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Sym004 vs Standard of Care in Subjects With Metastatic Colorectal Cancer

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ClinicalTrials.gov Identifier: NCT02083653
Recruitment Status : Completed
First Posted : March 11, 2014
Results First Posted : December 24, 2018
Last Update Posted : April 16, 2019
Sponsor:
Information provided by (Responsible Party):
Symphogen A/S

Tracking Information
First Submitted Date  ICMJE March 7, 2014
First Posted Date  ICMJE March 11, 2014
Results First Submitted Date  ICMJE September 12, 2018
Results First Posted Date  ICMJE December 24, 2018
Last Update Posted Date April 16, 2019
Actual Study Start Date  ICMJE March 6, 2014
Actual Primary Completion Date October 24, 2016   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 21, 2018)
Overall Survival (OS) Time [ Time Frame: From randomization until the date of death (assessed up to 32 months). ]
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.
Original Primary Outcome Measures  ICMJE
 (submitted: March 7, 2014)
Overall Survival (OS) Time [ Time Frame: Up to 2.5 years ]
OS time is defined as the time from randomization to the date of death, assessed up to 2.5 years.
Change History Complete list of historical versions of study NCT02083653 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: April 9, 2019)
  • Best Overall Response (OR) According to the Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST v1.1) [ Time Frame: 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). ]
    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).
  • Progression Free Survival (PFS) Time [ Time Frame: 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). ]
    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.
  • Time to Treatment Failure (TTF) [ Time Frame: From randomization until treatment discontinuation for any reason, including disease progression or death (assessed up to 32 months). ]
    TTF based on product-limit (Kaplan-Meier) estimates. Confidence intervals for the median are calculated according to Brookmeyer and Crowley.
  • Occurrence and Nature of Adverse Events (AEs), as Assessed by the Common Terminology Criteria for AEs (Version 4.03) (CTCAE v4.03). [ Time Frame: From Baseline up to 28 days after the last IMP administration. ]
    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.
  • Relative Dose Intensity of Sym004 [ Time Frame: From first dose of study drug until disease progression (assessed up to 32 months). ]
    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.
  • Pharmacokinetic (PK) Parameters: Sym004 Concentrations [ Time Frame: Weeks 3, 5, and 7 and at the End of Treatment visit, including a Week 1 and Week 2 subset. ]
    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.
  • Pharmacokinetic (PK) Parameters: Time of Maximum Plasma Concentration (Tmax) [ Time Frame: Day 1 on Weeks 1-3 followed by Week 5 Day 1 and Week 7 Day 1. ]
    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.
  • Host Immune Response: Number of Subjects With Anti-drug Antibodies (ADAs) to Sym004 Over Time [ Time Frame: 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 ]
    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.
  • Quality of Life Assessed by the EORTC QLQ-C30 (Version 3) [ Time Frame: Assessed every 6 weeks (week 1 and week 7 reported) ]
    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).
  • Quality of Life Assessed by EORTC QLQ-CR29 [ Time Frame: Assessed every 6 weeks (week 1 and week 7 reported) ]
    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).
  • Quality of Life Assessed by FACT-EGFRI-18 for Skin Rash [ Time Frame: Assessed every 3 weeks (week 1 and week 4 reported) ]
    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.
Original Secondary Outcome Measures  ICMJE
 (submitted: March 7, 2014)
  • Best overall response according to Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST v1.1) [ Time Frame: 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 2.5 years ]
  • Progression Free Survival (PFS) Time [ Time Frame: Time 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 2.5 years ]
  • Time to treatment failure [ Time Frame: Time from randomization to treatment failure or last tumor assessment, assessed up to 2.5 years ]
  • Relative Dose Intensity of Sym004 [ Time Frame: From first dose of study drug until unacceptable toxicity, disease progression, or consent withdrawal, assessed up to 2.5 years ]
  • Pharmacokinetic parameters: AUC (0-168 hours), t1/2, CL, Vd, Cmax, tmax and C(trough) [ Time Frame: Up to Year 2.5 ]
  • Host immune response: Number of subjects with anti-drug antibodies (ADAs) [ Time Frame: Up to Week 24 ]
  • Biomarkers level related to the Epidermal growth factor receptor (EGFR) pathway [ Time Frame: Screening (Within 14 days prior to Day 1) ]
  • Quality of life assessed by European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Lung Cancer 30 (EORTC QLQ-C30) (Version 3) [ Time Frame: Every 6 weeks up to 2.5 years ]
  • Quality of life assessed by EORTC QLQ module for colorectal cancer (EORTC QLQ-CR29) [ Time Frame: Every 6 weeks up to 2.5 years ]
  • Quality of life assessed by Functional Assessment of Cancer Therapy-Epidermal Growth Factor Receptor Inhibitor 18 (FACT-EGFR 18) [ Time Frame: Every 3 weeks up to 2.5 years ]
  • Number of subjects with adverse events (AEs), serious AEs, treatment emergent AEs, AEs leading to death, and AEs with National Cancer Institute-Common Terminology Criteria for AEs (NCI−CTCAE Version 4.03) Grade greater than or equal to 3 [ Time Frame: Baseline up to 28 days after the last dose administration or up to 21 months ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Sym004 vs Standard of Care in Subjects With Metastatic Colorectal Cancer
Official Title  ICMJE 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
Brief 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).
Detailed 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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Metastatic Colorectal Cancer
Intervention  ICMJE
  • 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.
  • Drug: 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.
    Other Name: Adrucil
  • Drug: Capecitabine
    Capecitabine will be administered at doses and schedules as per Investigator's discretion and in line with the local package insert.
    Other Name: Xeloda
Study Arms  ICMJE
  • Experimental: Arm A: Sym004 (12 mg/kg)
    Sym004 will be administered as an intravenous infusion at a dose of 12 milligrams per kilogram (mg/kg) weekly until unacceptable toxicity, disease progression, or consent withdrawal.
    Intervention: Drug: Sym004 (12 mg/kg)
  • Experimental: Arm B: Sym004 (9/6 mg/kg)
    Sym004 will be administered as an intravenous infusion at a loading dose of 9 mg/kg followed by 6 mg/kg weekly until unacceptable toxicity, disease progression, or consent withdrawal.
    Intervention: Drug: Sym004 (9/6 mg/kg)
  • Active Comparator: Arm C: Investigator's Choice
    Best supportive care (BSC) or Fluorouracil (5-FU) or Capecitabine will be given as per Investigator's discretion.
    Interventions:
    • Other: Best Supportive Care (BSC)
    • Drug: Fluorouracil (5-FU)
    • Drug: Capecitabine
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: October 29, 2015)
254
Original Estimated Enrollment  ICMJE
 (submitted: March 7, 2014)
240
Actual Study Completion Date  ICMJE April 26, 2017
Actual Primary Completion Date October 24, 2016   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Austria,   Belgium,   France,   Germany,   Hungary,   Italy,   Poland,   Russian Federation,   Spain,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02083653
Other Study ID Numbers  ICMJE Sym004-05
2013-003829-29 ( EudraCT Number )
EMR200637-002 ( Other Identifier: Merck KGaA )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Undecided
Responsible Party Symphogen A/S
Study Sponsor  ICMJE Symphogen A/S
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Josep Tabernero, MD, PhD Vall d'Hebron University Hospital
PRS Account Symphogen A/S
Verification Date April 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP