Flavopiridol in Treating Patients with Relapsed or Refractory Acute Myeloid Leukemia, Acute Lymphoblastic Leukemia, or Chronic Myelogenous Leukemia
| Type | Status | Age Range (yrs.) | Sponsor | Protocol ID |
|---|
| Treatment | Active | 1-17 | OSU | OSU 0479 |
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 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.
Objectives
Primary
- Determine the maximum tolerated dose of flavopiridol in adult (stratum 1) and pediatric (stratum 2) patients with relapsed or refractory acute myeloid leukemia, acute lymphoblastic leukemia, or chronic myelogenous leukemia in blast crisis.
- Determine the qualitative and quantitative toxic effects of this drug, in terms of organ specificity, time course, predictability, and reversibility, in these patients.
- Determine, preliminarily, the clinical activity of this drug in these patients.
- Determine the plasma and cellular pharmacokinetics of this drug in these patients.
Secondary
- Determine the pharmacodynamics of this drug in these patients.
- Correlate drug-induced apoptosis of acute leukemia cells in vitro with clinical response in patients treated with this drug.
- Correlate inflammatory cytokine levels with pharmacokinetics, pharmacodynamics, and laboratory and clinical parameters of treatment in patients treated with this drug.
Projected Accrual
A total of 88 patients will be accrued for this study within 1-24 months.
Mechanism of Action
HMR 1275 (flavopiridol), a synthetic flavone, has been shown to have antineoplastic properties. HMR 1275 is best classified as a cyclin-dependent kinase (CDK) inhibitor. It has demonstrated specificity and nanomolar potency against CDKs compared to other protein kinases (protein kinase A, protein kinase C, and epidermal growth factor receptor tyrosine kinase). CDKs transiently associate with distinct members of the cyclin protein family to regulate cell cycle progression. HMR 1275 targets the ATP-binding site of the CDKs. The drug down-regulates cyclin D1 transcription and arrests cell cycle progress at the G2/M and G1/S boundaries. Other proposed mechanisms of action include anti-angiogenesis (VEGF depletion), induction of apoptosis by p53 and bcl-2 independent pathways, and promotion cell differentiation, among others.
Entry Criteria
Disease Characteristics:
- 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 relapsed 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 Patient Characteristics:
Age
- ≥ 18 (stratum 1)
- 1 to 17.99 (stratum 2)
Performance status
- ECOG ≥ 2 for patients > 10 years of age
- Lansky 50-100% for patients ≤ 10 years of age
Life expectancy
Hematopoietic
Hepatic
- Bilirubin ≤ 2 times upper limit of normal (ULN)* (unless due to Gilbert's syndrome)
- ALT and AST ≤ 5 times ULN
Renal
- Creatinine ≤ 2.0 mg/dL* (stratum 1)
- Creatinine ≤ 1.3 times ULN (stratum 2)
Cardiovascular
- 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
Other
- No chronic systemic anticoagulant therapy (e.g., no previous history of deep venous thrombosis, atrial fibrillation, etc.)
- Not pregnant or nursing
- Negative pregnancy test
- Fertile patients must use effective contraception
- HIV negative
- No history of allergy to any of the drugs or medications used in the study
- 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
Prior Concurrent Therapy
Biologic therapy
- 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)
Chemotherapy
- 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 NOTE: *For patients with rapidly proliferating disease, hydroxyurea within 24 hours is permitted, but hydroxyurea shall not be given within 8 hours of initiation of flavopiridol. The definition of "highly proliferative disease" is 1) absolute blast count >7500/uL on the day prior to therapy and 2) patients who in the opinion of the principal investigator are likely to have blasts >7500/uL at initiation of therapy if hydroxurea is stopped 24 hours ahead to time
Endocrine therapy
- 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)
Radiotherapy
- See Disease Characteristics
- Recovered from all prior radiotherapy treatment-related toxicity (stratum 2)
- More than 2 weeks since prior radiotherapy
- No concurrent palliative radiotherapy
Surgery
Other
- 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)
- Central line catheter for administration of Flavopiridol infusion is required for all patients enrolled in this study
Who should I contact for more information?
Rebecca Turner, MS, CCRP
Cincinnati Children's Hospital Medical Center
Division of Hematology/Oncology
3333 Burnet Ave., Cincinnati, OH 45229-3039
Phone: 513-636-2799
cancer@cchmc.org
