Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outcomes
Outline
Trial Contact Information
Registry Information

Alternate Title

Vorinostat and Flavopiridol in Treating Patients With Advanced Solid Tumors

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase I	Biomarker/Laboratory analysis, Treatment	Completed	18 and over	NCI	MSKCC-05109 6858, NCI-6858, NCT00324480

Objectives

1. Determine the maximum tolerated dose of vorinostat (SAHA) when given in combination with flavopiridol in patients with advanced solid tumors.
2. Obtain preliminary data on the therapeutic activity of SAHA and flavopiridol in these patients.
3. Evaluate the role of p21, p53, and apoptotic markers relative to treatment response in patients treated with this regimen.

Entry Criteria

Disease Characteristics:

• Histologically confirmed solid tumor
  • Metastatic or unresectable disease
  • Standard curative or palliative measures do not exist or are no longer effective
• No hematologic malignancies
• No known brain metastases

Prior/Concurrent Therapy:

• Recovered from prior therapy
• At least 2 weeks since prior histone acetylase inhibitors, including valproic acid
• At least 2 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin)
• At least 2 weeks since prior investigational therapy
• At least 2 weeks since prior radiotherapy
• No concurrent combination antiretroviral therapy for HIV-positive patients
• No concurrent commonly used vitamins, antioxidants, or herbal preparations and supplements
  • A single tablet multivitamin is allowed
• No other concurrent anticancer agents or therapies for this mailgnancy
• No other concurrent investigational agents

Patient Characteristics:

• ECOG performance status (PS) 0-2 OR Karnofsky PS 60-100%
• WBC ≥ 3,000/mm³
• Absolute neutrophil count ≥ 1,500/mm³
• Platelet count ≥ 100,000/mm³
• Bilirubin ≤ 1.5 mg/dL
• AST and 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
• No history of allergic reactions attributed to compounds of similar chemical or biologic composition to study drugs
• No uncontrolled intercurrent illness, including, but not limited to, any of the following:
  • Ongoing or active infection
  • Symptomatic congestive heart failure
  • Unstable angina pectoris
  • Cardiac arrhythmia
  • Psychiatric illness or social situations that would preclude study compliance

Expected Enrollment

Approximately 60 patients will be accrued for this study.

Outcomes

Maximum tolerated dose

Clinical pharmacokinetics of vorinostat (SAHA)
Therapeutic activity of SAHA and flavopiridol
Expression of p21, p53, and apoptotic markers relative to treatment response from baseline to 2 weeks after completion of study treatment

Outline

This is a multicenter, open label, non-randomized, dose-escalation study of vorinostat (SAHA).

Before beginning course 1 of study therapy, patients receive oral SAHA on days 1-3 in order to ensure tolerability of the drug.

Beginning 1 week later, patients receive oral SAHA once daily on days 1-3 and 8-10 and fixed-dose flavopiridol IV over 1 hour on days 2 and 9. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of SAHA until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 6 patients experience dose-limiting toxicity. An additional 10 patients are treated at the MTD of SAHA in combination with fixed-dose flavopiridol.

Once the MTD of SAHA in combination with fixed-dose flavopiridol is determined, patients receive oral SAHA at one dose level below the MTD once daily on days 1-3 and 8-10 and divided-dose flavopiridol IV over 30 minutes followed by flavopiridol IV over 4 hours on days 2 and 9. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity.

If this schedule is well-tolerated, the MTD of SAHA in combination with divided-dose flavopiridol is determined as above. An additional 10 patients are treated at the MTD of SAHA in combination with divided-dose flavopiridol.

Patients undergo blood draws on days 1 and 9 of course 1 for pharmacokinetic analysis.

After completion of study treatment, patients are followed for 4 weeks.

Trial Contact Information

Trial Lead Organizations

Memorial Sloan-Kettering Cancer Center

Gary K. Schwartz, MD, Protocol chair		Ph: 212-639-8324; 800-525-2225

Registry Information
Official Title		A Phase I Study of Suberoylanilide Hydroxamic Acid (SAHA) in Combination with Flavopiridol in Advanced Solid Tumors
Trial Start Date		2006-03-02
Trial Completion Date		2009-04-28
Registered in ClinicalTrials.gov		NCT00324480
Date Submitted to PDQ		2006-03-02
Information Last Verified		2008-12-14
NCI Grant/Contract Number		CA08748, CA69856

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