This randomized phase II trial studies how well gemcitabine hydrochloride works with or without pazopanib hydrochloride in treating patients with refractory soft tissue sarcoma. Drugs used in chemotherapy, such as gemcitabine hydrochloride, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Pazopanib hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Pazopanib hydrochloride may also stop the growth of tumor cells by blocking blood flow to the tumor. It is not yet known whether gemcitabine hydrochloride is more effective with or without pazopanib hydrochloride in treating patients with soft tissue sarcoma.
PRIMARY OBJECTIVES: I. To investigate whether treatment with gemcitabine (gemcitabine hydrochloride) plus pazopanib (pazopanib hydrochloride) improves the median progression-free survival (PFS) of patients with metastatic soft tissue sarcoma when compared to gemcitabine plus placebo. SECONDARY OBJECTIVES: I. To assess overall response in this population to gemcitabine plus pazopanib compared to gemcitabine plus placebo. II. To assess overall survival (OS) in this population to gemcitabine plus pazopanib compared to gemcitabine plus placebo. III. To investigate differences in treatment response in different histologic subgroups (liposarcoma vs. all other eligible soft tissue sarcoma subtypes). IV. To evaluate the safety and tolerability of the combination of gemcitabine plus pazopanib. V. To assess the progression-free survival and overall response in patients treated with single agent pazopanib following administration of gemcitabine in the cross-over portion of this study. VI. To collect specimens for an exploratory analysis of potential biomarkers that predict response in patients receiving combination therapy with gemcitabine plus pazopanib. OUTLINE: Patients are randomized to 1 of 2 treatment arms. ARM I: Patients receive gemcitabine hydrochloride intravenously (IV) over 30 minutes on days 1 and 8 and pazopanib hydrochloride orally (PO) on days 1-21. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. ARM II: Patients receive gemcitabine hydrochloride IV over 30 minutes on days 1 and 8 and placebo PO on days 1-21. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients who experience disease progression may receive single-agent pazopanib hydrochloride PO daily. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. After the completion of study treatment, patients are followed up every 3 months.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
DOUBLE
Enrollment
54
OHSU Knight Cancer Institute
Portland, Oregon, United States
Fred Hutch/University of Washington Cancer Consortium
Seattle, Washington, United States
Progression-free Survival (PFS)
Compared using a one-sided Gehan-Wilcoxon test stratified by sarcoma subtype. Kaplan-Meier estimates for each treatment arm will be presented with the estimated hazard ratios and their associated confidence intervals. Progression is defined using Response Evaluation Criteria in Solid Tumors (RECIST) v1.0 as at least a 20% increase in the sum of the longest diameters of target lesions (taking as reference the smallest sum on study) with an absolute increase of at least 5 mm (target lesions), or measurable increase in non-target lesions (unequivocal progression), or appearance of one or more new lesions.
Time frame: Calculated as the time from randomization to the first documented progression or death, whichever occurs first, or until time of last contact if no progression or death occurred, assessed up to 3 years
Progression-free Survival (PFS) for a Sub-group of Patients Treated With Open-label Pazopanib Hydrochloride Following Administration of Gemcitabine Hydrochloride in the Cross-over Portion of This Study
Participants who progress during treatment and are found to be part of the gemcitabine+placebo arm after unblinding are eligible to receive open-label pazopanib with gemcitabine. This is the crossover population. Statistical analysis is exploratory and requires sufficient crossover participants to assess Kaplan-Meier estimated hazard ratio and associated 95% confidence interval. This represents the participants second progression. In both cases progression is defined using Response Evaluation Criteria in Solid Tumors (RECIST) v1.0 as at least a 20% increase in the sum of the longest diameters of target lesions with an absolute increase of at least 5 mm (target lesions), or measurable increase in non-target lesions (unequivocal progression), or appearance of one or more new lesions. First progression uses the smallest sum on study as a reference; progression for the crossover population uses first progression measurements as the reference.
Time frame: Calculated as the time from receiving open-labeled pazopanib hydrochloride to the next documented progression or death whichever occurs first, assessed up to 3 years
Percentage of Participants Achieving Best Overall Objective Response (CR+PR)
Response is evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, where RECIST combines assessments for target, non-target and presence of new lesions. Best Overall Objective Response is the sum of all CR+PR divided by all randomized participants, where the strongest recorded response is used for the evaluation (CR\>PR\>SD\>PD). Objective response (CR+PR) requires at least a 30% decrease in the sum of the largest diameter target lesions (with respective to the baseline sum); disappearance of all or persistence of one or more non-target lesions, maintenance of tumor marker levels above normal limits, and no new lesions. Estimated odds ratio of best overall objective response are reported with 95% confidence interval for the two histologic sarcoma subgroups (liposarcoma vs all other eligible soft tissue sarcoma subtypes). One-sided proportions test is used to determine whether best overall objective response is greater for the gemcitabine plus pazopanib group.
Time frame: Best overall objective response recorded from the start of treatment until disease progression/recurrence assessed up to 3 years
Overall Survival
Two treatment arms will be compared using a one-sided log-rank test stratified by sarcoma subtype and study site. Kaplan-Meier estimates and the survival curves for each treatment arm will be presented with the estimated hazard ratios and their associated confidence interval.
Time frame: From randomization to death due to any cause, or until last patient contact if the patient did not die, assessed up to 3 years
This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.