Study of Tepotinib Combined With Cetuximab in Participants With Left-Sided RAS/BRAF Wild Type Metastatic Colorectal Cancer (PERSPECTIVE)

A Phase II Single-Arm Study to Investigate Tepotinib Combined With Cetuximab in RAS/BRAF Wild-Type Left-Sided mCRC Patients Having Acquired Resistance to Anti-EGFR Antibody Targeting Therapy Due to MET Amplification (PERSPECTIVE)

The purpose of this study was to assess the preliminary antitumor activity, safety and tolerability of tepotinib in combination with cetuximab in participants with RAS/BRAF wild-type left-sided Metastatic Colorectal Cancer (mCRC) having acquired resistance to anti-epidermal growth factor receptor (EGFR) antibody targeted therapy due to mesenchymal epithelial transition (MET) amplification.

Study Overview

• Status: Terminated
• Conditions: Colorectal Neoplasms
• Intervention / Treatment: Drug: Tepotinib; Biological: Cetuximab

• Study Type: Interventional
• Enrollment (Actual): 3
• Phase: Phase 2

Contacts and Locations

Study Locations

• Belgium
  • Antwerp, Belgium
    • Antwerp University Hospital
  • Leuven, Belgium
    • UZ Leuven
• Czechia
  • Brno, Czechia
    • Universtity Hospital Brno
  • Olomouc, Czechia
    • University Hospital Olomouc
  • Prague, Czechia
    • Dept. of Oncology Faculty Hospital Motol
  • Prague, Czechia
    • Hospital Na Bulovce
• France
  • Besancon Cedex, France
    • CHU Besancon Hopital Jean Minjoz
  • Besançon, France
    • University Hospital of Besancon
  • Clermont Ferrand Cedex 1, France
    • CHU Estaing
  • Clermont-Ferrand, France
    • CHU Estaing
  • Créteil, France
    • CHU Hôpital Henri Mondor
  • Le Mans, France
    • Clinique Victor Hugo
  • Le Mans Cedex 02, France
    • Clinique Victor Hugo
  • Poitiers, France
    • CHU de Poitiers
  • Saint Cloud, France
    • Curie Institute
  • Saint-Cloud, France
    • Institut Curie - René-Huguenin Hospital
• Italy
  • Meldona, Italy
    • Istituto Scientifico Romagnolo per lo Studio e la Cura die Tumori
  • Milan, Italy
    • Istituto Europeo di Oncologia
  • Milan, Italy
    • Grande Ospedale Metropolitano Niguarda
  • Milan, Italy
    • Fondazione IRCCS - Istituto Tumori Milano
  • Napoli, Italy
    • Istituto Nazionale Tumori, Fondazione G. Pascale Napoli
  • Napoli, Italy
    • UOC Oncoematologia AOU Vanvitelli
  • Padova, Italy
    • Istituto Oncologico Veneto IRCCS
  • Pisa, Italy
    • Azienda Ospedaliero Universitaria Pisana-Ospedale Santa Chiara
  • Rome, Italy
    • Fondazione Policlinico Universitario Agostino Gemelli
  • San Giovanni Rotondo FG, Italy
    • Foundation IRCCS Casa Sollievo della Sofferenza
• Russian Federation
  • Arkhangelsk, Russian Federation
    • Arkangelsk Clinical Oncological Dyspensary
  • Chelyabinsk, Russian Federation
    • Chelyabinsk Regional Clinical Center Of Oncology And Nuclear Medicine
  • Kislino, Russian Federation
    • Kursk Regional Clinical Oncology Dispensary
  • Moscow, Russian Federation
    • FSBI "National Medical Research Center of Oncology n.a. N.N. Blokhina" of the MoH of the RF
  • Moscow, Russian Federation
    • Limited Liability Company Medicine 24/7
  • Moscow, Russian Federation
    • Russian Cancer research center n.a. N.N. Blokhin
  • Omsk, Russian Federation
    • Omsk Regional Oncology Dispensary
  • Pyatigorsk, Russian Federation
    • LLC Clinica UZI 4D
  • St. Petersburg, Russian Federation
    • Pavlov First Saint Petersburg State Medical University
  • Tomsk, Russian Federation
    • Tomsk National Research Medical Center
  • Tyumen, Russian Federation
    • MKMC Medical City
  • Ufa, Russian Federation
    • SAHI Republican Clinical Oncology Dispensary
• Spain
  • Barcelona, Spain
    • Hospital Clinic de Barcelona
  • Barcelona, Spain
    • Hospital del Mar
  • Barcelona, Spain
    • VHIO Valle de Hebron Instituto de Oncologia
  • Madrid, Spain
    • Hospital Universitario 12 de Octubre
  • Madrid, Spain
    • Hospital Universitario La Paz
  • Madrid, Spain
    • H.U. Ramón y Cajal
  • Madrid, Spain
    • HM-CIOCC
  • Madrid, Spain
    • Hospital de Madrid Norte Sanchinarro
  • Santander, Spain
    • H.U.Marqués de Valdecilla
  • Sevilla, Spain
    • HUVirgen del Rocio
  • Valencia, Spain
    • Consorcio Hospital General Universitario de Valencia
• United Kingdom
  • Bristol, United Kingdom
    • Bristol Oncology Centre
  • Glasgow, United Kingdom
    • Beatson WJSCC
  • London, United Kingdom
    • The Royal Marsden Hospital
  • London, United Kingdom
    • Guy's & St Thomas' NHS Foundation Trust
  • Sutton, United Kingdom
    • The Royal Marsden Hospital
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85054
      • Mayo Clinic
  • California
    • La Jolla, California, United States, 92093
      • Moores Cancer Center
    • Santa Monica, California, United States, 90404
      • University of California, Los Angeles (UCLA)
  • District of Columbia
    • Washington, District of Columbia, United States, 20007
      • Georgetown Lombardi Comprehensive Cancer Center
  • Florida
    • Jacksonville, Florida, United States, 322224-1865
      • Mayo Clinic Hospital
  • Kansas
    • Wichita, Kansas, United States, 67214-3728
      • Cancer Center of Kansas
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
  • New York
    • Lake Success, New York, United States, 11042
      • North Shore-LIJ Monter Cancer Center
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15212
      • Allegheny-Singer Research Institute
  • Texas
    • Houston, Texas, United States, 77030
      • The University of Texas MD Anderson Cancer Center
    • Temple, Texas, United States, 76508-0001
      • Scott & White Vasicek Cancer Treatment Center
  • Washington
    • Seattle, Washington, United States, 98109-1023
      • Seattle Cancer Care Alliance
  • Wisconsin
    • Wauwatosa, Wisconsin, United States, 53226
      • Aurora Cancer Care - Milwaukee West

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Advanced (locally advanced or metastatic) left sided (from splenic flexure to rectum - National Comprehensive Cancer Network [NCCN] version 4.2020) colorectal cancer (CRC) with RAS/BRAF wild-type at study entry confirmed prior to enrollment, with previous anti-epidermal growth factor receptor (anti-EGFR) therapy and acquired resistance on the most recent anti-EGFR monoclonal antibody therapy (panitumumab or cetuximab) by radiological documentation of disease progression according to RECIST Version 1.1
• Mesenchymal epithelial transition (MET) amplification detected by a positive liquid biopsy and/or tissue with appropriate regulatory status (collected after disease progression of the previous anti-EGFR therapy)
• Measurable disease by Investigator in accordance with RECIST Version 1.1
• Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1
• Life expectancy greater than 3 months
• Participants having at least one systemic treatment for mCRC including 1 anti-EGFR monoclonal antibody therapy as the most recent line of therapy for mCRC before study treatment and must have shown a radiologically confirmed by RECIST Version 1.1 complete response (CR) or partial response (PR), both for at least 4 months or stable disease (SD) for at least 6 months to that therapy prior to disease progression
• Less than 2 months between the last administration of the most recent EGFR containing regimen and first dosing in this study
• Adequate hematological function, hepatic and renal functions as defined in the protocol
• Signed and dated informed consent indicating that the participants had been informed of all the pertinent aspects of the trial prior to enrollment
• Contraceptive use by males or females will be consistent with local regulations on contraception methods for those participating in clinical studies
• Other protocol defined inclusion criteria could apply

Exclusion Criteria:

• Participants with symptomatic central nervous system (CNS) metastases who are neurologically unstable or have required increasing doses of steroids within the 2 weeks prior to study entry to manage CNS metastases. Also excluded are participants with carcinomatous meningitis
• Participants who have brain metastasis as the only measurable lesion
• Prior chemotherapy, biological therapy, radiation therapy, hormonal therapy for anti-cancer purposes, targeted therapy, or other investigational anticancer therapy (not including palliative radiotherapy at focal sites) within 21 days prior to the first dose of study intervention, except for the anti-EGFR containing regimen including associated chemotherapy if applicable, which may be continued until enrollment of the participant in the study
• Any unresolved toxicity Grade 2 or more according to the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0, from previous anticancer therapy excluding neuropathy, alopecia and rash
• Severe hypersensitivity reactions to monoclonal antibodies (Grade greater than or equal to [>=] 3 NCI-CTCAE v 5.0), any history of anaphylaxis, or uncontrolled asthma (i.e., 3 or more occurrences of partially controlled asthma)
• Discontinuation of the most recent cetuximab or panitumumab containing therapy due to an adverse event
• Prior treatment with other agents targeting the hepatocyte growth factor (HGF)/Mesenchymal epithelial transition (MET) pathway
• Impaired cardiac function: Left ventricular ejection fraction less than [<] 45 percent [%] defined by echocardiography (a screening assessment not required for participants without a history of congestive heart failure unless clinically indicated); Serious arrhythmia; Unstable angina pectoris; New York Heart Association heart failure Class III and IV; Myocardial infarction within the last 12 months prior to study entry and Symptomatic pericardial effusion; Corrected QT interval by Fridericia (QTcF) greater than (>) 480 milliseconds (ms)
• Hypertension uncontrolled by standard therapies (not stabilized to less than [< ]150/90 millimeter of mercury [mmHg])
• History of neoplasm other than mCRC
• History of difficulty swallowing, malabsorption, or other chronic gastrointestinal disease, or conditions that may hamper compliance and/or absorption of the test products
• Known infection with human immunodeficiency virus, or an active infection with hepatitis B or hepatitis C virus
• Major surgery within 28 days prior to Day 1 of study intervention
• History of Interstitial lung disease (ILD) or interstitial pneumonitis including radiation pneumonitis that required steroid treatment
• Other protocol defined exclusion criteria could apply

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Tepotinib + Cetuximab

Drug: Tepotinib; Participants received Tepotinib film-coated tablets at a dose of 500 milligrams (mg) orally, once daily (QD) until disease progression (according to Response Evaluation Criteria in Solid Tumors Version 1.1 [RECIST v1.1]), death, Adverse event (AE) leading to discontinuation, study withdrawal, or withdrawal of consent, whichever occurs first.; Other Names: MSC2156119J; Biological: Cetuximab; Participants received weekly intravenous infusions of Cetuximab at a dose of 250 milligrams per square meter (mg/m^2) until disease progression (according to Response Evaluation Criteria in Solid Tumors Version 1.1 [RECIST v1.1]), death, Adverse event (AE) leading to discontinuation, study withdrawal, or withdrawal of consent, whichever occurs first.; Other Names: Erbitux®; MSB0010442D

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants Who Experienced Dose Limiting Toxicities (DLTs) According to National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI-CTCAE) Version 5.0	DLTs are defined as any of the following toxicities and judged by Investigator and/ Sponsor to be not attributable to the disease/disease-related processes under investigation: Grade 4 neutropenia for more than 7 days; Grade greater than or equal to [>=] 3 febrile neutropenia with absolute neutrophil count < 1000 per cube millimeter (per mm^3) and a single temperature of > 38.3 degree Celsius/a sustained temperature of >= 38 degree Celsius for more than 1 hour; Grade 4/Grade 3 thrombocytopenia with non-traumatic bleeding; Grade 3 uncontrolled nausea/vomiting and/diarrhea that has not improved within 72 hours despite adequate and optimal treatment; Grade 4 vomiting and/diarrhea; Grade >= 3 skin toxicity that has not resolved to Grade 2 after 14 days of adequate treatment; Any other Grade >= 3 non-hematological AE will be defined as DLT. Exceptions are alopecia/an isolated lipase and/amylase elevation of Grade >= 3 without clinical/radiological evidence of pancreatitis.	Day 1 to Day 21 of Cycle 1 (each cycle is of 21 days)
Number of Participants With Objective Response (OR) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) Assessed by Investigators	OR is defined as a best overall response (BOR) of complete response (CR) or partial response (PR). CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30% reduction from baseline in the sum of the longest diameter (SLD) of all target lesions.	Time from first study treatment assessed up to 218 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Duration of Response (DoR) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) Assessed by Investigator	For participants with objective response, DoR is the time from when the complete response (CR) or partial response (PR) (whichever is first) criteria are first met until progression disease (PD) or death due to any cause within the period of 2 scheduled tumor assessments (84 or 168 days) after the last tumor assessment, whichever occurs first. PD is defined as at least a 20 percent (%) increase in the sum of the longest diameter (SLD), taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions.	Time from the first dose of study drug until occurrence of PD, death due to any cause or last tumor assessment (assessed up to 218 days)
Progression-Free Survival (PFS) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) Assessed by Investigators	PFS is defined as the time (in months) from first administration of study intervention to the date of the first documentation of progression disease (PD) or death due to any cause within the period of 2 scheduled tumor assessments (84 or 168 days) after the last tumor assessment, whichever occurs first. PD is defined as at least a 20 percent (%) increase in the sum of the longest diameter (SLD), taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. PFS was to be estimated using Kaplan-Meier (KM) plots.	Time from the first dose of study drug until occurrence of PD, death due to any cause or last tumor assessment (assessed up to 218 days)
Overall Survival (OS) Assessed by Investigators	OS is defined as the time (in months) from first administration of study intervention to the date of death. OS was to be estimated using Kaplan-Meier (KM) plots.	Time from first study treatment until death, assessed up to 218 days
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Related TEAEs	An adverse event (AE) is defined as any untoward medical occurrence in a participant or clinical study participant, temporally associated with the use of study intervention, whether considered related to the study intervention or not. A serious AE was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. TEAEs were defined as events that started or worsened after first dose of study intervention until 30 days after last dose. TEAEs included both serious and non-serious TEAEs. Treatment-related TEAEs is defined as reasonably related to the study intervention.	Time from first study treatment up to 30 days after the last dose, assessed up to 226 days
Number of Participants With Clinically Significant Changes From Baseline in Vital Signs	Vital sign assessment included assessments of height, weight, temperature, pulse rate, respiratory rate, and blood pressure. Clinical significance was determined by the investigator. Number of participants who had any clinically significant changes from baseline in vital signs were reported.	Time from first study treatment up to 30 days after the last dose, assessed up to 226 days
Number of Participants With Clinically Significant Changes From Baseline in Laboratory Parameters	Laboratory investigation included hematology, biochemistry, coagulation, routine urinalysis and other screening tests (Follicle-stimulating hormone (FSH) and estradiol, Serum or highly sensitive urine human chorionic gonadotropin (hCG) pregnancy test, Serology (HIV antibody, hepatitis B surface antigen [HBsAg], and hepatitis C virus antibody) and all of the safety labs were performed locally. Clinical significance was determined by the investigator. The number of participants with clinically significant changes from baseline in laboratory parameters were reported.	Time from first study treatment up to 30 days after the last dose, assessed up to 226 days
Number of Participants With Clinically Significant Changes From Baseline in 12-Lead Electrocardiogram (ECG) Findings	12-lead ECG recordings included heart rate and measures PR, QRS, QT and QTcF intervals. 12-lead ECG recordings were obtained after the participants have rested for at least 5 minutes in semi-supine or supine position. Clinical significance was determined by the investigator. The number of participants with clinically significant changes from baseline in 12-lead ECG findings were reported.	Time from first study treatment up to 30 days after the last dose, assessed up to 226 days
Number of Participants With At Least 1 Postive Anti-Drug Antibodies (ADAs) for Cetuximab	Serum samples were analyzed by a validated electrochemiluminescence immunoassay method to detect the presence of antidrug antibodies (ADA). Number of participants with positive ADA were reported.	At Day 1 of cycle 1 (each cycle is of 21 days) and at End of Treatment (14 days after last dose, assessed up to 210 days)

Collaborators and Investigators

• Sponsor: EMD Serono Research & Development Institute, Inc.
• Collaborators: Merck KGaA, Darmstadt, Germany

Publications and helpful links

Helpful Links

• US Medical Information website, Medical Resources
• Targeting MET Clinical Trial Program
• Trial Awareness and Transparency website

Study record dates

Study Major Dates

• Study Start (Actual): January 28, 2021
• Primary Completion (Actual): March 14, 2022
• Study Completion (Actual): March 31, 2022

Study Registration Dates

• First Submitted: August 11, 2020
• First Submitted That Met QC Criteria: August 13, 2020
• First Posted (Actual): August 17, 2020

Study Record Updates

• Last Update Posted (Estimate): December 22, 2022
• Last Update Submitted That Met QC Criteria: November 30, 2022
• Last Verified: November 1, 2022

More Information

Terms related to this study

• Keywords: Colorectal cancer; Cetuximab; Panitumumab; Erbitux; Tepotinib; RAS wild-type; Epidermal growth factor receptor resistance; Hepatocyte growth factor; Mesenchymal epithelial transition
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Antineoplastic Agents; Antineoplastic Agents, Immunological; Cetuximab; Tepotinib
• Other Study ID Numbers: MS202202_0002; 2020-001776-15 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: We are committed to enhancing public health through responsible sharing of clinical trial data. Following approval of a new product or a new indication for an approved product in both the US and European Union, the study sponsor and/or its affiliated companies will share study protocols, anonymized patient data and study level data, and redacted clinical study reports with qualified scientific and medical researchers, upon request, as necessary for conducting legitimate research. Further information on how to request data can be found on our website bit.ly/IPD21
• IPD Sharing Time Frame: Within six months after the approval of a new product or a new indication for an approved product in both the United States and the European Union
• IPD Sharing Access Criteria: Qualified scientific and medical researchers can request the data. Such requests must be submitted in writing to the company's portal and will be internally reviewed regarding criteria for researchers' qualification and legitimacy of the research proposal.
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP); Clinical Study Report (CSR); Analytic Code

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No