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This is an open-label, two-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 gemcitabine (Arm A) or pazopanib, gemcitabine, and cisplatin (Arm B) in patients with advanced solid tumors. Patients will be enrolled in cohorts of 3 to receive escalating doses of pazopanib and gemcitabine or pazopanib, gemcitabine and cisplatin. 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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Arm A | Experimental | Dose Escalation - Patients will be entered into dose cohorts of three patients. Each cohort will be assigned to a dose level for the duration of the study. There will be no intra-patient dose-escalation. The starting dose will be 400 mg daily of pazopanib, and 1000 mg/m2 gemcitabine. Intermediate dose levels may also be explored. Intravenous gemcitabine will be given on Day 1 and 8 of Cycle 1 and each subsequent cycle. Cohort expansion phase - patients will receive gemcitabine alone, at the OTR dose starting on Day 1 of Cycle 1. Pazopanib will be administered at the OTR beginning on Day 2 Cycle 1 after the last blood sample for gemcitabine analysis is collected, and pazopanib administration will continue for the duration of the study. Patients will return to the clinic on Day 8 of Cycle 1 for simultaneous administration of gemcitabine and pazopanib. On Day 1 of Cycle 2 patients will receive the simultaneous administration of gemcitabine and pazopanib |
|
| Arm B | Experimental | Dose Escalation - Patients will be entered into dose cohorts of three patients. Each cohort will be assigned to a dose level for the duration of the study. There will be no intra-patient dose-escalation. The starting dose will be 400 mg daily of pazopanib, 1000 mg/m2 gemcitabine and 60 mg/m2 cisplatin. Doses of gemcitabine may range from 600 to 1250 mg/m2. Doses of cisplatin may range from 60 to 80 mg/m2. Intermediate dose levels may also be explored. Pazopanib administered starting on Day 1 of Cycle 1, gemcitabine co-administration on Day 1 and 8, and cisplatin on Day 1 in each 21-day cycle. Cohort expansion - patients will receive gemcitabine and cisplatin alone, at the OTR doses, starting on Day 1 of Cycle 1. Pazopanib will be administered at the OTR dose beginning on Day 2 of Cycle 1, and pazopanib administration will continue for the duration of the study. Patients will return to the clinic on Day 8 of Cycle 1 for simultaneous administration of gemcitabine and pazopanib |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Pazopanib (GW786034) | Drug | initial dose 400mg daily in 21-day cycles; increase in dose up to 800mg daily following evaluation of safety and tolerability |
|
| Measure | Description | Time Frame |
|---|---|---|
| Optimum tolerated regimen (OTR) for each regimen in each arm of the study. OTR determined evaluation of AEs and change in lab values. OTR defined as the highest dosing regimen that results in dose limiting toxicity in no more than 1 of 6 subjects | Until disease progression |
| Measure | Description | Time Frame |
|---|---|---|
| Anti-tumor activity evaluated using RECIST criteria (if subjects have measurable disease). Assessments of disease every 6 to 12 weeks, recorded as complete response (CR), partial response (PR), stable disease (SD) or progressive disease (PD). | Until Disease progression | |
| Pharmacokinetic parameters AUC(0-24), Cmax, and tmax of pazopanib, gemcitabine, and ultrafilterable platinum. |
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Inclusion Criteria:
Exclusion Criteria:
Cardiac angioplasty or stenting; myocardial infarction; unstable angina; symptomatic peripheral vascular disease; Class III or IV congestive heart failure as defined by the New York Heart Association
Note: Prior use of bevacizumab is allowed.
Note: For prior bevacizumab therapy at least 40 days should have elapsed since last dose.
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| Name | Affiliation | Role |
|---|---|---|
| GSK Clinical Trials | GlaxoSmithKline | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| GSK Investigational Site | Essen | North Rhine-Westphalia | 45122 | Germany | ||
| GSK Investigational Site |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 23064954 | Background | Plummer R, Madi A, Jeffels M, Richly H, Nokay B, Rubin S, Ball HA, Weller S, Botbyl J, Gibson DM, Scheulen ME. A Phase I study of pazopanib in combination with gemcitabine in patients with advanced solid tumors. Cancer Chemother Pharmacol. 2013 Jan;71(1):93-101. doi: 10.1007/s00280-012-1982-z. Epub 2012 Oct 11. |
| Label | URL |
|---|---|
| Results for study VEG109599 can be found on the GSK Clinical Study Register. | View source |
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| Gemcitabine | Drug | Gemcitabine on Days 1 and 8 of each cycle; initial dose 600 mg/m2 increase to 1,000mg/m2 after evaluation of safety and tolerability; increase to 1250mg/m2 after evaluation of safety and tolerability |
|
| Cisplatin | Drug | Cisplatin on Day 1 of each 21-day cycle initial dose 60mg/m2; increase to 80mg/m2 after evaluation of safety and tolerability |
|
| Dose Expansion - Cycle; Dose-Expansion Cycle 2 |
| Levels of circulating cytokine and angiogenic factors (CAF) biomarkers (such as IL 2, IL-10, VEGF, sVEGFR2) in plasma will be determined | Day 1 of each cycle until disease progression |
| Genetic variants in select candidate genes in the host DNA will be evaluated | Day 1 of first cycle |
| Newcastle upon Tyne |
| Northumberland |
| NE4 6BE |
| United Kingdom |
| ID | Term |
|---|---|
| D002289 | Carcinoma, Non-Small-Cell Lung |
| ID | Term |
|---|---|
| D002283 | Carcinoma, Bronchogenic |
| D001984 | Bronchial Neoplasms |
| D008175 | Lung Neoplasms |
| D012142 | Respiratory Tract Neoplasms |
| D013899 | Thoracic Neoplasms |
| D009371 | Neoplasms by Site |
| D009369 | Neoplasms |
| D008171 | Lung Diseases |
| D012140 | Respiratory Tract Diseases |
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| ID | Term |
|---|---|
| C516667 | pazopanib |
| D000093542 | Gemcitabine |
| D002945 | Cisplatin |
| ID | Term |
|---|---|
| D006571 | Heterocyclic Compounds |
| D003841 | Deoxycytidine |
| D003562 | Cytidine |
| D011741 | Pyrimidine Nucleosides |
| D011743 | Pyrimidines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D017606 | Chlorine Compounds |
| D007287 | Inorganic Chemicals |
| D017672 | Nitrogen Compounds |
| D017671 | Platinum Compounds |
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