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

This study has been terminated.
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT00101231
First received: January 7, 2005
Last updated: June 3, 2013
Last verified: June 2013
  Purpose

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.


Condition Intervention Phase
Adult Acute Basophilic Leukemia
Adult Acute Eosinophilic Leukemia
Adult Acute Megakaryoblastic Leukemia (M7)
Adult Acute Minimally Differentiated Myeloid Leukemia (M0)
Adult Acute Monoblastic Leukemia (M5a)
Adult Acute Monocytic Leukemia (M5b)
Adult Acute Myeloblastic Leukemia With Maturation (M2)
Adult Acute Myeloblastic Leukemia Without Maturation (M1)
Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities
Adult Acute Myeloid Leukemia With Inv(16)(p13;q22)
Adult Acute Myeloid Leukemia With t(16;16)(p13;q22)
Adult Acute Myeloid Leukemia With t(8;21)(q22;q22)
Adult Acute Myelomonocytic Leukemia (M4)
Adult Erythroleukemia (M6a)
Adult Pure Erythroid Leukemia (M6b)
Blastic Phase Chronic Myelogenous Leukemia
Recurrent Adult Acute Lymphoblastic Leukemia
Recurrent Adult Acute Myeloid Leukemia
Relapsing Chronic Myelogenous Leukemia
Drug: alvocidib
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: 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

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • Maximal tolerable dose of flavopiridol [ Time Frame: Day 21 ] [ Designated as safety issue: Yes ]

Enrollment: 88
Study Start Date: October 2004
Primary Completion Date: November 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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

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.

  Eligibility

Ages Eligible for Study:   1 Year and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00101231

Locations
United States, Ohio
Ohio State University Medical Center
Columbus, Ohio, United States, 43210
Sponsors and Collaborators
Investigators
Principal Investigator: William Blum Ohio State University
  More Information

No publications provided by National Cancer Institute (NCI)

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT00101231     History of Changes
Other Study ID Numbers: NCI-2012-01461, OSU 0479, NCI-6947, OSU-2004C0085, OSU-0479, CDR0000404374, U01CA076576
Study First Received: January 7, 2005
Last Updated: June 3, 2013
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia, Lymphoid
Leukemia
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Leukemia, Myelomonocytic, Acute
Leukemia, Myelomonocytic, Chronic
Blast Crisis
Leukemia, Monocytic, Acute
Hypereosinophilic Syndrome
Leukemia, Megakaryoblastic, Acute
Leukemia, Erythroblastic, Acute
Leukemia, Basophilic, Acute
Leukemia, Eosinophilic, Acute
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Myeloproliferative Disorders
Bone Marrow Diseases
Hematologic Diseases
Myelodysplastic-Myeloproliferative Diseases
Cell Transformation, Neoplastic
Carcinogenesis
Neoplastic Processes
Pathologic Processes
Eosinophilia

ClinicalTrials.gov processed this record on September 15, 2014