Study of Pazopanib, Irinotecan and Cetuximab in Combination to Treat 2nd Line Metastatic Colorectal Cancer

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline
ClinicalTrials.gov Identifier:
NCT00540943
First received: October 5, 2007
Last updated: March 15, 2012
Last verified: February 2011
  Purpose

Subjects will be entered into cohorts of 3 for the dose escalation phase so that the maximum tolerated dose can be determined. 18 additional patients will be recruited once the maximum tolerated dose (MTD) is determined for disease assessment.


Condition Intervention Phase
Neoplasms, Colorectal
Colorectal Cancer
Drug: pazopanib
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase I, Open Label, Study of the Safety, Tolerability and Pharmacokinetics of Pazopanib in Combination With Irinotecan and Cetuximab for the Relapsed or Refractory Metastatic Colorectal Cancer

Resource links provided by NLM:


Further study details as provided by GlaxoSmithKline:

Primary Outcome Measures:
  • The safety and tolerability of the maximum tolerated dose defined as a dose regimen where no more than 1 of 6 subjects experiences a dose limiting toxicity. [ Time Frame: End of 2009 ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • pharmacokinetics disease assessment [ Time Frame: 2010 ]
  • Clearance of irinotecan (if data permit) and AUC, Cmax, tmax, and t1/2 of irinotecan and SN-38 after administration of irinotecan plus cetuximab. [ Time Frame: 2010 ]
  • AUC(0-24), Cmax, tmax, and t1/2 of pazopanib when administered with irinotecan and cetuximab [ Time Frame: 2010 ]
  • AUC(0-24), Cmax, and tmax of cetuximab when administered with irinotecan alone [ Time Frame: 2010 ]
  • AUC(0-24), Cmax, and tmax of cetuximab when administered with irinotecan plus pazopanib. [ Time Frame: 2010 ]
  • The ratio of SN-38 AUC(0-24) and irinotecan AUC(0-24) on Cycle 1 Day 1 and on Cycle 2 Day 1. [ Time Frame: 2010 ]
  • Objective response rate (complete response (CR) plus partial response (PR)) will be the primary measure of antitumor activity [ Time Frame: 2010 ]
  • Stable disease (SD) at 4 months [ Time Frame: 4 months ]
  • Time to progression

Enrollment: 24
Study Start Date: July 2007
Study Completion Date: May 2010
Primary Completion Date: May 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Single Arm
irinotecan and cetuximab in combination with pazopanib.
Drug: pazopanib
Pazopanib is a potent, multi-targeted tyrosine kinase inhibitor of VEGFR-1, -2, -3, PDGFR-alpha and -beta and c-kit.

  Eligibility

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

Inclusion criteria:

  • Male or female at least 18 years of age.
  • Willing and able to sign a written informed consent.
  • Is either affiliated to or a beneficiary of a social security category
  • Histologically or cytologically confirmed diagnosis of colorectal cancer. Subjects should have metastatic disease which is refractory or relapsed following prior treatment.
  • Documented disease progression after prior treatment with 5-FU, oxaliplatin and irinotecan containing regimens.
  • Complete recovery from surgical or radiotherapy procedures.
  • Eastern Cooperative Oncology Group performance status of 0 or 1, or Karnofsky score ≥ 70%.
  • Able to swallow and retain oral medications.
  • Adequate bone marrow function (absolute neutrophil count greater than or equal to 1,500/mm3, platelet count greater than or equal to 100,000/mm3, hemoglobin levels greater than or equal to 10g/dL).
  • Adequate renal function as determined by a creatinine clearance greater than 50 mL/minute calculated by the Cockcroft-Gault Formula. Measured creatinine clearance greater than or equal to 50 mL/minute by 24 hour urine collection will be acceptable in lieu of a calculated value.
  • Urine Protein Creatinine (UPC) Ratio of ≤ 1 as assessed in a random or spot urine sample.
  • Adequate hepatic function determined by total bilirubin within the normal range and aspartate aminotransferase (AST or SGOT) or alanine aminotransferase (ALT or SGPT) less than or equal to 2.5 times the upper limit of normal.
  • Prothrombin time (PT), international normalized ratio (INR), and partial thromboplastin time (PTT) less than or equal to 1.2 times the ULN.
  • A female subject is eligible to enter and participate in the study if she is:

    ·Non-childbearing potential (i.e., physiologically incapable of becoming pregnant) including any woman who:

  • Has had a hysterectomy, or
  • Has had a bilateral oophorectomy (ovariectomy), or
  • Has had a bilateral tubal ligation, or
  • Is post-menopausal (demonstrate total cessation of menses for greater than or equal to 1 year).
  • Childbearing potential, has a negative serum pregnancy test at screening, and agrees to one of the following:
  • An intrauterine device with a documented failure rate of less than 1% per year.
  • Vasectomized partner who is sterile prior to the subject's entry and is the sole sexual partner for that woman.
  • Complete abstinence from sexual intercourse for 14 days before exposure to investigation product, throughout the clinical trial, and for at least 21 days after the last dose of investigational product.
  • Double barrier contraception defined as condom with spermicidal jelly, foam, suppository, or film; OR diaphragm with spermicide; OR male condom and diaphragm.
  • A male patient with a female partner of childbearing potential is eligible to enter and participate in the study if he uses a barrier method of contraception or abstinence during the study.
  • Predicted life expectancy of at least 12 weeks.
  • Able to understand and comply with protocol requirements and instructions and intends to complete the study as planned.

Exclusion criteria:

  • Has participated in any study using an investigational drug during the previous 28 days.
  • Has had any major surgery, chemotherapy, investigational agent, or radiotherapy within the last 28 days and/or not recovered from prior therapy.
  • Any history of grade III toxicity related to prior treatment with anti VEGF compound other than grade 3 hypertension subsequently controlled with antihypertensive agents.
  • Has received prior treatment with pazopanib / investigational anti-angiogenic compounds or cetuximab. Prior treatment with Avastin is permitted. Known contraindications to the use of irinotecan and cetuximab.
  • Unable to tolerate 180mg/m2 of irinotecan every two weeks during previous treatment.
  • Is unable to discontinue prohibited medications, as stipulated in the protocol for 14 days prior to Visit 1 and for the duration of the study
  • Has received Amiodarone for arrythmias within the last 6 months prior to Visit 1
  • Has known allergy to penicillin.
  • Women who are pregnant or lactating.
  • Poorly controlled hypertension (systolic blood pressure [SBP] of 140 mmHg or higher, or diastolic blood pressure [DBP] of 90 mmHg or higher). Initiation or adjustment of blood pressure medication is permitted prior to study entry provided the subject has 2 consecutive blood pressure readings less than 140/90 mmHg, each separated by a minimum of 24 hours. These readings need to be collected prior to the first dose.
  • Corrected QT (QTc) prolongation defined as a QTc interval greater than or equal to 480 msec and a prior history of cardiovascular disease, arrhythmias, or significant ECG abnormalities.
  • Has Class III or IV heart failure as defined by the New York Heart Association functional classification system.
  • Arterial thrombi, myocardial infarction, admission for unstable angina, uncontrolled or symptomatic arrhythmia, cardiac angioplasty, or stenting within the last 6 months.
  • Any history of cerebrovascular accident (CVA), or pulmonary embolism within the last 6 months.
  • History of untreated deep venous thrombosis (DVT) within the past 6 months (e.g. calf vein thrombosis). Note: Patients with recent DVT who have been treated with therapeutic anti-coagulant agents (excluding therapeutic warfarin) for at least 6 weeks are eligible.
  • Current use of therapeutic warfarin. NOTE: Low molecular weight heparin and prophylactic low-dose warfarin (no more than 1mg per day) are permitted. PT/PTT and INR must be within 1.2 times the upper limit of normal.
  • Known history of leptomeningeal or brain metastases. NOTE: Computed tomography or magnetic resonance imaging (MRI) scans are not required to rule out central nervous system metastases unless the subject is exhibiting neurologic signs or symptoms. If, however, CT or MRI scans are performed and document central nervous system disease, the subject is ineligible, regardless of whether neurologic signs or symptoms are present.
  • Any serious and/or unstable pre-existing medical, psychiatric, or other condition (including laboratory abnormalities) that could interfere with subject safety or obtaining informed consent.
  • History of mal-absorption syndrome, disease significantly affecting gastrointestinal function or major resection of the stomach or small bowel that could affect absorption, distribution, metabolism, or excretion of study drugs.
  • History of any unresolved bowel obstruction or diarrhea.
  • The subject has a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to the study drug, irinotecan, or cetuximab, unless enrolment is approved by the GSK Medical Monitor following discussion with the Investigator.
  • Psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol.
  • Is on any specifically prohibited medication or requires any of these medications during treatment with pazopanib.
  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: NCT00540943

Locations
France
GSK Investigational Site
Saint Herblain, France, 44805
GSK Investigational Site
Toulouse, France, 31052
Sponsors and Collaborators
GlaxoSmithKline
Investigators
Study Director: GSK Clinical Trials GlaxoSmithKline
  More Information

No publications provided

Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT00540943     History of Changes
Other Study ID Numbers: VEG108925
Study First Received: October 5, 2007
Last Updated: March 15, 2012
Health Authority: France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)

Keywords provided by GlaxoSmithKline:
cetuximab
irinotecan,
pazopanib,
Colorectal cancer,

Additional relevant MeSH terms:
Colorectal Neoplasms
Colonic Diseases
Digestive System Diseases
Digestive System Neoplasms
Gastrointestinal Diseases
Gastrointestinal Neoplasms
Intestinal Diseases
Intestinal Neoplasms
Neoplasms
Neoplasms by Site
Rectal Diseases
Cetuximab
Irinotecan
Antineoplastic Agents
Antineoplastic Agents, Phytogenic
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Radiation-Sensitizing Agents
Therapeutic Uses
Topoisomerase I Inhibitors
Topoisomerase Inhibitors

ClinicalTrials.gov processed this record on October 30, 2014