Clinical trial NCT02648724: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Oncology
MET Gene Amplification
NSCLC
MET Gene Mutation
Non Small Cell Lung Cancer
Keywords: Advanced Solid Tumor Malignancies
MET Gene Amplification
MET Amplification
Wild-type
NSCLC
METex14del
Non-Small Cell Lung Carcinoma
Lead sponsor: Symphogen A/S
Sponsor class: INDUSTRY
First posted: 2016-01-07
Enrollment: 57
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
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).
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Part 1: Occurrence of DLTs During Cycle 1 of Sym015 Administration
timeFrame: Cycle 1, the initial 28-day period of Q2W dosing
measure: Part 2: Documented, Confirmed Objective Response (OR)
timeFrame: 24 months
Secondary outcomes:
measure: Part 1: Determine a Q2W RP2D of Sym015.
timeFrame: 12 Months
measure: Immunogenicity of Sym015: Part 1.
timeFrame: 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)
measure: Immunogenicity of Sym015: Part 2.
timeFrame: 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)
measure: Part 1: Area Under the Concentration-time Curve in a Dosing Interval (AUC) Following 1st Dose
timeFrame: 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.
measure: Part 2: Area Under the Concentration-time Curve in a Dosing Interval (AUC)
timeFrame: 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.
measure: Part 1: Cmax
timeFrame: 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.
measure: Part 2: Cmax
timeFrame: 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.
measure: Part 1: Time to Reach Maximum Concentration (Tmax)
timeFrame: 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.
measure: Part 2: Time to Reach Maximum Concentration (Tmax)
timeFrame: 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.
measure: Part 1: Trough Concentration (Ctrough)
timeFrame: 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.
measure: Part 2: Trough Concentration (Ctrough)
timeFrame: 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.
measure: Part 1: Elimination Half-life (T½)
timeFrame: 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.
measure: Part 2: Elimination Half-life (T½)
timeFrame: 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.
measure: Part 1: Clearance (CL)
timeFrame: 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.
measure: Part 2: Clearance (CL)
timeFrame: 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.
measure: 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.
timeFrame: 24 Months
measure: 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.
timeFrame: 24 Months
Other outcomes:
Locations:
city: Aurora
country: United States
facility: University of Colorado Cancer Center
state: Colorado
city: Chicago
country: United States
facility: University of Chicago Medical Center
state: Illinois
city: Indianapolis
country: United States
facility: Indiana University Health Melvin and Bren Simon Cancer Center
state: Indiana
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Dana Farber Cancer Institute/D -1251
state: Massachusetts
city: Las Vegas
country: United States
facility: Comprehensive Cancer Centers of Nevada
state: Nevada
city: Cleveland
country: United States
facility: University Hospitals Cleveland Medical Center
state: Ohio
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center
state: Texas
city: Houston
country: United States
facility: The University of Texas M.D. Anderson Cancer Center
state: Texas
city: San Antonio
country: United States
facility: South Texas Accelerated Research Therapeutics, LLC
state: Texas
city: Copenhagen
country: Denmark
facility: Rigshospitalet
city: Hong Kong
country: Hong Kong
facility: Queen Mary Hospital
city: Seongnam-si
country: Korea, Republic of
facility: CHA Bundang Medical Center, CHA University
state: Gyeonggi-do
city: Seoul
country: Korea, Republic of
facility: Severance Hospital, Yonsei University Health System
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center
city: Seoul
country: Korea, Republic of
facility: Gangnam Severance Hospital, Yonsei University Health System
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
city: Seoul
country: Korea, Republic of
facility: Korea University Guro Hospital
city: Barcelona
country: Spain
facility: Hospital Universitario Quiron Dexeus
state: Barcelona/Cataluna
city: Barcelona
country: Spain
facility: Hospital Universitario Vall d'Hebron
state: Barcelona/Cataluna
city: Barcelona
country: Spain
facility: Hospital Clinic de Barcelona
state: Barcelona/Cataluna
city: Madrid
country: Spain
facility: Centro Oncologico MD Anderson
city: Taichung
country: Taiwan
facility: China Medical University Hospital
city: Taichung
country: Taiwan
facility: Taichung Veterans General Hospital
city: Tainan
country: Taiwan
facility: National Cheng Kung University Hospital
city: Taipei
country: Taiwan
facility: Taipei Medical University Hospital
city: Taipei
country: Taiwan
facility: Tri-Service General Hospital
Study officials:
affiliation: South Texas Accelerated Research Therapeutics, LLC
name: Amita Patnaik, MD, FRCP(C)
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Colorado, Denver
name: David Ross Camidge, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.