Sorafenib Tosylate in Treating Patients With Desmoid Tumors or Aggressive Fibromatosis

This study is currently recruiting participants. (see Contacts and Locations)
Verified September 2014 by National Cancer Institute (NCI)
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT02066181
First received: February 17, 2014
Last updated: October 17, 2014
Last verified: September 2014
  Purpose

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.


Condition Intervention Phase
Desmoid Tumor
Drug: sorafenib tosylate
Other: placebo
Other: laboratory biomarker analysis
Other: quality-of-life assessment
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Crossover Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
Official Title: A Phase III, Double Blind, Randomized, Placebo-Controlled Trial of Sorafenib in Desmoid Tumors or Aggressive Fibromatosis (DT/DF)

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • PFS [ Time Frame: Time from randomization to the first occurrence of progression or death due to any cause, assessed up to 3 years ] [ Designated as safety issue: No ]
    Data following cross over will be analyzed and summarized separately from the data from the main course of treatment for these patients. Intention to treat principles will be used.


Secondary Outcome Measures:
  • Incidence of adverse events, using the PRO-CTCAE v4.0 [ Time Frame: Up to 3 years ] [ Designated as safety issue: Yes ]
    Frequency tables, summary statistics, and categorical analysis will be used to compare the distributions of toxicity for patients treated with sorafenib tosylate vs placebo. Data for patients who have crossed over or having received surgical or radiotherapy intervention will be summarized independently from their primary course of study treatment.

  • Time to surgical intervention during treatment [ Time Frame: Time between randomization to the patient undergoing therapeutic surgical resection for this disease, assessed up to 3 years ] [ Designated as safety issue: No ]
    A log rank test will be used to compare the distributions of time to surgical intervention between the two arms using a 2-sided test and alpha=0.05 level of significance. Kaplan-Meier methodology will be used to estimate various time points and 95% confidence intervals will be calculated for these estimates. Surgery will be classified by outcome (eg, complete-macroscopic, complete-microscopic, or partial), type, location (eg, limb), thereafter analyzed by categorical analysis and descriptive statistics. Non-parametric methods will be used, as appropriate.

  • Overall survival (OS) [ Time Frame: Time between the date of randomization to until death, assessed up to 3 years ] [ Designated as safety issue: No ]
    Kaplan-Meier methodology and log rank tests will be used to compare OS between the groups at various time points (eg, 1 year rate, 2 year rate, etc) and 95% confidence intervals will be calculated for these estimates. Data following crossover will be analyzed and summarized separately from the main course of treatment for these patients.

  • Best objective status between the two treatment arms according to RECIST v1.1 [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]
    Compared between the two treatment arms and using the Cochran-Mantel-Haenszel test.

  • Duration of response [ Time Frame: Time between first tumor response and progression, assessed up to 3 years ] [ Designated as safety issue: No ]
    Kaplan Meier methodology will be used to estimate the distribution of duration of response and the log-rank test will be used to test for a difference in duration of response between the two arms.


Other Outcome Measures:
  • Percent change in tumor size by RECIST v1.1 (Correlative Companion Study-Imaging study) [ Time Frame: Baseline up to 3 years ] [ Designated as safety issue: No ]
    Best RECIST response (ordinal variable) will be correlated by Spearman's rho.

  • Percent changes in MRI T2 signal (Correlative Companion Study-Imaging study) [ Time Frame: Baseline up to 3 years ] [ Designated as safety issue: No ]
    Percent T2 signal change (continuous) will be correlated by Spearman's rho. The percent changes in MRI T2 signal from Week 8 to subsequent imaging will be compared between groups with > 30% pain palliation using t-test or a nonparametric alternative (e.g., Wilcoxon rank-sum test).

  • Time to pain progression measured by the "worst pain" item of the Brief Pain Inventory Short Form (Correlative Companion Study- A091105-H01 QOL study) [ Time Frame: Date of randomization to the earliest date that pain progression is observed, assessed up to 12 weeks ] [ Designated as safety issue: No ]
    Defined as a >= 30% increase compared with baseline in the worst pain intensity score (BPI-SF "worst pain" item) or either a >= 30% increase in the average daily use of any type of opioid narcotic or the addition of a new opioid narcotic compared with baseline. Estimated for each arm using Kaplan-Meier estimates and will be compared between arms using a log- rank test. Descriptive statistics will include means, standard deviations, medians, and ranges for each continuous or ordinal scale/subscale/item by group at each time point.

  • Time to pain palliation measured by the "worst pain" item of the Brief Pain Inventory Short Form (Correlative Companion Study-A091105-H01 QOL study) [ Time Frame: Date of randomization to the earliest date that confirmed pain palliation is observed, assessed up to 12 weeks ] [ Designated as safety issue: No ]
    Defined at each time point as >= 30% decrease from baseline in the worst pain intensity score (BPI-SF "worst pain" item), with neither a concomitant >= 30% increase in average daily use of any opioid narcotic, nor addition of any new opioid narcotic, relative to baseline. Estimated for each arm using Kaplan-Meier estimates and will be compared between arms using a log- rank test. Descriptive statistics will include means, standard deviations, medians, and ranges for each continuous or ordinal scale/subscale/item by group at each time point.

  • Duration of pain palliation measured by the "worst pain" item of the Brief Pain Inventory Short Form (Correlative Companion Study- A091105-H01 QOL study) [ Time Frame: Time from the earliest date that confirmed pain palliation is observed to the earliest date that pain progression is observed, assessed up to 12 weeks ] [ Designated as safety issue: No ]
    Defined for all patients who experience confirmed pain palliation. Descriptive statistics will include means, standard deviations, medians, and ranges for each continuous or ordinal scale/subscale/item by group at each time point. Descriptive graphical techniques will include mean plots by group for each continuous or ordinal scale/subscale/item. Relative frequencies of responses for each ordinal item will also be generated at each time point by group.

  • Rate of pain palliation measured by the "worst pain" item of the Brief Pain Inventory Short Form (Correlative Companion Study-A091105-H01 QOL study) [ Time Frame: Baseline up to 12 weeks ] [ Designated as safety issue: No ]
    Rate of pain palliation at week 8 confirmed as week 12 will be compared between arms using a two-sided alpha=0.05 chi-squared tests at the time of the final analysis. Descriptive statistics will include means, standard deviations, medians, and ranges for each continuous or ordinal scale/subscale/item by group at each time point. Descriptive graphical techniques will include mean plots by group for each continuous or ordinal scale/subscale/item. Relative frequencies of responses for each ordinal item will also be generated at each time point by group.

  • Cadherin-associated protein, beta 1 (CTNNB1) genotype (Correlative Companion Study-A091105-ST1 study) [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]
    Associations among the possible predictors of response to sorafenib and CTNNBI mutations will be examined using Fisher's exact test, Kruskal-Wallis test, or Spearman's correlation coefficient as appropriate. Strata will be compared by using the log-rank test. Multivariate models will be constructed by introducing all variables aforementioned simultaneously into the model and then eliminating variables using the backward selection method. P values will be two-tailed and considered significant at alpha 0.05.

  • False discovery rate (FDR) (Correlative Companion Study- A091105-ST1 study) [ Time Frame: Up to day 8 ] [ Designated as safety issue: No ]
    Permutation testing of the same selection will be performed 1000 times and the sample group labels switched around in each permutation. A two-sided t-test will be used to identify differentially expressed genes on log transformed data and those with a twofold change. False discovery rate (FDR) will be assessed by permutation testing (n = 1000) of the sample group labels. Enrichment will be assessed by one-sided Fisher's exact test with estimated FDR.

  • Treatment-specific gene expression signature (Correlative Companion Study- A091105-ST1 study) [ Time Frame: Up to day 8 ] [ Designated as safety issue: No ]
    The analysis will identify over- and under-expressed genes in pre-treatment and day 8 biopsies as compared to all control samples.

  • Changes in immunohistochemistry (IHC) score of vascular endothelial growth factor (VEGF) (Correlative Companion Study- A091105-ST1 study) [ Time Frame: Baseline up to day 8 ] [ Designated as safety issue: No ]
    Compared by paired t-test. Quantitative changes will be correlated with disease status at 1 year by Fishers exact test.

  • Changes in IHC score of platelet-derived growth factor receptor (PDGFR) (Correlative Companion Study- A091105-ST1 study) [ Time Frame: Baseline up to day 8 ] [ Designated as safety issue: No ]
    Compared by paired t-test. Quantitative changes will be correlated with disease status at 1 year by Fishers exact test.

  • Changes in IHC score of beta-catenin cytoplasm/nuclear ratio (Correlative Companion Study- A091105-ST1 study) [ Time Frame: Baseline up to day 8 ] [ Designated as safety issue: No ]
    Compared by paired t-test. Quantitative changes will be correlated with disease status at 1 year by Fishers exact test.


Estimated Enrollment: 83
Study Start Date: March 2014
Estimated Primary Completion Date: March 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Arm I (sorafenib tosylate)
Patients receive sorafenib tosylate PO QD on days 1-28.
Drug: sorafenib tosylate
Given PO
Other Names:
  • BAY 43-9006
  • BAY 43-9006 Tosylate Salt
  • BAY 54-9085
  • Nexavar
  • SFN
Other: laboratory biomarker analysis
Optional correlative studies
Other: quality-of-life assessment
Optional ancillary studies
Other Name: quality of life assessment
Placebo Comparator: Arm II (placebo)
Patients receive placebo PO QD on days 1-28. Patients may crossover to Arm I upon disease progression.
Other: placebo
Given PO
Other Name: PLCB
Other: laboratory biomarker analysis
Optional correlative studies
Other: quality-of-life assessment
Optional ancillary studies
Other Name: quality of life assessment

Detailed Description:

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 version of the 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.

  Eligibility

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

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 antiinflammatory 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
  • 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
  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: NCT02066181

  Show 121 Study Locations
Sponsors and Collaborators
Investigators
Principal Investigator: Mrinal Gounder Cancer and Leukemia Group B
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT02066181     History of Changes
Other Study ID Numbers: NCI-2014-00264, NCI-2014-00264, A091105, A091105, U10CA031946
Study First Received: February 17, 2014
Last Updated: October 17, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Fibromatosis, Aggressive
Fibroma
Neoplasms, Fibrous Tissue
Neoplasms, Connective Tissue
Neoplasms, Connective and Soft Tissue
Neoplasms by Histologic Type
Neoplasms
Sorafenib
Niacinamide
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Vitamin B Complex
Vitamins
Micronutrients
Growth Substances
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on October 19, 2014