Flavopiridol in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia, Acute Lymphoblastic Leukemia, or Chronic Myelogenous Leukemia

June 3, 2013 updated by: National Cancer Institute (NCI)

A Dose Escalation Study of Flavopiridol (NSC 649890) Administered as a 30 Minute Loading Dose Followed by a 4-Hour Infusion in Patients With Relapsed and Refractory Acute Leukemias

This phase I trial is studying the side effects and best dose of flavopiridol in treating patients with relapsed or refractory acute myeloid leukemia, acute lymphoblastic leukemia, or chronic myelogenous leukemia. Drugs used in chemotherapy, such as flavopiridol, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing.

Study Overview

Status

Terminated

Conditions

Intervention / Treatment

Detailed Description

PRIMARY OBJECTIVES:

I. To determine the maximal tolerable dose of flavopiridol in relapsed or refractory acute leukemia in adults (Stratum 1) and children (Stratum 2).

II. To define the qualitative and quantitative toxicities of flavopiridol in regard to organ specificity, time course, predictability, and reversibility.

III. To determine the preliminary clinical activity of flavopiridol in adults (Stratum 1) and children (Stratum 2) using this novel schedule in acute leukemia.

IV. To evaluate the plasma and cellular pharmacokinetics of flavopiridol in patients enrolled on this study.

SECONDARY OBJECTIVES:

I. To measure pharmacodynamic measurements including effects on cell cycle; down modulation of bcl-2, mcl-1, XIAP, bax, RNA polymerase II phosphorylation; and signaling via the VEGF (VEGF, VEGF-R1, VEGF-R2, HIF-1), NF-Kappa B pathway, and PI3kinase pathway; and correlate with Css and other pharmacokinetic features.

II. To assess drug induced apoptosis of acute leukemia cells in vitro and subsequent relationship to clinical response based upon Css of flavopiridol attained in vivo.

II. To determine if increase in inflammatory cytokines (TNF-alpha, gamma-IFN, IL-6 and IL-8) correlate with pharmacokinetics, pharmacodynamics, laboratory (decrease in serum albumin) and clinical (hypotension observed with the first administration of flavopiridol) parameters of treatment.

OUTLINE: This is a dose-escalation study. Patients are stratified according to age group (adult [≥ 18 years] vs pediatric [1-17 years]).

Patients receive flavopiridol intravenously (IV) over 30 minutes followed by a 4-hour infusion on days 1-3. Treatment repeats every 21 days for up to 6 courses in the absence of unacceptable toxicity or disease progression. 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 3 or 2 of 6 patients experience dose-limiting toxicity.

Patients are followed up every 2 months for 1 year and then every 6 months for 4 years.

Study Type

Interventional

Enrollment (Actual)

88

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Ohio
      • Columbus, Ohio, United States, 43210
        • Ohio State University Medical Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

1 year and older (Child, Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Histologically confirmed diagnosis of one of the following:

    • Acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL) meeting 1 of the following criteria:

      • Refractory to initial treatment (stratum 1)
      • Recurrent disease after prior high-dose chemotherapy with or without stem cell support (stratum 1)
      • High-risk refractory disease defined as failed ≥ 2 regimens for remission induction (i.e., twice induction failure) (stratum 2)
      • High-risk relaspsed disease defined as disease in second or greater bone marrow relapse (stratum 2)

    • Chronic myelogenous leukemia in blast crisis (stratum 1)

      • Myeloid or lymphoid blast crisis that did not respond to or progressed after prior high-dose imatinib mesylate (600-800 mg/day for ≥ 2 weeks)
  • No acute promyelocytic leukemia

  • Ineligible for or unwilling to undergo potentially curative allogeneic or autologous stem cell transplantation

    • Patients with relapsed AML that is refractory to re-induction therapy comprising an active, intensive salvage regimen are eligible
  • CNS involvement allowed provided there are no residual leukemic cells in the cerebrospinal fluid after intrathecal chemotherapy or radiotherapy
  • Performance status - ECOG ≥ 2 for patients > 10 years of age
  • Performance status - Lansky 50-100% for patients ≤ 10 years of age
  • At least 8 weeks
  • Bilirubin ≤ 2 times upper limit of normal (ULN)* (unless due to Gilbert's syndrome)
  • ALT and AST ≤ 5 times ULN*
  • Creatinine ≤ 2.0 mg/dL* (stratum 1)
  • Creatinine > 1.3 times ULN (stratum 2)
  • LVEF ≥ 40% by echocardiogram or MUGA (stratum 1)
  • Shortening fraction ≥ 28% by echocardiogram (stratum 2)
  • No symptomatic congestive heart failure
  • No unstable angina pectoris
  • No cardiac arrhythmia
  • Not pregnant or nursing
  • Negative pregnancy test
  • Fertile patients must use effective contraception
  • HIV negative
  • No history of allergy to study drug
  • No active infection requiring IV antibiotics
  • No serious medical or psychiatric illness that would preclude giving informed consent or limit survival
  • No other uncontrolled illness
  • See Disease Characteristics
  • Recovered from all prior immunotherapy treatment-related toxicity (stratum 2)
  • More than 8 weeks since prior biological agents (e.g., monoclonal antibodies) (stratum 2)
  • See Disease Characteristics
  • Recovered from all prior chemotherapy treatment-related toxicity (stratum 2)
  • More than 24 hours since prior hydroxyurea (for patients who do not have highly proliferative disease)*
  • More than 2 weeks since other prior chemotherapy (6 weeks for nitrosourea or mitomycin)
  • No other concurrent chemotherapy
  • Prior hydrea and/or steroids allowed (stratum 2)
  • No concurrent hormones, except steroids for adrenal failure or infusional toxicity (i.e., cytokine release syndrome) or hormones for non-disease-related conditions (e.g., insulin for diabetes)
  • See Disease Characteristics
  • Recovered from all prior radiotherapy treatment-related toxicity (stratum 2)
  • More than 2 weeks since prior radiotherapy
  • No concurrent palliative radiotherapy
  • Post stem cell transplant allowed provided completion ≥ 4 months prior to study entry and no evidence of active acute or chronic graft vs host disease (stratum 2)
  • No other concurrent investigational agents

  • No concurrent chronic systemic anticoagulant therapy for a medical condition (e.g., deep vein thrombosis or atrial fibrillation)

    • Concurrent heparin allowed to maintain central line patency (i.e., catheter flush)
  • No other concurrent anticancer therapy

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Treatment (flavopiridol)
Patients receive flavopiridol IV over 30 minutes followed by a 4-hour infusion on days 1-3. Treatment repeats every 21 days for up to 6 courses in the absence of unacceptable toxicity or disease progression.
Drug: alvocidib
Given IV
Other Names:
  • FLAVO
  • flavopiridol
  • HMR 1275
  • L-868275

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Maximal tolerable dose of flavopiridol
Time Frame: Day 21
Day 21

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

National Cancer Institute (NCI)

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

October 1, 2004

Primary Completion (Actual)

November 1, 2012

Study Registration Dates

First Submitted

January 7, 2005

First Submitted That Met QC Criteria

January 7, 2005

First Posted (Estimate)

January 10, 2005

Study Record Updates

Last Update Posted (Estimate)

June 4, 2013

Last Update Submitted That Met QC Criteria

June 3, 2013

Last Verified

June 1, 2013

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • NCI-2012-01461
  • U01CA076576 (U.S. NIH Grant/Contract)
  • OSU 0479
  • NCI-6947
  • OSU-2004C0085
  • OSU-0479
  • CDR0000404374

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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