Sym004 vs Standard of Care in Subjects With Metastatic Colorectal Cancer

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Metastatic Colorectal Cancer

Intervention / Treatment
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* Drug: Sym004 (12 mg/kg)
* Drug: Sym004 (9/6 mg/kg)
* Other: Best Supportive Care (BSC)
* Drug: Fluorouracil (5-FU)
* Drug: Capecitabine


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A: Sym004 (12 mg/kg)<br>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. | Drug: Sym004 (12 mg/kg)<br>* Sym004 is a 1:1 mixture of two mAbs (futuximab and modotuximab) which bind to two non-overlapping epitopes of the EGFR.<br>|
| Experimental: Arm B: Sym004 (9/6 mg/kg)<br>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. | Drug: Sym004 (9/6 mg/kg)<br>* Sym004 is a 1:1 mixture of two mAbs (futuximab and modotuximab) which bind to two non-overlapping epitopes of the EGFR.<br>|
| Active Comparator: Arm C: Investigator's Choice<br>Best supportive care (BSC) or Fluorouracil (5-FU) or Capecitabine will be given as per Investigator's discretion. | Other: Best Supportive Care (BSC)<br>* 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.<br>Drug: Fluorouracil (5-FU)<br>* 5-FU will be administered at doses and schedules as per Investigator's discretion and in line with the local package insert.<br>* Other names: Adrucil;Drug: Capecitabine<br>* Capecitabine will be administered at doses and schedules as per Investigator's discretion and in line with the local package insert.<br>* Other names: Xeloda;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). | 
| 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). | 
| 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). | 
| 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. | 
| 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). | 
| 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. | 
| 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. | 
| 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 | 
| 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) | 
| 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) | 
| 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) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Sym004, Metastatic Colorectal Cancer, Best Supportive Care, Capecitabine, Fluorouracil (5-FU)