SB939 in Treating Patients With Locally Advanced or Metastatic Solid Tumors

Study Overview
=================
Brief Summary
-----------------
RATIONALE: SB939 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. PURPOSE: This phase I trial is studying the side effects and best dose of SB939 in treating patients with locally advanced or metastatic solid tumors.

Detailed Description
-----------------
OBJECTIVES: Primary To determine the recommended phase II dose of oral SB939 in patients with solid tumors. Secondary To determine the toxic effects of SB939 and its association with dose and pharmacokinetics. To assess the pharmacokinetic profile of SB939. To assess preliminary evidence of antitumor effects of SB939 in patients with measurable disease as documented by objective response. To establish proof-of-principle for SB939 effects on histone acetylation by evaluation of histone acetylation and other biomarkers in peripheral blood mononuclear cells (PBMCs) at all dose levels. OUTLINE: Patients receive oral SB939 once daily on days 1-5 and 15-19. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients undergo blood sample collection periodically during course 1 for pharmacokinetic and pharmacodynamic studies. Samples are analyzed for levels of SB939 via LC-MS/MS method and levels of acetylated histone 3 (AcH3), target effect, downstream consequences, and tumor response via western blot, immunohistochemistry, or ELISA methods. After completion of study treatment, patients are followed at 4 weeks and then every 3 months thereafter.

Official Title
-----------------
A Phase I Clinical and Pharmacokinetic Study of SB939 in Patients With Advanced Cancer

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

Intervention / Treatment
-----------------
* Drug: HDAC inhibitor SB939
* Other: immunoenzyme technique
* Other: immunohistochemistry staining method
* Other: immunologic technique
* Other: laboratory biomarker analysis
* Other: liquid chromatography
* Other: mass spectrometry
* Other: pharmacological study


Participation Criteria
=================
Eligibility Criteria
-----------------
DISEASE CHARACTERISTICS: Inclusion criteria: Histologically or cytologically confirmed locally advanced or metastatic solid tumor Refractory to standard therapy or for which conventional therapy is not reliably effective Exclusion criteria: Patients with documented CNS metastases PATIENT CHARACTERISTICS: Inclusion criteria: ECOG performance status of 0, 1, or 2 Must have a life expectancy of ≥ 12 weeks Granulocytes (AGC) ≥ 1.5 x 10^9/L Platelets ≥ 100 x 10^9/L Bilirubin ≤ upper limit of normal (ULN) AST and ALT ≤ 2.5 x ULN (< 5 x ULN if liver metastases are present) Serum creatinine ≤ 1.2 x ULN OR creatinine clearance ≥ 60 mL/min QTc ≤ 450 msec LVEF ≥ 50% by ECHO or MUGA Troponin I or T ≤ ULN Must be within 1½ hour's driving distance Exclusion criteria: Pathologic cardiac arrhythmia requiring active treatment Patients with a history of arrhythmia must be > 12 months since last treatment with no recurrence of arrhythmia in the interval Inability to take oral medication Patients must be able to swallow SB939 capsules and have no gastrointestinal abnormalities (e.g., bowel obstruction or previous gastric resection) which would lead to inadequate absorption of SB939 Pregnant or lactating women Urine or serum B-HCG must be negative Women or men of child-bearing potential unless using effective contraception Presence of any clinically significant co-morbidities (i.e., pulmonary disease, active CNS disease, or active infection) Presence of any other significant CNS disorder that would hamper the patient's compliance Presence of any significant psychiatric disorder that would hamper the patient's compliance Other acute or chronic medical condition, psychiatric condition, or laboratory abnormality that may increase the risks associated with study participation/study drug administration or may interfere with the interpretation of study results Pre-existing peripheral neuropathy ≥ grade 2 Known HIV or hepatitis B or C infection PRIOR CONCURRENT THERAPY: Inclusion criteria: Previous anticancer treatment must be discontinued at least 28 days prior to the first dose of study treatment (42 days [6 weeks] for nitrosoureas or mitomycin C) At least 28 days since prior radiation therapy restricted to ≤ 30% of the bone marrow and recovered from toxic effects Exceptions may be made for low-dose nonmyelosuppressive radiotherapy Must be ≥ 14 days since any major surgery Pre-existing bisphosphonate or luteinizing hormone-releasing hormone (LHRH) analog therapy (for men with hormone refractory prostate cancer) may be continued during study participation Exclusion criteria: Previous treatment with a histone deacetylase (HDAC) inhibitor Treatment with another investigational therapy within 28 days prior to study entry Other concurrent anticancer treatment or investigational therapy Concurrent agents with a known risk of Torsade de Pointes Concurrent G-CSF, GM-CSF, or other hematopoietic growth factors may not be used as a substitute for a scheduled dose reduction (may be used in the management of acute toxicity)

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: SB939<br> | Drug: HDAC inhibitor SB939<br>* SB939 will be administered initially for 3 consecutive days every other week at the first dose level and then for 5 consecutive days every other week at escalating doses.<br>Other: immunoenzyme technique<br> <br> Other: immunohistochemistry staining method<br> <br> Other: immunologic technique<br> <br> Other: laboratory biomarker analysis<br> <br> Other: liquid chromatography<br> <br> Other: mass spectrometry<br> <br> Other: pharmacological study<br> <br> |

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Recommended phase II dose | Assess for safety, tolerability, toxicity profile and dose limiting toxicities | Each dose level | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety | Safety, tolerability, toxicity profile, dose limiting toxicities of SB939. | Each dose level | 
| Pharmacokinetic profile | Samples collected over multiple timepoints | Cycle 1 day 1 and 15 | 
| SB939 effects on histone H3 acetylation | Levels of AcH3 will be determined using wetern Blot, immunohistochemistry or Elisa method. | Cycle 1 days 1 and 15 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
unspecified adult solid tumor, protocol specific