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

L

Ludwig Maximilian University of Munich

Status and phase

Not yet enrolling
Phase 2

Conditions

Treatment Related Cancer

Treatments

Drug: 5-FU
Drug: Folinic acid
Drug: Irinotecan
Drug: Panitumumab

Study type

Interventional

Funder types

Other
Industry

Identifiers

Details and patient eligibility

About

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)

Enrollment

120 estimated patients

Sex

All

Ages

18+ years old

Volunteers

No Healthy Volunteers

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

Trial design

Primary purpose

Treatment

Allocation

Randomized

Interventional model

Parallel Assignment

Masking

None (Open label)

120 participants in 3 patient groups

RAS mutations frequency <= 7%
Other group
Description:
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
Treatment:
Drug: Folinic acid
Drug: Irinotecan
Drug: 5-FU
Drug: Panitumumab
RAS mutation frequency >7% to <=14%
Other group
Description:
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
Treatment:
Drug: Folinic acid
Drug: Irinotecan
Drug: 5-FU
Drug: Panitumumab
RAS mutation frequency >14% to <=20%
Other group
Description:
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
Treatment:
Drug: Folinic acid
Drug: Irinotecan
Drug: 5-FU
Drug: Panitumumab

Trial contacts and locations

1

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Central trial contact

Sebastian Stintzing, Prof. Dr.; Volker Heinemann, Prof. Dr.

Data sourced from clinicaltrials.gov

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