Sym004 vs Standard of Care in Subjects With Metastatic Colorectal Cancer

Metastatic Colorectal Cancer Clinical Trial

Official title:

Open-label, Randomized, Controlled, Multicenter Phase II Trial Investigating 2 Sym004 Doses Versus Investigator`s Choice (Best Supportive Care, Capecitabine, 5-FU) in Subjects With Metastatic Colorectal Cancer and Acquired Resistance to Anti-EGFR Monoclonal Antibodies

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02083653
• Other study ID #: Sym004-05
• Secondary ID: 2013-003829-29EM
• Status: Completed
• Phase: Phase 2
• Start date: March 6, 2014
• Est. completion date: April 26, 2017

Study information

• Verified date: April 2019
• Source: Symphogen A/S
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is a Phase 2, open-label, randomized, 3-arm trial investigating the efficacy of two Sym004 doses (Arm A and Arm B) compared with a control group (Arm C) in subjects with metastatic colorectal cancer (mCRC) and acquired resistance to anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (mAbs).

Description:

This trial assesses the efficacy of two different weekly dosing regimens of Sym004 (Arm A: 12 mg/kg/week versus Arm B: 9 mg/kg loading dose followed by 6 mg/kg/week) compared with investigator's choice in terms of overall survival time in subjects with mCRC. Subjects assigned to Arm C will receive best supportive care (BSC), Fluorouracil (5-FU), or Capecitabine, per local standard of care.

Subjects will receive treatment until unacceptable toxicity, disease progression, withdrawal of consent, or until the subject meets any of the criteria for treatment discontinuation or trial discontinuation. Therefore, the duration of treatment will differ among individuals and cannot be fixed in advance.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 254
• Est. completion date: April 26, 2017
• Est. primary completion date: October 24, 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Written informed consent obtained before undergoing any study-related activities

• Male or female, at least 18 years of age

• Subjects with histologically or cytologically confirmed mCRC, Kirsten rat sarcoma wild-type (KRAS WT) at initial diagnosis

• Failure of or intolerance to 5-FU, Oxaliplatin, and Irinotecan

• Acquired resistance to marketed anti-EGFR mAbs as defined in the protocol

• Measurable disease defined as one or more target lesions according to RECIST

• Life expectancy of at least 3 months

• Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 1

• Other protocol defined inclusion criteria could apply

Exclusion Criteria:

• Pretreatment with regorafenib.

• Subjects who in the opinion of the subject and investigator would benefit more from regorafenib treatment (except where regorafenib is not reimbursed in the country)

• Skin rash Common Terminology Criteria for AEs (CTCAE) Grade greater than 1 from previous anti-EGFR therapy at time of randomization

• Magnesium less than 0.9 milligram per deciliter (mg/dL)

• Known hypersensitivity to any of the treatment ingredients. Known previous Grade 3-4 infusion related reactions with anti-EGFR mABs

• Other protocol defined exclusion criteria could apply

Related Conditions & MeSH terms

• Colorectal Neoplasms
• Metastatic Colorectal Cancer

Intervention

Drug:
• Sym004 (12 mg/kg)
Sym004 is a 1:1 mixture of two mAbs (futuximab and modotuximab) which bind to two non-overlapping epitopes of the EGFR.
• Sym004 (9/6 mg/kg)
Sym004 is a 1:1 mixture of two mAbs (futuximab and modotuximab) which bind to two non-overlapping epitopes of the EGFR.

Other:
• Best Supportive Care (BSC)
BSC is the best palliative care as per Investigator's discretion, excluding antineoplastic agents. BSC may include, but is not limited to, antibiotics, analgesics, antiemetics, blood transfusions, and nutritional support.

Drug:
• Fluorouracil (5-FU)
5-FU will be administered at doses and schedules as per Investigator's discretion and in line with the local package insert.
• Capecitabine
Capecitabine will be administered at doses and schedules as per Investigator's discretion and in line with the local package insert.

Locations

Country	Name	City	State
Austria	SMZ Süd - Kaiser Franz Josef Spital Wien	Wien
Belgium	Cliniques Universitaires Saint-Luc	Bruxelles
Belgium	ULB Hôpital Erasme	Bruxelles
Belgium	Universitair Ziekenhuis Gent	Gent
Belgium	UZ Leuven	Leuven
Belgium	CHU Ambroise Paré	Mons
Belgium	Clinique et Maternité Sainte-Elisabeth	Namur
Belgium	CHU Mont-Godinne	Yvoir
France	ICO - Site Paul Papin	Angers Cedex 9
France	Institut Sainte Catherine	Avignon
France	Groupe Hospitalier Saint André - Hôpital Saint André	Bordeaux Cedex
France	Centre Georges François Leclerc	Dijon Cedex
France	Centre Léon Bérard	Lyon
France	CRLCC Eugene Marquis	Rennes Cedex
France	ICO - Site René Gauducheau	Saint Herblain
France	CHU de Toulouse - Hôpital Rangueil	Toulouse Cedex 9
Germany	Universitaetsklinikum Carl Gustav Carus TU Dresden	Dresden
Germany	Klinikum der Johann Wolfgang Goethe-Universitaet	Frankfurt
Hungary	Uzsoki Utcai Korhaz	Budapest
Hungary	Borsod-Abauj-Zemplen Megyei Korhaz es Egyetemi Oktato Korhaz	Miskolc
Hungary	SzSzB Megyei Korhazak es Egyetemi Oktatokorhaz	Nyiregyhaza
Hungary	Jasz-Nagykun-Szolnok Megyei Korhaz-Rendelointezet	Szolnok
Italy	Azienda Ospedaliero Universitaria Ospedali Riuniti	Ancona
Italy	Azienda Ospedaliero Universitaria San Martino	Genova
Italy	Azienda Ospedaliera Ospedale Niguarda Ca' Granda	Milano
Italy	Seconda Università degli Studi di Napoli	Napoli
Italy	IOV - Istituto Oncologico Veneto IRCCS	Padova
Italy	Azienda Ospedaliero Universitaria Pisana	Pisa
Italy	Policlinico Universitario Agostino Gemelli	Roma
Italy	Presidio Ospedaliero SS. Trinità Sora	Sora
Italy	Azienda Ospedaliera S. Maria Di Terni	Terni
Poland	SPZOZ MSW zWarminsko-MazurskimCen.Onko.wOlsztynie	Olsztyn
Poland	Wielkopolskie Centrum Onkologii	Poznan
Poland	Wojewodzki Szpital Zespolony im. L. Rydygiera w Toruniu	Torun
Poland	Centrum Onkologii-Instytut im. M. Sklodowskiej Curie	Warszawa
Russian Federation	BHI of Omsk region "Clinical Oncology Dispensary"	Omsk
Russian Federation	St. Petersburg SHI "City Clinical Oncology Dispensary"	St. Petersburg
Spain	Hospital Clinic i Provincial de Barcelona	Barcelona
Spain	Hospital del Mar	Barcelona
Spain	Hospital Universitari Vall d'Hebron	Barcelona
Spain	ICO l´Hospitalet - Hospital Duran i Reynals	Barcelona
Spain	Centro Integral Oncologico Clara Campal	Madrid
Spain	Hospital General Universitario Gregorio Marañon	Madrid
Spain	Hospital Universitario Central de Asturias	Oviedo
Spain	Hospital Universitario Virgen del Rocio	Sevilla
United States	Florida Cancer Specialists-Broadway	Fort Myers	Florida
United States	Comprehensive Cancer Centers of Nevada	Henderson	Nevada
United States	USC Norris Comprehensive Cancer Center	Los Angeles	California
United States	Hematology - Oncology Associates of Treasure Coast	Port Saint Lucie	Florida
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	Florida Cancer Specialists	Saint Petersburg	Florida
United States	Sharp Memorial Hospital	San Diego	California
United States	Mercy Research	Springfield	Missouri
United States	Texas Oncology, P.A.	Tyler	Texas

Sponsors (1)

Lead Sponsor	Collaborator
Symphogen A/S

Countries where clinical trial is conducted

United States,  Austria,  Belgium,  France,  Germany,  Hungary,  Italy,  Poland,  Russian Federation,  Spain, 

References & Publications (2)

Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ, Filiberti A, Flechtner H, Fleishman SB, de Haes JC, et al. The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst. 1993 Mar 3;85(5):365-76. — View Citation

Fayers PM, Aaronson NK, Bjordal K, Groenvold M, Curran D, Bottomley A, on behalf of the EORTC Quality of Life Group. The EORTC QLQ-C30 Scoring Manual (3rd Edition). Published by: European Organisation for Research and Treatment of Cancer, Brussels 2001.

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Overall Survival (OS) Time	OS based on product-limit (Kaplan-Meier) estimates. Confidence intervals for the median are calculated according to Brookmeyer and Crowley.; If a subject had not died, survival time was censored at the last date the subject was known to be alive.	From randomization until the date of death (assessed up to 32 months).
Secondary	Best Overall Response (OR) According to the Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST v1.1)	Tumor assessments were done via computed tomography (CT) or magnetic resonance imaging (MRI) scans and evaluated per RECIST v1.1. The assessment for measurable disease during screening (within 14 days prior to Day 1) acts as the baseline assessment. Best OR was summarized for each treatment group by means of counts and percentages for the following categories: Complete Response (CR: disappearance of all target lesions), Partial Response (PR: at least a 30% decrease in the sum of diameters of target lesions), Progressive Disease (PD: at least a 20% increase in the sum of diameters of target lesions), Stable Disease (SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD) or Not Evaluable (NE).	From randomization until first radiological confirmed or clinical progression event, or death due to any cause, within 12 weeks after last tumor assessment (assessed up to 32 months).
Secondary	Progression Free Survival (PFS) Time	PFS based on product-limit (Kaplan-Meier) estimates. Confidence intervals for the median are calculated according to Brookmeyer and Crowley. Death will only be considered as an event if it occurs within 12 weeks after last tumor response assessment without progression.	From randomization until first event, where an event can be a progression (radiological confirmed or clinical progression) or death due to any cause (assessed up to 32 months).
Secondary	Time to Treatment Failure (TTF)	TTF based on product-limit (Kaplan-Meier) estimates. Confidence intervals for the median are calculated according to Brookmeyer and Crowley.	From randomization until treatment discontinuation for any reason, including disease progression or death (assessed up to 32 months).
Secondary	Occurrence and Nature of Adverse Events (AEs), as Assessed by the Common Terminology Criteria for AEs (Version 4.03) (CTCAE v4.03).	AEs were coded according to the Medical Dictionary for Regulatory Activities (MedDRA) classification. The incidence and type of AEs (i.e., serious AE [SAE], treatment-emergent AE [TEAE]) were summarized by dose cohort according to MedDRA system organ classes and preferred terms. An AE was considered as treatment-emergent if it occurred during or after the first IMP administration. An AE that occurred before the first IMP administration and worsened thereafter was also considered an AE. Worsening was reported as a new AE.	From Baseline up to 28 days after the last IMP administration.
Secondary	Relative Dose Intensity of Sym004	Treatment duration (weeks) is calculated as [(last dose date of Sym004 - first dose date of Sym004)+7] / 7 days.; Sym004 dose received (mg/kg) is calculated as (total dose administered (mg)/weight (kg)).; Dose Intensity is calculated as (cumulative Sym004 dose (mg/kg) / treatment duration (weeks)).; Relative Dose Intensity is calculated as (dose intensity / planned dose intensity at randomization)*100.; Percentages are based on the number of subjects in the safety analysis set.	From first dose of study drug until disease progression (assessed up to 32 months).
Secondary	Pharmacokinetic (PK) Parameters: Sym004 Concentrations	The Sym004 serum concentration used for the PK evaluation was calculated as the sum of the serum concentrations of the 2 component monoclonal antibodies of Sym004 (futuximab and modotuximab).; Trough Concentration (Ctrough) is equivalent to the concentration collected at the pre-dose timepoint.; Maximum Concentration (Cmax) is equivalent to the concentration collected at the end of infusion (EOI) timepoint.	Weeks 3, 5, and 7 and at the End of Treatment visit, including a Week 1 and Week 2 subset.
Secondary	Pharmacokinetic (PK) Parameters: Time of Maximum Plasma Concentration (Tmax)	Tmax was defined as the time the PK sample was taken at end of infusion (EOI) relative to the start time of infusion (i.e., time between the start of infusion and the time of the EOI sample). For presentation of individual PK parameters and calculation of mean parameters, half of the lower limit of quantitation (LLOQ) value was used for concentration values below the LLOQ. The Sym004 serum concentration used for the PK evaluation was calculated as the sum of the serum concentrations of the 2 component monoclonal antibodies of Sym004, futuximab and modotuximab.	Day 1 on Weeks 1-3 followed by Week 5 Day 1 and Week 7 Day 1.
Secondary	Host Immune Response: Number of Subjects With Anti-drug Antibodies (ADAs) to Sym004 Over Time	A validated double antigen bridging ELISA was used for screening, confirmation, and titration of patient samples for anti-Sym004 ADA. Using rabbit anti-Sym004 as an ADA control antibody, the lower limit of detection was 54 ng/mL in the absence of Sym004 and 500 ng/mL in the presence of Sym004 at 5 µg/mL The timepoints for ADA sampling were chosen by the original sponsor for this trial. After the trial was transferred to Symphogen A/S, it was determined that not all samples were necessary for analysis. This is why the collection time points specified in the Outcome Measure Time Frame do not match with the Outcome Measure Data Table.	Every two weeks (Days 15, 29, and 43) followed by every six weeks thereafter (Days 78, 120, 162, etc.) until the End of Treatment Visit
Secondary	Quality of Life Assessed by the EORTC QLQ-C30 (Version 3)	Scale: European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (Version 3) [QLQ-C30, Version 3].; The QLQ-C30 is a 30-question scale used to assess cancer patients' quality of life based on 15 factors (e.g., global health status, physical functioning, role functioning, etc.). The scale is composed of both multi-item scales and single-item measures. All of the scales and single-item measures range in score from 0 to 100: A high score for a functional scale represents a healthy level of functioning.; A high score for the global health status represents a high quality of life.; A high score for a symptom scale/item represents a high level of symptomatology (problems).	Assessed every 6 weeks (week 1 and week 7 reported)
Secondary	Quality of Life Assessed by EORTC QLQ-CR29	Scale: European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire - Colorectal Cancer Module (QLQ-CR29).; The QLQ-CR29 is a 29-question scale used to assess colorectal cancer patients' quality of life based on 22 factors (e.g., body image, anxiety, weight, etc.). The scale is composed of both multi-item scales and single-item measures. All of the scales and single-item measures range in score from 0 to 100: A high score for a functional scale/item represents an unhealthy level of functioning, with the exception of one (1) scale pertaining to sexual interest (separated by sex).; A high score for a symptom scale/item represents a high level of symptomatology (problems).	Assessed every 6 weeks (week 1 and week 7 reported)
Secondary	Quality of Life Assessed by FACT-EGFRI-18 for Skin Rash	Scale: Functional Assessment of Cancer Therapy-Epidermal Growth Factor Receptor Inhibitor 18 (FACT-EGFRI-18).; The FACT-EGFRI-18 is an 18-question scale used to assess EGFR-inhibitor-treated cancer patients' quality of life relative to their experience of skin rash based on three (3) multi-item subscales. The subscales combined (i.e., Symptom Index) range in score from 0 to 72. A higher score represents a high level of symptomatology (problems).; High scores for all subscales represent a worse outcome: The Physical subscale ranges in score from 0 to 28.; The Social/Emotional subscale ranges in score from 0 to 24.; The Functional subscale ranges in score from 0 to 20.	Assessed every 3 weeks (week 1 and week 4 reported)