Vorinostat and Bortezomib in Treating Patients With Metastatic or Unresectable Solid Tumors

Study Overview
=================
Brief Summary
-----------------
This phase I trial is studying the side effects and best dose of vorinostat and bortezomib in treating patients with metastatic or unresectable solid tumors. Drugs used in chemotherapy, such as vorinostat, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. 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
-----------------
PRIMARY OBJECTIVES: I. Determine the maximum tolerated dose of vorinostat (SAHA) and bortezomib in patients with metastatic or unresectable solid tumors. SECONDARY OBJECTIVES: I. Determine the pharmacokinetics and antitumor activity of this regimen in these patients. II. Determine the toxic effects of this regimen in these patients. OUTLINE: This is a dose-escalation study. Patients receive oral vorinostat (SAHA) twice daily on days 1-14 in step A. Patients receive oral vorinostat (SAHA) twice daily on days 1-4 and 8-11 in Step B and bortezomib IV over 3-5 seconds on days 2, 5, 9, and 12 during the first course and on days 1, 4, 8, and 11 during subsequent courses in both steps A and B. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Cohorts of 1-6 patients receive escalating doses of bortezomib until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. Up to 6 additional patients receive bortezomib at the MTD. Subsequent cohorts of 3-6 patients receive escalating doses of SAHA until the MTD of that drug is determined.

Official Title
-----------------
A Phase I Study of Suberoylanilide Hydroxamic Acid (SAHA) in Combination With Bortezomib in Patients With Advanced Malignancies

Conditions
-----------------
Unspecified Adult Solid Tumor, Protocol Specific

Intervention / Treatment
-----------------
* Drug: bortezomib
* Drug: vorinostat


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Histologically confirmed malignancy, metastatic or unresectable disease Standard curative or palliative measures do not exist OR are no longer effective Measurable or evaluable disease No known brain metastases ECOG 0-2 OR Karnofsky 60-100% Life expectancy > 12 weeks WBC ≥ 3,000/mm^3 Absolute neutrophil count ≥ 1,500/mm^3 Platelet count ≥ 100,000/mm^3 Bilirubin normal AST and ALT ≤ 2.5 times upper limit of normal Creatinine normal OR creatinine clearance ≥ 60 mL/min No history of myocardial infarction No symptomatic congestive heart failure No unstable angina pectoris No cardiac arrhythmia No severe pulmonary disease requiring oxygen Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception during and for 28 days after study participation No history of allergic reaction attributed to compounds of similar chemical or biological composition to study drugs or agents No pre-existing neuropathy ≥ grade 2 No uncontrolled illness No ongoing or active infection No psychiatric illness or social situation that would preclude study compliance More than 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin) and recovered No prior radiotherapy to > 25% of bone marrow At least 4 weeks since prior radiotherapy and recovered At least 2 weeks since prior valproic acid No prior bortezomib No concurrent enzyme-inducing anticonvulsant agents No other concurrent investigational agents No concurrent combination antiretroviral therapy for HIV-positive patients No other concurrent anticancer therapy

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I<br>Patients receive oral vorinostat (SAHA) twice daily on days 1-14 in step A. Patients receive oral vorinostat (SAHA) twice daily on days 1-4 and 8-11 in Step B and bortezomib IV over 3-5 seconds on days 2, 5, 9, and 12 during the first course and on days 1, 4, 8, and 11 during subsequent courses in both steps A and B. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Cohorts of 1-6 patients receive escalating doses of bortezomib until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. Up to 6 additional patients receive bortezomib at the MTD. Subsequent cohorts of 3-6 patients receive escalating doses of SAHA until the MTD of that drug is determined. | Drug: bortezomib<br>* Given IV<br>* Other names: VELCADE;Drug: vorinostat<br>* Given orally<br>* Other names: Zolinza;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose (MTD) determined according to dose-limiting toxicities (DLTs) graded using Common Terminology Criteria for Adverse Events version 3.0 (CTCAE v3.0) |  | 21 days | 
| Frequency and severity of toxicity incidents assessed by Common Terminology Criteria for Adverse Events version 3.0 (CTCAE v3.0) |  | Up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Anti-tumor activity by tumor measurements assessed by RECIST |  | Up to 5 years | 
| Peak plasma concentration (Cmax) of SAHA |  | Days 1, 2, and 12 | 
| Time to SAHA Cmax (Tmax) |  | Days 1, 2, and 12 | 
| Clearance of SAHA |  | Days 1, 2, and 12 |