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


Phase 1
60 Years
N/A
Not Enrolling
Both
Acute Myeloid Leukemia

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Trial Information

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


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


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

Type of Study:

Interventional

Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Median time to complete response (CR)

Outcome Time Frame:

1 year

Safety Issue:

Yes

Principal Investigator

James M Foran, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

University of Alabama at Birmingham

Authority:

United States: Food and Drug Administration

Study ID:

F040114019

NCT ID:

NCT00081822

Start Date:

January 2004

Completion Date:

August 2011

Related Keywords:

  • Acute Myeloid Leukemia
  • Foran
  • clofarabine
  • cytosine arabinoside
  • acute myeloid leukemia
  • Leukemia
  • Leukemia, Myeloid, Acute
  • Leukemia, Myeloid

Name

Location

University of Alabama at BirminghamBirmingham, Alabama  35294-3300
The Cleveland Clinic FoundationCleveland, Ohio  
The University of NebraskaOmaha, Nebraska  68198