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Vorinostat and Alvocidib in Treating Patients With Advanced Solid Tumors

Sponsor
National Cancer Institute (NCI) (NIH)
Overall Status
Completed
CT.gov ID
NCT00324480
Collaborator
(none)
60
Enrollment
1
Location
1
Arm

Study Details

Study Description

Brief Summary

This phase I trial is studying the side effects and best dose of vorinostat when given together with alvocidib in treating patients with advanced solid tumors. Drugs used in chemotherapy, such as vorinostat and alvocidib, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Vorinostat may also stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving vorinostat together with alvocidib may kill more tumor cells.

Condition or Disease Intervention/Treatment Phase
Phase 1

Detailed Description

OBJECTIVES:

  1. Determine the maximum tolerated dose of vorinostat (SAHA) when given in combination with flavopiridol (alvocidib) 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.

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.

Study Design

Study Type:
Interventional
Actual Enrollment :
60 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Phase I Study of Suberoylanilide Hydroxamic Acid (SAHA) in Combination With Flavopiridol in Advanced Solid Tumors
Study Start Date :
Mar 1, 2006
Actual Primary Completion Date :
Apr 1, 2009

Arms and Interventions

Arm Intervention/Treatment
Experimental: Treatment (chemotherapy, enzyme inhibitor)

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 IV over 1 hour on days 2 and 9. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity.

Drug: alvocidib
Given IV
Other Names:
  • FLAVO
  • flavopiridol
  • HMR 1275
  • L-868275

    • Drug: vorinostat
    Given orally
    Other Names:
  • L-001079038
  • SAHA
  • suberoylanilide hydroxamic acid
  • Zolinza

    • Other: pharmacological study
    Correlative studies
    Other Names:
  • pharmacological studies

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Maximum tolerated dose of vorinostat when administered in combination with a fixed dose of weekly flavopiridol [Course 1]

      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.

    Secondary Outcome Measures

    1. Clinical pharmacokinetics of vorinostat (SAHA) [Week 1 of course 1]

    2. Therapeutic activity of SAHA and flavopiridol [Not Provided]

    3. Expression of p21, p53, and apoptotic markers relative to treatment response [Baseline to 2 weeks after completion of study treatment]

      Evaluated using immunohistochemistry.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    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

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Memorial Sloan-Kettering Cancer Center New York New York United States 10065

    Sponsors and Collaborators

    • National Cancer Institute (NCI)

    Investigators

    • Principal Investigator: Gary Schwartz, Memorial Sloan Kettering Cancer Center

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    National Cancer Institute (NCI)
    ClinicalTrials.gov Identifier:
    NCT00324480
    Other Study ID Numbers:
    • NCI-2009-00090
    • NCI-2009-00090
    • MSKCC-05109
    • CDR0000472411
    • NCI-6858
    • 05-109
    • 6858
    • P30CA008748
    • U01CA069856
    • NCT01645514
    • NCT01664377
    First Posted:
    May 11, 2006
    Last Update Posted:
    Feb 24, 2014
    Last Verified:
    Oct 1, 2011
    Additional relevant MeSH terms:
    Neoplasms
    Vorinostat
    Alvocidib

    Study Results

    No Results Posted as of Feb 24, 2014