Optimal anti-EGFR Treatment of mCRC Patients with Low-Frequency RAS Mutatio

Phase 1

Active, not recruiting

• Conditions: RAS-mutant metastatic colorectal cancer; MedDRA version: 21.0Level: LLTClassification code 10052362Term: Metastatic colorectal cancerSystem Organ Class: 100000004864; Therapeutic area: Diseases [C] - Cancer [C04]

• Registration Number: EUCTR2018-002849-11-DE
• Lead Sponsor: Klinikum der Universität München, Ludwig-Maximilians-Universität München, represented by the managing medical director

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Study Start: 2018-12-27
• Last Update Posted: 28 June 2021

Recruitment & Eligibility

• Status: Not Recruiting
• Sex: All
• Target Recruitment: 135

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
• Documented RAS mutation determined by the local pathology
• Low level RAS mutation in the tumor (KRAS and NRAS exon 2, 3, 4) with frequency of RAS mutation = 20 % according to the central or local molecular pathology report. Tumour material (biopsy specimen and/or surgical specimen taken at the time of primary diagnosis) will be used.
Note: The frequency of the RAS mutation (number of mutant RAS alleles/number of analyzed RAS alleles) analyzed by a digital NGS method has to be <20% (or <0.2). The coverage of the NGS method should be >200 copies with respect to the RAS gene. Therefore the number of analyzed RAS genes, the number of RAS mutant alleles and the coverage has to be evident in the local pathological report.
Refer to Section 8.4.1
• 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
• Tumor tissue from primary tumor or metastasis available and patient consents to storage and molecular and genetic profiling of tumor material. Molecular profiling of blood samples is optionally performed.
• Females of childbearing potential (FCBPs) and men must agree to use two highly effective contraceptive measures simultaneously (Pearl index <1) or practice true abstinence from any heterosexual intercourse for the duration of the study treatment and for at least 6 months after last administration of study medication. Complete sexual abstinence is acceptable only if the subject is refraining from heterosexual intercourse during the entire study treatment and up to 6 months after the discontinuation of all study drugs and the reliability of sexual abstinence is in line with the preferred and usual lifestyle of the subject. A woman will be considered as being of childbearing potential unless she is at least 50 years old and moreover has gone through menopause for at least 2 years or has been surgically sterilised.
• 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 two cycles of FOLFIRI prior to study treatment.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range

Exclusion Criteria

• Previous chemotherapy for metastatic disease with the exception of two 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
• Additional cancer treatment (chemotherapy, radiation, immunotherapy or hormone treatment) during the study treatment (treatments that are conducted as part of an anthroposophic or homeopathic treatment approach, e.g. mistletoe therapy do not represent an exclusion criterion)
• 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 or simultaneous participation in another investigational clinical study while taking part in 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
• 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).
• Known complete DPD deficiency (specific screening as recommended in the respective SmPC for 5-FU in effect; patients with a known complete DPD deficiency must be excluded; patients with a known partial DPD deficiency may be included at the discretion of the investigator)
• 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 b

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified