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

Primary Purpose

Colorectal Cancer

Status
Completed
Phase
Phase 2
Locations
Spain
Study Type
Interventional
Intervention
FOLFIRI (m)
FOLFOX-6 (m)
Cetuximab
Sponsored by
Grupo Espanol Multidisciplinario del Cancer Digestivo
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional screening trial for Colorectal Cancer focused on measuring colorectal cancer, advanced, metastatic, KRAS, biomarkers (BRAF, IGF1P/MMp7,PI3K-PTEN), cetuximab

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Hospital Provincial de Castellón
  • Hospital Son Espases
  • Hospital Son Llàtzer
  • Hospital Sant Joan de Reus
  • Complejo Hospitalario Universitario de Albacete
  • Hospital Infanta Cristina de Badajoz
  • Hospital de Barbastro
  • Hospital Clínic de Barcelona
  • Hospital General Yagüe
  • Hospital Sant Jaume de Calella
  • Hospital San Pedro de Alcántara
  • Hospital General Universitario de Elche
  • Hospital de Jaén
  • Hospital Universitario de Gran Canaria Dr. Negrín
  • Hospital Universitari Arnau de Vilanova de Lleida
  • Fundación Jimenez Díaz
  • Hospital de Móstoles
  • Hospital Universitario la Paz
  • Hospital de Mataró
  • Clínica Universitaria de Navarra
  • Hospital de Navarra
  • Hospital de Sagunto
  • Mutua de Terrassa
  • Hospital Virgen de la Salud
  • Instituto Valenciano de Oncología
  • Hospital Clínico Universitario Lozano Blesa
  • Hospital Miguel Servet

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

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

Arm Description

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

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

Overall Survival
Measured as time in months from start of study treatment to death or lost to follow up. Results are reported by subgroups to compare outcome measure according to BRAF mutation. All patients belong to same treatment/study arm.
Response Duration
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)
Frequency of Adverse Events
Frequency and type of adverse events (AEs). AEs were coded according to NCI CTCAE V3.0 and classified by frequency, relatedness to study treatment (related/not related) and severity (Grade). Severity ranges from grade 1 (low intensity) to Grade 5 (max. intensity, death)
Secondary Biomarkers Analysis
The secondary biomarkers in serum and tumoral tissue will be analysed in order to predict the acquired resistance.
Tumoral Response
Measurements according to RECIST 1.1 criteria (Response Evaluation Criteria in Solid Tumors). Main techniques: CT-scan. Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR Results are reported by subgroups to compare outcome measure according to BRAF mutation. All patients belong to same treatment/study arm.

Full Information

First Posted
January 12, 2011
Last Updated
June 11, 2021
Sponsor
Grupo Espanol Multidisciplinario del Cancer Digestivo
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1. Study Identification

Unique Protocol Identification Number
NCT01276379
Brief Title
Study Evaluating Biomarkers in Patients With Colorectal Cancer and Native KRAS Treated With Chemotherapy + Cetuximab
Acronym
POSIBA
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
Study Type
Interventional

2. Study Status

Record Verification Date
June 2021
Overall Recruitment Status
Completed
Study Start Date
January 2011 (undefined)
Primary Completion Date
March 15, 2017 (Actual)
Study Completion Date
December 21, 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Grupo Espanol Multidisciplinario del Cancer Digestivo

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Colorectal Cancer
Keywords
colorectal cancer, advanced, metastatic, KRAS, biomarkers (BRAF, IGF1P/MMp7,PI3K-PTEN), cetuximab

7. Study Design

Primary Purpose
Screening
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
221 (Actual)

8. Arms, Groups, and Interventions

Arm Title
FOLFIRI (m) or FOLFOX-6 (m) + cetuximab
Arm Type
Experimental
Arm Description
FOLFOX/FOLFIRI + cetuximab 500mg/m2 bi-weekly for 6 months, then bi-weekly cetuximab as monotherapy.
Intervention Type
Drug
Intervention Name(s)
FOLFIRI (m)
Other Intervention Name(s)
folinic acid, fluorouracil and irinotecan.
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
FOLFOX-6 (m)
Other Intervention Name(s)
folinic acid, fluorouracil and oxaliplatin.
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Cetuximab
Other Intervention Name(s)
erbitux
Intervention Description
- 500 mg/m2 i.v. Every 2 weeks.
Primary Outcome Measure Information:
Title
Progression Free Survival
Description
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.
Time Frame
4 years
Secondary Outcome Measure Information:
Title
Overall Survival
Description
Measured as time in months from start of study treatment to death or lost to follow up. Results are reported by subgroups to compare outcome measure according to BRAF mutation. All patients belong to same treatment/study arm.
Time Frame
4 years
Title
Response Duration
Description
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)
Time Frame
4 years
Title
Frequency of Adverse Events
Description
Frequency and type of adverse events (AEs). AEs were coded according to NCI CTCAE V3.0 and classified by frequency, relatedness to study treatment (related/not related) and severity (Grade). Severity ranges from grade 1 (low intensity) to Grade 5 (max. intensity, death)
Time Frame
4 years
Title
Secondary Biomarkers Analysis
Description
The secondary biomarkers in serum and tumoral tissue will be analysed in order to predict the acquired resistance.
Time Frame
4 years
Title
Tumoral Response
Description
Measurements according to RECIST 1.1 criteria (Response Evaluation Criteria in Solid Tumors). Main techniques: CT-scan. Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR Results are reported by subgroups to compare outcome measure according to BRAF mutation. All patients belong to same treatment/study arm.
Time Frame
4 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility 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: 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 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Jesús García Foncillas, MD
Organizational Affiliation
Grupo Espanol Multidisciplinario del Cancer Digestivo
Official's Role
Study Chair
First Name & Middle Initial & Last Name & Degree
Xavier García-Albeniz, MD
Organizational Affiliation
Grupo Espanol Multidisciplinario del Cancer Digestivo
Official's Role
Study Chair
Facility Information:
Facility Name
Hospital Provincial de Castellón
City
Castelló de la Plana
State/Province
Castellón
Country
Spain
Facility Name
Hospital Son Espases
City
Palma
State/Province
Malllorca
Country
Spain
Facility Name
Hospital Son Llàtzer
City
Palma
State/Province
Mallorca
Country
Spain
Facility Name
Hospital Sant Joan de Reus
City
Reus
State/Province
Tarragona
Country
Spain
Facility Name
Complejo Hospitalario Universitario de Albacete
City
Albacete
Country
Spain
Facility Name
Hospital Infanta Cristina de Badajoz
City
Badajoz
Country
Spain
Facility Name
Hospital de Barbastro
City
Barbastro
Country
Spain
Facility Name
Hospital Clínic de Barcelona
City
Barcelona
Country
Spain
Facility Name
Hospital General Yagüe
City
Burgos
Country
Spain
Facility Name
Hospital Sant Jaume de Calella
City
Calella
Country
Spain
Facility Name
Hospital San Pedro de Alcántara
City
Cáceres
Country
Spain
Facility Name
Hospital General Universitario de Elche
City
Elche
Country
Spain
Facility Name
Hospital de Jaén
City
Jaén
Country
Spain
Facility Name
Hospital Universitario de Gran Canaria Dr. Negrín
City
Las Palmas de Gran Canaria
Country
Spain
Facility Name
Hospital Universitari Arnau de Vilanova de Lleida
City
Lleida
Country
Spain
Facility Name
Fundación Jimenez Díaz
City
Madrid
Country
Spain
Facility Name
Hospital de Móstoles
City
Madrid
Country
Spain
Facility Name
Hospital Universitario la Paz
City
Madrid
Country
Spain
Facility Name
Hospital de Mataró
City
Mataró
Country
Spain
Facility Name
Clínica Universitaria de Navarra
City
Pamplona
Country
Spain
Facility Name
Hospital de Navarra
City
Pamplona
Country
Spain
Facility Name
Hospital de Sagunto
City
Sagunto
Country
Spain
Facility Name
Mutua de Terrassa
City
Terrassa
Country
Spain
Facility Name
Hospital Virgen de la Salud
City
Toledo
Country
Spain
Facility Name
Instituto Valenciano de Oncología
City
Valencia
Country
Spain
Facility Name
Hospital Clínico Universitario Lozano Blesa
City
Zaragoza
Country
Spain
Facility Name
Hospital Miguel Servet
City
Zaragoza
Country
Spain

12. IPD Sharing Statement

Citations:
PubMed Identifier
35100697
Citation
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.
Results Reference
derived
PubMed Identifier
31235483
Citation
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.
Results Reference
derived
Links:
URL
http://www.gemcad.es/
Description
GEMCAD group

Learn more about this trial

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

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