Carcinoma, Colorectal Cancer Metastatic, Metastatic Colorectal Cancer
Conditions
Keywords
Metastatic Colorectal Cancer, Colorectal Cancer, Carcinoma, Sym004, futuximab, modotuximab
Brief summary
This is a Phase 2, randomized, open-label, 3-arm trial in the ratio of 1:1:1 to either Sym004 (Arm A) versus each of its component monoclonal antibodies (mAbs), futuximab (Arm B) or modotuximab (Arm C), in genomically-selected patients with chemotherapy-refractory metastatic colorectal carcinoma (mCRC) and acquired resistance to anti-epidermal growth factor receptor (anti-EGFR) mAb therapy. The study is designed to evaluate the relative antitumor activity of each agent as assessed by imaging studies performed after 8 weeks of treatment.
Detailed description
Following consent and prior to randomization, genomic analysis will be conducted on blood samples obtained from each potential patient. Triple-negative (TN) results as defined in trial eligibility criteria will be required for initial eligibility. Patients with TNmCRC will continue in the screening process. Once deemed fully eligible, patients will be randomized to Arm A, Arm B, or Arm C. Dosing cycles of 28 days will continue until documented disease progression (PD) or another criterion for discontinuation is met. Antitumor activity will be assessed at the end of every 2 cycles (every 8 weeks \[Q8W\]). At the End of Cycle 2 (EOC2) tumor assessment: * Patients assigned to Arm A (Sym004) with a documented objective response (OR) or stable disease (SD) will continue to receive Sym004; patients at the EOC2 with documented PD will be discontinued from study * Patients assigned to Arm B (futuximab) or Arm C (modotuximab) with a documented OR or SD will be crossed-over to receive Sym004; patients with documented PD at the EOC2 (or prior to the EOC2) will be offered the opportunity to crossover to receive Sym004 or will be discontinued from study To be considered evaluable for antitumor activity assessment, patients must have completed 2 cycles of dosing inclusive of EOC2 disease imaging studies and must have received any amount of their assigned investigational medicinal product (IMP) during that period, or have PD documented by imaging studies prior to the EOC2. Non-evaluable patients and patients discontinuing from study prior to the EOC2 for reasons other than documented PD will not be replaced. Note: In December 2018, the decision was made to terminate the trial and enrollment was prematurely discontinued. The primary, secondary, and exploratory objectives are no longer applicable. Only clinical safety-related evaluations will be conducted.
Interventions
DRUGModotuximab
Modotuximab is one of two mAb components that constitute Sym004.
DRUGSym004
Sym004 is a 1:1 mixture of two recombinant mAbs (futuximab and modotuximab) which bind specifically to non-overlapping epitopes located in the extracellular domain (ECD) of the EGFR.
DRUGFutuximab
Futuximab is one of two mAb components that constitute Sym004.
Sponsors
Symphogen A/S
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male or female patients, ≥ 18 years of age at the time of obtaining informed consent. * Histologically- or cytologically-confirmed mCRC. * Microsatellite instability-high (MSI-H) / mismatch repair-deficient (dMMR) tumors must have received prior therapy with pembrolizumab, nivolumab, or other programmed cell death protein-1 (PD-1)/programmed death-ligand 1 (PD-L1) pathway blocker, and must have progressed on that therapy. * Meeting the protocol definition of TNmCRC assessed in the screening blood test. * mCRC currently not amenable to surgical intervention due to either medical contraindications or non-resectability of the tumor. * Measurable disease according to RECIST v1.1, and willingness to undergo a total of 2 biopsies of a primary or metastatic tumor site(s) considered safely accessible for biopsy. * Must have received at least 2 prior regimens of standard chemotherapy for mCRC and must have been refractory to or failed (includes intolerance to) those regimens. Prior standard chemotherapy may not have included TAS-102 or regorafenib, but must have included agents as specified in the protocol. * Acquired resistance to commercially available anti-EGFR mAbs approved for the treatment of mCRC must have: 1. Received treatment with an anti-EGFR for ≥16 weeks 2. Progressive disease (PD) documented by imaging or clinical findings less than or equal to 6 calendar months after cessation of previous anti-EGFR mAb treatment 3. No more than 6 calendar months from last dose of previous anti-EGFR mAb treatment to date of consent for this trial (regardless of the line of therapy in which it was used) * Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1 * Not of childbearing potential or who agree to use a highly effective method of contraception during the study beginning within 2 weeks prior to the first dose and continuing until 3 months after the last dose of study drug.
Exclusion criteria
* Women who are pregnant or lactating or intending to become pregnant before, during, or within 3 months after the last dose of study drug. * Prior history of specific mutations (specified in the protocol) in the tumor at the time of any previous assessment. * Known, untreated central nervous system (CNS) or leptomeningeal metastases, or spinal cord compression; patients with any of these not controlled by prior surgery or radiotherapy, or patients with symptoms suggesting CNS involvement for which treatment is required * An active second malignancy or history of another malignancy within the last 5 years, with exceptions. * Active thrombosis, or a history of deep vein thrombosis (DVT) or pulmonary embolism (PE) within 4 weeks prior to first administration of study drug unless adequately treated and considered by the Investigator to be stable. * Active uncontrolled bleeding or a known bleeding diathesis * Known clinically significant cardiovascular disease or condition. * Non-healing wounds on any part of the body. * Significant gastrointestinal abnormality. * Skin rash \> Grade 1 from prior anti-EGFR therapy at the time of randomization. * Unresolved \> Grade 1 toxicity associated with any prior antineoplastic therapy Drugs and Other Treatments
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events (AEs) by Nature, Severity, and Occurrence. | 4 months | Measured From Baseline to End of Trial Participation, as Assessed by the Common Terminology Criteria for AEs (Version 5) (CTCAE v5). AEs will be coded according to the Medical Dictionary for Regulatory Activities (MedDRA) terminology and the severity of the toxicities will be graded according to the CTCAE v5, where applicable. |
Countries
Germany, Italy, Spain, United States
Participant flow
Recruitment details
The intended number of patients to be included in this trial was approximately 54 (18 evaluable per Arm). As of the trial termination date, 2 patients were enrolled.
Pre-assignment details
The first patient was randomized to Arm B prior to the trial termination date and crossed over to Sym004 at the EOC1. The second patient was randomized to Arm B after the trial termination date, but enrolled to Arm A per Sponsor decision.
Participants by arm
| Arm | Count |
|---|---|
| Arm A (Sym004) Sym004 will be given as a loading dose of 9 mg/kg on Cycle 1/Day 1 (C1D1), followed by weekly doses of 6 mg/kg beginning C1D8. | 1 |
| Arm B (Futuximab) Futuximab will be given as a loading dose of 4.5 mg/kg on C1D1, followed by weekly doses of 3 mg/kg beginning C1D8. At the End of Cycle 2 (EOC2), ongoing patients will be crossed-over to Sym004; crossover may occur prior to the EOC2 in the event of early radiographic documentation of progressive disease (PD). Sym004 will be given at the dose level that contains the corresponding dose level of the individual antibody futuximab prior to crossover. | 1 |
| Arm C (Modotuximab) Modotuximab will be given as a loading dose of 4.5 mg/kg on C1D1, followed by weekly doses of 3 mg/kg beginning C1D8. At the EOC2, ongoing patients will be crossed-over to Sym004; crossover may occur prior to the EOC2 in the event of early radiographic documentation of PD. Sym004 will be given at the dose level that contains the corresponding dose level of the individual antibody modotuximab prior to crossover. | 0 |
| Total | 2 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Clinical Progression | 0 | 1 | 0 |
| Overall Study | Progressive Disease | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Arm A (Sym004) | Arm B (Futuximab) | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 1 Participants | 1 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 1 Participants | 1 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 1 Participants | 1 Participants | 2 Participants |
| Region of Enrollment United States | 1 participants | 1 participants | 2 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 1 Participants | 1 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 2 | 0 / 1 |
| other Total, other adverse events | 2 / 2 | 1 / 1 |
| serious Total, serious adverse events | 1 / 2 | 0 / 1 |
Outcome results
Primary
Number of Participants With Adverse Events (AEs) by Nature, Severity, and Occurrence.
Measured From Baseline to End of Trial Participation, as Assessed by the Common Terminology Criteria for AEs (Version 5) (CTCAE v5). AEs will be coded according to the Medical Dictionary for Regulatory Activities (MedDRA) terminology and the severity of the toxicities will be graded according to the CTCAE v5, where applicable.
Time frame: 4 months
Population: The first patient was randomized to Arm B prior to the trial termination date and crossed over to Sym004 at the EOC1. The second patient was randomized to Arm B after the trial termination date, but enrolled to Arm A per Sponsor decision.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm A (Sym004) | Number of Participants With Adverse Events (AEs) by Nature, Severity, and Occurrence. | At least one AE | 2 participants |
| Arm A (Sym004) | Number of Participants With Adverse Events (AEs) by Nature, Severity, and Occurrence. | At least one SAE | 1 participants |
| Arm A (Sym004) | Number of Participants With Adverse Events (AEs) by Nature, Severity, and Occurrence. | At least one AE related to Sym004 | 2 participants |
| Arm A (Sym004) | Number of Participants With Adverse Events (AEs) by Nature, Severity, and Occurrence. | At least one AE related to futuximab | 0 participants |
| Arm A (Sym004) | Number of Participants With Adverse Events (AEs) by Nature, Severity, and Occurrence. | At least one SAE related to Sym004 | 0 participants |
| Arm A (Sym004) | Number of Participants With Adverse Events (AEs) by Nature, Severity, and Occurrence. | At least one SAE related to futuximab | 0 participants |
| Arm B (Futuximab) | Number of Participants With Adverse Events (AEs) by Nature, Severity, and Occurrence. | At least one SAE related to Sym004 | 0 participants |
| Arm B (Futuximab) | Number of Participants With Adverse Events (AEs) by Nature, Severity, and Occurrence. | At least one AE | 1 participants |
| Arm B (Futuximab) | Number of Participants With Adverse Events (AEs) by Nature, Severity, and Occurrence. | At least one AE related to futuximab | 0 participants |
| Arm B (Futuximab) | Number of Participants With Adverse Events (AEs) by Nature, Severity, and Occurrence. | At least one SAE | 0 participants |
| Arm B (Futuximab) | Number of Participants With Adverse Events (AEs) by Nature, Severity, and Occurrence. | At least one SAE related to futuximab | 0 participants |
| Arm B (Futuximab) | Number of Participants With Adverse Events (AEs) by Nature, Severity, and Occurrence. | At least one AE related to Sym004 | 0 participants |