Flavopiridol, Cytarabine, and Mitoxantrone in Treating Patients With Relapsed or Refractory Acute Leukemia

• ClinicalTrials.gov Identifier: NCT00470197
• Recruitment Status: Completed
• First Posted: May 7, 2007
• Last Update Posted: September 30, 2013
• Sponsor: National Cancer Institute (NCI)
• Information provided by (Responsible Party): National Cancer Institute (NCI)

Tracking Information

• First Submitted Date: May 3, 2007
• First Posted Date: May 7, 2007
• Last Update Posted Date: September 30, 2013
• Study Start Date: April 2007
• Actual Primary Completion Date: January 2011 (Final data collection date for primary outcome measure)
• Current Primary Outcome Measures (submitted: January 8, 2013): Maximum tolerated dose determined by dose-limiting toxicities graded according to NCI-CTC version 3.0 [ Time Frame: Up to 63 days ]

Original Primary Outcome Measures (submitted: May 3, 2007)

• Toxicity
• Clinical response

• Current Secondary Outcome Measures: Not Provided
• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Flavopiridol, Cytarabine, and Mitoxantrone in Treating Patients With Relapsed or Refractory Acute Leukemia
• Official Title: Phase I Study of a Pharmacologically Derived Hybrid Bolus-Infusion Schedule of Flavopiridol (NSC 649890, IND 46,211) Given in Timed Sequential Combination With Cytosine Arabinoside (Ara-C) and Mitoxantrone for Adults With Relapsed and Refractory Acute Leukemias
• Brief Summary: Drugs used in chemotherapy, such as flavopiridol, cytarabine, and mitoxantrone, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving a new schedule of more than one drug (combination chemotherapy) may kill more cancer cells. This phase I trial is studying the side effects, best dose, and best schedule for flavopiridol when given together with cytarabine and mitoxantrone in treating patients with relapsed or refractory acute leukemia.

Detailed Description

OBJECTIVES:

I. Determine the toxicities of escalating doses of flavopiridol administered by "hybrid" bolus-infusion schedule and given in timed sequence with cytarabine and mitoxantrone hydrochloride in patients with refractory or relapsed acute leukemia.

II. Determine the incidence of clinical response in patients treated with this regimen.

OUTLINE: This is a dose-escalation study of flavopiridol. Patients receive flavopiridol IV over 30 minutes on days 1, 2, and 3.

Patients receive cytarabine IV continuously over 72 hours beginning on day 6 and mitoxantrone hydrochloride IV over 60-120 minutes on day 9. Treatment repeats every 35-63 days for up to 2 courses 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 1 of 3 or 2 of 6 patients experience dose-limiting toxicity.

Serum and bone marrow samples are collected at baseline, during, and after completion of treatment for future studies. Flavopiridol levels are measured at baseline and on days 1-3 for pharmacokinetics.

• Study Type: Interventional
• Study Phase: Phase 1
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• 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)
• Malignant Neoplasm
• Recurrent Adult Acute Lymphoblastic Leukemia
• Recurrent Adult Acute Myeloid Leukemia

Intervention

• Drug: alvocidib
  Given IV
  Other Names:

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

  • ARA-C
  • arabinofuranosylcytosine
  • arabinosylcytosine
  • Cytosar-U
  • cytosine arabinoside
• Drug: mitoxantrone hydrochloride
  Given IV
  Other Names:

  • CL 232315
  • DHAD
  • DHAQ
  • Novantrone
• Other: pharmacological study
  Correlative study
  Other Name: pharmacological studies

Study Arms

Experimental: Arm I

Patients receive flavopiridol IV over 30 minutes on days 1, 2, and 3. Patients receive cytarabine IV continuously over 72 hours beginning on day 6 and mitoxantrone hydrochloride IV over 60-120 minutes on day 9.

Interventions:

• Drug: alvocidib
• Drug: cytarabine
• Drug: mitoxantrone hydrochloride
• Other: pharmacological study

• Publications *: Karp JE, Smith BD, Resar LS, Greer JM, Blackford A, Zhao M, Moton-Nelson D, Alino K, Levis MJ, Gore SD, Joseph B, Carraway H, McDevitt MA, Bagain L, Mackey K, Briel J, Doyle LA, Wright JJ, Rudek MA. Phase 1 and pharmacokinetic study of bolus-infusion flavopiridol followed by cytosine arabinoside and mitoxantrone for acute leukemias. Blood. 2011 Mar 24;117(12):3302-10. doi: 10.1182/blood-2010-09-310862. Epub 2011 Jan 14.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: May 3, 2007): 35
• Original Enrollment: Same as current
• Study Completion Date: Not Provided
• Actual Primary Completion Date: January 2011 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Pathologically confirmed acute myeloid leukemia or acute lymphoblastic leukemia:

  • Relapsed >= 1 time OR refractory disease:

    • Patients who fail primary induction therapy or who relapse after achieving complete remission are eligible if they have received =< 3 prior courses of induction/reinduction therapy
• Relapsed >= 1 time OR refractory disease
• Patients who fail primary induction therapy or who relapse after achieving complete remission are eligible if they have received =< 3 prior courses of induction/reinduction therapy
• No active CNS leukemia
• ECOG performance status 0-2
• AST and ALT =< 5 times upper limit normal (ULN)
• Alkaline phosphatase =< 5 times ULN
• Bilirubin =< 2.0 mg/dL
• Creatinine =< 2.0 mg/dL
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• LVEF >= 45% by MUGA or ECHO
• No active, uncontrolled infection
• No other life-threatening illness
• No mental deficits and/or psychiatric history that would preclude study compliance
• No active graft-vs-host disease
• Recovered from all prior therapies
• At least 24 hours since prior hydroxyurea, steroids, imatinib mesylate, arsenic trioxide, interferon, or leukapheresis for blast count control
• At least 4 weeks since prior stem cell transplantation (autologous or allogeneic)
• At least 4 days since prior growth factors
• At least 3 weeks since prior chemotherapy, except for non-aplasia producing treatments (e.g., low-dose cyclophosphamide, hydroxyurea, interferon, imatinib mesylate, mercaptopurine, thalidomide, azacitidine, or decitabine)
• No prior flavopiridol
• No other concurrent chemotherapy, radiotherapy, or immunotherapy
• No acute promyelocytic leukemia (M3)
• No hyperleukocytosis with > 50,000 blasts/mm^3

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT00470197
• Other Study ID Numbers: NCI-2009-00243; NCI-2009-00243 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); J06133; CDR0000543443; J06133 ( Other Identifier: Johns Hopkins University ); 7889 ( Other Identifier: CTEP ); U01CA070095 ( U.S. NIH Grant/Contract ); U01CA062491 ( U.S. NIH Grant/Contract )
• Has Data Monitoring Committee: Not Provided
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: National Cancer Institute (NCI)
• Study Sponsor: National Cancer Institute (NCI)
• Collaborators: Not Provided

Investigators

• Principal Investigator: Judith Karp; Johns Hopkins University

• PRS Account: National Cancer Institute (NCI)
• Verification Date: September 2013