Sorafenib Tosylate in Treating Patients With Desmoid Tumors or Aggressive Fibromatosis

A Phase III, Double Blind, Randomized, Placebo-Controlled Trial of Sorafenib in Desmoid Tumors or Aggressive Fibromatosis (DT/DF)

This randomized phase III trial compares the effects, good and/or bad, of sorafenib tosylate in treating patients with desmoid tumors or aggressive fibromatosis. Sorafenib tosylate may stop the growth of tumor cells by blocking some of the proteins needed for cell growth. [Funding Source - FDA OOPD]

PRIMARY OBJECTIVES:

I. To compare the progression-free survival (PFS) rates of patients with desmoid tumors (DT)/deep fibromatosis (DF) who receive either sorafenib (sorafenib tosylate) or placebo using a double-blinded randomized phase III study.

SECONDARY OBJECTIVES:

I. To assess toxicity. II. To assess time to surgical intervention. III. To assess tumor response rates and survival.

TERTIARY OBJECTIVES:

I. To evaluate changes in magnetic resonance imaging (MRI) Tesla (T)2 to predict (or correlate) with a biological effect such as tumor growth (by Response Evaluation Criteria in Solid Tumors [RECIST] version [v]1.1), and pain palliation. (Correlative companion study) II. The mechanism of action of sorafenib in DT/DF remains unknown. In patients consenting to undergo the paired tumor biopsies (A091105-ST1), treatment induced changes will be quantified by histology, gene expression profiling, proteomic changes and selected interrogation of key pathways by western blot and reverse transcription-polymerase chain reaction (RT-PCR). (Correlative companion study) III. To collect archival tissue, baseline (tumor, blood) and day 8 (tumor, blood) specimens for basic science research (A091105-ST1). (Correlative companion study) IV. To assess patient-reported adverse events and quality of life (QOL) as measured by the Patient-Reported Outcomes-Common Terminology Criteria for Adverse Events (PRO-CTCAE) and the single-item overall Linear Analogue Self-Assessment (LASA) (A091105-HO1). (Correlative companion study) V. To assess pain palliation measured by the "worst pain" item of the Brief Pain Inventory Short Form (A091105-HO1). (Correlative companion study)

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive sorafenib tosylate orally (PO) once daily (QD) on days 1-28.

ARM II: Patients receive placebo PO QD on days 1-28. Patients may crossover to Arm I upon disease progression.

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

After completion of study treatment, patients are followed up annually for up to 3 years.

Inclusion Criteria:

• Patients must have confirmation of DT/DF by local pathologist prior to registration

• Patients may have been treated with locoregional therapies such as major surgery, radiation, radiofrequency ablation, or cryosurgery provided this has been completed at least 4 weeks prior to registration and recovered from therapy related toxicity to less than CTCAE grade 2

• Patients may have been treated with cytotoxic, biologic (antibody), immune or experimental therapy, tyrosine kinase inhibitors, hormone inhibitors or nonsteroidal anti-inflammatory drugs (NSAIDs) provided this has been completed at least 4 weeks prior to registration (6 weeks for mitomycin and nitrosoureas) and recovered from any therapy related toxicity to less than CTCAE grade 2

• Patients with prior or current treatment of sorafenib are excluded

• No concomitant treatment, in therapeutic doses, with anticoagulants such as warfarin or warfarin-related agents, heparin, thrombin or Factor Xa inhibitors, or antiplatelet agents (e.g., clopidogrel); low dose aspirin (=< 81 mg/day), low-dose warfarin (=< 1 mg/day), and prophylactic low molecular weight heparin (LMWH) are permitted; please note that drugs that strongly induce or inhibit cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) or are associated with a risk of torsades are not allowed; chronic concomitant treatment of CYP3A4 inducers is not allowed (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, and St. John's wort); as part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product; the following drugs are strong inhibitors of CYP3A4 and are not allowed during the treatment with sorafenib:

  • Boceprevir

  • Indinavir

  • Nelfinavir

  • Lopinavir/ritonavir

  • Saquinavir

  • Telaprevir

  • Ritonavir

  • Clarithromycin

  • Conivaptan

  • Itraconazole

  • Ketoconazole

  • Mibefradil

  • Nefazodone

  • Posaconazole

  • Voriconazole

  • Telithromycin

    • Drugs with possible or conditional risk of torsades should be used with caution knowing that sorafenib could prolong the QT interval

• Chronic daily NSAID use as treatment for controlling desmoid tumors is not allowed, and should be stopped >= 3 days prior to registration; NSAIDS are allowed when used for desmoid tumor-related pain or for symptoms that are unrelated to desmoid disease (eg. headache, arthritis)

• Patients must have measurable disease

• Patients have to meet one of the following criteria to be eligible:

  • Disease determined unresectable or entailing unacceptably morbid surgery based on 1 or more of the following characteristics:

    • Multifocal disease
    • Disease in which there is involvement or inadequate plane from: neurovascular bundle, bone, skin, or viscera
    • Large size in relationship to location OR multi-compartment involvement

  • Progression by radiographic imaging (10% increase in size by RECIST v1.1 within 6 months of registration)

  • Patients with symptomatic disease which meets the following criteria Brief Pain Inventory (BPI) score greater than or equal to 3 AND one of the following:

    • Inability to control pain with NSAIDs and considering addition of narcotics OR
    • > 30% increase in current use of narcotics OR
    • Addition of a new opioid narcotic

• Eastern Cooperative Oncology Group (ECOG) performance status =< 2

• Patients who are pregnant or nursing are not eligible

• No patients with a history of cardiac disease: congestive heart failure > class II New York Heart Association (NYHA); active coronary artery disease (CAD) (myocardial infarction or unstable angina within 6 months prior to study entry)

• No patients with inadequately controlled hypertension (defined as a blood pressure of >= 150 mmHg systolic and/or >= 90 mmHg diastolic), or any prior history of hypertensive crisis or hypertensive encephalopathy

• No patients with clinically significant gastrointestinal (GI) bleeding or bleeding diathesis within 30 days prior to registration

• Absolute neutrophil count >= 1,500/mm^3

• Hemoglobin >= 8 g/dl

• Platelets >= 75,000/mm^3

• Total bilirubin =< 1.5 x upper limits of normal (ULN)

• Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST])/serum glutamate pyruvate transaminase (SGPT) (aspartate aminotransferase [ALT]) =< 1.5 x ULN

• Calculated creatinine clearance >= 50 mL/min using the Cockcroft-Gault equation