A Phase I, Open-label, Study of Pazopanib in Combination With Epirubicin or Doxorubicin for Advanced Solid Tumors

NCT ID: NCT00722293

Last Updated: 2017-11-13

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 111 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2008-07-08
• Study Completion Date: 2014-02-25

Brief Summary

This is an open-label, four-arm, Phase I, dose escalation study to evaluate the safety and tolerability and to determine the optimal tolerated regimen (OTR) of pazopanib in combination with epirubicin or doxorubicin in patients with advanced solid tumors. Patients will be enrolled in cohorts of 3 to receive escalating doses of pazopanib and epirubicin or doxorubicin. Dose escalation schemas for each study arm are described in the protocol. For each arm, the OTR will be defined as the highest dose combination of the agents where no more than one out of six patients experiences a dose-limiting toxicity. Twelve additional patients in each arm will be studied with the OTR to evaluate toxicity and pharmacokinetics. This will allow an assessment of potential drug-drug interactions. Antitumor activity will be assessed using RECIST criteria.

Conditions

Neoplasms, Breast

Keywords

Solid tumors; Cancer; Neoplasms, Ovarian; doxorubicin; epirubicin; anti-angiogenesis; pharmacodynamics; pazopanib (GW786034); pharmacokinetics; Soft Tissue; Sarcoma

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Arm A

once daily oral administration of pazopanib for Days 1-21 days in combination with epirubicin given as a bolus intravenous administration on Day 3

Group Type: EXPERIMENTAL

Pazopanib (GW786034)

Intervention Type: DRUG

Arm A - daily administration of pazopanib on Days 1 through 21 starting at 200mg with a maximum dose of 800mg; Arm B daily administration of pazopanib on Days 1 through 8 of a 3-week cycle starting at 200mg escalating to a maximum dose of 800mg; Arm C daily dose of pazopanib on Days 14 through 21 of a 3-week cycle starting at 200mg escalating to a maximum dose of 800mg; Arm D once daily administration of pazopanib (according to schedule selected from Arm A, B, or C) starting at 400mg escalating to a maximum dose of 800mg

Epirubicin

Intervention Type: DRUG

Arm A and Arm B - epirubicin given as a bolus intravenous injection on Day 3 starting dose 60mg/m2 increase to 90mg/m2 if tolerated; Arm C - epirubicin given as a bolus intravenous injection on Day 1 starting dose 60mg/m2 increase to 90mg/m2 if tolerated

Arm B

once daily oral administration of pazopanib for Days 1-8 of a 3-week cycle in combination with epirubicin (bolus intravenous administration) on Day 3

Group Type: EXPERIMENTAL

Pazopanib (GW786034)

Intervention Type: DRUG

Arm A - daily administration of pazopanib on Days 1 through 21 starting at 200mg with a maximum dose of 800mg; Arm B daily administration of pazopanib on Days 1 through 8 of a 3-week cycle starting at 200mg escalating to a maximum dose of 800mg; Arm C daily dose of pazopanib on Days 14 through 21 of a 3-week cycle starting at 200mg escalating to a maximum dose of 800mg; Arm D once daily administration of pazopanib (according to schedule selected from Arm A, B, or C) starting at 400mg escalating to a maximum dose of 800mg

Epirubicin

Intervention Type: DRUG

Arm A and Arm B - epirubicin given as a bolus intravenous injection on Day 3 starting dose 60mg/m2 increase to 90mg/m2 if tolerated; Arm C - epirubicin given as a bolus intravenous injection on Day 1 starting dose 60mg/m2 increase to 90mg/m2 if tolerated

Arm C

epirubicin (bolus intravenous administration) on Day 1 with once-daily oral administration of pazopanib for Days 14-21 of a 3-week cycle

Group Type: EXPERIMENTAL

Epirubicin

Intervention Type: DRUG

Arm A and Arm B - epirubicin given as a bolus intravenous injection on Day 3 starting dose 60mg/m2 increase to 90mg/m2 if tolerated; Arm C - epirubicin given as a bolus intravenous injection on Day 1 starting dose 60mg/m2 increase to 90mg/m2 if tolerated

Arm D

once-daily oral administration of pazopanib (according to schedule selected from either Arm A, B, or C) (3 week cycle) in combination with doxorubicin (bolus intravenous administration) on Day 1 or 3, depending on the schedule selected from either Arm A, B, or C

Group Type: EXPERIMENTAL

Doxorubicin

Intervention Type: DRUG

Arm D - doxorubicin given as a intravenous bolus injection on Day 1 or Day 3 depending on schedule selected from Arm A, B or C - starting dose 60 mg/m2 and increase to 75mg/m2

Pazopanib (GW786034)

Intervention Type: DRUG

Arm A - daily administration of pazopanib on Days 1 through 21 starting at 200mg with a maximum dose of 800mg; Arm B daily administration of pazopanib on Days 1 through 8 of a 3-week cycle starting at 200mg escalating to a maximum dose of 800mg; Arm C daily dose of pazopanib on Days 14 through 21 of a 3-week cycle starting at 200mg escalating to a maximum dose of 800mg; Arm D once daily administration of pazopanib (according to schedule selected from Arm A, B, or C) starting at 400mg escalating to a maximum dose of 800mg

Interventions

Doxorubicin

Arm D - doxorubicin given as a intravenous bolus injection on Day 1 or Day 3 depending on schedule selected from Arm A, B or C - starting dose 60 mg/m2 and increase to 75mg/m2

Intervention Type: DRUG

Pazopanib (GW786034)

Arm A - daily administration of pazopanib on Days 1 through 21 starting at 200mg with a maximum dose of 800mg; Arm B daily administration of pazopanib on Days 1 through 8 of a 3-week cycle starting at 200mg escalating to a maximum dose of 800mg; Arm C daily dose of pazopanib on Days 14 through 21 of a 3-week cycle starting at 200mg escalating to a maximum dose of 800mg; Arm D once daily administration of pazopanib (according to schedule selected from Arm A, B, or C) starting at 400mg escalating to a maximum dose of 800mg

Intervention Type: DRUG

Epirubicin

Arm A and Arm B - epirubicin given as a bolus intravenous injection on Day 3 starting dose 60mg/m2 increase to 90mg/m2 if tolerated; Arm C - epirubicin given as a bolus intravenous injection on Day 1 starting dose 60mg/m2 increase to 90mg/m2 if tolerated

Intervention Type: DRUG

Other Intervention Names

Doxorubicin; Pazopanib (GW786034)

Eligibility Criteria

Inclusion Criteria

• Patients must provide written informed consent prior to performance of study specific procedures or assessments, and must be willing to comply with treatment and follow up
• Histologically or cytologically confirmed diagnosis of advanced solid tumor that has failed standard therapy or for which there is no standard therapy and is indicated for treatment with anthracyclines.
• Age greater than or equal to 18 years.
• Adequate organ system function as defined by the protocol.
• ECOG performance value of 0 or 1.
• Less than or equal to one prior line of chemotherapy for advanced disease. Patients with metastatic disease to the brain should have definitive therapy for their brain metastases, should be asymptomatic. (Patients with previously treated brain metastases who are asymptomatic, off steroids and anti-seizure medications for greater than 3 months are eligible for the study).
• There must be measurable disease or evaluable disease for subjects to be included in the cohort expansion phase. Measurable disease is not a criterion for subjects enrolling in the dose escalation phase.
• Has a left ventricular ejection fraction (LVEF) greater than or equal to 50% or greater than or equal to the institution's LLN.
• Women of childbearing potential must have a negative pregnancy test within 2 weeks of starting study drug and use acceptable birth control methods as outlined in the protocol.
• Women may participate if they are of non childbearing potential (bilateral tubal ligation, hysterectomy, post menopausal or bilateral ovariectomy.
• Males with female partners of childbearing potential may participate if they practice acceptable methods of birth control as outlined in the study protocol.
• Able to swallow and retain oral medications.
• Less than or equal to one prior line of chemotherapy for advanced disease.
• Life expectancy of at least 12 weeks.

Exclusion Criteria

• Prior use of pazopanib or prior treatment with anthracyclines. Prior therapy with other angiogenesis inhibitors is permitted.
• Clinically significant gastrointestinal abnormalities which might interfere with oral dosing.
• Any unstable or serious concurrent condition (e.g., active infection requiring systemic therapy).
• QTc > 480 msecs.
• History of any one or more of the following cardiovascular conditions within the past 6 months:

• Cardiac angioplasty or stenting
• Myocardial infarction
• Unstable angina
• Symptomatic peripheral vascular disease
• Class III or IV congestive heart failure
• Any major surgery or trauma within the last 28 days and or presence of non-healing wound, fracture, or ulcer.
• Any unstable or serious concurrent condition.
• Poorly controlled hypertension [defined as systolic blood pressure (SBP) of =140mmHg or diastolic blood pressure (DBP) of = 90mmHg].
• History of cerebrovascular accident (CVA), pulmonary embolism or untreated deep venous thrombosis (DVT) within the past 6 months. Subjects with a recent DVT who have been treated with therapeutic agents (excluding therapeutic warfarin) for at least 6 weeks are eligible.
• Prior major surgery or trauma within 28 days prior to first dose of study drug and /or presence of any non-healing wound, fracture, or ulcer.
• Hemoptysis within 6 weeks prior to first dose of study drug.
• Any serious and/or unstable pre-existing medical, psychiatric, or other condition that could interfere with patient's safety, provision of informed consent, or compliance to study procedures.
• Is unable or unwilling to discontinue prohibited medications for 14 days or five half-lives of a drug prior to Visit 1 and for the duration of the study.
• Use of an investigational agent, including an investigational anti-cancer agent, within 28 days or 5 half-lives, whichever is longer, prior to the first dose of study drug.
• Is now undergoing and/or has undergone within 28 days immediately prior to first dose of study drug, any cancer therapy (major surgery, investigational agent, tumor embolization, chemotherapy, radiation therapy, immunotherapy, biological therapy, or hormonal therapy).
• Clinically assessed as having inadequate venous access for PK sampling.
• Lactating and pregnant women should discontinue lactation prior to first use of study drug and refrain from nursing throughout the treatment period and for 14 days after final dose.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

GlaxoSmithKline

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

GSK Clinical Trials

Role: STUDY_DIRECTOR

GlaxoSmithKline

Locations

GSK Investigational Site

Milan, Lombardy, Italy

GSK Investigational Site

Bellinzona, , Switzerland

GSK Investigational Site

Lausanne, , Switzerland

GSK Investigational Site

Sankt Gallen, , Switzerland

Countries

Italy; Switzerland

Other Identifiers

VEG109603

Identifier Type: -

Identifier Source: org_study_id