SB939 in Treating Patients With Locally Advanced or Metastatic Solid Tumors

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

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.

Study Overview

• Status: Completed
• Conditions: Unspecified Adult Solid Tumor, Protocol Specific
• Intervention / Treatment: Other: pharmacological study; Other: laboratory biomarker analysis; Other: immunoenzyme technique; Other: mass spectrometry; Other: immunohistochemistry staining method; Other: immunologic technique; Other: liquid chromatography; Drug: HDAC inhibitor SB939

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.

• Study Type: Interventional
• Enrollment (Actual): 39
• Phase: Phase 1

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Hamilton, Ontario, Canada, L8V 5C2
      • Juravinski Cancer Centre at Hamilton Health Sciences
    • Toronto, Ontario, Canada, M5G 2M9
      • Univ. Health Network-Princess Margaret Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: SB939

Other: pharmacological study; Other: laboratory biomarker analysis; Other: immunoenzyme technique; Other: mass spectrometry; Other: immunohistochemistry staining method; Other: immunologic technique; Other: liquid chromatography; Drug: HDAC inhibitor SB939; 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.

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

Collaborators and Investigators

• Sponsor: NCIC Clinical Trials Group
• Collaborators: S*BIO
• Investigators: Study Chair: Lillian L. Siu, MD, FRCPC, Princess Margaret Hospital, Canada

Publications and helpful links

General Publications

• Razak AR, Hotte SJ, Siu LL, Chen EX, Hirte HW, Powers J, Walsh W, Stayner LA, Laughlin A, Novotny-Diermayr V, Zhu J, Eisenhauer EA. Phase I clinical, pharmacokinetic and pharmacodynamic study of SB939, an oral histone deacetylase (HDAC) inhibitor, in patients with advanced solid tumours. Br J Cancer. 2011 Mar 1;104(5):756-62. doi: 10.1038/bjc.2011.13. Epub 2011 Feb 1.

Study record dates

Study Major Dates

• Study Start (Actual): September 14, 2007
• Primary Completion (Actual): April 22, 2010
• Study Completion (Actual): June 21, 2011

Study Registration Dates

• First Submitted: July 17, 2007
• First Submitted That Met QC Criteria: July 17, 2007
• First Posted (Estimated): July 19, 2007

Study Record Updates

• Last Update Posted (Actual): August 4, 2023
• Last Update Submitted That Met QC Criteria: August 3, 2023
• Last Verified: April 1, 2020

More Information

Terms related to this study

• Keywords: unspecified adult solid tumor, protocol specific
• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Histone Deacetylase Inhibitors
• Other Study ID Numbers: I188; CAN-NCIC-IND188 (Registry Identifier: NCI US - Physician Data Query); S*BIO-SB939-2007-002 (Other Identifier: S*BIO); CDR0000558934 (Other Identifier: PDQ)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No