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

• Status: Not yet recruiting
• Trial end date: 2026-08-01
• Target enrollment: 0
• Participant gender: All

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)

• Phase: Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Ludwig-Maximilians - University of Munich
• Collaborators: Amgen; ClinAssess GmbH
• Treatments: Folic Acid; Irinotecan; Leucovorin; Levoleucovorin; Panitumumab

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