Clinical trial NCT01288339: Study Assessing Potential Predictive Tumor Markers in Metastatic Colorectal Cancer
Official title: An Open Label, Phase II Study Assessing Potential Predictive Tumor Markers in Patients With Metastatic Colorectal Cancer and Wild Type K-RAS Tumor Treated With FOLFOX Plus Panitumumab as First-line Therapy
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Metastatic Colorectal Cancer
Lead sponsor: Grupo Espanol Multidisciplinario del Cancer Digestivo
Sponsor class: OTHER
Collaborators: name: Amgen
name: TFS Trial Form Support
First posted: 2011-02-02
Enrollment: 78
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: To estimate the progression free survival for subjects treated with panitumumab in combination with a chemotherapy regimen of oxaliplatin, 5-Fluorouracil (5-FU) and leucovorin (FOLFOX) as first-line chemotherapy regimen for subjects with metastatic colorectal cancer with WT (wild type) KRAS according to the IGFRp (protein receptor insulin growth factor) and MMP-7 (Matrilysin) expression.

Detailed description: By transactivation, phosphorylated insulin growth factor receptor I (p-IGF-IR) can activate epidermal growth factor receptor (EGFR). Matrilysin (MMP-7), can activate IGF-IR (insulin-like growth factor receptor ) by degrading IGFBP-3 (Insulin-like growth factor-binding protein 3) and releasing IGF-I (Insulin-like growth factor 1). Concomitant expression of MMP-7 and p-IGF-IR (using a specific monoclonal antibody (p-1316) recognizing the phosphorylated carboxy-terminal part of the IGF-IR) (DP (Double Positivity)) correlates with poor prognosis in WT KRAS patients treated with anti-EGFR antibodies plus irinotecan.The primary objective of this trial is to estimate the progression free survival (PFS) by DP (Double Positivity)immunohistochemistry (IHC) expression in patients with wild-type KRAS mCRC (metastatic colorectal cancer)treated with panitumumab and mFOLFOX6. Two groups are established by DP status (MMP7+/p-IGF-IR+ vs. MMP7+/p-IGF-IR-, MMP7-/p-IGF-IR+ or MMP7-/p-IGF-IR-). With a power of 80% and a bilateral alpha level of 0.05, assuming an accrual period of 12 months (m) and a follow-up period of 18 m, 40 patients are planned to be included in each group to detect a Hazard Ratio of 2. The median PFS of the DP group is expected to be 6 m and the total number of expected events is 56. Secondary objectives include disease control rate, duration of response, time to response and survival according the DP status. Neither interim analysis nor multiple comparison adjustment is planned.Treatment: Both groups will receive panitumumab 6 mg/kg and mFOLFOX6 every 2 weeks. If patients have not progressed after 6 m of treatment they will continue with panitumumab monotherapy until disease progression.

Eligibility criteria: Inclusion Criteria:

* Man or woman ≥ 18 years.
* Competent to comprehend, sign, and date an IEC-approved (Ethics Committee) informed consent form
* Histologically-confirmed metastatic adenocarcinoma of the colon or rectum by the investigator.
* Wild Type K-RAS colorectal cancer determined by the designated Central Laboratory prior to inclusion in the study in the primary tumor and/or at least one metastasis.
* At least 1 uni-dimensionally measurable lesion of at least \> 10 mm with spiral CT per modified RECIST criteria 1.1. (Response Evaluation Criteria In Solid Tumors)
* Patients with the following characteristics will be included:

  1. Recurrence after adjuvant treatment with 5-fluorouracil/folinic acid or capecitabine +/- radiotherapy with a disease-free interval \> than 6 months after its completion.
  2. Recurrence after adjuvant treatment with oxaliplatin +/- radiotherapy with a disease-free interval \> than 12 months
  3. De novo diagnosis of the disease.
* Eastern Cooperative Oncology Group performance status of 0 or 1.
* Life expectancy ≥ 3 months
* Adequate bone marrow function
* Adequate Hepatic and metabolic functions
* Adequate Renal function
* Magnesium \> LLN (Lower limit of Normal)

Exclusion Criteria:

* Patients they have received prior systemic therapy for the treatment of metastatic colorectal carcinoma.
* Prior anti-EGFr antibody therapy (eg, cetuximab) or treatment small molecule EGFr tyrosine kinase inhibitors (eg, erlotinib) or EGFR signal transduction inhibitors.
* Patients who had resection of metastatic disease
* Central nervous system/brain metastases
* Prior malignant tumor in the last 5 years, except a history of basal cell carcinoma of the skin or pre-invasive cervical cancer.
* Unresolved toxicities from prior systemic therapy that, in the opinion of the investigator, does not qualify the patient for inclusion
* Presence of peripheral neuropathy (Common Toxicity Criteria (CTC) version 3.0 \> grade 1), and of serious nonhealing wound, ulcer, or bone fracture.
* Hormonal therapy, immunotherapy or experimental or approved proteins/antibodies (eg, bevacizumab) ≤ 30 days before inclusion
* Significant cardiovascular disease including unstable angina or myocardial infarction within 12 months before initiating study treatment or a history of ventricular arrhythmia.
* History of interstitial pneumonitis or pulmonary fibrosis or evidence of interstitial pneumonitis or pulmonary fibrosis on baseline chest CT scan
* Treatment for systemic infection within 14 days before initiating study treatment
* Acute or sub-acute intestinal occlusion and /or active inflammatory bowel disease or other bowel disease causing chronic diarrhea (defined as \> 4 loose stools per day).
* Known positive test for human immunodeficiency virus infection, hepatitis C virus, chronic active hepatitis B infection
* Any investigational agent within 30 days before enrollment
* Subject who is pregnant or breast feeding
* Surgery (excluding diagnostic biopsy or central venous catheter placement) and/or radiotherapy within 14 days prior to inclusion in the study.
* Woman or man of childbearing potential not consenting to use adequate contraceptive precautions

Primary outcomes:
measure: Progression-free survival time according to the MMP7 status (PFS)
timeFrame: 5 years
Secondary outcomes:
measure: Duration of response (DOR)
timeFrame: 5 years
measure: Time to response (TTR)
timeFrame: 5 years
measure: Time to treatment failure (TtTF)
timeFrame: 5 years
measure: Objective response rate (ORR)
timeFrame: 5 years
measure: Disease Control Rate (DCR)
timeFrame: 5 years
measure: Overall Survival (OS)
timeFrame: 5 years
measure: Time To Progression (TTP)
timeFrame: 5 years
measure: Duration of Stable Disease (DoSD)
timeFrame: 5 years
measure: Incidence and severity of AEs
timeFrame: 5 years
measure: Molecular predictive markers for response.
timeFrame: 5 years
Other outcomes:
Locations:
city: Elche
country: Spain
facility: Hospital General Universitario de Elche
state: Alicante
city: Hospitalet de Llobregat
country: Spain
facility: Hosptial General de l'Hospitalet de Barcelona
state: Barcelona
city: Sabadell
country: Spain
facility: Corporació Sanitaria Parc Taulí de Barcelona
state: Barcelona
city: Santa Coloma De Gramenet
country: Spain
facility: Hospital de l'Esperit Sant
state: Barcelona
city: Castellón De La Plana
country: Spain
facility: Consorcio Hospitalario Provincial de Castellon
state: Castellon
city: Palma De Mallorca
country: Spain
facility: Hospital Son Espases de Mallorca
state: Illes Balears
city: Palma De Mallorca
country: Spain
facility: Hosptial Son Llatzer de Mallorca
state: Illes Balears
city: Logroño
country: Spain
facility: Hosptial de Logroño
state: La Rioja
city: Madrid
country: Spain
facility: Hospital Universitario La Paz de Madrid
state: Madrdi
city: Pamplona
country: Spain
facility: Clínica Universitaria de Navarra
state: Navarra
city: Pamplona
country: Spain
facility: Hospital de Navarra
state: Navarra
city: Vigo
country: Spain
facility: Hospital Xeral Cies de Vigo
state: Pontevedra
city: Barcelona
country: Spain
facility: Hospital Clínic i Provincial de Barcelona
city: Barcelona
country: Spain
facility: Hospital de la Santa Creu i Sant Pau de Barcelona
city: Burgos
country: Spain
facility: Complejo Asitencia de Burgos. Hospital General Yague
city: Ciudad Real
country: Spain
facility: Hospital General de Ciudad Real
city: Girona
country: Spain
facility: Institut Català d'Oncologia (ICO) de Girona
city: La Coruña
country: Spain
facility: Centro Oncológico de Galícia
city: Las Palmas de Gran Canaria
country: Spain
facility: Hosptial Dr. Negrin de Las Palmas de Gran Canaria
city: Lleida
country: Spain
facility: Hospital Arnau de Vilanova de Lleida
city: Madrid
country: Spain
facility: Hospital Infanta Sofía de Madrid
city: Madrid
country: Spain
facility: Hospital Universitario Puerta de Hierro de Madrid
city: Madrid
country: Spain
facility: Hospital de Fuenlabrada de Madrid
city: Murcia
country: Spain
facility: Hospital Morales Meseguer
city: Tarragona
country: Spain
facility: Hosptial de Sant Pau i Santa Tecla de Tarragona
city: Valencia
country: Spain
facility: Hospital La Fe de Valencia
city: Valencia
country: Spain
facility: Instituto Valenciano de Oncología de Valencia
city: Valencia
country: Spain
facility: Hospital General de Valencia
city: Valencia
country: Spain
facility: Hospital Dr. Peset de Valencia
city: Zaragoza
country: Spain
facility: Hospital Miguel Servet de Zaragoza
Study officials:
affiliation: Hospital Clinic i provincial de Barcelona
name: Joan Maurel, MD
role: STUDY_CHAIR
affiliation: Hospital de la Santa Creu i Sant Pau de Barcelona
name: Marta Martín, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital Arnau de Vilanova de Lleida
name: Antonia Salud, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital Son Llatzer de Mallorca
name: Antonio Arrivi, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Intitut Català d' Oncologia (ICO) de Girona
name: Xavier Hernández, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital General de l'Hospitalet de Barcelona
name: Ólbia Serra, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Corporació Sanitaria Parc Taulí de Barcelona
name: Carles Pericay, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Consorcio Hospitalario Provincial de Castellon
name: Isabel Busquier, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Instituto Valenciano de Oncología de Valencia
name: Carlos Fernandez-Martos, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital Universitario La Fe de Valencia
name: Jorge Aparicio, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital General Universitario de Valencia
name: Maria José Safont, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital Dr. Peset de Valencia
name: Carles Bosch, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hosptial General Universitario de Elche
name: Javier Gallego, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hosptial Morales Meseguer
name: Alberto Carmona, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hosptial Universitario La Paz de Madrid
name: Jaume Feliu, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital de Fuenlabrada de Madrid
name: Ana Ruíz, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital Infanta Sofía de Madrid
name: Enrique Casado, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital Universitario Puerta de Hierro de Madrid
name: Ricardo Cubedo, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hosptial General de Ciudad Real
name: Juana Maria Cano, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital Miguel Servet de Zaragoza
name: Vicente Alonso, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital Xeral Cies de Vigo
name: Monica Jorge, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital Son Dureta de Mallorca
name: Herminio Manzano, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Clínica Universitaria de Navarra
name: Javier Rodríguez, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hosptial Dr. Negrin de Las Palmas de Gran Canaria
name: Uriel Bohn, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital de Logroño
name: Miriam Zorrilla, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital de Navarra
name: Ruth Vera, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Complejo Asistencial de Burgos. Hospital General Yague
name: Carlos García, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital de l'Esperit Sant de Barcelona
name: Santiago Albiol, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Centro Oncológico de Galicia (La Coruña)
name: José Carlos Méndez, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital de Sant Pau i Santa Tecla de Tarragona
name: Francisco Javier Ramos, MD
role: PRINCIPAL_INVESTIGATOR
References:
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.