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

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborators:
Amgen
TFS Trial Form Support
Information provided by (Responsible Party):
Grupo Espanol Multidisciplinario del Cancer Digestivo
ClinicalTrials.gov Identifier:
NCT01288339
First received: December 24, 2010
Last updated: September 13, 2013
Last verified: November 2012
  Purpose

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.


Condition Intervention Phase
Metastatic Colorectal Cancer
Drug: Panitumumab + FOLFOX (DP)
Drug: Panitumumab + FOLFOX (no-DP)
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
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

Resource links provided by NLM:


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

Primary Outcome Measures:
  • Progression-free survival time according to the MMP7 status (PFS) [ Time Frame: 5 years ] [ Designated as safety issue: No ]
    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-).


Secondary Outcome Measures:
  • Duration of response (DOR) [ Time Frame: 5 years ] [ Designated as safety issue: No ]
    Time from first confirmed objective response to radiologic disease progression per modified RECIST criteria.

  • Time to response (TTR) [ Time Frame: 5 years ] [ Designated as safety issue: No ]
    Time from randomization date to date of first confirmed objective response

  • Time to treatment failure (TtTF) [ Time Frame: 5 years ] [ Designated as safety issue: No ]
    Time from enrolment to the date the decision was made to end the treatment phase for any reason.

  • Objective response rate (ORR) [ Time Frame: 5 years ] [ Designated as safety issue: No ]
    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.

  • Disease Control Rate (DCR) [ Time Frame: 5 years ] [ Designated as safety issue: No ]
    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.

  • Overall Survival (OS) [ Time Frame: 5 years ] [ Designated as safety issue: No ]
    Time from randomization date to date of death.

  • Time To Progression (TTP) [ Time Frame: 5 years ] [ Designated as safety issue: No ]
    Time from randomization date to date of radiologic disease progression per modified RECIST criteria.

  • Duration of Stable Disease (DoSD) [ Time Frame: 5 years ] [ Designated as safety issue: No ]
    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

  • Incidence and severity of AEs [ Time Frame: 5 years ] [ Designated as safety issue: Yes ]
    Incidence and severity of AEs (Common Toxicity Criteria version 3.0)

  • Molecular predictive markers for response. [ Time Frame: 5 years ] [ Designated as safety issue: No ]
    Molecular predictive markers for response.


Estimated Enrollment: 80
Study Start Date: November 2010
Estimated Study Completion Date: September 2015
Estimated Primary Completion Date: April 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.

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

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  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: NCT01288339

Locations
Spain
Hospital General Universitario de Elche
Elche, Alicante, Spain, 03203
Hosptial General de l'Hospitalet de Barcelona
Hospitalet de Llobregat, Barcelona, Spain, 08906
Corporació Sanitaria Parc Taulí de Barcelona
Sabadell, Barcelona, Spain, 08208
Hosptial de l'Esperit Sant de Barcelona
Santa Coloma de Gramanet, Barcelona, Spain, 08923
Hosptial Son Llatzer de Mallorca
Mallorca, Illes Balears, Spain, 07198
Hospital Son Espases de Mallorca
Mallorca, Illes Balears, Spain, 07010
Hosptial de Logroño
Logroño, La Rioja, Spain, 26006
Hospital Universitario La Paz de Madrid
Madrid, Madrdi, Spain, 28046
Hospital Xeral Cies de Vigo
Vigo, Pontevedra, Spain, 36204
Hospital Clínic i Provincial de Barcelona
Barcelona, Spain, 08036
Hospital de la Santa Creu i Sant Pau de Barcelona
Barcelona, Spain, 08041
Complejo Asitencia de Burgos. Hospital General Yague
Burgos, Spain, 09005
Consorcio Hospitalario Provincial de Castellon
Castellon, Spain, 12002
Hospital General de Ciudad Real
Ciudad Real, Spain, 13005
Institut Català d'Oncologia (ICO) de Girona
Girona, Spain, 17007
Centro Oncológico de Galícia
La Coruña, Spain, 15009
Hosptial Dr. Negrin de Las Palmas de Gran Canaria
Las Palmas de Gran Canaria, Spain, 35010
Hospital Arnau de Vilanova de Lleida
Lleida, Spain, 25198
Hospital Infanta Sofía de Madrid
Madrid, Spain, 28072
Hospital Universitario Puerta de Hierro de Madrid
Madrid, Spain, 28222
Hospital de Fuenlabrada de Madrid
Madrid, Spain, 28942
Hospital Morales Meseguer
Murcia, Spain, 30008
Clínica Universitaria de Navarra
Navarra, Spain, 31008
Hospital de Navarra
Navarra, Spain, 31008
Hosptial de Sant Pau i Santa Tecla de Tarragona
Tarragona, Spain, 43003
Hospital La Fe de Valencia
Valencia, Spain, 46009
Instituto Valenciano de Oncología de Valencia
Valencia, Spain, 46009
Hospital General de Valencia
Valencia, Spain, 46014
Hospital Dr. Peset de Valencia
Valencia, Spain, 46017
Hospital Miguel Servet de Zaragoza
Zaragoza, Spain, 50009
Sponsors and Collaborators
Grupo Espanol Multidisciplinario del Cancer Digestivo
Amgen
TFS Trial Form Support
Investigators
Study Chair: Joan Maurel, Dr. Hospital Clinic i Provincial de Barcelona
Principal Investigator: Marta Martín, Dra. Hospital de la Santa Creu i Sant Pau de Barcelona
Principal Investigator: Antonia Salud, Dra. Hospital Arnau de Vilanova de Lleida
Principal Investigator: Antonio Arrivi, Dr. Hospital Son Llatzer de Mallorca
Principal Investigator: Xavier Hernández, Dr. Intitut Català d' Oncologia (ICO) de Girona
Principal Investigator: Ólbia Serra, Dra. Hospital General de l'Hospitalet de Barcelona
Principal Investigator: Carles Pericay, Dra. Corporació Sanitaria Parc Taulí de Barcelona
Principal Investigator: Isabel Busquier, Dra. Consorcio Hospitalario Provincial de Castellon
Principal Investigator: Carlos Fernandez-Martos, Dr. Instituto Valenciano de Oncología de Valencia
Principal Investigator: Jorge Aparicio, Dr. Hospital Universitario La Fe de Valencia
Principal Investigator: Maria José Safont, Dra. Hospital General de Valencia
Principal Investigator: Carles Bosch, Dr. Hospital Dr. Peset de Valencia
Principal Investigator: Javier Gallego, Dr. Hosptial General Universitario de Elche
Principal Investigator: Alberto Carmona, Dr. Hosptial Morales Meseguer
Principal Investigator: Jaume Feliu, Dr. Hosptial Universitario La Paz de Madrid
Principal Investigator: Ana Ruíz, Dra. Hospital de Fuenlabrada de Madrid
Principal Investigator: Enrique Casado, Dr. Hospital Infanta Sofía de Madrid
Principal Investigator: Ricardo Cubedo, Dr. Hospital Universitario Puerta de Hierro de Madrid
Principal Investigator: Juana Maria Cano, Dra. Hosptial General de Ciudad Real
Principal Investigator: Vicente Alonso, Dr. Hospital Miguel Servet de Zaragoza
Principal Investigator: Monica Jorge, Dra. Hospital Xeral Cies de Vigo
Principal Investigator: Herminio Manzano, Dr. Hospital Son Dureta de Mallorca
Principal Investigator: Javier Rodríguez, Dr. Clínica Universitaria de Navarra
Principal Investigator: Uriel Bohn, Dr. Hosptial Dr. Negrin de Las Palmas de Gran Canaria
Principal Investigator: Miriam Zorrilla, Dra. Hospital de Logroño
Principal Investigator: Ruth Vera, Dra. Hospital de Navarra
Principal Investigator: Carlos García, Dr. Complejo Asistencial de Burgos. Hospital General Yague
Principal Investigator: Santiago Albiol, Dr. Hospital de l'Esperit Sant de Barcelona
Principal Investigator: José Carlos Méndez, Dr. Centro Oncológico de Galicia (La Coruña)
Principal Investigator: Francisco Javier Ramos, Dr. Hospital de Sant Pau i Santa Tecla de Tarragona
  More Information

No publications provided

Responsible Party: Grupo Espanol Multidisciplinario del Cancer Digestivo
ClinicalTrials.gov Identifier: NCT01288339     History of Changes
Other Study ID Numbers: GEMCAD-0903, 2009-017331-18
Study First Received: December 24, 2010
Last Updated: September 13, 2013
Health Authority: Spain: Spanish Agency of Medicines

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
Antibodies, Monoclonal
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions

ClinicalTrials.gov processed this record on September 18, 2014