Pazopanib Hydrochloride Followed by Chemotherapy and Surgery in Treating Patients With Soft Tissue Sarcoma

Not Applicable

Completed

Conditions: Stage IIA Adult Soft Tissue Sarcoma
Stage IV Adult Soft Tissue Sarcoma
Stage III Adult Soft Tissue Sarcoma

Interventions: Drug: Doxorubicin Hydrochloride
Radiation: External Beam Radiation Therapy
Drug: Ifosfamide
Other: Laboratory Biomarker Analysis
Drug: Pazopanib Hydrochloride
Other: Pharmacological Study
Other: Placebo
Procedure: Therapeutic Conventional Surgery

Registration Number: NCT01446809

Lead Sponsor: University of Washington

Brief 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.

Detailed 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 23

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm I (pazopanib hydrochloride)	Pharmacological Study	Patients receive pazopanib hydrochloride PO QD. Treatment continues for 14 days in the absence of disease progression or unacceptable toxicity.
Arm I (pazopanib hydrochloride)	Therapeutic Conventional Surgery	Patients receive pazopanib hydrochloride PO QD. Treatment continues for 14 days in the absence of disease progression or unacceptable toxicity.
Arm I (pazopanib hydrochloride)	Laboratory Biomarker Analysis	Patients receive pazopanib hydrochloride PO QD. Treatment continues for 14 days in the absence of disease progression or unacceptable toxicity.
Arm II (placebo)	Laboratory Biomarker Analysis	Patients receive placebo PO QD. Treatment continues for 14 days in the absence of disease progression or unacceptable toxicity.
Arm I (pazopanib hydrochloride)	Pazopanib Hydrochloride	Patients receive pazopanib hydrochloride PO QD. Treatment continues for 14 days in the absence of disease progression or unacceptable toxicity.
Arm II (placebo)	Pharmacological Study	Patients receive placebo PO QD. Treatment continues for 14 days in the absence of disease progression or unacceptable toxicity.
Arm II (placebo)	External Beam Radiation Therapy	Patients receive placebo PO QD. Treatment continues for 14 days in the absence of disease progression or unacceptable toxicity.
Arm I (pazopanib hydrochloride)	External Beam Radiation Therapy	Patients receive pazopanib hydrochloride PO QD. Treatment continues for 14 days in the absence of disease progression or unacceptable toxicity.
Arm II (placebo)	Placebo	Patients receive placebo PO QD. Treatment continues for 14 days in the absence of disease progression or unacceptable toxicity.
Arm II (placebo)	Therapeutic Conventional Surgery	Patients receive placebo PO QD. Treatment continues for 14 days in the absence of disease progression or unacceptable toxicity.
Arm I (pazopanib hydrochloride)	Doxorubicin Hydrochloride	Patients receive pazopanib hydrochloride PO QD. Treatment continues for 14 days in the absence of disease progression or unacceptable toxicity.
Arm I (pazopanib hydrochloride)	Ifosfamide	Patients receive pazopanib hydrochloride PO QD. Treatment continues for 14 days in the absence of disease progression or unacceptable toxicity.
Arm II (placebo)	Doxorubicin Hydrochloride	Patients receive placebo PO QD. Treatment continues for 14 days in the absence of disease progression or unacceptable toxicity.
Arm II (placebo)	Ifosfamide	Patients receive placebo PO QD. Treatment continues for 14 days in the absence of disease progression or unacceptable toxicity.

Primary Outcome Measures

Name	Time	Method
Change in Maximum SUV of Tumors Measured by FDG-PET Pre- and Post Receipt of Pazopanib Versus Placebo	From baseline to 15 days	Change in maximum SUV (standardized uptake value) of tumors measured by FDG-PET. Comparison conducted using a two-sided Wilcoxon rank sum test.
Change in Maximum SUV of Tumors Measured by FDG-PET Post Receipt of 2 Courses of Preoperative Chemotherapy	From baseline to 8 weeks	Change in maximum SUV of tumors measured by FDG-PET. Comparison conducted using a two-sided Wilcoxon rank sum test.
Pharmacokinetic Profile of Pazopanib	Up to 14 days	Trough plasma pazopanib concentration measured during the 14 day run-in period on days 10 through 14.
Tumor Response by RECIST Criteria	At 8 weeks	RECIST measurements will be performed on serial MRIs to evaluate the correlation with FDG-PET. The longest diameter (LD) of the target lesions will be measured and reported as the baseline LD. The baseline LD will be used as reference to further characterize the objective tumor response of the measurable dimension of the disease.Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Progression (PD), a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions

Secondary Outcome Measures

Name	Time	Method
Overall Survival	Up to 3 years	Defined as the interval of time from randomization until death from any cause.
Number of Participants With Pathologic Response at the Time of Surgery as Measured by % Tumor Viability ( >= 95% Necrosis)	An expected average of 12 weeks	Estimate the amount of viable tumor, and report the percentage of necrosis. Analysis was only completed on a subset of participants.
Progression Free Survival	Up to 3 years	Defined as the duration of time from randomization to progressive disease (per RECIST), local recurrence, distant metastatic disease (exclusive of stage IV subjects), or death, whichever occurs first.
Change in Levels of VEGF and Soluble VEGFR2 Assessed by ELISA on Plasma and Tumor Extracts	At baseline and after 14 days	Plasma will be collected for measurement of VEGF and soluble VEGFR2 (sVEGFR2) at baseline, after the 14 day Run-in period of pazopanib, after completion of neoadjuvant chemotherapy and approximately every 3 months thereafter until completion of pazopanib maintenance therapy, when indicated. Quantitative enzyme-linked immunosorbent assays (ELISA) for VEGF and sVEGFR2 will be performed on plasma and tumor extracts. Plasma will also be collected for micro RNA at baseline, after the 14 day Run-in period of pazopanib, following neoadjuvant chemotherapy and every 3 months thereafter until completion of pazopanib maintenance therapy, when indicated.