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

NCT01276379 | Completed Phase 2 Results DMC

• 2 other identifiers: GEMCAD-10022010-019236-12
• Study Type: interventional
• Target: 221
• Locations: 1 country
• Sites: 27

Brief Summary

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.

Conditions

Colorectal Cancer

Keywords

colorectal cancer; advanced; metastatic; KRAS; biomarkers (BRAF, IGF1P/MMp7,PI3K-PTEN); cetuximab

Outcome Measures

Primary Outcomes (1)

• Progression Free Survival

  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% Results are reported by subgroups to compare outcome measure according to BRAF mutation. All patients belong to same treatment/study arm.

  4 years

Secondary Outcomes (5)

• Overall Survival

  4 years

• Response Duration

  4 years

• Frequency of Adverse Events

  4 years

• Secondary Biomarkers Analysis

  4 years

• Tumoral Response

  4 years

Study Arms (1)

FOLFIRI (m) or FOLFOX-6 (m) + cetuximab

EXPERIMENTAL

FOLFOX/FOLFIRI + cetuximab 500mg/m2 bi-weekly for 6 months, then bi-weekly cetuximab as monotherapy.

Drug: FOLFIRI (m); Drug: FOLFOX-6 (m); Drug: Cetuximab

Interventions

FOLFIRI (m) DRUG

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.

Also known as: folinic acid, fluorouracil and irinotecan.

FOLFIRI (m) or FOLFOX-6 (m) + cetuximab

FOLFOX-6 (m) DRUG

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.

Also known as: folinic acid, fluorouracil and oxaliplatin.

FOLFIRI (m) or FOLFOX-6 (m) + cetuximab

Cetuximab DRUG

\- 500 mg/m2 i.v. Every 2 weeks.

Also known as: erbitux

FOLFIRI (m) or FOLFOX-6 (m) + cetuximab

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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:
• Progression free survival \> 6 months after adjuvant treatment +/- radiotherapy
• "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:
• 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)
• Creatinine clearance or creatinine clearance during 24 hours ≥ 50 mL/min
• Magnesium ≥ LLN, calcium ≥ LLN

You may not qualify if:

• 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
• Prior malignant tumor in the last 5 years, except: basal cell carcinoma of the skin or pre-invasive cervical cancer
• Presence of peripheral neuropathy (degree \> 1 in the ctc version 3.0) and serious nonhealing wound, ulcer, or bone fracture
• 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

Sponsors & Collaborators

• Grupo Espanol Multidisciplinario del Cancer Digestivo: lead

Study Sites (27)

Hospital Provincial de Castellón

Castellon, Castellón, Spain

Location

Hospital Son Espases

Palma, Malllorca, Spain

Location

Hospital Son Llàtzer

Palma, Mallorca, Spain

Location

Hospital Sant Joan de Reus

Reus, Tarragona, Spain

Location

Complejo Hospitalario Universitario de Albacete

Albacete, Spain

Location

Hospital Infanta Cristina de Badajoz

Badajoz, Spain

Location

Hospital de Barbastro

Barbastro, Spain

Location

Hospital Clínic de Barcelona

Barcelona, Spain

Location

Hospital General Yagüe

Burgos, Spain

Location

Hospital Sant Jaume de Calella

Calella, Spain

Location

Hospital San Pedro de Alcántara

Cáceres, Spain

Location

Hospital General Universitario de Elche

Elche, Spain

Location

Hospital de Jaén

Jaén, Spain

Location

Hospital Universitario de Gran Canaria Dr. Negrín

Las Palmas de Gran Canaria, Spain

Location

Hospital Universitari Arnau de Vilanova de Lleida

Lleida, Spain

Location

Fundación Jimenez Díaz

Madrid, Spain

Location

Hospital de Móstoles

Madrid, Spain

Location

Hospital Universitario la Paz

Madrid, Spain

Location

Hospital de Mataró

Mataró, Spain

Location

Clínica Universitaria de Navarra

Pamplona, Spain

Location

Hospital de Navarra

Pamplona, Spain

Location

Hospital de Sagunto

Sagunto, Spain

Location

Mutua de Terrassa

Terrassa, Spain

Location

Hospital Virgen de la Salud

Toledo, Spain

Location

Instituto Valenciano de Oncología

Valencia, Spain

Location

Hospital Clínico Universitario Lozano Blesa

Zaragoza, Spain

Location

Hospital Miguel Servet

Zaragoza, Spain

Location

Related Publications (2)

• Maurel J, Alonso V, Escudero P, Fernandez-Martos C, Salud A, Mendez M, Gallego J, Rodriguez JR, Martin-Richard M, Fernandez-Plana J, Manzano H, Mendez JC, Zanui M, Falco E, Gil-Raga M, Aparicio J, Feliu J, Garcia-Albeniz X, Torres F, Rojo F, Bellosillo B, Mendiola M, Fernandez V, Reig O, Claes B, Maertens G, Sablon E, Jacobs B, Montagut C. Clinical Impact of Circulating Tumor RAS and BRAF Mutation Dynamics in Patients With Metastatic Colorectal Cancer Treated With First-Line Chemotherapy Plus Anti-Epidermal Growth Factor Receptor Therapy. JCO Precis Oncol. 2019 Dec;3:1-16. doi: 10.1200/PO.18.00289.

  PMID: 35100697 DERIVED

• Garcia-Albeniz X, Alonso V, Escudero P, Mendez M, Gallego J, Rodriguez JR, Salud A, Fernandez-Plana J, Manzano H, Zanui M, Falco E, Feliu J, Gil M, Fernandez-Martos C, Bohn U, Alonso C, Calderero V, Rojo F, Cuatrecasas M, Maurel J. Prospective Biomarker Study in Advanced RAS Wild-Type Colorectal Cancer: POSIBA Trial (GEMCAD 10-02). Oncologist. 2019 Nov;24(11):e1115-e1122. doi: 10.1634/theoncologist.2018-0728. Epub 2019 Jun 24.

  PMID: 31235483 DERIVED

Related Links

• GEMCAD group

MeSH Terms

Conditions

Colorectal Neoplasms; Neoplasm Metastasis; Hereditary Sensory and Autonomic Neuropathies

Interventions

Leucovorin; Fluorouracil; Irinotecan; Oxaliplatin; Cetuximab

Condition Hierarchy (Ancestors)

Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases; Neoplastic Processes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Nervous System Malformations; Nervous System Diseases; Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Polyneuropathies; Peripheral Nervous System Diseases; Neuromuscular Diseases; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Genetic Diseases, Inborn

Intervention Hierarchy (Ancestors)

Formyltetrahydrofolates; Tetrahydrofolates; Folic Acid; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Coenzymes; Enzymes and Coenzymes; Uracil; Pyrimidinones; Pyrimidines; Heterocyclic Compounds, 1-Ring; Camptothecin; Alkaloids; Coordination Complexes; Organic Chemicals; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Results Point of Contact

• Title: Joan Maurel Santasusana
• Organization: GEMCAD

JMAUREL@clinic.cat

+ 34 93 434 44 12

Study Officials

• Jesús García Foncillas, MD

  Grupo Espanol Multidisciplinario del Cancer Digestivo

  STUDY CHAIR

• Xavier García-Albeniz, MD

  Grupo Espanol Multidisciplinario del Cancer Digestivo

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: SCREENING
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 12, 2011
• First Posted: January 13, 2011
• Study Start: January 1, 2011
• Primary Completion: March 15, 2017
• Study Completion: December 21, 2017
• Last Updated: July 2, 2021
• Results First Posted: July 2, 2021

Record last verified: 2021-06

Locations

ES (27)