Study of Clofarabine & Cytosine Arabinoside Therapy for Older Adults With Acute Myeloid Leukemia

A Phase I Study of Clofarabine & Cytosine Arabinoside Therapy for Older Adults With Acute Myeloid Leukemia

The purpose of this study is to determine the recommended phase II dose of clofarabine when administered in combination with standard dose Ara-C to older (>=60 years of age) patients with newly diagnosed acute myeloid leukemia (AML).

Study Overview

• Status: Completed
• Conditions: Acute Myeloid Leukemia
• Intervention / Treatment: Drug: clofarabine; Drug: Ara-C

Detailed Description

This phase I/II trial will include an initial dose escalation of clofarabine with a fixed standard dose of Ara-C in phase I to determine the 'optimal phase II dose'. Patients will be enrolled into phase I in cohorts of 3-6 beginning at Dose Level I of clofarabine (30 mg/m2/day, days 2-6). If 0/3 or 1/6 patients experience dose-limiting toxicity (DLT), clofarabine will be escalated to Dose Level II (40mg/m2/day, days 2-6). If >1/3 or ≥2/6 patients experience DLT on Dose Level II, then Dose Level I will be declared the optimal phase II dose. However, if 0/3 or 1/6 patients experience DLT on Dose Level II, then Dose Level II will be declared the optimal phase II dose. In the event that ≥2 patients experience DLT at Dose Level I, clofarabine will be dose reduced to Dose Level -I (22.5mg/m2/day, days 2-6). Accrual will continue in cohorts of 3-6 patients, in a phase I fashion. If 0/3 or 1/6 patients experience DLT, then Dose Level -I will be declared the 'optimal phase II dose'. In the event that ≥2 patients experience DLT at Dose Level -I, clofarabine will be further dose reduced to Dose Level -II (15mg/m2/day, days 2-6). Accrual will again proceed in cohorts of 3-6 patients. If 0/3 or 1/6 experience DLT, then Dose Level -II will be declared the 'optimal phase II dose'. In the event that ≥2 patients experience DLT at Dose Level -II, accrual to the protocol will be halted.

Enrollment will proceed at the optimal phase II dose in a Simon 2-stage design to determine the CR rate and treatment-related mortality initially in 16 patients; if the CR rate and TRM is acceptable , then enrollment will continue to approximately 46 patients or until complete.

Induction Therapy (cycle 1)

• 7 day cycle Day 1 Aggressive Hydration x12-24hrs, followed by Ara-C 100mg/m2/day by 24hr IV continuous infusion days 1-7
• PK analysis Ara-C alone on Day 1 (plasma & intracellular) Day 2 Dexamethasone 10mg IV QD prior to clofarabine days 2-6 Clofarabine 2 hour daily infusion days 2-6
• PK analysis of Ara-C & clofarabine on Day 2
• Bone Marrow Apoptosis analysis (plasma & intracellular) Day 3 *Bone Marrow Apoptosis analysis (plasma & intracellular) Day 6 *PK analysis of Ara-C and clofarabine (plasma only) (UAB only) Day 8 Initiation of prophylactic antibiotic, antifungal & antiviral therapy Day 15 *QOL analysis Day 15-22 Restaging BM Re-Induction if appropriate (see below) Day 16 GM-CSF 250μg/m2 daily until ANC >1,500/μl (if D15 BM aplasia, no residual AML) Day 28-49 Outcome BM, assessment of response Re-Induction (PR) or Post-Remission therapy (CR)
• QOL analysis 2 weeks after hospital discharge (approximately Day 42)

Re-Induction (cycle 2 if appropriate) (if Partial Remission after Induction, day 15-49) *5 day cycle Aggressive Hydration x12-24hrs Day 1 Dexamethasone 10mg IV QD days 1-5 Day 1 Clofarabine 2 hour daily infusion days 1-5 Day 1 Ara-C 100mg/m2/day days 1-5 (begin 4 hours after end of clofarabine infusion) Day 7 GM-CSF 250μg/m2 daily may be used until recovery ANC >1,500/μl Day 7 Initiation of prophylactic antibiotic, antifungal & antiviral therapy

Post-Remission Therapy (cycles 2 & 3 if appropriate) (if Complete Remission after Induction; must have ANC>1,000/μl , platelets >100/μl)

*5 day cycle Aggressive Hydration x12-24hrs Day 1 Dexamethasone 10mg IV QD days 1-5 Day 1 Clofarabine 2 hour daily infusion days 1-5 Day 1 Ara-C 100mg/m2/day days 1-5 (begin 4 hours after end of clofarabine infusion) Day 7 GM-CSF 250μg/m2 daily may be used until recovery ANC >1,500/μl Day 7 Initiation of prophylactic antibiotic, antifungal & antiviral therapy

Follow-up Monthly x 12 months 3-monthly x 2 years 4-monthly x 1 year 6-monthly x 1 year Annually thereafter

• Study Type: Interventional
• Enrollment (Actual): 23
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • University of Alabama at Birmingham
  • Nebraska
    • Omaha, Nebraska, United States, 68198
      • The University of Nebraska
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • The Cleveland Clinic Foundation

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 60 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Have newly diagnosed AML (FAB classification types M0-M2 or M4-M7 or WHO classification) excluding acute promyelocytic leukemia (APL) or AML with any of the following chromosomal translocations: t(15;17)(q22;q21); t(11;17)(q23;q21); t(11;17)(q13;q21); t(5;17)(q32;q12)..
• Have greater than or equal to 20% blasts in the bone marrow.
• Have greater than or equal to 20% cellularity in the bone marrow.
• Provide written informed consent.
• Must be 60-75 years of age at diagnosis.
• Have an Karnofsky performance status of ≥60.
• Women of childbearing potential (<1 year post-menopausal unless surgically sterilized) and sexually active males must have a negative urine pregnancy test, and agree to use an effective barrier method of birth control (i.e. latex condom, diaphragm, cervical cap, etc) to avoid pregnancy.
• Able to comply with study procedures and follow-up examinations.
• Have adequate organ function as indicated by the following laboratory values, obtained within 7 days prior to registration:

Parameter Required Value (IS units) Renal Serum creatinine <1.1 mg/dL Hepatic Serum bilirubin <2 x ULN AST and ALT ≤5 x ULN ULN = Institutional Upper Limit of Normal. Inclusion Laboratory Values

Exclusion Criteria:

• Patients with pre-existing myelodysplastic syndrome, or with antecedent hematologic disorder of >3 months duration, will be excluded. Those with concomitant myelodysplasia/trilineage dysplasia noted at the time of diagnosis of AML will be eligible 74
• Have secondary AML (AML following chemotherapy or radiation therapy).
• Have an active, uncontrolled systemic infection considered opportunistic, life threatening, or clinically significant at the time of treatment.
• Have a psychiatric disorder(s) that would interfere with consent, study participation or follow-up.
• Are receiving other chemotherapy or corticosteroids (unless the latter is administered at a low dose for pre-medication purposes or for the treatment of chronic conditions - e.g., rheumatoid arthritis).
• Have received prior treatment for leukemia. Patients who have received growth factors, cytokine support, leukapheresis, hydroxyurea, or cranial irradiation will be allowed but must discontinue treatment at least 24 hours prior to beginning treatment with clofarabine. If used, hydroxyurea must be discontinued 48 hours prior to the initiation of chemotherapy.
• Have any other severe concurrent disease (severe coronary artery disease (NYHA class >II), significant neurological disorder, uncontrolled diabetes, etc.), which, in the judgment of the investigator, would make the patient inappropriate for entry into this study.
• Have active central nervous system involvement with leukemia.
• Other malignancy within the past year, with the exception of basal cell or non-metastatic squamous cell carcinoma of the skin

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

Other: Clofarabine + Ara-C; An initial dose escalation of clofarabine with a fixed standard dose of Ara-C in phase I will be used to determine an optimal phase II dose.

Drug: clofarabine; Clofarabine should be administered by daily intravenous infusion over 2 hours.Following demonstration of DLT at Dose Level -I (22.5 mg/m2/day days 2-6) and demonstration that Dose Level -II (15mg/m2day days 2-6) is the 'optimal phase II dose', an additional Dose Level -1½ (20mg/m2/day, days 2-6) will be added to explore an increased dose of clofarabine intermediate between Dose Levels -I and -II.; Other Names: CLOFAREX TM; Drug: Ara-C; Ara-C: Administer Ara-C by continuous infusion of 100mg/m2/day on days 1 to 7 for cycle 1, and on days 1 to 5 for cycles 2 & 3.; Other Names: Cytosar-U; Cytosine arabinoside; Cytarabine; Arabinosyl

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Median time to complete response (CR)	1 year

Secondary Outcome Measures

Outcome Measure	Time Frame
To evaluate quality of life parameters before, during and after therapy in the older adult (>60 years) population	1 year

Collaborators and Investigators

• Sponsor: University of Alabama at Birmingham
• Collaborators: Genzyme, a Sanofi Company
• Investigators: Principal Investigator: James M Foran, MD, University of Alabama at Birmingham

Study record dates

Study Major Dates

• Study Start: January 1, 2004
• Primary Completion (Actual): April 1, 2009
• Study Completion (Actual): August 1, 2011

Study Registration Dates

• First Submitted: April 21, 2004
• First Submitted That Met QC Criteria: April 22, 2004
• First Posted (Estimate): April 23, 2004

Study Record Updates

• Last Update Posted (Estimate): April 20, 2012
• Last Update Submitted That Met QC Criteria: April 18, 2012
• Last Verified: April 1, 2012

More Information

Terms related to this study

• Keywords: acute myeloid leukemia; clofarabine; cytosine arabinoside; Foran
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Clofarabine; Cytarabine
• Other Study ID Numbers: F040114019; UAB 0341 (Other Identifier: Institutional study protocol number)