Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outcomes
Outline
Trial Contact Information
Registry Information

Alternate Title

Pazopanib in Treating Patients With Metastatic Soft Tissue Sarcoma That Has Relapsed or Not Responded to Treatment

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase III	Treatment	Active	18 and over	Other, Pharmaceutical / Industry	EORTC-62072 EORTC 62072, EU-20887, NCT00753688, PALETTE, GSK-VEG110727, EUDRACT-2008-001307-33

Objectives

Primary

1. Investigate whether treatment with pazopanib hydrochloride improves the outcome of patients with metastatic soft tissue sarcoma, when compared with placebo.

Entry Criteria

Disease Characteristics:

• Histologically or cytologically confirmed high- or intermediate-grade* malignant soft tissue sarcoma, including any of the following subtypes:
  • Fibroblastic tumor (e.g., adult fibrosarcoma, myxofibrosarcoma, sclerosing epithelioid fibrosarcoma, and malignant solitary fibrous tumors)
  • Fibrohistiocytic tumor (e.g., pleomorphic malignant fibrous histiocytoma [MFH], giant cell MFH, and inflammatory MFH)
  • Leiomyosarcoma
  • Malignant glomus tumors
  • Skeletal muscle tumors (e.g., pleomorphic and alveolar rhabdomyosarcoma)
  • Vascular tumor (e.g., epithelioid hemangioendothelioma, and angiosarcoma)
  • Uncertain differentiation (e.g., synovial, epithelioid, alveolar soft part, clear cell, desmoplastic small round cell, extra-renal rhabdoid, malignant mesenchymoma, perivascular epithelioid cell tumor [PEComa], intimal sarcoma)
  • Malignant peripheral nerve sheath tumors
  • Undifferentiated soft tissue sarcomas not otherwise specified
  • Other types of sarcoma, if approved by the medical monitors

   [Note: *Low-grade tumors are allowed provided there is disease progression.]




• Measurable disease
  • New lesions occurring in previously irradiated field are considered measurable
  • No previously irradiated lesions only disease



• Disease progression by RECIST confirmed by radiological evaluation when compared to a disease assessment done within the past 6 months
  • Assessment may be done within the past 12 months in patients who had only received prior systemic neoadjuvant or adjuvant therapy



• No more than 4 lines* of prior systemic therapy (including 2 combination regimens) for advanced disease and meeting the following criteria:
  • Disease has progressed on or after anthracycline-based regimen OR patients intolerant to the therapy
  • Disease has progressed on or after available standard chemotherapies unless medically contraindicated, therapy refused by patient, or patients intolerant to the therapy

   [Note: *Neoadjuvant, adjuvant, and maintenance treatments are not counted for this criterion.]




• Metastatic disease
  • No locally advanced disease only
  • No known history of leptomeningeal or brain metastases



• The following tumor types are not allowed:
  • Adipocytic sarcomas (all types)
  • Embryonal rhabdomyosarcoma
  • Chondrosarcoma
  • Osteosarcoma
  • Ewing tumors and primitive neuroectodermal tumors
  • Gastrointestinal stromal tumors
  • Dermofibromatosis sarcoma protuberans
  • Inflammatory myofibroblastic sarcoma
  • Malignant mesothelioma
  • Mixed mesodermal tumors of the uterus

Prior/Concurrent Therapy:

• See Disease Characteristics
• Recovered from prior therapy
  • Toxicity from prior therapy has resolved to ≤ grade 1 (except alopecia)
• No cardiac angioplasty or stenting within the past 6 months
• More than 6 months since prior and no concurrent amiodarone
• No major surgery within the past 28 days
• No other concurrent investigational agent, including an investigational anti-cancer agent, within the past 28 days prior to the first dose of study drug
• More than 14 days since last dose of prior therapy
• More than 14 days since prior and no concurrent substrates for the CYP450 enzymes, including any of the following:
  • Oral hypoglycemics (tolbutamide, chlorpropamide)
  • Ergot derivatives (dihydroergotamine, ergonovine, ergotamine, methylergonovine)
  • Neuroleptics (pimozide)
  • Antiarrhythmics (bepridil, flecainide, lidocaine, mexilitine, guanidine, propafenone)
  • Immune modulators (cyclosporine, tacrolimus, sirolimus)
  • Miscellaneous (theophylline, quetiapine, risperidone, tacrine, clozapine, atomoxetine)
• No prior inhibitors of angiogenesis and/or VEGF- or VEGFR-targeting agents
  • mTOR inhibitors are not considered angiogenesis inhibitors
• No major resection of the stomach or small bowel that could affect the absorption of study drug
• No concurrent therapy with any specifically prohibited medication or requirement for using any of these medications during treatment with pazopanib hydrochloride
• No concurrent hormone replacement therapy

Patient Characteristics:

• WHO performance status 0-1
• ANC > 1,500/mm³
• Platelet count > 100,000/mm³
• Hemoglobin ≥ 9 g/dL
• Prothrombin time ≤ 1.2 times upper limit of normal (ULN)
• Partial thromboplastin time OR INR ≤ 1.2 times ULN
• Bilirubin ≤ 1.5 times ULN
• AST and ALT ≤ 2.5 times ULN
• Serum creatinine ≤ 1.5 mg/dL OR creatinine clearance ≥ 50 mL/min
• Urine protein-creatinine ration (mg/dL) ≤ 1 OR 24-hour protein ≤ 150 mg
• Not pregnant
• Not nursing during study and for at least 14 days after completion of study treatment
• Negative pregnancy test
• Fertile patients must use effective contraception
• No other prior malignancies within the past 3 years except for basal cell or squamous cell carcinoma of the skin or carcinoma in situ of the cervix or breast
• Able to swallow and retain oral medication
• Cardiac function normal by 12 lead ECG and no history of any cardiovascular conditions within the past 6 months including any of the following:
  • Myocardial infarction
  • Unstable angina
  • Symptomatic peripheral vascular disease
  • NYHA class III-IV congestive heart failure
• No prolongation of QTc interval > 480 msecs by 12-lead ECG
• LVEF normal by MUGA or ECHO
• No poorly controlled hypertension (i.e., BP > 150/90 mm Hg)
  • Initiation or adjustment of antihypertensive medication is permitted prior to study entry and BP must be reassessed twice separated by ≥ 1 hour resulting in ≤ 150/90 mm Hg
• Any of the following conditions are not allowed:
  • Prior cerebrovascular accident
  • Transient ischemic attack in the past 6 months
  • Deep venous thrombosis (DVT) or a pulmonary embolism in the past 6 months
    • Recent DVT treated with therapeutic anti-coagulating agents and remaining stable for at least 6 weeks allowed
• No history of clinically significant gastrointestinal disorders including any of the following:
  • Malabsorption syndrome
  • Active peptic ulcer disease
  • Inflammatory bowel disease
  • Ulcerative colitis
  • Gastrointestinal conditions with increased risk of perforation
  • Abdominal fistula
  • Gastrointestinal perforation
  • Intra-abdominal abscess within the past 28 days
• No evidence of active bleeding or bleeding diathesis
• No hemoptysis within the past 6 weeks
  • Any patient with prior hemoptysis associated with metastatic disease must have endobronchial lesions ruled out by bronchoscopy
• No major trauma within the past 28 days
• No presence of any non-healing wound, fracture, or ulcer
• No psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule
• No known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to pazopanib hydrochloride

Expected Enrollment

Outcomes

Overall progression-free survival as define by RECIST criteria

Overall survival
Adverse events as assessed by NCI CTCAE v 3.0

Outline

This is a multicenter study. Patients are stratified according to the number of prior chemotherapy regimens for advanced disease (1 vs 2 or more), and WHO performance status (0 vs 1). Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients receive oral pazopanib hydrochloride once daily for 28 days.



• Arm II: Patients receive oral placebo once daily for 28 days.

In both arms, courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study therapy, patients are followed every 8 weeks until disease progression and then every 3 months thereafter.

Trial Contact Information

Trial Lead Organizations

European Organization for Research and Treatment of Cancer

Winette Van der Graaf, MD, PhD, Principal investigator		Ph: 31-24-361-0353

Netherlands
	Nijmegen
	European Organization for Research and Treatment of Cancer
		Winette Van der Graaf, MD, PhD	Ph:  31-24-361-0353

Registry Information
Official Title		A randomized double blind phase III trial of Pazopanib versus placebo in patients with soft tissue sarcoma whose disease has progressed during or following prior therapy.
Trial Start Date		2008-10-01
Registered in ClinicalTrials.gov		NCT00753688
Date Submitted to PDQ		2008-11-06
Information Last Verified		2008-12-23