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

• ClinicalTrials.gov Identifier: NCT02648724
• Recruitment Status: Completed
• First Posted: January 7, 2016
• Results First Posted: June 22, 2022
• Last Update Posted: June 22, 2022
• Sponsor: Symphogen A/S
• Information provided by (Responsible Party): Symphogen A/S

Tracking Information

• First Submitted Date: January 4, 2016
• First Posted Date: January 7, 2016
• Results First Submitted Date: December 21, 2021
• Results First Posted Date: June 22, 2022
• Last Update Posted Date: June 22, 2022
• Actual Study Start Date: March 2016
• Actual Primary Completion Date: December 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 24, 2022)

• Part 1: Occurrence of DLTs During Cycle 1 of Sym015 Administration [ Time Frame: Cycle 1, the initial 28-day period of Q2W dosing ]
  The primary objective of Part 1 was to assess the safety and tolerability of Sym015 on a Q2W schedule. This was assessed by evaluating the occurrence of dose-limiting toxicities (DLTs) during Cycle 1 of Sym015 administration. Q2W = every second week.
• Part 2: Documented, Confirmed Objective Response (OR) [ Time Frame: 24 months ]
  The primary objective of Part 2 was to evaluate the antitumor activity of Sym015 when administered at the Q2W RP2D to patients in the different cohorts. Documented OR was defined as partial response [PR] or complete response [CR]) as assessed by CT or MRI using the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 at any time during trial participation by Investigator assessment. PR = At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters; CR = Disappearance of all non-target lesions and normalisation of tumour marker level. All lymph nodes must be non-pathological in size (<10 mm short axis). Q2W = every second week. RP2D = recommended phase 2 dose.

Original Primary Outcome Measures (submitted: January 5, 2016)

• Part 1: Assess the safety and tolerability of Sym015 by occurrence of dose-limiting toxicities (DLT) measured during Cycle 1 of Sym015 administration on an every second week or every third week dosing schedule. [ Time Frame: 12 months ]
• Part 2: Confirmed objective antitumor response by RECIST v1.1 [ Time Frame: 24 months ]

Current Secondary Outcome Measures (submitted: May 24, 2022)

• 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. Q2W = every second week. RP2D = recommended phase 2 dose.
• Immunogenicity of Sym015: Part 1. [ Time Frame: Cycle 1: Day (D) 1, Cycle 3, 5, 7: D1 (+-2), End of treatment: At or by D10, Follow-up: 1 month after last dose of study treatment (30+7D) ]
  Serum sampling was done to assess the potential for anti-drug antibody (ADA) formation.
• Immunogenicity of Sym015: Part 2. [ Time Frame: Cycle 1: Day (D) 1, Cycle 2, 3, 5, 7: D1 (+-2), End of treatment: At or by D10, Follow-up: 1 month after last dose of study treatment (30+7D) ]
  Serum sampling was done to assess the potential for anti-drug antibody (ADA) formation.
• Part 1: Area Under the Concentration-time Curve in a Dosing Interval (AUC) Following 1st Dose [ Time Frame: From time zero to 48 hours after dosing. Samples taken pre-dosing and at 1, 2, 4, 8, 24 and 48 hours after end of infusion. ]
  Estimated using non-compartmental methods and actual time points following the first dose of Sym015.
• Part 2: Area Under the Concentration-time Curve in a Dosing Interval (AUC) [ Time Frame: From time zero to 48 hours after dosing. Samples taken pre-dosing and at 1, 2, 4, 8, 24 and 48 hours after end of infusion. ]
  Estimated using non-compartmental methods and actual time points following the first dose of Sym015 for the whole basket cohort.
• Part 1: Cmax [ Time Frame: From time zero to 48 hours after dosing. Samples taken pre-dosing and at 1, 2, 4, 8, 24 and 48 hours after end of infusion. ]
  Maximum serum concentration was derived from observed data.
• Part 2: Cmax [ Time Frame: From time zero to 48 hours after dosing. Samples taken pre-dosing and at 1, 2, 4, 8, 24 and 48 hours after end of infusion. ]
  Maximum serum concentration was derived from observed data following the first dose of Sym015 for the full basket cohort.
• Part 1: Time to Reach Maximum Concentration (Tmax) [ Time Frame: From time zero to 48 hours after dosing. Samples taken pre-dosing and at 1, 2, 4, 8, 24 and 48 hours after end of infusion. ]
  Time to reach maximum concentration (Tmax) was derived from observed data.
• Part 2: Time to Reach Maximum Concentration (Tmax) [ Time Frame: From time zero to 48 hours after dosing. Samples taken pre-dosing and at 1, 2, 4, 8, 24 and 48 hours after end of infusion. ]
  Time to reach maximum concentration (Tmax) was derived from observed data following the first dose of Sym015 for the full basket cohort.
• Part 1: Trough Concentration (Ctrough) [ Time Frame: From time zero to 48 hours after dosing. Samples taken pre-dosing and at 1, 2, 4, 8, 24 and 48 hours after end of infusion. ]
  Ctrough was derived from observed data.
• Part 2: Trough Concentration (Ctrough) [ Time Frame: From time zero to 48 hours after dosing. Samples taken pre-dosing and at 1, 2, 4, 8, 24 and 48 hours after end of infusion. ]
  Ctrough was derived from observed data following the first dose of Sym015 for the whole basket cohort.
• Part 1: Elimination Half-life (T½) [ Time Frame: From time zero to 48 hours after dosing. Samples taken pre-dosing and at 1, 2, 4, 8, 24 and 48 hours after end of infusion. ]
  Estimated using non-compartmental methods and actual time points.
• Part 2: Elimination Half-life (T½) [ Time Frame: From time zero to 48 hours after dosing. Samples taken pre-dosing and at 1, 2, 4, 8, 24 and 48 hours after end of infusion. ]
  Estimated using non-compartmental methods and actual time points following the first dose of Sym015 for the whole basket cohort.
• Part 1: Clearance (CL) [ Time Frame: From time zero to 48 hours after dosing. Samples taken pre-dosing and at 1, 2, 4, 8, 24 and 48 hours after end of infusion. ]
  Estimated using non-compartmental methods and actual time points.
• Part 2: Clearance (CL) [ Time Frame: From time zero to 48 hours after dosing. Samples taken pre-dosing and at 1, 2, 4, 8, 24 and 48 hours after end of infusion. ]
  Estimated using non-compartmental methods and actual time points following the first dose of Sym015 for the whole basket cohort.
• Part 2: Additional Preliminary Evaluation of the Antitumor Activity of Sym015 When Administered at the Q2W RP2D in a Subset of Patients. Assessed by OR. [ 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. Objective Response (OR) is presented. Documented OR was defined as partial response [PR] or complete response [CR]) as assessed by CT or MRI using the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 at any time during trial participation by Investigator assessment. PR = At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters; CR = Disappearance of all non-target lesions and normalisation of tumour marker level. All lymph nodes must be non-pathological in size (<10 mm short axis).
• Part 2: Additional Preliminary Evaluation of the Antitumor Activity of Sym015 When Administered at the Q2W RP2D in a Subset of Patients. Assessed by DCR. [ 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. Disease control rate (DCR) is presented. The DCR was defined as the percentage of patients who had BOR of confirmed CR or confirmed PR or SD (including unconfirmed CR/PR, provided 6 weeks minimum criteria for SD duration was met). BOR = Best Overall Response. CR = Complete Response. PR = Partial Response. SD = Stable Disease.

Original Secondary Outcome Measures (submitted: January 5, 2016)

• Determine dosing regimen for Sym015 by evaluating the patient data for DLT's from Part 1 of the study. [ Time Frame: 12 Months ]
• Evaluate the anti-drug antibody profile of patients treated with Sym015 for immunogencity [ Time Frame: 36 Months ]
• Evaluate the action, and estimate, if feasible, the magnitude of biological activity by evaluating various biomarkers. [ Time Frame: 36 Months ]
• Area under the concentration-time curve in a dosing interval (i.e. from time zero (end of infusion) up to 168 hours or 336 hours depending on regimes). [ Time Frame: 36 Months ]
• Maximum concentration (Cmax) [ Time Frame: 36 months ]
• Time to reach maximum concentration (Tmax) [ Time Frame: 36 Months ]
• Trough concentration (Ctrough) [ Time Frame: 36 Months ]
• Elimination half-life (T½) [ Time Frame: 36 Months ]
• Clearance (CL) [ Time Frame: 36 Months ]
• Last quantifiable concentration (Cz) [ Time Frame: 36 Months ]
• Terminal rate constant [ Time Frame: 36 Months ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• 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
• 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.

• Study Type: Interventional
• Study Phase: Phase 1; Phase 2

Study Design

Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Intervention Model Description:

Arms 1-4 comprises part 1 (dose-escalation), which is an as evaluation of 4 different dose levels (DL), 6, 12, 18, and 24 mg/kg. DL data from part 1 is presented as merged in the other sections. This is due to that there were no dose level toxicities reported during the study.

Arms 5-7 comprises part 2 (dose-expansion).

Masking: None (Open Label)
Primary Purpose: Treatment

Condition

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

Intervention

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

Study Arms

• Experimental: 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.
  Intervention: Drug: Sym015
• Experimental: 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.
  Intervention: Drug: Sym015
• Experimental: 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.
  Intervention: Drug: Sym015
• Experimental: 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.
  Intervention: Drug: Sym015
• Experimental: 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.
  Intervention: Drug: Sym015
• Experimental: 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.
  Intervention: Drug: Sym015
• Experimental: 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.
  Intervention: Drug: Sym015

• Publications *: 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: January 12, 2021): 57
• Original Estimated Enrollment (submitted: January 5, 2016): 70
• Actual Study Completion Date: December 2020
• Actual Primary Completion Date: December 2020 (Final data collection date for primary outcome measure)

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Denmark, Hong Kong, Korea, Republic of, Spain, Taiwan, United States

Administrative Information

• NCT Number: NCT02648724
• Other Study ID Numbers: Sym015-01; 2016-003912-11 ( EudraCT Number )
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Symphogen A/S
• Original Responsible Party: Same as current
• Current Study Sponsor: Symphogen A/S
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Amita Patnaik, MD, FRCP(C); South Texas Accelerated Research Therapeutics, LLC
• Principal Investigator: David Ross Camidge, MD, PhD; University of Colorado, Denver

• PRS Account: Symphogen A/S
• Verification Date: April 2022