Study of Clofarabine & Cytosine Arabinoside Therapy for Older Adults With Acute Myeloid Leukemia - Full Text View

Sponsor:	University of Alabama at Birmingham
Collaborator:	Genzyme
Information provided by:	University of Alabama at Birmingham
ClinicalTrials.gov Identifier:	NCT00081822

Purpose

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).

Condition	Intervention	Phase
Acute Myeloid Leukemia	Drug: clofarabine Drug: Ara-C	Phase I

Study Type:	Interventional
Study Design:	Allocation: Non-Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Single Group Assignment Masking: Open Label Primary Purpose: Treatment
Official Title:	A Phase I Study of Clofarabine & Cytosine Arabinoside Therapy for Older Adults With Acute Myeloid Leukemia

Resource links provided by NLM:

MedlinePlus related topics: Acute Myeloid Leukemia Leukemia

Drug Information available for: Cytarabine hydrochloride Clofarabine Cytarabine

U.S. FDA Resources

Further study details as provided by University of Alabama at Birmingham:

Primary Outcome Measures:

Median time to complete response (CR) [ Time Frame: 1 year ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:

To evaluate quality of life parameters before, during and after therapy in the older adult (>60 years) population [ Time Frame: 1 year ] [ Designated as safety issue: No ]

Enrollment:	23
Study Start Date:	January 2004
Estimated Study Completion Date:	August 2011
Primary Completion Date:	April 2009 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
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 Name: 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: Cytosine arabinoside Cytarabine Cytosar-U Arabinosyl

Arms

Assigned Interventions

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 Name: 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:

Cytosine arabinoside
Cytarabine
Cytosar-U
Arabinosyl

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

Eligibility

Ages Eligible for Study:	60 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

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

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00081822

Locations

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

Sponsors and Collaborators

University of Alabama at Birmingham

Genzyme

Investigators

Principal Investigator:

James M Foran, MD

University of Alabama at Birmingham

More Information

No publications provided

Responsible Party:	James M. Foran, M.D./Principal Investigator, Mayo Clinic in Jacksonville, FL
ClinicalTrials.gov Identifier:	NCT00081822 History of Changes
Other Study ID Numbers:	F040114019, UAB 0341
Study First Received:	April 21, 2004
Last Updated:	April 19, 2011
Health Authority:	United States: Food and Drug Administration

Keywords provided by University of Alabama at Birmingham:

Foran
clofarabine
cytosine arabinoside
acute myeloid leukemia

Additional relevant MeSH terms:

Leukemia
Leukemia, Myeloid, Acute
Leukemia, Myeloid
Neoplasms by Histologic Type
Neoplasms
Cytarabine
Clofarabine
Antimetabolites, Antineoplastic
Antimetabolites

Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antineoplastic Agents
Therapeutic Uses
Antiviral Agents
Anti-Infective Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on February 09, 2012