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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04034173
Recruitment Status : Not yet recruiting
First Posted : July 26, 2019
Last Update Posted : July 26, 2019
Sponsor:
Collaborators:
Amgen
ClinAssess GmbH
Information provided by (Responsible Party):
PD Dr. med. Volker Heinemann, Ludwig-Maximilians - University of Munich

Tracking Information
First Submitted Date  ICMJE January 22, 2019
First Posted Date  ICMJE July 26, 2019
Last Update Posted Date July 26, 2019
Estimated Study Start Date  ICMJE August 1, 2019
Estimated Primary Completion Date August 1, 2024   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 24, 2019)
Overall Response Rate [ Time Frame: up to 60 months ]
As primary endpoint ORR according to RECIST 1.1 will be evaluated separately for each arm of patients with defined low-frequency RAS mutation
Original Primary Outcome Measures  ICMJE Same as current
Change History No Changes Posted
Current Secondary Outcome Measures  ICMJE
 (submitted: July 24, 2019)
  • Progression free survival (PFS) [ Time Frame: up to 60 months ]
    PFS, separately for each arm of patients with defined low-frequency RAS mutation
  • Overall Survival (OS) [ Time Frame: up to 60 months ]
    OS, separately for each arm of patients with defined low-frequency RAS mutation
  • Investigation of Early Tumor shrinkage (ETS) as an alternative early-on-treatment predictor of treatment efficacy [ Time Frame: up to 48 months ]
    ETS, separately for each group of patients with defined low-frequency RAS mutation
  • Investigation of Depth of Response (DpR) to define the nadir of tumour response [ Time Frame: up to 48 months ]
    DpR, separately for each arm of patients with defined low-frequency RAS Mutation.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Optimal Anti-EGFR Treatment of mCRC Patients With Low-Frequency RAS Mutation
Official Title  ICMJE FIRE-5 -Study: Optimal Anti-EGFR Treatment of mCRC Patients With Low-Frequency RAS Mutation
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)
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Treatment Related Cancer
Intervention  ICMJE
  • Drug: Panitumumab

    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.

  • Drug: Irinotecan
    Irinotecan 180 mg/m² BSA i.v., 30 - 90 min D1
  • Drug: Folinic acid
    Folinic acid (racemic) 400 mg/m²BSA i.v., 120 min D1
  • Drug: 5-FU
    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
Study Arms  ICMJE
  • RAS mutations frequency <= 7%

    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

    Interventions:
    • Drug: Panitumumab
    • Drug: Irinotecan
    • Drug: Folinic acid
    • Drug: 5-FU
  • RAS mutation frequency >7% to <=14%

    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

    Interventions:
    • Drug: Panitumumab
    • Drug: Irinotecan
    • Drug: Folinic acid
    • Drug: 5-FU
  • RAS mutation frequency >14% to <=20%

    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

    Interventions:
    • Drug: Panitumumab
    • Drug: Irinotecan
    • Drug: Folinic acid
    • Drug: 5-FU
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Not yet recruiting
Estimated Enrollment  ICMJE
 (submitted: July 24, 2019)
120
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE August 1, 2026
Estimated Primary Completion Date August 1, 2024   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Volker Heinemann, Prof. Dr. +49 89 4400 ext 0 volker.heinemann@med.med.uni-muenchen.de
Contact: Sebastian Stintzing, Prof. Dr. +49 30 45051 ext 3002 sebastian.stintzing@charite.de
Listed Location Countries  ICMJE Germany
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04034173
Other Study ID Numbers  ICMJE FIRE-5
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party PD Dr. med. Volker Heinemann, Ludwig-Maximilians - University of Munich
Study Sponsor  ICMJE Ludwig-Maximilians - University of Munich
Collaborators  ICMJE
  • Amgen
  • ClinAssess GmbH
Investigators  ICMJE
Study Chair: Dominik Modest, PD Dr. Ludwigs Maximilians University Munich
PRS Account Ludwig-Maximilians - University of Munich
Verification Date July 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP