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

Phase 1
Completed
Conditions
MET Gene Amplification
NSCLC
MET Gene Mutation
Non Small Cell Lung Cancer
Oncology
Interventions
Drug: Sym015
Registration Number
NCT02648724
Lead Sponsor
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.

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.

Recruitment & Eligibility

Status
COMPLETED
Sex
All
Target Recruitment
57
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.
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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.
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Study & Design

Study Type
INTERVENTIONAL
Study Design
SEQUENTIAL
Arm && Interventions
GroupInterventionDescription
Part 1: 12 mg/kgSym015Sym015 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.
Part 1: 18 mg/kgSym015Sym015 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.
Part 1: 24 mg/kgSym015Sym015 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.
Part 2: Basket CohortSym015Patients 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.
Part 2: NSCLC MET-Amplified CohortSym015Patients 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.
Part 1: 6 mg/kgSym015Sym015 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.
Part 2: NSCLC METex14del CohortSym015Patients 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.
Primary Outcome Measures
NameTimeMethod
Part 1: Occurrence of DLTs During Cycle 1 of Sym015 AdministrationCycle 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)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.

Secondary Outcome Measures
NameTimeMethod
Part 1: Determine a Q2W RP2D of Sym015.12 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.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.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 DoseFrom 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)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: CmaxFrom 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: CmaxFrom 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 2: Additional Preliminary Evaluation of the Antitumor Activity of Sym015 When Administered at the Q2W RP2D in a Subset of Patients. Assessed by DCR.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.

Part 1: Time to Reach Maximum Concentration (Tmax)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)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)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)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)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)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)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)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.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).

Trial Locations

Locations (27)

University Hospitals Cleveland Medical Center

🇺🇸

Cleveland, Ohio, United States

University of Texas Southwestern Medical Center

🇺🇸

Dallas, Texas, United States

Massachusetts General Hospital

🇺🇸

Boston, Massachusetts, United States

Comprehensive Cancer Centers of Nevada

🇺🇸

Las Vegas, Nevada, United States

The University of Texas M.D. Anderson Cancer Center

🇺🇸

Houston, Texas, United States

Rigshospitalet

🇩🇰

Copenhagen, Denmark

Taichung Veterans General Hospital

🇨🇳

Taichung, Taiwan

South Texas Accelerated Research Therapeutics, LLC

🇺🇸

San Antonio, Texas, United States

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

Severance Hospital, Yonsei University Health System

🇰🇷

Seoul, Korea, Republic of

Dana Farber Cancer Institute/D -1251

🇺🇸

Boston, Massachusetts, United States

Queen Mary Hospital

🇭🇰

Hong Kong, Hong Kong

CHA Bundang Medical Center, CHA University

🇰🇷

Seongnam-si, Gyeonggi-do, Korea, Republic of

Gangnam Severance Hospital, Yonsei University Health System

🇰🇷

Seoul, Korea, Republic of

Asan Medical Center

🇰🇷

Seoul, Korea, Republic of

Samsung Medical Center

🇰🇷

Seoul, Korea, Republic of

Hospital Universitario Quiron Dexeus

🇪🇸

Barcelona, Barcelona/Cataluna, Spain

Hospital Clinic de Barcelona

🇪🇸

Barcelona, Barcelona/Cataluna, Spain

China Medical University Hospital

🇨🇳

Taichung, Taiwan

Hospital Universitario Vall d'Hebron

🇪🇸

Barcelona, Barcelona/Cataluna, Spain

Centro Oncologico MD Anderson

🇪🇸

Madrid, Spain

National Cheng Kung University Hospital

🇨🇳

Tainan, Taiwan

Taipei Medical University Hospital

🇨🇳

Taipei, Taiwan

Tri-Service General Hospital

🇨🇳

Taipei, Taiwan

Korea University Guro Hospital

🇰🇷

Seoul, Korea, Republic of

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