SB939 in Treating Patients With Locally Advanced or Metastatic Solid Tumors

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.

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)