Sym004 in Combination With FOLFIRI in Metastatic Colorectal Cancer Patients

• Sponsor: Symphogen A/S (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT02568046
• Collaborator: (none)
• Enrollment: 10
• Locations: 8
• Arms: 3
• Actual Duration (Months): 25.7
• Patients Per Site: 1.3
• Patients Per Site Per Month: 0

Study Details

Study Description

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).

Condition or Disease	Intervention/Treatment	Phase
Metastatic Colorectal Cancer	Drug: Sym004; Drug: FOLFIRI	Phase 1/Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 10 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open Label, Multi-Center Phase 1b/2a Trial Investigating Different Doses of Sym004 in Combination With FOLFIRI in Patients With Metastatic Colorectal Cancer Progressing After First-Line Therapy
• Actual Study Start Date: Mar 15, 2016
• Actual Primary Completion Date: May 15, 2017
• Actual Study Completion Date: May 5, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Sym004 12 mg/kg + FOLFIRI Phase 1b, Dose-Escalation: Dose Level 1	Drug: Sym004; 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).; Drug: FOLFIRI; 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).; Other Names: Irinotecan (Camptosar) Folinic Acid (Leucovorin) Fluorouracil (5-FU)
Experimental: Sym004 9 mg/kg + FOLFIRI Phase 1b, Dose-Escalation: Dose Level -1	Drug: Sym004; 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).; Drug: FOLFIRI; 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).; Other Names: Irinotecan (Camptosar) Folinic Acid (Leucovorin) Fluorouracil (5-FU)
Experimental: Sym004 (RP2D) + FOLFIRI Phase 2a, Dose-Expansion: Sym004 in the RP2D in combination with FOLFIRI	Drug: Sym004; 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).; Drug: FOLFIRI; 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).; Other Names: Irinotecan (Camptosar) Folinic Acid (Leucovorin) Fluorouracil (5-FU)

Outcome Measures

Primary Outcome Measures

1. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

1. Eligible for FOLFIRI

2. 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	UCLA School of Medicine	Los Angeles	California	United States	90095
2	Sharp Memorial Hosptal	San Diego	California	United States	92123
3	Georgetown University Medical Center	Washington	District of Columbia	United States	20007
4	University Cancer & Blood Center, LLC	Athens	Georgia	United States	30607
5	University of Michigan Health System	Ann Arbor	Michigan	United States	48109
6	Hospital del Mar	Barcelona		Spain	08003
7	Hospital Universitari Vall d'Hebron	Barcelona		Spain	08035
8	Hospital Universitario Madrid Sanchinarro	Madrid		Spain	28050

Sponsors and Collaborators

• Symphogen A/S

Investigators

• Principal Investigator: Josep Tabernero, MD, PhD, Vall d'Hebron University Hospital

Study Documents (Full-Text)

• Study Protocol - Feb 22, 2017
• Statistical Analysis Plan - Jun 7, 2017

More Information

Publications

None provided.

• Responsible Party: Symphogen A/S
• ClinicalTrials.gov Identifier: NCT02568046
• Other Study ID Numbers: Sym004-09; 2015-003047-19
• First Posted: Oct 5, 2015
• Last Update Posted: Mar 26, 2019
• Last Verified: Mar 1, 2019

• Individual Participant Data (IPD) Sharing Statement: Undecided
• Plan to Share IPD: Undecided
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Symphogen A/S: Metastatic Colorectal Cancer
• Additional relevant MeSH terms: Colorectal Neoplasms; Leucovorin; Fluorouracil; Irinotecan

Study Results

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.

Arm/Group Title	Dose Level 1: Sym004 12 mg/kg + FOLFIRI	Dose Level -1: Sym004 9 mg/kg + FOLFIRI
Arm/Group Description	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).	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).
Period Title: Overall Study
STARTED	5	5
COMPLETED	0	2
NOT COMPLETED	5	3

Baseline Characteristics

Arm/Group Title	Dose Level 1: Sym004 12 mg/kg + FOLFIRI	Dose Level -1: Sym004 9 mg/kg + FOLFIRI	Total
Arm/Group Description	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).	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).	Total of all reporting groups
Overall Participants	5	5	10
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	69.3 (8.55)	61.1 (9.95)	65.2 (9.76)
Sex: Female, Male (Count of Participants)
Female	2 40%	2 40%	4 40%
Male	3 60%	3 60%	6 60%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 20%	2 40%	3 30%
Not Hispanic or Latino	4 80%	3 60%	7 70%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%
White	5 100%	5 100%	10 100%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (Count of Participants)
United States	3 60%	2 40%	5 50%
Spain	2 40%	3 60%	5 50%
Height (centimeters (cm)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [centimeters (cm)]	170.4 (8.57)	171.3 (4.47)	170.9 (6.46)
Weight (kilograms (kg)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kilograms (kg)]	76.6 (11.97)	82.5 (16.10)	79.6 (13.73)
Body Mass Index (BMI) (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	26.5 (4.20)	28.0 (4.52)	27.3 (4.19)
Body Surface Area (BSA) (m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [m^2]	1.9 (0.17)	2.0 (0.24)	1.9 (0.20)

Outcome Measures

1. Primary Outcome

Title	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).
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Dose Level 1: Sym004 12 mg/kg + FOLFIRI	Dose Level -1: Sym004 9 mg/kg + FOLFIRI
Arm/Group Description	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).	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).
Measure Participants	5	5
At least 1 TEAE	5 100%	5 100%
At least 1 Serious TEAE	3 60%	2 40%
At least 1 Serious TEAE related to Sym004 only	0 0%	0 0%
At least 1 TEAE leading to Sym004 dose reduction	1 20%	2 40%
At least 1 TEAE leading to interruption of Sym004	3 60%	5 100%
At least 1 TEAE leading to Sym004 withdrawal	2 40%	2 40%
At least 1 TEAE leading to FOLFIRI withdrawal	1 20%	2 40%
At least 1 TEAE leading to trial termination	0 0%	1 20%
At least 1 TEAE related to Sym004 + FOLFIRI	4 80%	3 60%
At least 1 TEAE related to Sym004 only	4 80%	5 100%
At least 1 TEAE related to FOLFIRI only	4 80%	4 80%
At least 1 TEAE Grade ≥3 related to Sym004+FOLFIRI	2 40%	2 40%
At least 1 TEAE Grade ≥ 3 related to Sym004 only	0 0%	2 40%
At least 1 TEAE Grade ≥ 3 related to FOLFIRI only	1 20%	1 20%
At least 1 dermatologic toxicity	3 60%	5 100%
At least 1 TEAE of hypomagnesaemia	3 60%	0 0%
At least 1 Infusion related reaction TEAE	3 60%	3 60%
At least 1 TEAE resulting in death	0 0%	0 0%

Adverse Events

Time Frame	The adverse event data collection period was 15 months.
Adverse Event Reporting Description	Adverse event data were collected beginning with the signing of informed consent and continued through 1 month (i.e., at least 28 days) after the last administration of treatment (i.e., after both Sym004 and FOLFIRI were discontinued). After the decision was made to prematurely discontinue the trial, collection of adverse event data continued through 1 month after the last administration of Sym004.
Arm/Group Title	Dose Level 1: Sym004 12 mg/kg + FOLFIRI		Dose Level -1: Sym004 9 mg/kg + FOLFIRI
Arm/Group Description	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).		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).
All Cause Mortality
	Dose Level 1: Sym004 12 mg/kg + FOLFIRI		Dose Level -1: Sym004 9 mg/kg + FOLFIRI
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/5 (40%)		0/5 (0%)
Serious Adverse Events
	Dose Level 1: Sym004 12 mg/kg + FOLFIRI		Dose Level -1: Sym004 9 mg/kg + FOLFIRI
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/5 (60%)		2/5 (40%)
Gastrointestinal disorders
Diarrhoea	2/5 (40%)		0/5 (0%)
Intestinal obstruction	0/5 (0%)		1/5 (20%)
Metabolism and nutrition disorders
Hyponatraemia	1/5 (20%)		0/5 (0%)
Nervous system disorders
Syncope	0/5 (0%)		1/5 (20%)
Other (Not Including Serious) Adverse Events
	Dose Level 1: Sym004 12 mg/kg + FOLFIRI		Dose Level -1: Sym004 9 mg/kg + FOLFIRI
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/5 (100%)		5/5 (100%)
Blood and lymphatic system disorders
Neutropenia	1/5 (20%)		4/5 (80%)
Lymphopenia	1/5 (20%)		0/5 (0%)
Eye disorders
Cataract	0/5 (0%)		1/5 (20%)
Gastrointestinal disorders
Diarrhoea	3/5 (60%)		2/5 (40%)
Stomatitis	3/5 (60%)		2/5 (40%)
Vomiting	2/5 (40%)		3/5 (60%)
Cheilitis	2/5 (40%)		1/5 (20%)
Nausea	2/5 (40%)		1/5 (20%)
Abdominal pain	1/5 (20%)		1/5 (20%)
Abdominal pain upper	1/5 (20%)		0/5 (0%)
Ascites	1/5 (20%)		0/5 (0%)
Chapped lips	1/5 (20%)		0/5 (0%)
Dry mouth	1/5 (20%)		0/5 (0%)
Odynophagia	0/5 (0%)		1/5 (20%)
Oral pain	1/5 (20%)		0/5 (0%)
General disorders
Fatigue	4/5 (80%)		2/5 (40%)
Asthenia	1/5 (20%)		1/5 (20%)
Non-cardiac chest pain	0/5 (0%)		2/5 (40%)
Oedema peripheral	2/5 (40%)		0/5 (0%)
Chest discomfort	0/5 (0%)		1/5 (20%)
Chills	0/5 (0%)		1/5 (20%)
Hepatobiliary disorders
Hyperbilirubinaemia	1/5 (20%)		0/5 (0%)
Infections and infestations
Conjunctivitis	0/5 (0%)		1/5 (20%)
Cystitis	0/5 (0%)		1/5 (20%)
Hordeolum	0/5 (0%)		1/5 (20%)
Influenza	0/5 (0%)		1/5 (20%)
Paronychia	0/5 (0%)		1/5 (20%)
Pneumonia	0/5 (0%)		1/5 (20%)
Injury, poisoning and procedural complications
Infusion related reaction	3/5 (60%)		3/5 (60%)
Investigations
Weight decreased	1/5 (20%)		1/5 (20%)
Aspartate aminotransferase increased	1/5 (20%)		0/5 (0%)
Blood bilirubin increased	1/5 (20%)		0/5 (0%)
Lipase increased	1/5 (20%)		0/5 (0%)
Weight increased	0/5 (0%)		1/5 (20%)
Metabolism and nutrition disorders
Decreased appetite	3/5 (60%)		0/5 (0%)
Hypomagnesaemia	3/5 (60%)		0/5 (0%)
Hyperglycaemia	1/5 (20%)		0/5 (0%)
Hyperkalaemia	1/5 (20%)		0/5 (0%)
Hypoalbuminaemia	1/5 (20%)		0/5 (0%)
Hypokalaemia	0/5 (0%)		1/5 (20%)
Hypophosphataemia	1/5 (20%)		0/5 (0%)
Hypovolaemia	1/5 (20%)		0/5 (0%)
Nervous system disorders
Dysgeusia	1/5 (20%)		1/5 (20%)
Syncope	1/5 (20%)		0/5 (0%)
Amnesia	0/5 (0%)		1/5 (20%)
Aphasia	0/5 (0%)		1/5 (20%)
Dizziness	0/5 (0%)		1/5 (20%)
Hypoaesthesia	0/5 (0%)		1/5 (20%)
Paraesthesia	0/5 (0%)		1/5 (20%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	1/5 (20%)		2/5 (40%)
Epistaxis	0/5 (0%)		2/5 (40%)
Nasal inflammation	0/5 (0%)		1/5 (20%)
Skin and subcutaneous tissue disorders
Dermatitis acneiform	2/5 (40%)		5/5 (100%)
Dry skin	0/5 (0%)		2/5 (40%)
Skin fissures	1/5 (20%)		1/5 (20%)
Dermatitis allergic	0/5 (0%)		1/5 (20%)
Dermatitis contact	0/5 (0%)		1/5 (20%)
Rash maculo-papular	1/5 (20%)		0/5 (0%)
Skin toxicity	0/5 (0%)		1/5 (20%)
Vascular disorders
Hypotension	1/5 (20%)		1/5 (20%)
Capillary leak syndrome	1/5 (20%)		0/5 (0%)

Limitations/Caveats

The trial was terminated as development of Sym004 in combination with FOLFIRI was discontinued. The primary objective changed to assess the safety of the treatment combination; collection of data for secondary and exploratory objectives was omitted.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Publications shall not disclose any Sponsor confidential information and property (not including the trial results). The Sponsor reserves the right to review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The Sponsor cannot require changes to the communication and cannot extend the embargo.