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

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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

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)

Condition or disease Intervention/treatment Phase
Treatment Related Cancer Drug: Panitumumab Drug: Irinotecan Drug: Folinic acid Drug: 5-FU Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 120 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: FIRE-5 -Study: Optimal Anti-EGFR Treatment of mCRC Patients With Low-Frequency RAS Mutation
Estimated Study Start Date : August 1, 2019
Estimated Primary Completion Date : August 1, 2024
Estimated Study Completion Date : August 1, 2026

Arm Intervention/treatment
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

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

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

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

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

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




Primary Outcome Measures :
  1. 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


Secondary Outcome Measures :
  1. Progression free survival (PFS) [ Time Frame: up to 60 months ]
    PFS, separately for each arm of patients with defined low-frequency RAS mutation

  2. Overall Survival (OS) [ Time Frame: up to 60 months ]
    OS, separately for each arm of patients with defined low-frequency RAS mutation

  3. 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

  4. 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.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04034173


Contacts
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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

Locations
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Germany
Ludwigs Maximialians University Not yet recruiting
Munich, Germany, 81377
Contact: Volker Heinemann, Prof. Dr.    +49 89 4400 ext 0    volker.heinemann@med.uni-muenchen.de   
Contact: Dominik Modest, PD Dr.    +49 89 4400 ext 0    dominik.modest@med.uni-muenchen.de   
Principal Investigator: Volker Heinemann, Prof. Dr.         
Sub-Investigator: Dominik Modest, PD Dr.         
Sponsors and Collaborators
Ludwig-Maximilians - University of Munich
Amgen
ClinAssess GmbH
Investigators
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Study Chair: Dominik Modest, PD Dr. Ludwigs Maximilians University Munich

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Responsible Party: PD Dr. med. Volker Heinemann, Director of the CCC-Munich at the LMU Munich, Ludwig-Maximilians - University of Munich
ClinicalTrials.gov Identifier: NCT04034173     History of Changes
Other Study ID Numbers: FIRE-5
First Posted: July 26, 2019    Key Record Dates
Last Update Posted: July 26, 2019
Last Verified: July 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by PD Dr. med. Volker Heinemann, Ludwig-Maximilians - University of Munich:
colorectal cancer
FIRE
low-RAS
mCRC
Panitumumab
Additional relevant MeSH terms:
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Neoplasms, Second Primary
Neoplasms
Leucovorin
Folic Acid
Irinotecan
Panitumumab
Levoleucovorin
Topoisomerase I Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Physiological Effects of Drugs
Antineoplastic Agents, Immunological
Antidotes
Protective Agents
Vitamin B Complex
Vitamins
Micronutrients
Nutrients
Growth Substances
Hematinics