Now Available for Public Comment: Notice of Proposed Rulemaking (NPRM) for FDAAA 801 and NIH Draft Reporting Policy for NIH-Funded Trials

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

This study is currently recruiting participants. (see Contacts and Locations)
Verified June 2014 by University of Washington
Sponsor:
Collaborator:
Information provided by (Responsible Party):
University of Washington
ClinicalTrials.gov Identifier:
NCT01446809
First received: September 12, 2011
Last updated: June 16, 2014
Last verified: June 2014
  Purpose

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.


Condition Intervention
Adult Angiosarcoma
Adult Desmoplastic Small Round Cell Tumor
Adult Epithelioid Hemangioendothelioma
Adult Epithelioid Sarcoma
Adult Extraskeletal Chondrosarcoma
Adult Fibrosarcoma
Adult Leiomyosarcoma
Adult Liposarcoma
Adult Malignant Fibrous Histiocytoma
Adult Malignant Hemangiopericytoma
Adult Malignant Mesenchymoma
Adult Neurofibrosarcoma
Adult Synovial Sarcoma
Dermatofibrosarcoma Protuberans
Stage IIA Adult Soft Tissue Sarcoma
Stage III Adult Soft Tissue Sarcoma
Stage IV Adult Soft Tissue Sarcoma
Drug: pazopanib hydrochloride
Drug: doxorubicin hydrochloride
Drug: ifosfamide
Other: placebo
Procedure: therapeutic conventional surgery
Radiation: external beam radiation therapy
Other: pharmacological study
Other: laboratory biomarker analysis

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by University of Washington:

Primary Outcome Measures:
  • Absolute values and changes in maximum SUV of tumors measured by FDG-PET pre- and post receipt of pazopanib versus placebo, and post receipt of 2 courses of preoperative chemotherapy [ Time Frame: At baseline and 14 days ] [ Designated as safety issue: No ]
    Comparison will likely be conducted using a two-sided Wilcoxon rank sum test, often used as a nonparametric alternative to the two-sample t-test for studies with a small sample size.

  • Tumor response by RECIST criteria [ Time Frame: At 14 days ] [ Designated as safety issue: No ]
    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.

  • Correlation of pazopanib hydrochloride trough concentration with the change in SUV from FDG PET and change in RECIST measurements on MRIs [ Time Frame: At 14 days ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Safety profile of sequential treatment with pazopanib and pre-operative chemotherapy with doxorubicin and ifosfamide [ Time Frame: Up to 3 years ] [ Designated as safety issue: Yes ]
    All reported adverse events will be coded using the Cancer Therapy Evaluation Program (CTEP) Common Toxicity Criteria. Listings will be provided for all on-study deaths and adverse events that lead to withdrawal from study. Narratives of all serious adverse events and deaths on-study will be provided. The number and percent of subjects reporting adverse events (all, severe or worse, serious and related) will be quantified.

  • Pathologic response at the time of surgery as measured by % tumor viability [ Time Frame: An expected average of 12 weeks ] [ Designated as safety issue: No ]
    Estimate the amount of viable tumor, and report the percentage of necrosis. For purpose of analysis, tumors will be classified as either >= 95% necrosis or < 95% necrosis.

  • Progression free survival [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]
    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.

  • Overall survival [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]
    Defined as the interval of time from randomization until death from any cause.

  • Change in plasma and tumor angiogenic biomarker levels pre- and post neoadjuvant therapy [ Time Frame: At baseline and after 14 days ] [ Designated as safety issue: No ]

Estimated Enrollment: 21
Study Start Date: April 2012
Estimated Primary Completion Date: October 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Arm I (pazopanib hydrochloride)
Patients receive pazopanib hydrochloride PO QD. Treatment continues for 14 days in the absence of disease progression or unacceptable toxicity.
Drug: pazopanib hydrochloride
Given PO
Other Names:
  • GW786034B
  • Votrient
Drug: doxorubicin hydrochloride
Given IV
Other Names:
  • ADM
  • ADR
  • Adria
  • Adriamycin PFS
  • Adriamycin RDF
Drug: ifosfamide
Given IV
Other Names:
  • Cyfos
  • Holoxan
  • IFF
  • IFX
  • IPP
Procedure: therapeutic conventional surgery
Undergo surgery
Radiation: external beam radiation therapy
Undergo external beam radiation therapy
Other Name: EBRT
Other: pharmacological study
Correlative studies
Other Name: pharmacological studies
Other: laboratory biomarker analysis
Correlative studies
Placebo Comparator: Arm II (placebo)
Patients receive placebo PO QD. Treatment continues for 14 days in the absence of disease progression or unacceptable toxicity.
Drug: doxorubicin hydrochloride
Given IV
Other Names:
  • ADM
  • ADR
  • Adria
  • Adriamycin PFS
  • Adriamycin RDF
Drug: ifosfamide
Given IV
Other Names:
  • Cyfos
  • Holoxan
  • IFF
  • IFX
  • IPP
Other: placebo
Given PO
Other Name: PLCB
Procedure: therapeutic conventional surgery
Undergo surgery
Radiation: external beam radiation therapy
Undergo external beam radiation therapy
Other Name: EBRT
Other: pharmacological study
Correlative studies
Other Name: pharmacological studies
Other: laboratory biomarker analysis
Correlative studies

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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 a currently active second malignancy other than non-melanoma skin cancers
  • 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 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 because of the potential for pharmacokinetic interactions with pazopanib
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01446809

Locations
United States, Oregon
Oregon Health and Science University Not yet recruiting
Portland, Oregon, United States, 97239
Contact: Christopher W. Ryan    503-494-6594      
Principal Investigator: Christopher W. Ryan         
United States, Washington
Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium Recruiting
Seattle, Washington, United States, 98109
Contact: Robin L. Jones    206-288-7439      
Principal Investigator: Robin L. Jones         
Sponsors and Collaborators
University of Washington
Investigators
Principal Investigator: Robin Jones Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
  More Information

No publications provided

Responsible Party: University of Washington
ClinicalTrials.gov Identifier: NCT01446809     History of Changes
Other Study ID Numbers: 7487, NCI-2011-02488, 7487, P30CA015704
Study First Received: September 12, 2011
Last Updated: June 16, 2014
Health Authority: United States: Federal Government

Additional relevant MeSH terms:
Chondrosarcoma
Dermatofibrosarcoma
Desmoplastic Small Round Cell Tumor
Fibrosarcoma
Hemangioendothelioma
Hemangioendothelioma, Epithelioid
Hemangiopericytoma
Hemangiosarcoma
Histiocytoma
Histiocytoma, Benign Fibrous
Histiocytoma, Malignant Fibrous
Leiomyosarcoma
Liposarcoma
Liver Neoplasms
Mesenchymoma
Neurofibrosarcoma
Sarcoma
Sarcoma, Synovial
Digestive System Diseases
Digestive System Neoplasms
Hemangioma
Liver Diseases
Neoplasms
Neoplasms by Histologic Type
Neoplasms by Site
Neoplasms, Adipose Tissue
Neoplasms, Complex and Mixed
Neoplasms, Connective Tissue
Neoplasms, Connective and Soft Tissue
Neoplasms, Fibrous Tissue

ClinicalTrials.gov processed this record on November 24, 2014