered at the Q2W RP2D. [ Time Frame: 24 months ]
    Documented objective response (OR) (defined as partial response [PR] or complete response [CR]) in the Basket Cohort, assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 at any time during trial participation by Investigator assessment.


Secondary Outcome Measures :
  1. Part 1: Determine a Q2W RP2D of Sym015. [ Time Frame: 12 Months ]
    Determination based on an evaluation of the patient data for DLTs from Part 1.

  2. Parts 1 and 2: Evaluate the immunogenicity of Sym015. [ Time Frame: 36 Months ]
    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.

  3. Parts 1 and 2: Evaluate potential biomarkers of Sym015 action, and estimate, if feasible, the magnitude of biological activity. [ Time Frame: 36 Months ]
    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.

  4. Parts 1 and 2: Area under the concentration-time curve in a dosing interval (AUC) [ Time Frame: 36 Months ]
    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.

  5. Parts 1 and 2: Maximum concentration (Cmax) [ Time Frame: 36 months ]
    Will be derived from observed data. For Part 2, this applies to both the Basket Cohort and the NSCLC Cohort.

  6. Parts 1 and 2: Time to reach maximum concentration (Tmax) [ Time Frame: 36 Months ]
    Will be derived from observed data. For Part 2, this applies to both the Basket Cohort and the NSCLC Cohort.

  7. Parts 1 and 2: Trough concentration (Ctrough) [ Time Frame: 36 Months ]
    Will be derived from observed data. For Part 2, this applies to both the Basket Cohort and the NSCLC Cohort.

  8. Parts 1 and 2: Elimination half-life (T½) [ Time Frame: 36 Months ]
    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.

  9. Parts 1 and 2: Clearance (CL) [ Time Frame: 36 Months ]
    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.

  10. 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 ]
    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.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02648724


Locations
Show Show 27 study locations
Sponsors and Collaborators
Symphogen A/S
Investigators
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Principal Investigator: Amita Patnaik, MD, FRCP(C) South Texas Accelerated Research Therapeutics, LLC
Principal Investigator: David Ross Camidge, MD, PhD University of Colorado, Denver
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Symphogen A/S
ClinicalTrials.gov Identifier: NCT02648724    
Other Study ID Numbers: Sym015-01
2016-003912-11 ( EudraCT Number )
First Posted: January 7, 2016    Key Record Dates
Last Update Posted: January 13, 2021
Last Verified: January 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Symphogen A/S:
Advanced Solid Tumor Malignancies
MET Gene Amplification
MET Amplification
Wild-type
NSCLC
METex14del
Non-Small Cell Lung Carcinoma
Additional relevant MeSH terms:
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Neoplasms