Study Assessing Potential Predictive Tumor Markers in Metastatic Colorectal Cancer (PULSE)

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

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.

Study Overview

• Status: Completed
• Conditions: Metastatic Colorectal Cancer
• Intervention / Treatment: Drug: Panitumumab + FOLFOX (DP); Drug: Panitumumab + FOLFOX (no-DP)

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.

• Study Type: Interventional
• Enrollment (Actual): 78
• Phase: Phase 2

Contacts and Locations

Study Locations

• Spain
  • Barcelona, Spain, 08036
    • Hospital Clinic i Provincial de Barcelona
  • Barcelona, Spain, 08041
    • Hospital de la Santa Creu i Sant Pau de Barcelona
  • Burgos, Spain, 09005
    • Complejo Asitencia de Burgos. Hospital General Yague
  • Ciudad Real, Spain, 13005
    • Hospital General de Ciudad Real
  • Girona, Spain, 17007
    • Institut Català d'Oncologia (ICO) de Girona
  • La Coruña, Spain, 15009
    • Centro Oncologico de Galicia
  • Las Palmas de Gran Canaria, Spain, 35010
    • Hosptial Dr. Negrin de Las Palmas de Gran Canaria
  • Lleida, Spain, 25198
    • Hospital Arnau de Vilanova de Lleida
  • Madrid, Spain, 28072
    • Hospital Infanta Sofía de Madrid
  • Madrid, Spain, 28222
    • Hospital Universitario Puerta de Hierro de Madrid
  • Madrid, Spain, 28942
    • Hospital de Fuenlabrada de Madrid
  • Murcia, Spain, 30008
    • Hospital Morales Meseguer
  • Tarragona, Spain, 43003
    • Hosptial de Sant Pau i Santa Tecla de Tarragona
  • Valencia, Spain, 46009
    • Hospital La Fe de Valencia
  • Valencia, Spain, 46009
    • Instituto Valenciano de Oncología de Valencia
  • Valencia, Spain, 46014
    • Hospital General de Valencia
  • Valencia, Spain, 46017
    • Hospital Dr. Peset de Valencia
  • Zaragoza, Spain, 50009
    • Hospital Miguel Servet de Zaragoza
  • Alicante
    • Elche, Alicante, Spain, 03203
      • Hospital General Universitario de Elche
  • Barcelona
    • Hospitalet de Llobregat, Barcelona, Spain, 08906
      • Hosptial General de l'Hospitalet de Barcelona
    • Sabadell, Barcelona, Spain, 08208
      • Corporació Sanitaria Parc Taulí de Barcelona
    • Santa Coloma De Gramenet, Barcelona, Spain, 08923
      • Hospital de l'Esperit Sant
  • Castellon
    • Castellón De La Plana, Castellon, Spain, 12002
      • Consorcio Hospitalario Provincial de Castellon
  • Illes Balears
    • Palma De Mallorca, Illes Balears, Spain, 07010
      • Hospital Son Espases de Mallorca
    • Palma De Mallorca, Illes Balears, Spain, 07198
      • Hosptial Son Llatzer de Mallorca
  • La Rioja
    • Logroño, La Rioja, Spain, 26006
      • Hosptial de Logroño
  • Madrdi
    • Madrid, Madrdi, Spain, 28046
      • Hospital Universitario La Paz de Madrid
  • Navarra
    • Pamplona, Navarra, Spain, 31008
      • Clinica Universitaria de Navarra
    • Pamplona, Navarra, Spain, 31008
      • Hospital de Navarra
  • Pontevedra
    • Vigo, Pontevedra, Spain, 36204
      • Hospital Xeral Cies de Vigo

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Panitumumab + FOLFOX (DP); Panitumumab and FOLFOX will be administered to patients with DP (MMP7+/p-IGF-IR) once every 14 days until 6 months of treatment or until disease progression (PD) or unacceptable toxicity. If patients have not progressed after 6 months of treatment with panitumumab and FOLFOX they will continue with panitumumab monotherapy until disease progression.	Drug: Panitumumab + FOLFOX (DP); Panitumumab and FOLFOX will be administered to patients with DP once every 14 days until 6 months of treatment or until disease progression (PD) or unacceptable toxicity. If patients have not progressed after 6 months of treatment with panitumumab and FOLFOX they will continue with panitumumab monotherapy until disease progression.
Experimental: Panitumumab + FOLFOX (no-DP); Panitumumab and FOLFOX will be administered to patients with no-DP (MMP7+/p-IGF-IR-, MMP7-/p-IGF-IR+ or MMP7-/p-IGF-IR) once every 14 days until 6 months of treatment or until disease progression (PD) or unacceptable toxicity. If patients have not progressed after 6 months of treatment with panitumumab and FOLFOX they will continue with panitumumab monotherapy until disease progression.	Drug: Panitumumab + FOLFOX (no-DP); Panitumumab and FOLFOX will be administered to patients with no-DP (MMP7+/p-IGF-IR-, MMP7-/p-IGF-IR+ or MMP7-/p-IGF-IR) once every 14 days until 6 months of treatment or until disease progression (PD) or unacceptable toxicity. If patients have not progressed after 6 months of treatment with panitumumab and FOLFOX they will continue with panitumumab monotherapy until disease progression.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free survival time according to the MMP7 status (PFS)	To estimate the PFS by DP immunohistochemistry (IHC) expression in patients with wild-type KRAS mCRC 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-).	5 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Duration of response (DOR)	Time from first confirmed objective response to radiologic disease progression per modified RECIST criteria.	5 years
Time to response (TTR)	Time from randomization date to date of first confirmed objective response	5 years
Time to treatment failure (TtTF)	Time from enrolment to the date the decision was made to end the treatment phase for any reason.	5 years
Objective response rate (ORR)	Incidence of either a confirmed CR or PR per modified RECIST criteria. CRs or PRs will be confirmed no less than 28 days after the criteria for response are first met. All subjects without a confirmed response will be considered non-responders.	5 years
Disease Control Rate (DCR)	Incidence of either a confirmed CR or PR or stable disease (SD) while in the treatment phase; subjects prematurely discontinuing without a post baseline tumor response assessment or subjects with an observed response that is not confirmed will be considered non-responders otherwise.	5 years
Overall Survival (OS)	Time from randomization date to date of death.	5 years
Time To Progression (TTP)	Time from randomization date to date of radiologic disease progression per modified RECIST criteria.	5 years
Duration of Stable Disease (DoSD)	Calculated for only those subjects with a best response of SD during the treatment period, time from enrolment to date of first observed PD or death due to PD (whichever comes first) in either the combination or monotherapy phases	5 years
Incidence and severity of AEs	Incidence and severity of AEs (Common Toxicity Criteria version 3.0)	5 years
Molecular predictive markers for response.	Molecular predictive markers for response.	5 years

Collaborators and Investigators

• Sponsor: Grupo Espanol Multidisciplinario del Cancer Digestivo
• Collaborators: Amgen; TFS Trial Form Support
• Investigators: Study Chair: Joan Maurel, MD, Hospital Clinic i Provincial de Barcelona; Principal Investigator: Antonia Salud, MD, Hospital Arnau de Vilanova de Lleida; Principal Investigator: Antonio Arrivi, MD, Hospital Son Llatzer de Mallorca; Principal Investigator: Xavier Hernández, MD, Intitut Català d' Oncologia (ICO) de Girona; Principal Investigator: Ólbia Serra, MD, Hospital General de l'Hospitalet de Barcelona; Principal Investigator: Carles Pericay, MD, Corporació Sanitaria Parc Taulí de Barcelona; Principal Investigator: Isabel Busquier, MD, Consorcio Hospitalario Provincial de Castellon; Principal Investigator: Carlos Fernandez-Martos, MD, Instituto Valenciano de Oncología de Valencia; Principal Investigator: Jorge Aparicio, MD, Hospital Universitario La Fe de Valencia; Principal Investigator: Maria José Safont, MD, Hospital General Universitario de Valencia; Principal Investigator: Carles Bosch, MD, Hospital Dr. Peset de Valencia; Principal Investigator: Javier Gallego, MD, Hosptial General Universitario de Elche; Principal Investigator: Alberto Carmona, MD, Hosptial Morales Meseguer; Principal Investigator: Jaume Feliu, MD, Hosptial Universitario La Paz de Madrid; Principal Investigator: Ana Ruíz, MD, Hospital de Fuenlabrada de Madrid; Principal Investigator: Enrique Casado, MD, Hospital Infanta Sofía de Madrid; Principal Investigator: Ricardo Cubedo, MD, Hospital Universitario Puerta de Hierro de Madrid; Principal Investigator: Juana Maria Cano, MD, Hosptial General de Ciudad Real; Principal Investigator: Vicente Alonso, MD, Hospital Miguel Servet de Zaragoza; Principal Investigator: Monica Jorge, MD, Hospital Xeral Cies de Vigo; Principal Investigator: Herminio Manzano, MD, Hospital Son Dureta de Mallorca; Principal Investigator: Javier Rodríguez, MD, Clinica Universitaria de Navarra; Principal Investigator: Uriel Bohn, MD, Hosptial Dr. Negrin de Las Palmas de Gran Canaria; Principal Investigator: Miriam Zorrilla, MD, Hospital de Logroño; Principal Investigator: Carlos García, MD, Complejo Asistencial de Burgos. Hospital General Yague; Principal Investigator: Santiago Albiol, MD, Hospital de l'Esperit Sant de Barcelona; Principal Investigator: José Carlos Méndez, MD, Centro Oncológico de Galicia (La Coruña); Principal Investigator: Francisco Javier Ramos, MD, Hospital de Sant Pau i Santa Tecla de Tarragona

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): November 8, 2010
• Primary Completion (Actual): February 13, 2015
• Study Completion (Actual): February 13, 2015

Study Registration Dates

• First Submitted: December 24, 2010
• First Submitted That Met QC Criteria: February 1, 2011
• First Posted (Estimate): February 2, 2011

Study Record Updates

• Last Update Posted (Actual): May 16, 2018
• Last Update Submitted That Met QC Criteria: May 11, 2018
• Last Verified: May 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Protective Agents; Antineoplastic Agents, Immunological; Micronutrients; Vitamins; Antidotes; Vitamin B Complex; Fluorouracil; Oxaliplatin; Leucovorin; Panitumumab
• Other Study ID Numbers: GEMCAD-0903; 2009-017331-18 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No