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

NCT04034173 | Not Yet Recruiting Phase 2

• 1 other identifier: FIRE-5
• Study Type: interventional
• Target: 120
• Locations: 1 country
• Sites: 1

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

Keywords

colorectal cancer; FIRE; low-RAS; mCRC; Panitumumab

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (4)

• Progression free survival (PFS)

  up to 60 months

• Overall Survival (OS)

  up to 60 months

• Investigation of Early Tumor shrinkage (ETS) as an alternative early-on-treatment predictor of treatment efficacy

  up to 48 months

• Investigation of Depth of Response (DpR) to define the nadir of tumour response

  up to 48 months

Study Arms (3)

RAS mutations frequency <= 7%

OTHER

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; Drug: Irinotecan; Drug: Folinic acid; Drug: 5-FU

RAS mutation frequency >7% to <=14%

OTHER

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; Drug: Irinotecan; Drug: Folinic acid; Drug: 5-FU

RAS mutation frequency >14% to <=20%

OTHER

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; Drug: Irinotecan; Drug: Folinic acid; Drug: 5-FU

Interventions

Panitumumab 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.

RAS mutation frequency >14% to <=20%; RAS mutation frequency >7% to <=14%; RAS mutations frequency <= 7%

Irinotecan DRUG

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

RAS mutation frequency >14% to <=20%; RAS mutation frequency >7% to <=14%; RAS mutations frequency <= 7%

Folinic acid DRUG

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

RAS mutation frequency >14% to <=20%; RAS mutation frequency >7% to <=14%; RAS mutations frequency <= 7%

5-FU 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%; RAS mutation frequency >7% to <=14%; RAS mutations frequency <= 7%

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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:

You may not qualify if:

• 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
• 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

Sponsors & Collaborators

• Ludwig-Maximilians - University of Munich: lead
• Amgen: collaborator
• ClinAssess GmbH: collaborator

Study Sites (1)

Ludwigs Maximialians University

Munich, 81377, Germany

Location

MeSH Terms

Conditions

Neoplasms, Second Primary; Colorectal Neoplasms

Interventions

Panitumumab; Irinotecan; Leucovorin; Fluorouracil

Condition Hierarchy (Ancestors)

Neoplasms; Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Camptothecin; Alkaloids; Heterocyclic Compounds; Formyltetrahydrofolates; Tetrahydrofolates; Folic Acid; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Coenzymes; Enzymes and Coenzymes; Uracil; Pyrimidinones; Pyrimidines; Heterocyclic Compounds, 1-Ring

Study Officials

• Dominik Modest, PD Dr.

  Ludwigs Maximilians University Munich

  STUDY CHAIR

Central Study Contacts

Volker Heinemann, Prof. Dr.

CONTACT

+49 89 4400; volker.heinemann@med.med.uni-muenchen.de

Sebastian Stintzing, Prof. Dr.

CONTACT

+49 30 45051; sebastian.stintzing@charite.de

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Director of the CCC-Munich at the LMU Munich

Study Record Dates

• First Submitted: January 22, 2019
• First Posted: July 26, 2019
• Study Start: August 1, 2019
• Primary Completion: August 1, 2024
• Study Completion (Estimated): August 1, 2026
• Last Updated: July 26, 2019

Record last verified: 2019-07

Data Sharing

• IPD Sharing: Will not share

Locations

DE (1)