Vorinostat and Bortezomib in Treating Patients With Advanced Soft Tissue Sarcoma

Study Overview
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Brief Summary
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This phase II trial is studying how well giving vorinostat together with bortezomib works in treating patients with advanced soft tissue sarcoma. Vorinostat and bortezomib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving vorinostat together with bortezomib may kill more tumor cells.

Detailed Description
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PRIMARY OBJECTIVES: I. To determine the objective response rate in patients with advanced soft tissue sarcoma treated with vorinostat and bortezomib. SECONDARY OBJECTIVES: I. Characterize the toxicity of this regimen in these patients. II. Evaluate the progression-free survival and median overall survival of patients treated with this regimen. OUTLINE: Patients receive vorinostat orally (PO) once daily on days 1-14. Patients also receive bortezomib intravenously (IV) over 3-5 seconds on days 1, 4, 8, and 11. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. After completion of study therapy, patients are followed up every 6 months for up to 2 years. (As of Addendum 7, patient follow-up no longer required.)

Official Title
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A Phase II Study of Suberoylanilide Hydroxamic Acid and Bortezomib in Advanced Soft Tissue Sarcomas

Conditions
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Recurrent Adult Soft Tissue Sarcoma, Stage III Adult Soft Tissue Sarcoma, Stage IV Adult Soft Tissue Sarcoma

Intervention / Treatment
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* Drug: vorinostat
* Drug: bortezomib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed advanced, unresectable, or metastatic soft tissue sarcoma (STS) Measurable disease, defined as >= 1 lesion that can be accurately measured in >= 1 dimension as >= 2 cm by conventional techniques OR >= 1 cm by spiral computed tomography (CT) scan No small round cell tumors, including the following: Primitive neuroectodermal tumor Rhabdomyosarcoma Ewing sarcoma Osteosarcoma No known active and/or untreated brain metastases and/or brain metastases requiring ongoing therapy (e.g., corticosteroids) Treated, inactive brain metastases not requiring ongoing therapy allowed provided the brain metastases have been stable for >= 1 month as assessed by intracranial imaging AND there is no indication of increased vascularity of the treated metastases within 14 days before study entry as assessed by magnetic resonance imaging (MRI) Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1 OR Karnofsky PS 70-100% Life expectancy >= 12 weeks Absolute neutrophil count (ANC) >= 1,500/mm^3 Platelet count >= 100,000/mm^3 Total bilirubin normal Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) =< 2.5 times upper limit of normal Creatinine normal OR creatinine clearance >= 60 mL/min Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception Able to take oral medication No peripheral neuropathy >= grade 2 No concurrent uncontrolled illness including, but not limited to, any of the following: Ongoing or active infection Symptomatic congestive heart failure Unstable angina pectoris Cardiac arrhythmia or myocardial infarction within the past 6 months Psychiatric illness and/or social situation that would limit compliance with study requirements No history of Torsades de Pointes No history of allergic reactions attributed to compounds of similar chemical or biological composition to vorinostat or bortezomib No more than 1 prior systemic treatment for advanced STS, including investigational agents Adjuvant therapy is not considered a systemic regimen More than 2 weeks since prior valproic acid More than 4 weeks since prior and no concurrent chemotherapy (> 6 weeks for nitrosoureas or mitomycin C) or radiotherapy and recovered Radiotherapy to bone metastasis within the past 2 weeks allowed provided there is active non-bone disease outside the radiation port No prior radiotherapy to >= 33% of the bone marrow No prior vorinostat or bortezomib No concurrent category I medications that are generally accepted to have a risk of causing Torsades de Pointes, including any of the following: Quinidine, procainamide, disopyramide Amiodarone, sotalol, ibutilide, dofetilide Erythromycin, clarithromycin Chlorpromazine, haloperidol, mesoridazine, thioridazine, pimozide, cisapride, bepridil, droperidol, methadone, arsenic, chloroquine, domperidone, halofantrine, levomethadyl, pentamidine, sparfloxacin, lidoflazine No concurrent combination antiretroviral therapy for human immunodeficiency virus (HIV)-positive patients No other concurrent investigational agents for the primary malignancy No other concurrent anticancer therapy

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (vorinostat, bortezomib)<br>Patients receive 400 mg vorinostat orally once daily on days 1-14. Patients also receive 1.3 mg/m^2 bortezomib IV over 3-5 seconds on days 1, 4, 8, and 11. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. | Drug: vorinostat<br>* 400 mg given PO<br>* Other names: Zolinza;Drug: bortezomib<br>* 1.3 mg/m^2 given IV<br>* Other names: VELCADE;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Confirmed Tumor Responses | The number of confirmed tumor responses is defined as a complete response (CR) or partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST) on two consecutive evaluations at least six weeks apart. Complete Response (CR): Disappearance of all target lesions. Partial Response (PR): At least a 30% decrease in the sum of the longest dimension (LD) of target lesions taking as reference the baseline sum LD. | Up to 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival | Progression-free survival is defined as the time from registration to the time of progression or death, whichever comes first. The distribution and median of progression-free survival times will be estimated using the method of Kaplan-Meier. | Up to 2 years | 
| Overall Survival | The distribution of survival time will be estimated using the method of Kaplan-Meier. | Time from registration to death due to any cause, assessed up to 2 years |