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

November 8, 2017 updated by: GlaxoSmithKline

A Phase I, Open-label, Study of the Safety, Pharmacokinetics, and Pharmacodynamics Dose Escalation of Pazopanib in Combination With Epirubicin or Doxorubicin for Advanced Solid Tumors

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.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Completed

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
111

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Italy
    • Lombardia
      • Milano, Lombardia, Italy, 20133
        • GSK Investigational Site
  • Switzerland
      • Bellinzona, Switzerland
        • GSK Investigational Site
      • Lausanne, Switzerland, 1011
        • GSK Investigational Site
      • St Gallen, Switzerland, 9007
        • GSK Investigational Site

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Experimental: 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
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
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
Other Names:
  • Doxorubicin
  • Pazopanib (GW786034)
Experimental: 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
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
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
Other Names:
  • Doxorubicin
  • Pazopanib (GW786034)
Experimental: 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
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
Other Names:
  • Doxorubicin
  • Pazopanib (GW786034)
Experimental: 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
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
Drug: 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

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Time Frame
Optimum tolerated regimen (OTR) for each combination regimen in each arm of the study.OTR determined by evaluation of AEs and change in lab values.OTR defined as highest dosing regimen that results in dose limiting toxicity in no more than 1 of 6 subject
Time Frame: Subjects will continue on the study until disease progression occurs or one of the discontinuation criteria is met up to approximately 48 months.
Subjects will continue on the study until disease progression occurs or one of the discontinuation criteria is met up to approximately 48 months.

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Time Frame
Safety assessments, including routine physical exam findings, vital signs, clinical laboratory tests (chemistry and hematology to include coagulation factors), clinical monitoring and/or observation, and adverse event reporting.
Time Frame: Safety assessment timing is noted on the Time and Events Table. Subjects will continue on the study until disease progression occurs or one of the discontinuation criteria is met up to approximately 48 months.
Safety assessment timing is noted on the Time and Events Table. Subjects will continue on the study until disease progression occurs or one of the discontinuation criteria is met up to approximately 48 months.
Safety and tolerability endpoints will include cardiac function (left ventricular ejection fraction) monitored by either MUGA or ECHO. A 12-lead ECG will also be monitored.
Time Frame: Safety assessment timing is noted on the Time and Events Table. Subjects will continue on the study until disease progression occurs or one of the discontinuation criteria is met up to approximately 48 months.
Safety assessment timing is noted on the Time and Events Table. Subjects will continue on the study until disease progression occurs or one of the discontinuation criteria is met up to approximately 48 months.
Pharmacokinetic endpoints will be AUC, Cmax, Tmax, and t1/2 of pazopanib, epirubicin, and doxorubicin, and clearance of epirubicin and doxorubicin if data are sufficient.
Time Frame: PK samples will only be collected in Cycle 1 and Cycle 2. Subjects will continue on the study until disease progression occurs or one of the discontinuation criteria is met up to approximately 48 months.
PK samples will only be collected in Cycle 1 and Cycle 2. Subjects will continue on the study until disease progression occurs or one of the discontinuation criteria is met up to approximately 48 months.
Assessment of anti-tumor activity using RECIST criteria will be recorded as complete response, partial response, stable disease, or progressive disease.
Time Frame: Subjects will continue on the study until disease progression occurs or one of the discontinuation criteria is met up to approximately 48 months.
Subjects will continue on the study until disease progression occurs or one of the discontinuation criteria is met up to approximately 48 months.
Levels of circulating cytokine and angiogenic factors (CAF) biomarkers (such as IL 2, IL-10, VEGF, sVEGFR2) in plasma will be determined.
Time Frame: Biomarker samples will only be collected in Cycles 1, 2, and 3. Subjects will continue on the study until disease progression occurs or one of the discontinuation criteria is met up to approximately 48 months.
Biomarker samples will only be collected in Cycles 1, 2, and 3. Subjects will continue on the study until disease progression occurs or one of the discontinuation criteria is met up to approximately 48 months.
Assessment of circulating BMD angiogenic cells in cancer peripheral blood in patients before and during treatment with oral pazopanib (continuous and intermittent regimens) and epirubicin or doxorubicin.
Time Frame: Biomarker samples will only be collected in Cycles 1 and 2. Subjects will continue on the study until disease progression occurs or one of the discontinuation criteria is met up to approximately 48 months.
Biomarker samples will only be collected in Cycles 1 and 2. Subjects will continue on the study until disease progression occurs or one of the discontinuation criteria is met up to approximately 48 months.
Gene expression profiling in selected subpopulations of BMD angiogenic cells in peripheral blood of cancer patients before and during treatment with pazopanib (continuous or intermittent regimens) in combination with epirubicin or doxorubicin.
Time Frame: Biomarker samples will only be collected in Cycles 1 and 2. Subjects will continue on the study until disease progression occurs or one of the discontinuation criteria is met up to approximately 48 months.
Biomarker samples will only be collected in Cycles 1 and 2. Subjects will continue on the study until disease progression occurs or one of the discontinuation criteria is met up to approximately 48 months.
Genetic variants in candidate genes in the host DNA will be evaluated
Time Frame: One pharmacogenetic sample will be collected during the study ideally in Cycle 1. Subjects will continue on the study until disease progression occurs or one of the discontinuation criteria is met up to approximately 48 months.
One pharmacogenetic sample will be collected during the study ideally in Cycle 1. Subjects will continue on the study until disease progression occurs or one of the discontinuation criteria is met up to approximately 48 months.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
GlaxoSmithKline

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
July 8, 2008

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
June 11, 2012

Study Completion (Actual)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
February 25, 2014

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
July 23, 2008

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
July 24, 2008

First Posted (Estimate)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
July 25, 2008

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
November 13, 2017

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
November 8, 2017

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
November 1, 2017

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • VEG109603

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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