Metastatic Colorectal Cancer
Conditions
Keywords
Metastatic Colorectal Cancer
Brief summary
This is a Phase 1b/2a study investigating the safety and efficacy of Sym004, an investigational medicinal product (IMP), in combination with FOLFIRI (chemotherapy) when administered every second week (Q2W).
Detailed description
In the Phase 1b (Dose-Escalation) portion of the trial, patients will be sequentially enrolled to dose-escalation cohorts until establishment of the Maximum Tolerated Dose (MTD) and/or Recommended Phase 2 Dose (RP2D) of Sym004 in combination with FOLFIRI. The Phase 2a (Dose-Expansion) portion of the trial is expected to begin after establishing the RP2D. Note: In January 2017, the trial was terminated during Phase 1b and enrollment was prematurely discontinued. The primary objective changed to assess the safety of the treatment combination; collection of data for secondary and exploratory objectives was omitted.
Interventions
DRUGSym004
Sym004 is a 1:1 mixture of 2 monoclonal antibodies (mAbs), which bind specifically to 2 non-overlapping epitopes of the epidermal growth factor receptor (EGFR).
DRUGFOLFIRI
The standard FOLFIRI regimen consists of Irinotecan (180 mg/m\^2 IV, infused over 60-90 minutes) concurrently with Folinic Acid (400 mg/m\^2 IV, infused over 120 minutes) followed by 5-FU (400 mg/m\^2 IV bolus, then 2400 mg/m\^2 infused over 46 hours).
Sponsors
Symphogen A/S
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Main inclusion Criteria: 1. Male or female, at least 18 years of age at the time of informed consent 2. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1 3. Histologically or cytologically confirmed, locally advanced or metastatic colorectal cancer (CRC) that is documented to be without Kirsten rat sarcoma (KRAS) or neuroblastoma rat sarcoma (NRAS) gene mutations (i.e., tumors must express the KRAS and NRAS wild type \[WT\], exon 2, 3 and 4). 4. Failed (defined as radiologic progression) treatment for locally advanced or metastatic disease with first-line combination therapy of oxaliplatin and a fluoropyrimidine, with or without bevacizumab, during treatment or \< 3 months after the last dose of first-line therapy and within \< 3 months of C1/D1. Patients who discontinued first-line therapy due to toxicity may be enrolled provided progression occurred \< 6 months after the last dose of the first-line therapy regimen. or Failed (defined as radiologic progression) adjuvant therapy with combination therapy of oxaliplatin and a fluoropyrimidine during treatment or within \< 6 months after the last dose of oxaliplatin and within \< 6 months of C1/D1. 5. Eligible for FOLFIRI 6. Measurable disease according to RECIST v1.1 Main
Exclusion criteria
1. Prior therapy with anti-EGFR antibodies, anti-EGFR small molecule inhibitors or irinotecan (CPT-11) 2. Any antineoplastic agent (standard or investigational) within 4 weeks prior to C1/D1 3. Significant gastrointestinal abnormalities 4. Patients with a significant cardiovascular disease or condition 5. Abnormal hematologic, renal or hepatic function
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 4.03) (CTCAE v4.03). | 15 months | AEs were coded according to the Medical Dictionary for Regulatory Activities (MedDRA) classification. The incidence and type of AEs (e.g., treatment-emergent AE \[TEAE\]) were summarized according to MedDRA system organ classes and preferred terms. An AE was considered as treatment-emergent if it occurred after the first treatment administration. |
Countries
Spain, United States
Participant flow
Recruitment details
The first patient was enrolled in March 2016. In January 2017, the trial was terminated early and enrollment was prematurely discontinued.
Participants by arm
| Arm | Count |
|---|---|
| Dose Level 1: Sym004 12 mg/kg + FOLFIRI Sym004 is a 1:1 mixture of 2 monoclonal antibodies (mAbs), which bind to 2 non-overlapping epitopes of the epidermal growth factor receptor (EGFR).
The standard FOLFIRI regimen consists of Irinotecan (180 mg/m\^2 IV, infused over 60-90 minutes) concurrently with Folinic Acid (400 mg/m\^2 IV, infused over 120 minutes) followed by 5-FU (400 mg/m\^2 IV bolus, then 2400 mg/m\^2 infused over 46 hours). | 5 |
| Dose Level -1: Sym004 9 mg/kg + FOLFIRI Sym004 is a 1:1 mixture of 2 monoclonal antibodies (mAbs), which bind to 2 non-overlapping epitopes of the epidermal growth factor receptor (EGFR).
The standard FOLFIRI regimen consists of Irinotecan (180 mg/m\^2 IV, infused over 60-90 minutes) concurrently with Folinic Acid (400 mg/m\^2 IV, infused over 120 minutes) followed by 5-FU (400 mg/m\^2 IV bolus, then 2400 mg/m\^2 infused over 46 hours). | 5 |
| Total | 10 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 |
| Overall Study | Death | 2 | 0 |
| Overall Study | Other Events | 0 | 1 |
| Overall Study | Progressive Disease | 1 | 0 |
| Overall Study | Withdrawal by Subject | 2 | 1 |
Baseline characteristics
| Characteristic | Dose Level 1: Sym004 12 mg/kg + FOLFIRI | Dose Level -1: Sym004 9 mg/kg + FOLFIRI | Total |
|---|---|---|---|
| Age, Continuous | 69.3 years STANDARD_DEVIATION 8.55 | 61.1 years STANDARD_DEVIATION 9.95 | 65.2 years STANDARD_DEVIATION 9.76 |
| Body Mass Index (BMI) | 26.5 kg/m^2 STANDARD_DEVIATION 4.2 | 28.0 kg/m^2 STANDARD_DEVIATION 4.52 | 27.3 kg/m^2 STANDARD_DEVIATION 4.19 |
| Body Surface Area (BSA) | 1.9 m^2 STANDARD_DEVIATION 0.17 | 2.0 m^2 STANDARD_DEVIATION 0.24 | 1.9 m^2 STANDARD_DEVIATION 0.2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 2 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 4 Participants | 3 Participants | 7 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Height | 170.4 centimeters (cm) STANDARD_DEVIATION 8.57 | 171.3 centimeters (cm) STANDARD_DEVIATION 4.47 | 170.9 centimeters (cm) STANDARD_DEVIATION 6.46 |
| 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 | 5 Participants | 5 Participants | 10 Participants |
| Region of Enrollment Spain | 2 Participants | 3 Participants | 5 Participants |
| Region of Enrollment United States | 3 Participants | 2 Participants | 5 Participants |
| Sex: Female, Male Female | 2 Participants | 2 Participants | 4 Participants |
| Sex: Female, Male Male | 3 Participants | 3 Participants | 6 Participants |
| Weight | 76.6 kilograms (kg) STANDARD_DEVIATION 11.97 | 82.5 kilograms (kg) STANDARD_DEVIATION 16.1 | 79.6 kilograms (kg) STANDARD_DEVIATION 13.73 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 2 / 5 | 0 / 5 |
| other Total, other adverse events | 5 / 5 | 5 / 5 |
| serious Total, serious adverse events | 3 / 5 | 2 / 5 |
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 4.03) (CTCAE v4.03).
AEs were coded according to the Medical Dictionary for Regulatory Activities (MedDRA) classification. The incidence and type of AEs (e.g., treatment-emergent AE \[TEAE\]) were summarized according to MedDRA system organ classes and preferred terms. An AE was considered as treatment-emergent if it occurred after the first treatment administration.
Time frame: 15 months
Population: All safety analyses were conducted using the Full Analysis Set (FAS) population, defined as all patients who received at least 1 dose of trial treatment.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Dose Level 1: Sym004 12 mg/kg + FOLFIRI | 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 4.03) (CTCAE v4.03). | At least 1 TEAE | 5 Participants |
| Dose Level 1: Sym004 12 mg/kg + FOLFIRI | 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 4.03) (CTCAE v4.03). | At least 1 Serious TEAE | 3 Participants |
| Dose Level 1: Sym004 12 mg/kg + FOLFIRI | 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 4.03) (CTCAE v4.03). | At least 1 Serious TEAE related to Sym004 only | 0 Participants |
| Dose Level 1: Sym004 12 mg/kg + FOLFIRI | 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 4.03) (CTCAE v4.03). | At least 1 TEAE leading to Sym004 dose reduction | 1 Participants |
| Dose Level 1: Sym004 12 mg/kg + FOLFIRI | 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 4.03) (CTCAE v4.03). | At least 1 TEAE leading to interruption of Sym004 | 3 Participants |
| Dose Level 1: Sym004 12 mg/kg + FOLFIRI | 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 4.03) (CTCAE v4.03). | At least 1 TEAE leading to Sym004 withdrawal | 2 Participants |
| Dose Level 1: Sym004 12 mg/kg + FOLFIRI | 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 4.03) (CTCAE v4.03). | At least 1 TEAE leading to FOLFIRI withdrawal | 1 Participants |
| Dose Level 1: Sym004 12 mg/kg + FOLFIRI | 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 4.03) (CTCAE v4.03). | At least 1 TEAE leading to trial termination | 0 Participants |
| Dose Level 1: Sym004 12 mg/kg + FOLFIRI | 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 4.03) (CTCAE v4.03). | At least 1 TEAE related to Sym004 + FOLFIRI | 4 Participants |
| Dose Level 1: Sym004 12 mg/kg + FOLFIRI | 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 4.03) (CTCAE v4.03). | At least 1 TEAE related to Sym004 only | 4 Participants |
| Dose Level 1: Sym004 12 mg/kg + FOLFIRI | 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 4.03) (CTCAE v4.03). | At least 1 TEAE related to FOLFIRI only | 4 Participants |
| Dose Level 1: Sym004 12 mg/kg + FOLFIRI | 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 4.03) (CTCAE v4.03). | At least 1 TEAE Grade ≥3 related to Sym004+FOLFIRI | 2 Participants |
| Dose Level 1: Sym004 12 mg/kg + FOLFIRI | 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 4.03) (CTCAE v4.03). | At least 1 TEAE Grade ≥ 3 related to Sym004 only | 0 Participants |
| Dose Level 1: Sym004 12 mg/kg + FOLFIRI | 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 4.03) (CTCAE v4.03). | At least 1 TEAE Grade ≥ 3 related to FOLFIRI only | 1 Participants |
| Dose Level 1: Sym004 12 mg/kg + FOLFIRI | 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 4.03) (CTCAE v4.03). | At least 1 dermatologic toxicity | 3 Participants |
| Dose Level 1: Sym004 12 mg/kg + FOLFIRI | 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 4.03) (CTCAE v4.03). | At least 1 TEAE of hypomagnesaemia | 3 Participants |
| Dose Level 1: Sym004 12 mg/kg + FOLFIRI | 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 4.03) (CTCAE v4.03). | At least 1 Infusion related reaction TEAE | 3 Participants |
| Dose Level 1: Sym004 12 mg/kg + FOLFIRI | 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 4.03) (CTCAE v4.03). | At least 1 TEAE resulting in death | 0 Participants |
| Dose Level -1: Sym004 9 mg/kg + FOLFIRI | 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 4.03) (CTCAE v4.03). | At least 1 TEAE Grade ≥ 3 related to FOLFIRI only | 1 Participants |
| Dose Level -1: Sym004 9 mg/kg + FOLFIRI | 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 4.03) (CTCAE v4.03). | At least 1 TEAE | 5 Participants |
| Dose Level -1: Sym004 9 mg/kg + FOLFIRI | 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 4.03) (CTCAE v4.03). | At least 1 TEAE related to Sym004 only | 5 Participants |
| Dose Level -1: Sym004 9 mg/kg + FOLFIRI | 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 4.03) (CTCAE v4.03). | At least 1 Serious TEAE | 2 Participants |
| Dose Level -1: Sym004 9 mg/kg + FOLFIRI | 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 4.03) (CTCAE v4.03). | At least 1 TEAE resulting in death | 0 Participants |
| Dose Level -1: Sym004 9 mg/kg + FOLFIRI | 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 4.03) (CTCAE v4.03). | At least 1 Serious TEAE related to Sym004 only | 0 Participants |
| Dose Level -1: Sym004 9 mg/kg + FOLFIRI | 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 4.03) (CTCAE v4.03). | At least 1 TEAE related to FOLFIRI only | 4 Participants |
| Dose Level -1: Sym004 9 mg/kg + FOLFIRI | 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 4.03) (CTCAE v4.03). | At least 1 TEAE leading to Sym004 dose reduction | 2 Participants |
| Dose Level -1: Sym004 9 mg/kg + FOLFIRI | 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 4.03) (CTCAE v4.03). | At least 1 dermatologic toxicity | 5 Participants |
| Dose Level -1: Sym004 9 mg/kg + FOLFIRI | 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 4.03) (CTCAE v4.03). | At least 1 TEAE leading to interruption of Sym004 | 5 Participants |
| Dose Level -1: Sym004 9 mg/kg + FOLFIRI | 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 4.03) (CTCAE v4.03). | At least 1 TEAE Grade ≥3 related to Sym004+FOLFIRI | 2 Participants |
| Dose Level -1: Sym004 9 mg/kg + FOLFIRI | 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 4.03) (CTCAE v4.03). | At least 1 TEAE leading to Sym004 withdrawal | 2 Participants |
| Dose Level -1: Sym004 9 mg/kg + FOLFIRI | 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 4.03) (CTCAE v4.03). | At least 1 Infusion related reaction TEAE | 3 Participants |
| Dose Level -1: Sym004 9 mg/kg + FOLFIRI | 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 4.03) (CTCAE v4.03). | At least 1 TEAE leading to FOLFIRI withdrawal | 2 Participants |
| Dose Level -1: Sym004 9 mg/kg + FOLFIRI | 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 4.03) (CTCAE v4.03). | At least 1 TEAE Grade ≥ 3 related to Sym004 only | 2 Participants |
| Dose Level -1: Sym004 9 mg/kg + FOLFIRI | 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 4.03) (CTCAE v4.03). | At least 1 TEAE leading to trial termination | 1 Participants |
| Dose Level -1: Sym004 9 mg/kg + FOLFIRI | 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 4.03) (CTCAE v4.03). | At least 1 TEAE of hypomagnesaemia | 0 Participants |
| Dose Level -1: Sym004 9 mg/kg + FOLFIRI | 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 4.03) (CTCAE v4.03). | At least 1 TEAE related to Sym004 + FOLFIRI | 3 Participants |