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

NCT ID: NCT04034173

Last Updated: 2019-07-26

Basic Information

• Recruitment Status: NOT_YET_RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 120 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-08-01
• Study Completion Date: 2026-08-01

Brief Summary

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)

Conditions

Treatment Related Cancer

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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

Group Type: OTHER

Panitumumab

Intervention Type: DRUG

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.

Irinotecan

Intervention Type: DRUG

Irinotecan 180 mg/m² BSA i.v., 30 - 90 min D1

Folinic acid

Intervention Type: DRUG

Folinic acid (racemic) 400 mg/m²BSA i.v., 120 min D1

5-FU

Intervention Type: DRUG

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

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

Group Type: OTHER

Panitumumab

Intervention Type: DRUG

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.

Irinotecan

Intervention Type: DRUG

Irinotecan 180 mg/m² BSA i.v., 30 - 90 min D1

Folinic acid

Intervention Type: DRUG

Folinic acid (racemic) 400 mg/m²BSA i.v., 120 min D1

5-FU

Intervention Type: DRUG

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

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

Group Type: OTHER

Panitumumab

Intervention Type: DRUG

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.

Irinotecan

Intervention Type: DRUG

Irinotecan 180 mg/m² BSA i.v., 30 - 90 min D1

Folinic acid

Intervention Type: DRUG

Folinic acid (racemic) 400 mg/m²BSA i.v., 120 min D1

5-FU

Intervention Type: DRUG

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

Interventions

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.

Intervention Type: DRUG

Irinotecan

Irinotecan 180 mg/m² BSA i.v., 30 - 90 min D1

Intervention Type: DRUG

Folinic acid

Folinic acid (racemic) 400 mg/m²BSA i.v., 120 min D1

Intervention Type: 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

Intervention Type: DRUG

Eligibility Criteria

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Amgen

INDUSTRY

Sponsor Role: collaborator

ClinAssess GmbH

INDUSTRY

Sponsor Role: collaborator

Ludwig-Maximilians - University of Munich

OTHER

Sponsor Role: lead

Responsible Party

PD Dr. med. Volker Heinemann

Director of the CCC-Munich at the LMU Munich

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Dominik Modest, PD Dr.

Role: STUDY_CHAIR

Ludwigs Maximilians University Munich

Locations

Ludwigs Maximialians University

Munich, , Germany

Countries

Germany

Central Contacts

Volker Heinemann, Prof. Dr.

Role: CONTACT

volker.heinemann@med.med.uni-muenchen.de

+49 89 4400 ext. 0

Sebastian Stintzing, Prof. Dr.

Role: CONTACT

sebastian.stintzing@charite.de

+49 30 45051 ext. 3002

Facility Contacts

Volker Heinemann, Prof. Dr.

Role: primary

volker.heinemann@med.uni-muenchen.de

+49 89 4400 ext. 0

Dominik Modest, PD Dr.

Role: backup

dominik.modest@med.uni-muenchen.de

+49 89 4400 ext. 0

Other Identifiers

FIRE-5

Identifier Type: -

Identifier Source: org_study_id