A Phase I, Open-label, Study of Pazopanib in Combination With Epirubicin or Doxorubicin for Advanced Solid Tumors
Information source: GlaxoSmithKline
Information obtained from ClinicalTrials.gov on December 08, 2011
Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Neoplasms, Breast; Cancer
Intervention: Doxorubicin (Drug); Pazopanib (GW786034) (Drug); Epirubicin (Drug)
Phase: Phase 1
Status: Recruiting
Sponsored by: GlaxoSmithKline Official(s) and/or principal investigator(s):
GSK Clinical Trials, Study Director, Affiliation: GlaxoSmithKline
Overall contact:
US GSK Clinical Trials Call Center, Phone: 877-379-3718, Email: GSKClinicalSupportHD@gsk.com
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. Six to 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.
Clinical Details
Official title: 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
Study design: Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Primary outcome: 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
Secondary outcome: 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.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. 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. Assessment of anti-tumor activity using RECIST criteria will be recorded as complete response, partial response, stable disease, or progressive disease. Levels of circulating cytokine and angiogenic factors (CAF) biomarkers (such as IL 2, IL-10, VEGF, sVEGFR2) in plasma will be determined. Assessment of circulating BMD angiogenic cells in peripheral blood of healthy donors and patients before and during treatment with oral pazopanib (continuous and intermittent regimens) and epirubicin. Gene expression profiling in selected subpopulations of BMD angiogenic cells in peripheral blood of healthy donors and cancer patients before and during treatment with pazopanib, continuous or intermittent regimen, in combination with epirubicin Genetic variants in candidate genes in the host DNA will be evaluated
Eligibility
Minimum age: 18 Years.
Maximum age: N/A.
Gender(s): Both.
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 indictated
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. Patients with metastatic disease to the brain
should have definitive therapy for their brain metastases, should be asympomatic.
(Patients with previously treated brain metastases who are asymptomatic, off steriods
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 disese is not a criterion for subjects
enrolling in the dose escalation phase.
- Have an LVEF greater than or equal to 50%.
- 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 2 prior lines of chemotherapy for advanced disease.
- Life expectancy of at least 12 weeks.
Exclusion Criteria:
- Prior use of pazopanib or prior treatment with epirubicin greater than 450 mg/mm2 or
doxorubicin greater than 240 mg/mm2 cumulative dose. 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.
Locations and Contacts
US GSK Clinical Trials Call Center, Phone: 877-379-3718, Email: GSKClinicalSupportHD@gsk.com
GSK Investigational Site, Bellinzona, Switzerland; Recruiting
US GSK Clinical Trials Call Center, Phone: 877-379-3718, Email: GSKClinicalSupportHD@gsk.com
EU GSK Clinical Trials Call Center, Phone: +44 (0) 20 8990 4466, Email: GSKClinicalSupportHD@gsk.com
GSK Investigational Site, Lausanne 1011, Switzerland; Recruiting
US GSK Clinical Trials Call Center, Phone: 877-379-3718, Email: GSKClinicalSupportHD@gsk.com
EU GSK Clinical Trials Call Center, Phone: +44 (0) 20 8990 4466, Email: GSKClinicalSupportHD@gsk.com
GSK Investigational Site, St Gallen 9007, Switzerland; Recruiting
US GSK Clinical Trials Call Center, Phone: 877-379-3718, Email: GSKClinicalSupportHD@gsk.com
EU GSK Clinical Trials Call Center, Phone: +44 (0) 20 8990 4466, Email: GSKClinicalSupportHD@gsk.com
GSK Investigational Site, Milano, Lombardia 20133, Italy; Recruiting
US GSK Clinical Trials Call Center, Phone: 877-379-3718, Email: GSKClinicalSupportHD@gsk.com
EU GSK Clinical Trials Call Center, Phone: +44 (0) 20 8990 4466, Email: GSKClinicalSupportHD@gsk.com
Additional Information
Starting date: July 2008
Last updated: October 27, 2011
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