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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00540943
Recruitment Status : Completed
First Posted : October 8, 2007
Last Update Posted : November 29, 2017
Information provided by (Responsible Party):

Brief Summary:
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 or disease Intervention/treatment Phase
Neoplasms, Colorectal Drug: Pazopanib Drug: Cetuximab Drug: Irinotecan Phase 1

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 25 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase I Study of Safety and Pharmacokinetics of Pazopanib in Combination With Cetuximab and Irinotecan in Patients With Colorectal Cancer
Actual Study Start Date : July 13, 2007
Actual Primary Completion Date : May 3, 2010
Actual Study Completion Date : May 3, 2010

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Arm Intervention/treatment
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.

Drug: Cetuximab

Cetuximab will be supplied as a single-use 50 milliliter vial containing 100 micrograms of cetuximab as a sterile, preservative-free, injectable liquid at a concentration of 2 milligram per milliliter in phosphate.

buffered saline

Drug: Irinotecan
Irinotecan hydrochloride trihydrate is an antineoplastic agent of the topoisomerase I inhibitor class.

Primary Outcome Measures :
  1. 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 ]

Secondary Outcome Measures :
  1. pharmacokinetics disease assessment [ Time Frame: 2010 ]
  2. 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 ]
  3. AUC(0-24), Cmax, tmax, and t1/2 of pazopanib when administered with irinotecan and cetuximab [ Time Frame: 2010 ]
  4. AUC(0-24), Cmax, and tmax of cetuximab when administered with irinotecan alone [ Time Frame: 2010 ]
  5. AUC(0-24), Cmax, and tmax of cetuximab when administered with irinotecan plus pazopanib. [ Time Frame: 2010 ]
  6. 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 ]
  7. Objective response rate (complete response (CR) plus partial response (PR)) will be the primary measure of antitumor activity [ Time Frame: 2010 ]
  8. Stable disease (SD) at 4 months [ Time Frame: 4 months ]
  9. Time to progression [ Time Frame: 2010 ]

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT00540943

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

Additional Information:
Responsible Party: GlaxoSmithKline Identifier: NCT00540943     History of Changes
Other Study ID Numbers: VEG108925
First Posted: October 8, 2007    Key Record Dates
Last Update Posted: November 29, 2017
Last Verified: November 2017

Keywords provided by GlaxoSmithKline:
Colorectal cancer,

Additional relevant MeSH terms:
Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Topoisomerase I Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action