Study Evaluating Biomarkers in Patients With Colorectal Cancer and Native KRAS Treated With Chemotherapy + Cetuximab (POSIBA)

This study is currently recruiting participants. (see Contacts and Locations)
Verified April 2013 by Grupo Espanol Multidisciplinario del Cancer Digestivo
Sponsor:
Information provided by (Responsible Party):
Grupo Espanol Multidisciplinario del Cancer Digestivo
ClinicalTrials.gov Identifier:
NCT01276379
First received: January 12, 2011
Last updated: April 8, 2013
Last verified: April 2013
  Purpose

Advanced colorectal cancer (ACRC) is a heterogeneous disease and classification of patients is nowadays inefficient. Roughly twenty per cent of patients present with favorable figures (less than 4 liver nodules and less than 5 cm) and are suitable for local treatments (surgery or local-ablative therapies). Additionally, 10-15% of patients have poor performance status (PS >2) or are severe disabled due to geriatric syndromes or/and co-morbid diseases that preclude any treatment strategies than best supportive care alone. The rest of patients (fit patients not suitable for radical treatments) constitute the population of patients treated with palliative therapies. Despite of it not all these patients have the same prognosis. Patients with PS 0,1 and levels of LDH <ULN (Intermediate-risk patients) have better PFS and OS irrespective of therapy in all randomized clinical trials (de Gramont et al, JCO 2000; Douillard et al, Lancet 2000; Koopman et al, 2007).

CRYSTAL trial shows a benefit in PFS (1.5 months) in RASWT of FOLFIRI plus cetuximab compared with FOLFIRI alone. Nowadays the selection of patients for cetuximab treatment is based on mutational status of KRAS, which allow to select those patients who will not respond to therapy. Other surrogate markers of activity should be also evaluated. Our hypothesis is that the suggested biomarkers will allow the selection of the patients who will benefit the most from the biweekly cetuximab treatment.


Condition Intervention Phase
Colorectal Cancer
Drug: FOLFIRI (m)
Drug: FOLFOX-6 (m)
Drug: Cetuximab
Phase 2

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Screening
Official Title: Single-Arm, Multicenter, Prospective, Phase 2 Study for the Evaluation of Biomarkers in Patients With Advanced &/or Metastatic Colorectal Cancer With Wild Type KRAS Treated Biweekly With Chemotherapy and Cetuximab as First-Line Treatment

Resource links provided by NLM:


Further study details as provided by Grupo Espanol Multidisciplinario del Cancer Digestivo:

Primary Outcome Measures:
  • Progression free survival [ Time Frame: anticipated: 4 years ] [ Designated as safety issue: No ]

    Measurements according to RECIST 1.1 criteria (Response Evaluation Criteria in Solid Tumors). Main techniques: CT-scan. Two groups will be defined based on the score built from the proposed clinical variables and biomarkers. Instead of a binomial distribution, a Log-rank method has been used to calculate the sample size in order to include all the incidents during the follow-up. Expecting a minimum 20% difference (60 vs. 40%) on PFS at 12 months between groups and with the following assumptions:

    Alpha error (bilateral): 5% Beta error: 20%



Secondary Outcome Measures:
  • Overall survival [ Time Frame: anticipated: 4 years ] [ Designated as safety issue: No ]
  • Response duration [ Time Frame: anticipated: 4 years ] [ Designated as safety issue: No ]
    Duration of the partial or total response to the treatment. Evaluation and classification according to RECIST 1.1 criteria (Response Evaluation Criteria in Solid Tumors)

  • Toxicity [ Time Frame: anticipated: 4 years ] [ Designated as safety issue: Yes ]
  • Secondary biomarkers analysis [ Time Frame: anticipated: 4 years ] [ Designated as safety issue: No ]
    The secondary biomarkers in serum and tumoral tissue will be analysed in order to predict the acquired resistance.

  • Tumoral response [ Time Frame: anticipated: 4 years ] [ Designated as safety issue: No ]
    Measurements according to RECIST 1.1 criteria (Response Evaluation Criteria in Solid Tumors). Main techniques: CT-scan.


Estimated Enrollment: 170
Study Start Date: January 2011
Estimated Study Completion Date: December 2014
Estimated Primary Completion Date: October 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: FOLFIRI (m) or FOLFOX-6 (m) + cetuximab
FOLFOX/FOLFIRI + cetuximab 500mg/m2 bi-weekly for 6 months, then bi-weekly cetuximab as monotherapy.
Drug: FOLFIRI (m)

FOLFIRI (m) chemotherapy will be administered on day 1 of each 14-days-cycle. The administered doses will be:

  • Irinotecan 180 mg/m2 in infusion i.v., 120 minutes, on day 1 of each cycle.
  • l-Leucovorin 200 mg/m2 (or d,l-leucovorin 400 mg/m2), in infusion i.v., 120 minutes, on day 1.
  • One bolus i.v. (2-4 minutes) of 400 mg/m2 of 5-FU on day 1.
  • 5-FU in continuous infusion (2400 mg/m2) administered through an ambulatory pump during 46-48 hours.
Other Name: folinic acid, fluorouracil and irinotecan.
Drug: FOLFOX-6 (m)

FOLFOX6 (m) chemotherapy will be administered on day 1 of each 14-days-cycle. The administered doses will be:

  • Oxaliplatin 85 mg/m2 in infusion i.v., 120 minutes, on day 1 of each cycle.
  • l-Leucovorin 200 mg/m2 (or d,l-leucovorin 400 mg/m2) in infusion i.v., 120 minutes, on day 1.
  • One bolus i.v. (2-4 minutes) of 400 mg/m2 of 5-FU on day 1.
  • 5-FU in continuous infusion (2400 mg/m2) administered through an ambulatory pump during 46-48 hours.
Other Name: folinic acid, fluorouracil and oxaliplatin.
Drug: Cetuximab
- 500 mg/m2 i.v. Every 2 weeks.
Other Name: erbitux

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Male or female, age ≥ 18 years
  • Able to sign an informed consent form
  • Advanced and/or metastatic colorectal cancer
  • Colorectal cancer with KRAS wild type genotype
  • At least one unidimensionally measurable lesion according to RECIST criteria (1.1 revised) (to be assessed ≤ 28 days prior to the study treatment)
  • All patients with the following features will be included:

    1. Progression free survival > 6 months after adjuvant treatment +/- radiotherapy
    2. "De novo" diagnosis of the disease
  • Performance ECOG status of 0-2
  • Life expectancy ≥ 3 months
  • Adequate bone marrow function: neutrophils ≥1,5 x 10^9/L; platelets ≥ 100 x 10^9/L; hemoglobin ≥9 g/dL.
  • Adequate liver, renal and hematological function as follows:

    1. Adequate liver function: SGOT and SGPT 2.5 x ULN (5 x ULN in case of hepatic metastasis). Total bilirubin < 1,5 x ULN. Alkaline phosphatase 2,5 x LSN (5 x ULN if hepatic metastasis or 10 x ULN if bone metastasis)
    2. Creatinine clearance or creatinine clearance during 24 hours ≥ 50 mL/min
    3. Magnesium ≥ LLN, calcium ≥ LLN

Exclusion Criteria:

  • PS > 2 or elderly patients with fragility criteria
  • Previous surgery for metastasis
  • Previous systemic treatment for the metastatic colorectal cancer
  • Previous treatment with antibodies anti-EGFR or treatment with small-molecule EGFR tyrosine kinase inhibitors or EGFR signal transduction inhibitors. Subjects who suspend their first dose due to a reaction to the infusion can participate
  • Central nervous system metastasis (except: treated subjects with asymptomatic CNS metastasis who have not received steroids within the 30 days prior to inclusion)
  • Prior malignant tumor in the last 5 years, except: basal cell carcinoma of the skin or pre-invasive cervical cancer
  • Unresolved toxicities from a prior systemic treatment which do not qualify the patient for inclusion
  • Presence of peripheral neuropathy (degree > 1 in the ctc version 3.0) and serious nonhealing wound, ulcer, or bone fracture
  • Hormonal treatment, immunotherapy or experimental or approved antibodies/proteins ≤ 30 days before the inclusion
  • Uncontrolled serious cardiovascular disease or: congestive cardiac failure NYHA lll or lV, unstable angina pectoris, myocardial infarction precedents in the past 12 months, significant arrhythmias
  • Interstitial pneumonitis or pulmonary fibrosis precedents, or interstitial pneumonitis or pulmonary fibrosis signs on the thoracic CT-scan
  • Treatment for systemic infection within the 14 days prior to treatment
  • Acute/subacute intestinal occlusion and/or active inflammatory bowel disease or any other bowel disease producing chronic diarrhea
  • Precedent of Gilbert's syndrome or dihydropyrimidine dehydrogenase deficiency
  • Precedent of any disease which can increase the risks associated to the participation in the study or interfere in the study results
  • Known positive test for the following infections: HIV, Hepatitis C + abnormal liver enzymes values, active chronic Hepatitis B (except Hepatitis C seropositive with normal liver enzymes)
  • All concurrent diseases which can increase the toxicity risk
  • The individual presents a disorder of any kind which jeopardizes their ability to give their written consent form and/or fulfill the study procedures
  • Any investigational agent within 30 days before enrolment
  • Pregnant or breastfeeding woman, or planning to get pregnant within the 6 months after treatment
  • Surgery (excluding the diagnostic biopsy or placing of a central venous catheter)
  • Woman or man of childbearing potential not consenting to use adequate contraceptive precautions during the study and 6 months after de last administration for women, and 1 month for men
  • Unability to fulfill the study requirements by the patients
  • Psychological, family, sociological or geographical conditions that may interfere with the fulfillment of the study protocol and the follow-up calendar
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01276379

Contacts
Contact: Jesús García Foncillas, MD +34 93 434 44 12 secretaria@gemcad.org

Locations
Spain
Hospital Sant Joan de Reus Recruiting
Reus, Tarragona, Spain
Principal Investigator: Ines Cabezas, MD         
Complejo Hospitalario Universitario de Albacete Recruiting
Albacete, Spain
Principal Investigator: Ana Isabel Ferrer, MD         
Hospital Infanta Cristina de Badajoz Recruiting
Badajoz, Spain
Principal Investigator: Ramon Rodriguez, MD         
Hospital de Barbastro Recruiting
Barbastro, Spain
Principal Investigator: Veronica Calderero, MD         
Hospital Clínic de Barcelona Recruiting
Barcelona, Spain
Principal Investigator: Joan Maurel, MD         
Hospital General Yagüe Recruiting
Burgos, Spain
Principal Investigator: Carlos García Giron, MD         
Hospital Sant Jaume de Calella Recruiting
Calella, Spain
Principal Investigator: Isabel Antón, MD         
Hospital Provincial de Castellón Recruiting
Castellón, Spain
Principal Investigator: Jorge Molina         
Hospital San Pedro de Alcántara Recruiting
Cáceres, Spain
Principal Investigator: Mª Angeles Rodríguez, MD         
Hospital General Universitario de Elche Recruiting
Elche, Spain
Principal Investigator: Javier Gallego, MD         
Hospital de Jaén Recruiting
Jaén, Spain
Principal Investigator: Rosario Dueñas, MD         
Hospital Universitario de Gran Canaria Dr. Negrín Recruiting
Las Palmas de Gran Canaria, Spain
Principal Investigator: Uriel Bohn, MD         
Hospital Universitari Arnau de Vilanova de Lleida Recruiting
Lleida, Spain
Principal Investigator: Antonieta Salud, MD         
Fundación Jimenez Díaz Recruiting
Madrid, Spain
Principal Investigator: Ana León, MD         
Hospital de Móstoles Recruiting
Madrid, Spain
Principal Investigator: Miguel Méndez, MD         
Hospital Universitario la Paz Recruiting
Madrid, Spain
Principal Investigator: Jaime Feliu, MD         
Hospital de Mataró Recruiting
Mataró, Spain
Principal Investigator: Montserrat Zanui, MD         
Hospital Son Espases Recruiting
Palma de Mallorca, Spain
Principal Investigator: Hermini Manzano, MD         
Hospital Son Llàtzer Recruiting
Palma de Mallorca, Spain
Principal Investigator: Esther Falcó, MD         
Hospital de Navarra Recruiting
Pamplona, Spain
Principal Investigator: Ruth Vera, MD         
Clínica Universitaria de Navarra Recruiting
Pamplona, Spain
Principal Investigator: Javier Rodriguez, MD         
Hospital de Sagunto Recruiting
Sagunto, Spain
Principal Investigator: Mireia Gil, MD         
Mutua de Terrassa Recruiting
Terrassa, Spain
Principal Investigator: Julen Fernandez, MD         
Hospital Virgen de la Salud Recruiting
Toledo, Spain
Principal Investigator: Luis López, MD         
Instituto Valenciano de Oncología Recruiting
Valencia, Spain
Principal Investigator: Carlos Fernandez-Martos, MD         
Hospital Miguel Servet Recruiting
Zaragoza, Spain
Principal Investigator: Vicente Alonso, MD         
Hospital Clínico Universitario Lozano Blesa Recruiting
Zaragoza, Spain
Principal Investigator: Pilar Escudero, MD         
Sponsors and Collaborators
Grupo Espanol Multidisciplinario del Cancer Digestivo
Investigators
Study Chair: Jesús García Foncillas, MD Grupo Espanol Multidisciplinario del Cancer Digestivo
Study Chair: Xavier García-Albeniz, MD Grupo Espanol Multidisciplinario del Cancer Digestivo
  More Information

Additional Information:
No publications provided

Responsible Party: Grupo Espanol Multidisciplinario del Cancer Digestivo
ClinicalTrials.gov Identifier: NCT01276379     History of Changes
Other Study ID Numbers: GEMCAD-1002, 2010-019236-12
Study First Received: January 12, 2011
Last Updated: April 8, 2013
Health Authority: Spain: Agencia Española de Medicamentos y Productos Sanitarios
Spain: Comité Ético de Investigación Clínica

Keywords provided by Grupo Espanol Multidisciplinario del Cancer Digestivo:
colorectal cancer
advanced
metastatic
KRAS
biomarkers (BRAF, IGF1P/MMp7,PI3K-PTEN)
cetuximab

Additional relevant MeSH terms:
Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Fluorouracil
Oxaliplatin
Irinotecan
Cetuximab
Leucovorin
Folic Acid
Levoleucovorin
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antimetabolites, Antineoplastic
Antineoplastic Agents
Therapeutic Uses
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Vitamin B Complex
Vitamins
Micronutrients

ClinicalTrials.gov processed this record on August 28, 2014