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

Non Small Cell Lung Cancer Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02648724
• Other study ID #: Sym015-01
• Secondary ID: 2016-003912-11
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: March 2016
• Est. completion date: December 2020

Study information

• Verified date: April 2022
• Source: Symphogen A/S
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Completed
• Enrollment: 57
• Est. completion date: December 2020
• Est. primary completion date: December 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

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

Intervention

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

Locations

Country	Name	City	State
Denmark	Rigshospitalet	Copenhagen
Hong Kong	Queen Mary Hospital	Hong Kong
Korea, Republic of	CHA Bundang Medical Center, CHA University	Seongnam-si	Gyeonggi-do
Korea, Republic of	Asan Medical Center	Seoul
Korea, Republic of	Gangnam Severance Hospital, Yonsei University Health System	Seoul
Korea, Republic of	Korea University Guro Hospital	Seoul
Korea, Republic of	Samsung Medical Center	Seoul
Korea, Republic of	Severance Hospital, Yonsei University Health System	Seoul
Spain	Hospital Clinic de Barcelona	Barcelona	Barcelona/Cataluna
Spain	Hospital Universitario Quiron Dexeus	Barcelona	Barcelona/Cataluna
Spain	Hospital Universitario Vall d'Hebron	Barcelona	Barcelona/Cataluna
Spain	Centro Oncologico MD Anderson	Madrid
Taiwan	China Medical University Hospital	Taichung
Taiwan	Taichung Veterans General Hospital	Taichung
Taiwan	National Cheng Kung University Hospital	Tainan
Taiwan	Taipei Medical University Hospital	Taipei
Taiwan	Tri-Service General Hospital	Taipei
United States	University of Colorado Cancer Center	Aurora	Colorado
United States	Dana Farber Cancer Institute/D -1251	Boston	Massachusetts
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	University of Chicago Medical Center	Chicago	Illinois
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	Indiana University Health Melvin and Bren Simon Cancer Center	Indianapolis	Indiana
United States	Comprehensive Cancer Centers of Nevada	Las Vegas	Nevada
United States	South Texas Accelerated Research Therapeutics, LLC	San Antonio	Texas

Sponsors (1)

Lead Sponsor	Collaborator
Symphogen A/S

Countries where clinical trial is conducted

United States,  Denmark,  Hong Kong,  Korea, Republic of,  Spain,  Taiwan, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Part 1: Occurrence of DLTs During Cycle 1 of Sym015 Administration	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.	Cycle 1, the initial 28-day period of Q2W dosing
Primary	Part 2: Documented, Confirmed Objective Response (OR)	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.	24 months
Secondary	Part 1: Determine a Q2W RP2D of Sym015.	Determination based on an evaluation of the patient data for DLTs from Part 1. Q2W = every second week. RP2D = recommended phase 2 dose.	12 Months
Secondary	Immunogenicity of Sym015: Part 1.	Serum sampling was done to assess the potential for anti-drug antibody (ADA) formation.	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)
Secondary	Immunogenicity of Sym015: Part 2.	Serum sampling was done to assess the potential for anti-drug antibody (ADA) formation.	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)
Secondary	Part 1: Area Under the Concentration-time Curve in a Dosing Interval (AUC) Following 1st Dose	Estimated using non-compartmental methods and actual time points following the first dose of Sym015.	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.
Secondary	Part 2: Area Under the Concentration-time Curve in a Dosing Interval (AUC)	Estimated using non-compartmental methods and actual time points following the first dose of Sym015 for the whole basket cohort.	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.
Secondary	Part 1: Cmax	Maximum serum concentration was derived from observed data.	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.
Secondary	Part 2: Cmax	Maximum serum concentration was derived from observed data following the first dose of Sym015 for the full basket cohort.	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.
Secondary	Part 1: Time to Reach Maximum Concentration (Tmax)	Time to reach maximum concentration (Tmax) was derived from observed data.	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.
Secondary	Part 2: Time to Reach Maximum Concentration (Tmax)	Time to reach maximum concentration (Tmax) was derived from observed data following the first dose of Sym015 for the full basket cohort.	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.
Secondary	Part 1: Trough Concentration (Ctrough)	Ctrough was derived from observed data.	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.
Secondary	Part 2: Trough Concentration (Ctrough)	Ctrough was derived from observed data following the first dose of Sym015 for the whole basket cohort.	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.
Secondary	Part 1: Elimination Half-life (T½)	Estimated using non-compartmental methods and actual time points.	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.
Secondary	Part 2: Elimination Half-life (T½)	Estimated using non-compartmental methods and actual time points following the first dose of Sym015 for the whole basket cohort.	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.
Secondary	Part 1: Clearance (CL)	Estimated using non-compartmental methods and actual time points.	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.
Secondary	Part 2: Clearance (CL)	Estimated using non-compartmental methods and actual time points following the first dose of Sym015 for the whole basket cohort.	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.
Secondary	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.	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).	24 Months
Secondary	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.	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.	24 Months