Clinical Trials /

Anti-EGFR Therapy Rechallenge in Combination With Chemotherapy in Patients With Advanced Colorectal Cancer

NCT03311750

Description:

A-REPEAT (Anti-Epidermal Growth Factor Receptor -EGFR- rechallenge and plasma genotyping of patients with advanced colorectal tumors) is a Greek, investigator-initiated, single arm open-label phase II study of anti-EGFR therapy rechallenge in combination with chemotherapy in patients with advanced colorectal cancer. Patients with a metastatic, histologically proven colorectal carcinoma RAS wild type will be treated with a combination of panitumumab and third-line irinotecan-based or oxaliplatin-based chemotherapy (FOLFOX,FOLFIRI or irinotecan monotherapy).

Related Conditions:
  • Colorectal Adenocarcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Anti-EGFR Therapy Rechallenge in Combination With Chemotherapy in Patients With Advanced Colorectal Cancer
  • Official Title: Single-arm Phase II Study of Panitumumab Rechallenge in Combination With Oxaliplatin or Irinotecan-based Chemotherapy in Patients With RAS Wild Type Advanced Colorectal Cancer.

Clinical Trial IDs

  • ORG STUDY ID: HE6B/16
  • SECONDARY ID: 2016-003644-37
  • NCT ID: NCT03311750

Conditions

  • Advanced Colorectal Cancer

Interventions

DrugSynonymsArms
PanitumumabVectibixPanitumumab

Purpose

A-REPEAT (Anti-Epidermal Growth Factor Receptor -EGFR- rechallenge and plasma genotyping of patients with advanced colorectal tumors) is a Greek, investigator-initiated, single arm open-label phase II study of anti-EGFR therapy rechallenge in combination with chemotherapy in patients with advanced colorectal cancer. Patients with a metastatic, histologically proven colorectal carcinoma RAS wild type will be treated with a combination of panitumumab and third-line irinotecan-based or oxaliplatin-based chemotherapy (FOLFOX,FOLFIRI or irinotecan monotherapy).

Detailed Description

      Few clinical studies have evaluated the role of anti-EGFR therapy rechallenge in metastatic
      colorectal cancer patients and there is no prospective clinical trial assessing the activity
      of treatment rechallenge with panitumumab-based therapy after initial progression. This study
      aims at exploring the concept of evolution and expansion of RAS wild type clones in order to
      restore sensitivity of the tumor to prior anti-EGFR therapy after a time interval in which a
      different, non-anti-EGFR second-line therapy is administered. Based on aforementioned data,
      it is hypothesized that rescue through rechallenge with panitumumab-based third-line therapy
      combined with chemotherapy could be associated with further response and clinical benefit. A
      significant component of the proposed prospective trial is exploratory translational: cell
      free plasma and platelet-based genotyping for genetic mutations in different time points will
      be undertaken in order to study the genetic composition of the metastatic tumour at
      initiation of and at progression through, anti-EGFR rechallenge therapy.

      Primary endpoint will be to evaluate the efficacy, in terms of overall response rate, of the
      addition of panitumumab rechallenge to standard third-line irinotecan-based or
      oxaliplatin-based chemotherapy in patients with metastatic colorectal cancer initially
      treated with, and benefiting from, first line irinotecan-based or oxaliplatin-based
      chemotherapy combined with an anti-EGFR monoclonal antibody, followed by second line
      chemotherapy not containing anti-EGFR agents.

      Exploratory endpoints include to identify, in the context of translational research, tumour
      tissue and blood-based biomarkers with prognostic/predictive significance in patients with
      metastatic colorectal cancer treated with rechallenge panitumumab in combination with
      standard third-line irinotecan-based or oxaliplatin-based chemotherapy, who were initially
      treated with, and benefiting from, first line irinotecan-based or oxaliplatin-based
      chemotherapy combined with an anti-EGFR monoclonal antibody, followed by second line
      chemotherapy not containing anti-EGFR agent.
    

Trial Arms

NameTypeDescriptionInterventions
PanitumumabExperimentalOn day 1 of each cycle patients will receive panitumumab followed by 5-fluorouracil and leucovorin in combination with either irinotecan (FOLFIRI regimen) or oxaliplatin (FOLFOX regimen) or followed by irinotecan monotherapy. This treatment will be repeated every 2 weeks for FOLFIRI and FOLFOX regimens and every 3 weeks for irinotecan monotherapy.
  • Panitumumab

Eligibility Criteria

        Inclusion Criteria:

          -  Signed and dated informed consent, and willing and able to comply with protocol
             requirements,

          -  Histologically proven adenocarcinoma of the colon and/or rectum,

          -  Metastatic disease confirmed clinically/radiologically,

          -  Patients with Formalin-Fixed, Paraffin-Embedded tissue RAS wild type colorectal cancer
             at diagnosis, who had initial clinical benefit [complete response, partial response or
             stable disease] during first line irinotecan-based or oxaliplatin-based chemotherapy
             in combination with cetuximab or panitumumab,

          -  First- line treatment duration (FOLFIRI, FOLFOX with anti-EGFR monoclonal antibody, of
             whom at least 2/3 of cases will have involved panitumumab) of at least 3 months,

          -  Second line therapy consisting of any chemotherapy (with or without Bevacizumab)
             definitely without anti-EGFR therapy of at least 2 months, followed by disease
             progression,

          -  Eligible third line regimens include FOLFIRI or Irinotecan or FOLFOX, according to
             standard practice and approved indications. It is required that the third line regimen
             used will be different from the second line and similar to the first line regimen,

          -  At least one measurable or evaluable lesion as assessed by computed tomography scan or
             Magnetic Resonance Imaging according to RECIST version 1.1,

          -  First course of treatment planned less than 1 week (7 days) after registration,

          -  Age ≥18 years,

          -  Eastern Cooperative Oncology Group (ECOG) Performance status 0-2,

          -  Adequate hematological status: neutrophils (ANC) ≥1.5x109/L; platelets ≥100x109/L;
             haemoglobin ≥9g/dL,

          -  Adequate renal function: serum creatinine level <1.5 mg/dL or Glomelular Filtration
             Rate (GFR) >50mL/min by Cockroft/Gault formula,

          -  Adequate liver function: serum bilirubin ≤1.5 x upper normal limit (ULN), alkaline
             phosphatase, Aspartate aminotransferase (AST), Alanine aminotransferase (ALT) <5xULN,

          -  Regular follow up feasible.

          -  For female patients of childbearing potential, negative serum or urine pregnancy test
             within 1 week (7 days) prior of starting study treatment

          -  Female patients must commit to using reliable and appropriate methods of contraception
             until at least three months after the end of study treatment (when applicable). Male
             patients with a partner of childbearing potential must agree to use contraception in
             addition to having their partner use another contraceptive method during the trial,

          -  Archival tumor tissue is required for exploratory research at enrolment,

          -  Ability to undergo plasma sampling during the therapy course.

        Exclusion Criteria:

          -  Presence of central nervous system metastasis unless adequately treated (e.g. non
             irradiated central nervous system metastasis, seizures not controlled with standard
             medical therapy constitute non-eligibility criteria),

          -  Active infection (ie, body temperature ≥38°C due to infection),

          -  Intestinal obstruction, pulmonary fibrosis or interstitial pneumonitis, renal failure,
             liver failure, or cerebrovascular disorder,

          -  Uncontrolled diabetes,

          -  Myocardial infarction within the last 6 months, severe/unstable angina, symptomatic
             congestive heart failure New York Heart Association class III or IV,

          -  Known human immunodeficiency virus or acquired immunodeficiency syndrome-related
             illness, or hepatitis B or C,

          -  Autoimmune disorders or history of organ transplantation that require
             immunosuppressive therapy,

          -  Other concomitant or previous malignancy, except: i/ adequately treated in-situ
             carcinoma of the uterine cervix, ii/ basal or squamous cell carcinoma of the skin,
             iii/ cancer in complete remission for >5 years,

          -  Major surgery or traumatic injury within the last 28 days,

          -  Pregnant or breastfeeding women,

          -  Patients with known allergy to any excipients to study drugs,

          -  Other serious and uncontrolled chronic non-malignant disease,

          -  Known dihydropyrimidine dehydrogenase deficiency,

          -  Palliative radiation therapy within 4 weeks prior to registration,

          -  Life expectancy less than 12 weeks in the opinion of the Investigator,

          -  Treatment with any other investigational medicinal product within 28 days prior to
             study entry.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Evaluation of overall response rate of the addition of panitumumab rechallenge to standard third-line therapy
Time Frame:At baseline, every 8 weeks with a 2-week tumor evaluation window through study completion, an average of 30 months.
Safety Issue:
Description:Evaluation of efficacy of overall response rate, of the addition of panitumumab rechallenge to standard third-line irinotecan-based or oxaliplatin-based chemotherapy in patients with metastatic colorectal cancer initially treated with, and benefiting from, first line irinotecan-based or oxaliplatin-based chemotherapy combined with an anti-EGFR monoclonal antibody, followed by second line chemotherapy not containing anti-EGFR agents.

Secondary Outcome Measures

Measure:Evaluation of overall response rate by RAS status
Time Frame:At baseline, every 8 weeks with a 2-week tumor evaluation window through study completion, an average of 30 months.
Safety Issue:
Description:Overall response rate will be calculated separately for RAS mutant and wild type patients.Overall response rate is defined as the proportion of patients with confirmed complete response or partial response, as the best overall response to treatment, based on Response Evaluation Criteria in Solid Tumors version 1.1 guidelines
Measure:Evaluation of Progression Free Survival
Time Frame:From study entry to disease progression or death due to any cause assessed up to 30 months
Safety Issue:
Description:
Measure:Evaluation of Overall Survival
Time Frame:From study entry until date of death due to any cause or last contact assessed up to 30 months
Safety Issue:
Description:
Measure:Evaluation of safety of the combination of standard 3rd-line irinotecan-based or oxaliplatin-based chemotherapy with panitumumab rechallenge.
Time Frame:Per cycle (each cycle is repeated every 2 weeks for FOLFIRI and FOLFOX regimens and every 3 weeks for irinotecan monotherapy) assessed up to 30 months.
Safety Issue:
Description:
Measure:Mutation status of KRAS gene
Time Frame:At baseline
Safety Issue:
Description:
Measure:Mutation status of NRAS gene
Time Frame:At baseline
Safety Issue:
Description:
Measure:Next generation sequencing performed on plasma cell-free DNA.
Time Frame:At baseline, at cycle 3 or 4 (each cycle is repeated every 2 weeks for FOLFIRI and FOLFOX regimens and every 3 weeks for irinotecan monotherapy) and at progressive disease assessed up to 30 months
Safety Issue:
Description:
Measure:Mutations analysis on platelet-resorbed tumour RNA (with Real-time PCR) in Codon 12 of KRAS gene mutations
Time Frame:At baseline, at cycle 3 or 4 (each cycle is repeated every 2 weeks for FOLFIRI and FOLFOX regimens and every 3 weeks for irinotecan monotherapy) and at progressive disease assessed up to 30 months
Safety Issue:
Description:
Measure:Mutations analysis on platelet-resorbed tumour RNA (with Real-time PCR) in Codon 61 of KRAS gene mutations
Time Frame:At baseline, at cycle 3 or 4 (each cycle is repeated every 2 weeks for FOLFIRI and FOLFOX regimens and every 3 weeks for irinotecan monotherapy) and at progressive disease assessed up to 30 months
Safety Issue:
Description:
Measure:Mutations analysis on platelet-resorbed tumour RNA (with Real-time PCR) in exon 15 of BRAF gene mutations
Time Frame:At baseline, at cycle 3 or 4 (each cycle is repeated every 2 weeks for FOLFIRI and FOLFOX regimens and every 3 weeks for irinotecan monotherapy) and at progressive disease assessed up to 30 months
Safety Issue:
Description:
Measure:Mutations analysis on platelet-resorbed tumour RNA (with Real-time PCR) in Codon 12 of NRAS gene mutations
Time Frame:At baseline, at cycle 3 or 4 (each cycle is repeated every 2 weeks for FOLFIRI and FOLFOX regimens and every 3 weeks for irinotecan monotherapy) and at progressive disease assessed up to 30 months
Safety Issue:
Description:
Measure:Mutations analysis on platelet-resorbed tumour RNA (with Real-time PCR) in Codon 61 of NRAS gene mutations
Time Frame:At baseline, at cycle 3 or 4 (each cycle is repeated every 2 weeks for FOLFIRI and FOLFOX regimens and every 3 weeks for irinotecan monotherapy) and at progressive disease assessed up to 30 months
Safety Issue:
Description:
Measure:Mutations analysis on platelet-resorbed tumour RNA (with Real-time PCR) in exon 20 of PIK3CA gene mutations
Time Frame:At baseline, at cycle 3 or 4 (each cycle is repeated every 2 weeks for FOLFIRI and FOLFOX regimens and every 3 weeks for irinotecan monotherapy) and at progressive disease assessed up to 30 months
Safety Issue:
Description:

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Hellenic Cooperative Oncology Group

Last Updated

April 30, 2019