Overview

This trial is active, not recruiting.

Conditions stage iia adult soft tissue sarcoma, stage iii adult soft tissue sarcoma, stage iv adult soft tissue sarcoma
Treatments doxorubicin hydrochloride, external beam radiation therapy, ifosfamide, laboratory biomarker analysis, pazopanib hydrochloride, pharmacological study, placebo, therapeutic conventional surgery
Targets VEGF, PDGF, KIT
Sponsor University of Washington
Collaborator National Cancer Institute (NCI)
Start date April 2012
End date July 2016
Trial size 21 participants
Trial identifier NCT01446809, 7487, NCI-2011-02488, P30CA015704

Summary

This randomized pilot clinical trial studies pazopanib hydrochloride followed by chemotherapy and surgery in treating patients with soft tissue sarcoma. Pazopanib hydrochloride may stop the growth of tumor cells by blocking some of the enzymes that are needed for cell growth and may also stop the growth of soft tissue sarcoma by blocking blood flow to the tumor. Giving pazopanib hydrochloride and chemotherapy before surgery may make the tumor smaller and reduce the amount of tissue that needs to be removed.

United States No locations recruiting
Other Countries No locations recruiting

Study Design

Allocation randomized
Endpoint classification efficacy study
Intervention model parallel assignment
Masking double blind (subject, investigator)
Primary purpose treatment
Arm
(Experimental)
Patients receive pazopanib hydrochloride PO QD. Treatment continues for 14 days in the absence of disease progression or unacceptable toxicity.
doxorubicin hydrochloride 5,12-Naphthacenedione, 10-[(3-amino-2,3,6-trideoxy-alpha-L-lyxo-hexopyranosyl)oxy]-7,8, 9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxy-, hydrochloride, (8S-cis)- (9CI)
Given IV
external beam radiation therapy Definitive Radiation Therapy
Undergo external beam radiation therapy
ifosfamide Asta Z 4942
Given IV
laboratory biomarker analysis
Correlative studies
pazopanib hydrochloride GW786034B
Given PO
pharmacological study
Correlative studies
therapeutic conventional surgery
Undergo surgery
(Placebo Comparator)
Patients receive placebo PO QD. Treatment continues for 14 days in the absence of disease progression or unacceptable toxicity.
doxorubicin hydrochloride 5,12-Naphthacenedione, 10-[(3-amino-2,3,6-trideoxy-alpha-L-lyxo-hexopyranosyl)oxy]-7,8, 9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxy-, hydrochloride, (8S-cis)- (9CI)
Given IV
external beam radiation therapy Definitive Radiation Therapy
Undergo external beam radiation therapy
ifosfamide Asta Z 4942
Given IV
laboratory biomarker analysis
Correlative studies
pharmacological study
Correlative studies
placebo placebo therapy
Given PO
therapeutic conventional surgery
Undergo surgery

Primary Outcomes

Measure
Change in maximum SUV of tumors measured by FDG-PET pre- and post receipt of pazopanib versus placebo
time frame: At baseline and at approximately 14 days
Change in maximum SUV of tumors measured by FDG-PET post receipt of 2 courses of preoperative chemotherapy
time frame: At baseline and at approximately 8 weeks
Tumor response by RECIST criteria
time frame: At baseline and at approximately 14 days
Tumor response by RECIST criteria
time frame: At baseline and at approximately 8 weeks
Correlation of pazopanib hydrochloride trough concentration with the change in SUV from FDG PET and change in RECIST measurements on MRIs
time frame: At baseline and at approximately 14 days
Correlation of pazopanib hydrochloride trough concentration with the change in SUV from FDG PET and change in RECIST measurements on MRIs
time frame: At baseline and at approximately 8 weeks

Secondary Outcomes

Measure
Change in plasma and tumor angiogenic biomarker levels pre- and post neoadjuvant therapy
time frame: At baseline and after 14 days
Overall survival
time frame: Up to 3 years
Pathologic response at the time of surgery as measured by % tumor viability
time frame: An expected average of 12 weeks
Progression free survival
time frame: Up to 3 years
Safety profile of sequential treatment with pazopanib and pre-operative chemotherapy with doxorubicin and ifosfamide
time frame: Up to 3 years

Eligibility Criteria

Male or female participants at least 18 years old.

Inclusion Criteria: - Histologically or cytologically confirmed soft-tissue sarcoma, excluding alveolar and embryonal rhabdomyosarcoma, well- and dedifferentiated adipocytic sarcomas, Ewing's, osteosarcoma, or gastrointestinal stromal tumor; American Joint Committee on Cancer (AJCC) (6th Edition) Stage III or T2a Stage II or Stage IV treatment naive patients planned for resection of the primary tumor, with resectable metastatic disease - Measurable disease greater than 5 centimeters in greatest dimension; measurable lesions are defined as those that can be accurately measured in at least one dimension (longest diameter for non-nodal lesions and short axis for nodal lesions to be recorded) by chest x-ray, computed tomography (CT) scan, magnetic resonance imaging (MRI) or with calipers by clinical exam; all tumor measurements must be recorded in millimeters (or decimal fractions of centimeters) - Intermediate or high grade lesions: 2 or 3 on a scale of 1-3 or grades 2 to 4 on a scale of 1-4 - Sarcoma located on upper (includes shoulder) or lower (includes hip) extremities or on the body wall - Life expectancy of greater than 6 months - Eastern Cooperative Oncology Group (ECOG) performance status =< 1 - Karnofsky >= 80% - No prior chemotherapy, radiotherapy, or antiangiogenic therapy - Absolute neutrophil count (ANC) >= 1500/uL - Hemoglobin (Hgb) >= 9.0 g/dL - Platelets >= 100,000/uL - Creatinine =< 1.5 x upper limit of normal (ULN) - Bilirubin =< 1.5 mg/dL - Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 1.5 x ULN - Prothrombin time (PT)/international normalized ratio (INR)/partial thromboplastin time (PTT) within 1.2 X the ULN unless a subject is receiving Coumadin and has stable INR which is in range for the desired level of anticoagulation - Left ventricular ejection fraction (LVEF) >= 50% - Blood pressure (BP) no greater than 140 mmHg (systolic) and 90 mmHg (diastolic) for eligibility; initiation or adjustment of BP medication is permitted prior to study entry provided that the average of three BP readings on baseline assessment prior to enrollment is less than 140/90 mmHg - Eligibility of subjects receiving any medications or substances known to affect or with the potential to affect the activity or pharmacokinetics of pazopanib will be determined following review of their cases by the Principal Investigator - Women of child-bearing potential and men must agree to use adequate contraception - A female is eligible to enter and participate in this study if she is of non-childbearing potential (i.e., physiologically incapable of becoming pregnant) or if she is of childbearing potential - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Subjects with known brain metastases and/or unresectable sarcoma - Uncontrolled intercurrent illness including, active serious infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac ventricular arrhythmia requiring anti-arrhythmic therapy, serious hepatic impairment, or psychiatric illness/social situations that would limit compliance with study - Pregnant or lactating women - Subjects with no additional active malignancy within the last 3 years - Subjects receiving other investigational agents - Subjects with a history of allergic reactions attributed to compounds of similar chemical or biologic composition to pazopanib or other agents used in the study - Subjects who have both bilirubin > ULN and AST/ALT > ULN - Subjects with a urine protein/creatinine ratio greater than 1 - Subjects with a baseline corrected QT (QTc) of equal to or greater than 480 msecs or other significant electrocardiogram (ECG) abnormalities - Certain medications that act through the cytochrome P450 (CYP450) system are specifically prohibited in subjects receiving pazopanib and others should be avoided or administered with extreme caution and require principal investigator (PI) approval - Strong inhibitors of CYP3A4 such as ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole may increase pazopanib concentrations and are prohibited; grapefruit juice is also an inhibitor of CYP450 and should not be taken with pazopanib - Strong inducers of CYP3A4, such as rifampin, may decrease pazopanib concentrations, are prohibited - Medications which have narrow therapeutic windows and are substrates of CYP3A4, CYP2D6, or CYP2C8 should be avoided and, if necessary, administered with caution - Pazopanib, 800 mg once daily, has no effect on CYP2C9, CYP1A2, or CYP2C19 in vivo but does in vitro; therefore, therapeutic doses of warfarin, a substrate of CYP2C9, and omeprazole, a substrate of CYP2C19 are permitted; caffeine, a substrate of CYP1A2, is also permitted - Certain medications that are associated with a risk for QTc prolongation and/or Torsades de Pointes, although not prohibited, should be avoided or replaced with medications that do not carry these risks, if possible - Subjects who require heparin other than low-molecular weight heparin - Subjects with any condition that may impair the ability to swallow or absorb oral medications/investigational product including: - Any lesion, whether induced by tumor, radiation or other conditions, which makes it difficult to swallow capsules or pills - Prior surgical procedures affecting absorption including, but not limited to major resection of stomach or small bowel - Active peptic ulcer disease, not on a proton pump inhibitor - Malabsorption syndrome - Subjects with any condition that may increase the risk of gastrointestinal bleeding or gastrointestinal perforation, including - Active peptic ulcer disease, not on a proton pump inhibitor - Known intraluminal metastatic lesions - Inflammatory bowel disease (e.g., ulcerative colitis, Crohn's disease) or - Other gastrointestinal conditions which increase the risk of perforation - History of abdominal fistula, gastrointestinal perforation or intra-abdominal abscess within 28 days prior to beginning study treatment - Subjects with any of the following cardiovascular conditions within the past 6 months: - Cerebrovascular accident (CVA) or transient ischemic attack (TIA) - Cardiac arrhythmia - Admission for unstable angina - Cardiac angioplasty or stenting - Coronary artery bypass graft surgery - Pulmonary embolism, untreated deep venous thrombosis (DVT) or DVT which has been treated with therapeutic anticoagulation for less than 6 weeks - Arterial thrombosis - Symptomatic peripheral vascular disease - Class III or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system; a subject who has a history of Class II heart failure and is asymptomatic on treatment may be considered eligible - History of hemoptysis in excess of 2.5 mL (1/2 teaspoon ) within 8 weeks prior to first dose of study drug - History of serious or non-healing wound, ulcer, or bone fracture - Human immunodeficiency virus (HIV)-positive subjects on combination antiretroviral therapy are ineligible - Subjects with severe hepatic impairment - Bilirubin > 3 x ULN, regardless of any level of ALT

Additional Information

Official title The Effect of Antiangiogenic Therapy With Pazopanib Prior to Preoperative Chemotherapy for Subjects With Extremity Soft Tissue Sarcomas: A Randomized Study to Evaluate Response by Imaging
Principal investigator Darin Davidson
Description PRIMARY OBJECTIVES: I. To determine the absolute values and changes in standardized uptake values (SUV) by fludeoxyglucose F18 (FDG)-positron emission tomography (PET) before and after a 14 day Run-in period of pazopanib (pazopanib hydrochloride) versus placebo, and to compare this to the change in SUV following pre-operative chemotherapy. II. To evaluate the correlation between antiangiogenic activity and pazopanib drug exposure. III. To assess the response rate by Response Evaluation Criteria In Solid Tumors (RECIST) criteria after the 14 day Run-in period of pazopanib versus placebo and compare this to the response rate following pre-operative chemotherapy. SECONDARY OBJECTIVES: I. To examine the activity of antiangiogenic therapy with pazopanib combined with pre-operative chemotherapy for high risk extremity soft tissue sarcomas as measured by: histological necrosis at surgery; change in plasma and tumor biomarker assays of angiogenesis II. To evaluate the safety of sequential treatment with pazopanib and pre-operative chemotherapy with doxorubicin (doxorubicin hydrochloride) and ifosfamide. OUTLINE: Patients are randomized to 1 of 2 treatment arms. ARM I: Patients receive pazopanib hydrochloride orally (PO) once daily (QD). Treatment continues for 14 days in the absence of disease progression or unacceptable toxicity. ARM II: Patients receive placebo PO QD. Treatment continues for 14 days in the absence of disease progression or unacceptable toxicity. All patients then receive neoadjuvant chemotherapy comprising doxorubicin hydrochloride intravenously (IV) continuously over days 1-3 and ifosfamide IV on days 1-5. Treatment repeats every 21 days for 4 courses. Beginning 2-4 weeks later, all patients undergo surgery followed by 2 more courses of chemotherapy 2-4 weeks after completion of surgery. Some patients may also undergo adjuvant external beam radiation therapy 5 days a week for 5 days followed by a boost. Patients treated on Arm I may resume pazopanib hydrochloride 1 week after completion of all adjuvant therapy for up to 1 year. Treatment continues in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 30 days.
Trial information was received from ClinicalTrials.gov and was last updated in November 2016.
Information provided to ClinicalTrials.gov by University of Washington.
Location data was received from the National Cancer Institute and was last updated in November 2016.