Optimal Anti-EGFR Treatment of mCRC Patients With Low-Frequency RAS Mutation

FIRE-5 -Study: Optimal Anti-EGFR Treatment of mCRC Patients With Low-Frequency RAS Mutation

The present hypothesis is that anti-EGFR agents are active in tumors with low-level RAS mutation when the majority of tumor cells is still sensitive. While response rate may be high and may reflect sensitivity to anti-EGFR agents, PFS is anticipated to be shorter than in RAS wild-type patients due to the faster development of resistance when sensitive cells are eradicated and when the RAS-mutant anti-EGFR resistant clones become predominant.

The characteristics of low-level RAS mutant tumors would be:

• Objective response rate (ORR) high (reflecting the sensitive clone)
• Progression-free survival (PFS) short (reflecting the more rapid outgrowth of RAS mutant clones)

Study Overview

• Status: Not yet recruiting
• Conditions: Treatment Related Cancer
• Intervention / Treatment: Drug: Panitumumab; Drug: Irinotecan; Drug: Folinic acid; Drug: 5-FU

• Study Type: Interventional
• Enrollment (Anticipated): 120
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Volker Heinemann, Prof. Dr.; Phone Number: +49 89 4400; Email: volker.heinemann@med.med.uni-muenchen.de
• Study Contact Backup: Name: Sebastian Stintzing, Prof. Dr.; Phone Number: 3002 +49 30 45051; Email: sebastian.stintzing@charite.de

Study Locations

• Germany
  • Munich, Germany, 81377
    • Ludwigs Maximialians University
    • Contact: Volker Heinemann, Prof. Dr.; Phone Number: +49 89 4400; Email: volker.heinemann@med.uni-muenchen.de
    • Contact: Dominik Modest, PD Dr.; Phone Number: +49 89 4400; Email: dominik.modest@med.uni-muenchen.de
    • Principal Investigator: Volker Heinemann, Prof. Dr.
    • Sub-Investigator: Dominik Modest, PD Dr.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Histologically confirmed, UICC stage IV metastatic adenocarcinoma of the colon or rectum
• Primarily non-resectable metastases or surgical resection refused by the patient
• RAS mutation determined by the local pathology
• Age ≥18
• ECOG performance status 0-2
• Patients suitable for chemotherapy administration
• Patient's written declaration of consent obtained
• Estimated life expectancy > 3 months
• Presence of at least one measurable reference lesion according to the RECIST 1.1 criteria
• Primary tumor tissue available and patient consents to storage and molecular and genetic profiling of tumor material. Molecular profiling of blood samples is optionally performed.

• Adequate bone marrow function:

  • Leukocytes ≥ 3.0 x 109/L with neutrophils ≥ 1.5 x 109/L
  • Thrombocytes ≥ 100 x 109/L
  • Haemoglobin ≥ 5.6 mmol/L (equivalent to 9 g/dL)

• Adequate hepatic function:

  • Serum bilirubin ≤ 1.5 x upper limit of normal (ULN)
  • ALAT and ASAT ≤ 2.5 x ULN (in the presence of hepatic metastases, ALAT and ASAT ≤ 5 x ULN)

• Adequate renal function:

  ▫ Creatinine clearance (calculated according to Cockcroft and Gault) ≥ 50 mL/min

• No previous chemotherapy for metastatic disease. Patient with need of immediate treatment (high tumor load, symptoms) may have received one application of FOLFIRI prior to study treatment.

Exclusion Criteria:

• Previous chemotherapy for metastatic disease with the exception of one cycle of FOLFIRI (e.g. while waiting for the result of RAS mutation frequency).
• Patients planned to be treated with FOLFOX or another oxaliplatin-based regimen as first-line treatment
• Primarily resectable metastases and the patient agrees to resection
• Grade III or IV heart failure (NYHA classification)
• Medical or psychological impairments associated with restricted ability to give consent or not allowing conduct of the study
• Previous chemotherapy for the colorectal cancer with the exception of adjuvant treatment, completed at least 6 months before entering the study
• Participation in an investigational clinical study or experimental drug treatment within 30 days prior to study inclusion or within a period of 5 half-lives of the substances administered in the investigational clinical study or during an experimental drug treatment prior to inclusion in the study, depending on which period is longest
• Known hypersensitivity or allergic reaction to any of the following substances: 5-fluorouracil, folinic acid, panitumumab, irinotecan, and chemically related substances and/or hypersensitivity to any of the excipients of any of the aforementioned substances including known hypersensitivity reactions to monoclonal antibodies NCI CTCAE Grade ≥ 3.
• Known hypersensitivity to Chinese hamster ovary cell (CHO) - cellular products or other recombinant human or humanised monoclonal antibodies
• History of uncontrolled bronchial asthma
• Patients with interstitial pneumonitis or pulmonary fibrosis
• Patients with known brain metastasis
• History of acute or subacute intestinal occlusion or chronic inflammatory bowel disease or chronic diarrhoea
• Symptomatic peritoneal carcinomatosis
• Severe, non-healing wounds, ulcers or bone fractures
• Patients with acute or chronic infection requiring systemic therapy
• Known history of positive testing for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS)
• Active or chronic Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection (positive HBV surface antigen or HCV RNA if anti-HCV antibody screening test positive; serologic tests required in patients who receive study treatment).
• Known DPD deficiency (specific screening not required)
• Known glucuronidation deficiency (Gilbert's syndrome);(specific screening not required
• Treatment with sorivudine or brivudine within 28 days before study enrollment or requirement for concomitant antiviral treatment with sorivudine or brivudine
• History of a second primary malignancy during the past 5 years before inclusion in the study or during participation in the study, with the exception of a basal cell or squamous cell carcinoma of the skin or cervical carcinoma in situ, if these were treated curatively.
• Known previous or ongoing alcohol or drug abuse
• Pregnant or breast-feeding patients
• Any other severe concomitant disease or disorder which, in the investigator's opinion, could influence the patient's ability to participate in the study or influence his/her safety during the study or interfere with interpretation of study results
• Both, absent and restricted legal capacity

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
OTHER: RAS mutations frequency <= 7%; Panitumumab 6 mg/kg BW as 60-min i.v. infusion* D1 *If the 1st infusion is well tolerated, all subsequent infusions can be applied over 30-60 minutes. Followed by FOLFIRI regimen; Irinotecan 180 mg/m² BSA i.v., 30 - 90 min D1; Folinic acid (racemic) 400 mg/m²BSA i.v., 120 min D1; 5-FU 400 mg/m² BSA, bolus, D1; 5-FU 2400 mg/m² BSA i.v. infusion over a period of 46 h D1-2 q day 14	Drug: Panitumumab; Panitumumab 6 mg/kg BW as 60-min i.v. infusion* D1 *If the 1st infusion is well tolerated, all subsequent infusions can be applied over 30-60 minutes.; Drug: Irinotecan; Irinotecan 180 mg/m² BSA i.v., 30 - 90 min D1; Drug: Folinic acid; Folinic acid (racemic) 400 mg/m²BSA i.v., 120 min D1; Drug: 5-FU; 5-FU 400 mg/m² BSA, bolus, D1 5-FU 2400 mg/m² BSA i.v. infusion over a period of 46 h D1-2
OTHER: RAS mutation frequency >7% to <=14%; Panitumumab 6 mg/kg BW as 60-min i.v. infusion* D1 *If the 1st infusion is well tolerated, all subsequent infusions can be applied over 30-60 minutes. Followed by FOLFIRI regimen; Irinotecan 180 mg/m² BSA i.v., 30 - 90 min D1; Folinic acid (racemic) 400 mg/m²BSA i.v., 120 min D1; 5-FU 400 mg/m² BSA, bolus, D1; 5-FU 2400 mg/m² BSA i.v. infusion over a period of 46 h D1-2 q day 14	Drug: Panitumumab; Panitumumab 6 mg/kg BW as 60-min i.v. infusion* D1 *If the 1st infusion is well tolerated, all subsequent infusions can be applied over 30-60 minutes.; Drug: Irinotecan; Irinotecan 180 mg/m² BSA i.v., 30 - 90 min D1; Drug: Folinic acid; Folinic acid (racemic) 400 mg/m²BSA i.v., 120 min D1; Drug: 5-FU; 5-FU 400 mg/m² BSA, bolus, D1 5-FU 2400 mg/m² BSA i.v. infusion over a period of 46 h D1-2
OTHER: RAS mutation frequency >14% to <=20%; Panitumumab 6 mg/kg BW as 60-min i.v. infusion* D1 *If the 1st infusion is well tolerated, all subsequent infusions can be applied over 30-60 minutes. Followed by FOLFIRI regimen; Irinotecan 180 mg/m² BSA i.v., 30 - 90 min D1; Folinic acid (racemic) 400 mg/m²BSA i.v., 120 min D1; 5-FU 400 mg/m² BSA, bolus, D1; 5-FU 2400 mg/m² BSA i.v. infusion over a period of 46 h D1-2 q day 14	Drug: Panitumumab; Panitumumab 6 mg/kg BW as 60-min i.v. infusion* D1 *If the 1st infusion is well tolerated, all subsequent infusions can be applied over 30-60 minutes.; Drug: Irinotecan; Irinotecan 180 mg/m² BSA i.v., 30 - 90 min D1; Drug: Folinic acid; Folinic acid (racemic) 400 mg/m²BSA i.v., 120 min D1; Drug: 5-FU; 5-FU 400 mg/m² BSA, bolus, D1 5-FU 2400 mg/m² BSA i.v. infusion over a period of 46 h D1-2

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Response Rate	As primary endpoint ORR according to RECIST 1.1 will be evaluated separately for each arm of patients with defined low-frequency RAS mutation	up to 60 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression free survival (PFS)	PFS, separately for each arm of patients with defined low-frequency RAS mutation	up to 60 months
Overall Survival (OS)	OS, separately for each arm of patients with defined low-frequency RAS mutation	up to 60 months
Investigation of Early Tumor shrinkage (ETS) as an alternative early-on-treatment predictor of treatment efficacy	ETS, separately for each group of patients with defined low-frequency RAS mutation	up to 48 months
Investigation of Depth of Response (DpR) to define the nadir of tumour response	DpR, separately for each arm of patients with defined low-frequency RAS Mutation.	up to 48 months

Collaborators and Investigators

• Sponsor: Ludwig-Maximilians - University of Munich
• Collaborators: Amgen; ClinAssess GmbH
• Investigators: Study Chair: Dominik Modest, PD Dr., Ludwigs Maximilians University Munich

Study record dates

Study Major Dates

• Study Start (ANTICIPATED): August 1, 2019
• Primary Completion (ANTICIPATED): August 1, 2024
• Study Completion (ANTICIPATED): August 1, 2026

Study Registration Dates

• First Submitted: January 22, 2019
• First Submitted That Met QC Criteria: July 24, 2019
• First Posted (ACTUAL): July 26, 2019

Study Record Updates

• Last Update Posted (ACTUAL): July 26, 2019
• Last Update Submitted That Met QC Criteria: July 24, 2019
• Last Verified: July 1, 2019

More Information

Terms related to this study

• Keywords: colorectal cancer; Panitumumab; mCRC; FIRE; low-RAS
• Additional Relevant MeSH Terms: Neoplasms; Neoplasms, Second Primary; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protective Agents; Topoisomerase Inhibitors; Antineoplastic Agents, Immunological; Micronutrients; Vitamins; Topoisomerase I Inhibitors; Antidotes; Vitamin B Complex; Hematinics; Leucovorin; Irinotecan; Levoleucovorin; Folic Acid; Panitumumab
• Other Study ID Numbers: FIRE-5

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No