Sym004 in Combination With FOLFIRI in Metastatic Colorectal Cancer Patients

• ClinicalTrials.gov Identifier: NCT02568046
• Recruitment Status: Terminated
• First Posted: October 5, 2015
• Results First Posted: January 9, 2019
• Last Update Posted: March 26, 2019
• Sponsor: Symphogen A/S
• Information provided by (Responsible Party): Symphogen A/S

Tracking Information

• First Submitted Date: September 30, 2015
• First Posted Date: October 5, 2015
• Results First Submitted Date: December 19, 2018
• Results First Posted Date: January 9, 2019
• Last Update Posted Date: March 26, 2019
• Actual Study Start Date: March 15, 2016
• Actual Primary Completion Date: May 15, 2017 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 8, 2019)

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). [ Time Frame: 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.

Original Primary Outcome Measures (submitted: October 1, 2015)

• Phase 1b:Dose-Limiting Toxicities (DLT) observed during Cycle 1 of Sym004 administration in combination with FOLFIRI. [ Time Frame: 1 year ]
• Phase 2a: Confirmed objective antitumor response. [ Time Frame: 1 year ]

• Current Secondary Outcome Measures: Not Provided

Original Secondary Outcome Measures (submitted: October 1, 2015)

• Number of participants with treatment-related adverse events as assessed by NCI-CTCAE v4.03 [ Time Frame: 2 Years ]
  Assess the safety and tolerability of Sym004 when administered at the RP2D in combination with FOLFIRI.

  • Nature, incidence and severity of AEs measured from baseline to end of trial participation NOTE: Adverse Events are graded by the Investigator according to the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE v.4.03, in the following referred to as CTCAE)
  • AEs leading to dose-reductions, dose delays and permanent treatment cessation
  • Changes in safety laboratory values from baseline to end of trial participation
  • Changes in vital signs and physical examinations from baseline to end of trial participation
  • Occurrence of anti-drug antibodies (ADA) to Sym004 measured in serum at selected timepoints from baseline to end of trial participation
• Dose-normalized area under the concentration-time curve from End of Infusion (EOI) to 336 hours (AUCNorm, 0-336h) [ Time Frame: 1 Years ]
• Preliminary evaluation of the antineoplastic effect of Sym004 plus FOLFIRI as assessed by the Response Evaluation Criteria in Solid Tumors (RECIST v1.1) [ Time Frame: 2 Years ]
• Area under the concentration-time curve from EOI to 336 hours (AUC0-336h) [ Time Frame: 1 Year ]
• Maximum concentration (Cmax) [ Time Frame: 1 Year ]
• Time to reach maximum concentration (Tmax) [ Time Frame: 1 Year ]
• Trough concentration (Ctrough) [ Time Frame: 1 Year ]
• Elimination half-life (T½) [ Time Frame: 1 Year ]
• Clearance (CL) [ Time Frame: 1 Year ]
• Volume of distribution (V) [ Time Frame: 1 Year ]
• Urine and peripheral blood collection for assessment of biomarkers related to the EGFR pathway [ Time Frame: 2 Years ]
• Other potential biomarkers to be determined (i.e. genes, gene transcripts and proteins of the receptor tyrosine kinases (RTKs)) [ Time Frame: 2 Years ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Sym004 in Combination With FOLFIRI in Metastatic Colorectal Cancer Patients
• 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
• 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.

• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: Non-Randomized; Intervention Model: Sequential Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Metastatic Colorectal Cancer

Intervention

• 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)

Study Arms

• Experimental: Sym004 12 mg/kg + FOLFIRI
  Phase 1b, Dose-Escalation: Dose Level 1
  Interventions:

  • Drug: Sym004
  • Drug: FOLFIRI
• Experimental: Sym004 9 mg/kg + FOLFIRI
  Phase 1b, Dose-Escalation: Dose Level -1
  Interventions:

  • Drug: Sym004
  • Drug: FOLFIRI
• Experimental: Sym004 (RP2D) + FOLFIRI
  Phase 2a, Dose-Expansion: Sym004 in the RP2D in combination with FOLFIRI
  Interventions:

  • Drug: Sym004
  • Drug: FOLFIRI

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Terminated
• Actual Enrollment (submitted: January 17, 2017): 10
• Original Estimated Enrollment (submitted: October 1, 2015): 50
• Actual Study Completion Date: May 5, 2018
• Actual Primary Completion Date: May 15, 2017 (Final data collection date for primary outcome measure)

Eligibility 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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Spain, United States

Administrative Information

• NCT Number: NCT02568046
• Other Study ID Numbers: Sym004-09; 2015-003047-19 ( EudraCT Number )
• Has Data Monitoring Committee: No

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

• Plan to Share IPD: Undecided

• Current Responsible Party: Symphogen A/S
• Original Responsible Party: Same as current
• Current Study Sponsor: Symphogen A/S
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

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

• PRS Account: Symphogen A/S
• Verification Date: March 2019