A Phase I Study of Suberoylanilide Hydroxamic Acid (SAHA) in Combination With Flavopiridol in Advanced Solid Tumors
18 Years
N/A
Both
Unspecified Adult Solid Tumor, Protocol Specific
Trial Information
A Phase I Study of Suberoylanilide Hydroxamic Acid (SAHA) in Combination With Flavopiridol in Advanced Solid Tumors
OBJECTIVES:
I. Determine the maximum tolerated dose of vorinostat (SAHA) when given in combination with
flavopiridol (alvocidib) in patients with advanced solid tumors.
II. Obtain preliminary data on the therapeutic activity of SAHA and flavopiridol in these
patients.
III. Evaluate the role of p21, p53, and apoptotic markers relative to treatment response in
patients treated with this regimen.
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 alvocidib intravenously (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 alvocidib. Once the MTD of SAHA in combination with
fixed-dose alvocidib 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 alvocidib IV over 30 minutes followed
by alvocidib 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 alvocidib.
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.
Inclusion Criteria:
- 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
- ECOG performance status (PS) 0-2 OR Karnofsky PS 60-100%
- WBC ≥ 3,000/mm^3
- Absolute neutrophil count ≥ 1,500/mm^3
- Platelet count ≥ 100,000/mm^3
- 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
- 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
Type of Study:
Interventional
Study Design:
Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Outcome Measure:
Maximum tolerated dose of vorinostat when administered in combination with a fixed dose of weekly flavopiridol
Outcome Description:
Defined as the dose one level below the dose at which two or more of the patients in the initial cohort experience dose limiting toxicities (DLT) during the first treatment course. Graded using the Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 Term.
Outcome Time Frame:
Course 1
Safety Issue:
Yes
Principal Investigator
Gary Schwartz
Investigator Role:
Principal Investigator
Investigator Affiliation:
Memorial Sloan-Kettering Cancer Center
Authority:
United States: Food and Drug Administration
Study ID:
NCI-2009-00090
NCT ID:
NCT00324480
Start Date:
March 2006
Completion Date:
Related Keywords:
- Unspecified Adult Solid Tumor, Protocol Specific
- Neoplasms
Name | Location |
|---|---|
| Memorial Sloan Kettering Cancer Center | New York, New York 10021 |
