Flavopiridol and Vorinostat in Treating Patients With Relapsed or Refractory Acute Leukemia or Chronic Myelogenous Leukemia or Refractory Anemia

Phase I Trial of Vorinostat (SAHA) in Combination With Alvocidib (Flavopiridol) in Patients With Relapsed, Refractory, or (Selected) Poor Prognosis Acute Leukemia or Refractory Anemia With Excess Blasts-2

This phase I trial is studying the side effects and best dose of flavopiridol when given together with vorinostat in treating patients with relapsed or refractory acute leukemia or chronic myelogenous leukemia or refractory anemia. Flavopiridol and vorinostat may cause leukemia cells to look more like normal cells, and to grow and spread more slowly. Vorinostat may also stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving flavopiridol together with vorinostat may be an effective treatment for leukemia or refractory anemia.

Study Overview

• Status: Completed
• Conditions: Recurrent Adult Acute Myeloid Leukemia; Untreated Adult Acute Myeloid Leukemia; Recurrent Adult Acute Lymphoblastic Leukemia; Relapsing Chronic Myelogenous Leukemia; Untreated Adult Acute Lymphoblastic Leukemia; Refractory Anemia With Excess Blasts; Blastic Phase Chronic Myelogenous Leukemia
• Intervention / Treatment: Drug: vorinostat; Drug: alvocidib

Detailed Description

PRIMARY OBJECTIVE:

I. Determine recommended phase II doses for the combination of flavopiridol and vorinostat in patients with acute leukemia, chronic myelogenous leukemia in blast crisis, or refractory anemia with excess blasts-2.

SECONDARY OBJECTIVES:

I. Determine the safety, toxicity, tolerability, and maximum tolerated dose of this drug regimen.

II. Determine the pharmacodynamic and clinical anti-leukemic effects of this drug regimen.

III. Correlate leukemia gene expression patterns with response in patients treated with this regimen.

OUTLINE: This is an open-label, dose-escalation study of flavopiridol.

Patients receive flavopiridol IV over 1 hour on days 1-5 and oral vorinostat three times daily on days 1-14. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of flavopiridol 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.

• Study Type: Interventional
• Enrollment (Actual): 24
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Virginia
    • Richmond, Virginia, United States, 23298
      • Virginia Commonwealth University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Diagnosis of one of the following:

  • Relapsed or refractory acute leukemia (acute myeloid leukemia [AML], acute lymphoblastic leukemia [ALL], or acute leukemia unclassifiable) following at least one prior systemic treatment
  • Acute leukemia in a patient 60 years or older (no requirement for prior treatment)
  • Acute leukemia that has evolved from a prior myelodysplastic syndrome
  • Chronic myelogenous leukemia (CML) in blast crisis following prior imatinib mesylate therapy
  • Refractory anemia with excess blasts-2 (RAEB-2)
  • No known CNS leukemia
• ECOG performance status 0-2
• WBC < 50,000µL
• Hydroxyurea and/or leukaphereses may be used to lower WBC
• Creatinine =< 1.5 times upper limit of normal (ULN) OR creatinine clearance >= 50 mL/min
• Total bilirubin =< 2 times ULN
• AST/ALT =< 2.5 times ULN
• QTc interval =< 0.470 seconds
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception during and for 3 months after study participation
• No other condition that would preclude study participation
• At least 3 weeks since prior treatment (expect leukaphereses)
• No valproic acid therapy within the past 2 weeks
• No prior autologous or allogeneic bone marrow or stem cell transplantation
• No hydroxyurea use within the past 24 hours
• No concurrent treatment with other anti-cancer agents or investigational agents

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: Arm I; Patients will receive a 1-hour infusion of flavopiridol on 5 days in week 1 and vorinostat by mouth three times a day in weeks 1 and 2. Treatment may repeat every 3 weeks for as long as benefit is shown.	Drug: vorinostat; Given orally; Other Names: SAHA; Zolinza; L-001079038; suberoylanilide hydroxamic acid; Drug: alvocidib; Given by infusion; Other Names: FLAVO; flavopiridol; HMR 1275; L-868275

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
MTD for the combination of alvocidib and vorinostat, assessed by Common Toxicity Criteria version 3.0	21 days

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Steven Grant, Massey Cancer Center

Study record dates

Study Major Dates

• Study Start: January 1, 2006
• Primary Completion (Actual): October 1, 2009

Study Registration Dates

• First Submitted: January 16, 2006
• First Submitted That Met QC Criteria: January 16, 2006
• First Posted (Estimate): January 18, 2006

Study Record Updates

• Last Update Posted (Estimate): April 2, 2013
• Last Update Submitted That Met QC Criteria: April 1, 2013
• Last Verified: April 1, 2013

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Disease Attributes; Bone Marrow Diseases; Hematologic Diseases; Myeloproliferative Disorders; Neoplastic Processes; Cell Transformation, Neoplastic; Carcinogenesis; Myelodysplastic Syndromes; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Recurrence; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid; Anemia; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Blast Crisis; Anemia, Refractory, with Excess of Blasts; Anemia, Refractory; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Growth Substances; Growth Inhibitors; Protein Kinase Inhibitors; Histone Deacetylase Inhibitors; Vorinostat; Alvocidib
• Other Study ID Numbers: NCI-2009-00077; U01CA062490 (U.S. NIH Grant/Contract); MCC 6637; CDR0000656277; R21CA115260 (U.S. NIH Grant/Contract)