A Study of Imatinib With Reinduction Chemotherapy Using Mitoxantrone, Etoposide and Cytarabine in Patients With Relapsed/Refractory C-kit Positive (AML) Acute Myeloid Leukemia

A Phase I-II Study Evaluating the Safety and Efficacy of Imatinib Mesylate (Gleevec) Combined With Reinduction Chemotherapy Using Mitoxantrone, Etoposide and Cytarabine in Patients With Relapsed/Refractory C-kit Positive Acute Myeloid Leukemia

This is a Phase I-II study evaluating the toxicity and efficacy of imatinib combined with mitoxantrone, etoposide and high-dose cytarabine reinduction therapy in relapsed and refractory AML. Patients will be treated initially at a 200 mg dose of imatinib; if tolerated, the imatinib dose will be escalated in subsequent cohorts to 300 mg and 400 mg. Once the recommended dose is determined, the remaining patients will be treated at that dose, to evaluate the antileukemic activity of the regimen. Patients achieving complete remission will receive consolidation therapy with imatinib combined with high-dose cytarabine and mitoxantrone, followed by maintenance imatinib.

Study Overview

• Status: Completed
• Conditions: Leukemia
• Intervention / Treatment: Drug: Imatinib (Gleevec)

Detailed Description

Induction therapy:

• Imatinib 200-400 mg p.o. daily x 10 days, Days 1-10 (see dose escalation scheme in Section 5.4 below).
• Mitoxantrone 10 mg/m2 daily x 5 days, Days 4-8.
• Etoposide 100 mg/m2 daily x 5 days, Days 4-8.
• Cytarabine 1.5 grams/m2 q12h x 4 doses, Days 9-10 (for patients aged 60 years and over, 1.0 gram/m2).

Only one induction course will be permitted. Only patients achieving CR will proceed to consolidation and maintenance.

Consolidation therapy, maximum 2 cycles (for patients achieving CR):

• Imatinib 200-400 mg p.o. daily x 8 days, Days 1-8 (see dose escalation scheme in Section 5.4 below).
• Mitoxantrone 12 mg/m2 daily x 2 days, Days 4-5.
• Cytarabine 3 grams/m2 q12h x 6 doses, Days 4,6,8. For patients aged 60 years and over, the dose will be reduced to 1.5 grams/m2.

Maintenance therapy (for patients still in CR at end of consolidation):

Imatinib 600 mg p.o. daily, until relapse or toxicity (see dose modification criteria in Section 5.6.6 below). Patients must receive at least one consolidation cycle before being permitted to proceed to maintenance therapy (see Section 5.6 for details). Maintenance therapy with imatinib will be provided for a maximum period of 1 year.

Dose escalation scheme:

Imatinib will be used during induction and consolidation at one of the following dose levels:

Level -1 100 mg daily Level 1 200 mg daily Level 2 300 mg daily Level 3 400 mg daily

• Study Type: Interventional
• Enrollment (Actual): 35
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G 2M9
      • Princess Margaret Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 61 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• AML, all subtypes except APL.
• Prior induction therapy consisting of cytarabine 100-200 mg/m2 plus an anthracycline.

• One of the following:

  • persistent leukemia after induction therapy.
  • relapse within two years of achieving complete remission with induction therapy. Any consolidation therapy is acceptable, including stem cell transplantation.
• At least 10% bone marrow blasts, or biopsy confirmed extramedullary disease.
• Positivity for c-kit (CD117) in at least 30% of blasts as measured by flow cytometry.
• Aged 18-65.
• ECOG performance status < 3 (see Appendix I).
• No chemotherapy within the previous four weeks, other than hydroxyurea to control counts. If hydroxyurea is used, it must be stopped at least 24 hours prior to starting imatinib.
• Able to given informed consent.

Exclusion Criteria:

• Active uncontrolled infection.
• Active CNS leukemia.
• Serum creatinine > 200 umol/L.
• Serum bilirubin > 1.5 x ULN, AST or ALT > 2x ULN.
• Left ventricular ejection fraction < 50%.

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: one	Drug: Imatinib (Gleevec)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Toxicity (hematologic and non-hematologic) of the combination of Imatinib and Chemotherapy consisting of Mitoxantrone, Etoposide and Ara-c	Hematologic toxicity; Number of days to ANC > 0.5 and 1.0.; Number of days until platelets > 20 and > 50, independent of platelet transfusions.; Number of days until RBC transfusion independent. Non-hematologic toxicity, as per NCI common toxicity criteria Hematologic dose-limiting toxicity (DLT) defined as > 40 days to ANC > 0.5 or platelets > 20 independent of transfusions.	2 years
Response rate - CR, MLFS and PR as per section 7.1	Complete response; Morphologic leukemia-free state; Partial remission (PR•No response (NR): Does not meet the criteria for CR, MLFS or PR.	2 years
Maximum tolerated dose of Imatinib when given in combination with chemotherapy	Maximum tolerated dose (MTD) of Imatinib (200, 300, 400 mg) when used in combination with NOVE-HiDAC induction and consolidation. MTD defined as highest dose resulting in up to 2/6 grade III-IV hematologic (as defined above) or non-hematologic DLTs per dose level. Non-hematologic DLTs as defined by NCIC CTC.	2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Toxicity of imatinib maintenance therapy.	Hematologic; Number of days to ANC > 0.5 and 1.0.; Number of days until platelets > 20 and > 50, independent of platelet transfusions.; Number of days until RBC transfusion independent. Non-hematologic toxicity, as per NCI common toxicity criteria	2 years
Number of Participants with adverse events as a measure of safety and tolerability	Toxicity of imatinib maintenance therapy.	2 years
Remission-free survival and overall survival.	Median duration of remission free survival. Median overall survival and 2 year overall survival.	2 years
Total and phosphorylated c-kit activity at Days 1 and 4.	levels of total and phosphorylated c-kit - pre and post imatinib/Gleevec	2 years
Levels of downstream components of c-kit pathway at Days 1 & 4.	levels of phosphorylation ERK and AKT - pre and post imatinib/Gleevec	2 years

Collaborators and Investigators

• Sponsor: University Health Network, Toronto

Study record dates

Study Major Dates

• Study Start: July 1, 2004
• Primary Completion (Actual): September 1, 2009
• Study Completion (Actual): April 1, 2010

Study Registration Dates

• First Submitted: May 3, 2010
• First Submitted That Met QC Criteria: May 19, 2010
• First Posted (Estimate): May 20, 2010

Study Record Updates

• Last Update Posted (Estimate): June 24, 2015
• Last Update Submitted That Met QC Criteria: June 22, 2015
• Last Verified: June 1, 2015

More Information

Terms related to this study

• Keywords: Gleevec; c-kit; aml
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Leukemia, Myeloid; Leukemia; Leukemia, Myeloid, Acute; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Imatinib Mesylate
• Other Study ID Numbers: 04-0147-C