Clinical Trials /

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

NCT04034173

Description:

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)

Related Conditions:
  • Colorectal Adenocarcinoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Optimal Anti-EGFR Treatment of mCRC Patients With Low-Frequency RAS Mutation
  • Official Title: FIRE-5 -Study: Optimal Anti-EGFR Treatment of mCRC Patients With Low-Frequency RAS Mutation

Clinical Trial IDs

  • ORG STUDY ID: FIRE-5
  • NCT ID: NCT04034173

Conditions

  • Treatment Related Cancer

Interventions

DrugSynonymsArms
PanitumumabRAS mutations frequency <= 7%
IrinotecanRAS mutations frequency <= 7%
Folinic acidRAS mutations frequency <= 7%
5-FURAS mutations frequency <= 7%

Purpose

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)

Trial Arms

NameTypeDescriptionInterventions
RAS mutations frequency <= 7%OtherPanitumumab 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
  • Panitumumab
  • Irinotecan
  • Folinic acid
  • 5-FU
RAS mutation frequency >7% to <=14%OtherPanitumumab 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
  • Panitumumab
  • Irinotecan
  • Folinic acid
  • 5-FU
RAS mutation frequency >14% to <=20%OtherPanitumumab 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
  • Panitumumab
  • Irinotecan
  • Folinic acid
  • 5-FU

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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall Response Rate
Time Frame:up to 60 months
Safety Issue:
Description:As primary endpoint ORR according to RECIST 1.1 will be evaluated separately for each arm of patients with defined low-frequency RAS mutation

Secondary Outcome Measures

Measure:Progression free survival (PFS)
Time Frame:up to 60 months
Safety Issue:
Description:PFS, separately for each arm of patients with defined low-frequency RAS mutation
Measure:Overall Survival (OS)
Time Frame:up to 60 months
Safety Issue:
Description:OS, separately for each arm of patients with defined low-frequency RAS mutation
Measure:Investigation of Early Tumor shrinkage (ETS) as an alternative early-on-treatment predictor of treatment efficacy
Time Frame:up to 48 months
Safety Issue:
Description:ETS, separately for each group of patients with defined low-frequency RAS mutation
Measure:Investigation of Depth of Response (DpR) to define the nadir of tumour response
Time Frame:up to 48 months
Safety Issue:
Description:DpR, separately for each arm of patients with defined low-frequency RAS Mutation.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Ludwig-Maximilians - University of Munich

Trial Keywords

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

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