RAS-mutant metastatic colorectal cancer MedDRA version: 21.0 Level: LLT Classification code 10052362 Term: Metastatic colorectal cancer System Organ Class: 100000004864
Conditions
Interventions
Trade Name: Vectibix
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: PANITUMUMAB
CAS Number: 339177-26-3
Current Sponsor code: PANITUMUMAB
Concentration unit: mg/ml mil
Sponsors
Klinikum der Universität München, Ludwig-Maximilians-Universität München, represented by the managing medical director
Eligibility
Sex/Gender
All
Inclusion 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 • 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 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 =65 years) yes F.1.3.1 Number of subjects for this age range
Exclusion criteria
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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: The primary objective of the study is to define an optimal cut-off for anti-EGFR treatment with panitumumab in combination with FOLFIRI of patients with low-frequency RAS mutation defined by digital Next Generation Sequencing (dNGS) using the Oncomine cfDNA pan-cancer panel assay (52 genes) on an Ion Torrent S5 Prime platform. This assay combined with unique molecular identifier (UMI) or molecular barcode technique allows the exact quantification of mutation frequencies.;Secondary Objective: • To analyze efficacy parameters (progression-free survival [PFS] , overall survival [OS], early tumor shrinkage [ETS] , Depth of response [DpR]) in patients with low-frequency RAS-mutation treated with panitumumab in combination with FOLFIRI • To determine retrospectively a cut-off frequency for low-frequency RAS mutation as limit for treatment with anti EGFR agents • To analyze safety and tolerance of the first-line treatment ;Primary end point(s): As primary endpoint ORR according to RECIST 1.1 will be evaluated separately for each group of patients with defined low-frequency RAS mutation (Groups A, B and C). ;Timepoint(s) of evaluation of this end point: 8 weeks after start of panitumumab and every 12 Treatment weeks thereafter | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Efficacy variables: • PFS, separately for each group of patients with defined low-frequency RAS mutation (Groups A, B and C) • OS, separately for each group of patients with defined low-frequency RAS mutation (Groups A, B and C) • ETS, separately for each group of patients with defined low-frequency RAS mutation (Groups A, B and C) • DpR, separately for each group of patients with defined low-frequency RAS mutation (Groups A, B and C) • Retrospectively determined optimal cut-off frequency for low-frequency RAS mutation leading to RR, PFS and OS in ranges comparable to that of RAS-wildtype first-line patients treated with panitumumab in combination with chemotherapy • Prospective analysis of tumor marker level evolution (CEA and CA 19-9) Safety variables: • Type, incidence, relatedness, and severity of adverse events according to NCI CTCAE version 5.0;Timepoint(s) of evaluation of this end point: - Treatment Phase - 8 weeks after start of panitumumab and every 12 Treatment weeks thereafter - until progression - Follow-up Phase | — |
Countries
Germany
Contacts
Public ContactStudy secretariat
Klinikum der Ludwig-Maximilians-Universität München, Medizinische Klinik III, Campus Großhadern
Outcome results
None listed