Allogeneic Stem Cell Transplant With Clofarabine, Ara-C and TBI for AML and ALL

Pediatric patients with ALL who have multiple relapses show a declining reinduction rate
with each successive relapse. Chessels et al reported the results in 235 pediatric patients
with ALL in CR3 treated between 1972 and 1998. Only 18 of the 235 patients remained alive,
with multiple early treatment failures implying significant instability of the third
remission state. Factors that were found to be of significant influence on survival for
these patients in CR3 were length of CR2, type of second event, immunophenotype, type of
third treatment, type of first relapse, presenting leukocyte count, and length of CR1. The
3-year leukemia-free survival for patients with ALL in CR3 treated with hematopoietic
progenitor cell transplantation (HPCT) was reported as 20% in a single-institution report on
patients transplanted with unrelated donors between 1987 and 1999. This report found a 20%
relapse rate in ALL patients in CR3 and reported that patients transplanted after 1992 had a
higher rate of relapse, implying that as improved chemotherapy regimens become more
successful in curing patients, those who develop relapse may have disease more resistant to
treatment. Clofarabine ([2-chloro-9-(2-deoxy-2-fluoro-D-arabinofuranosyl)adenine];
Cl-F-ara-A; CAFdA) is a rationally designed, second-generation purine nucleoside
antimetabolite. Clofarabine was designed as a hybrid molecule to overcome the limitations
and incorporate the best qualities of fludarabine (F-ara-A) and cladribine (2-CdA, CdA), all
three molecules are currently approved by the FDA for treatment of hematologic malignancies.
In an open-label Phase II, pediatric patients with refractory or relapsed ALL received
clofarabine 52 mg/m2 by IVI over 2 hours for 5 consecutive days repeated every 2 to 6 weeks
depending on toxicity and response. Among the 49 patients evaluated for efficacy, the
overall remission rate was 20%. The median duration of remission could not be calculated for
the 6 patients who achieved a CR because 3 patients were still in remission at the time of
data cutoff. The median duration for the 4 patients who achieved a CRp was 20 weeks (Range:
4.6 to 28.6 weeks). Eight (16%) patients went on to receive a transplant with 7 (14%)
experiencing clinical benefit. In an open-label Phase II study, pediatric patients with
refractory or relapsed AML received clofarabine 52 mg/m2 by IVI over 2 hours for 5
consecutive days repeated every 2 to 6 weeks depending on toxicity and response. The overall
remission rate (CR + CRp) was 3%; 23% of patients achieved a PR. The median duration of
remission for patients who achieved at least a PR was 16.2 weeks. Twelve (34%) patients went
on to receive a transplant, 7 of whom were still alive at the time of data cutoff with
survival ranging from 16.4 weeks to 93.6 weeks.

Patients enrolling must have undergone an extensive pre-transplant evaluation to assess
remission status, assure adequate organ system function, and document freedom from active
viral, bacterial, and fungal infection. Patients should proceed to transplant as soon as
possible following their reinduction chemotherapy. Patients with delays in therapy due to
toxicity or donor procurement delays should receive maintenance chemotherapy if possible.
Patients must be scheduled to begin their preparative regimen within 10 days of enrolling on
the study. This will be a 2 part study. Part A will be the dose escalation phase. Once the
MTD and/or safe/tolerated dose of clofarabine has been established, Part B will accrue
patients to further define the event free, disease free and overall survival at the MTD or
safe/tolerated dose of clofarabine. At study entry during Part A, a clofarabine dose level
will be assigned to each patient. During Part B, the established MTD or safe/tolerated dose
of clofarabine will be used.

In Part A this study will enroll patients with ALL and ANLL in relapse, induction failure,
CR3 or CR3P and without prior AlloSCT. These patients will receive a conditioning regimen of
clofarabine, ARA-C and TBI followed by AlloSCT. Patients will start their pre-conditioning
regimen on Day -10. Patients will receive ARA-C (3000 mg/m2 [total ARA-C dose of 18g/m2])
daily on Days -10, -9, -8, -7, -6, and -5 and clofarabine (Dose assigned at enrollment, see
section 8.2.2 for dose escalation table for Part A) on Days -9, -8, -7, -6, and -5. On days
when clofarabine and ARA-C are both given, clofarabine will be given as a 2 hr infusion
followed by 4 hr rest and then ARA-C given as a 3 hr infusion. Fractionated TBI (200 cGy)
will be administered twice daily for 3 days on Day -4, -3 and -2. The AlloSCT will be
performed on Day 0. GVHD prophylaxis will consist of tacrolimus and MMF. In Part B, this
study will enroll patients with ALL or ANLL in CR3 or CR3P and without prior AlloSCT. The
pre-conditioning regimen will be the same as in Part A EXCEPT the established MTD or
safe/tolerated dose of clofarabine from Part A will be utilized.

Inclusion Criteria:

- Age: Patients must be <30 years of age.

- Disease Status: ALL in relapse, induction failure, CR3, or CR3P (Part A ONLY); AML in
relapse, induction failure, CR3, or CR3P (Part A ONLY); ALL in CR3 or CR3P (Part A
and Part B); AML in CR3 or CR3P (Part A and BONLY); CR3/CR3P must be documented by
bone marrow and CNS assessment within 14 days of initiation of the pre-transplant
conditioning regimen.

- Creatinine clearance >40 ml/min/m2 or >60 ml/min/1.73 m2 or an equivalent
radioisotope glomerular filtration rate (GFR) as determined by the institutional
normal range or serum creatinine based on age

- Adequate liver function defined as: Total bilirubin <2.5 mg/dl l, or SGOT (AST) or
SGPT (ALT) <5 x upper limit of normal

- Adequate cardiac function defined as: Shortening fraction >27% by echocardiogram, or
Ejection fraction of >50% by radionuclide angiogram or echocardiogram.

- Adequate pulmonary function defined as: Corrected DLCO >60% by pulmonary function
test; For children who are uncooperative, no evidence of dyspnea at rest, no exercise
intolerance, and a pulse oximetry >94% on room air.

- Performance Status: For patients age 1-16 years, Lansky score of >60; For patients >
16 years, Karnofsky score of >60.

- Patients must have received a minimum of one round of re-induction and one round of
consolidation chemotherapy after relapse #2

Exclusion Criteria:

- Patients with prior myeloablative allogeneic stem cell transplantation and /or TBI.

- Females who are pregnant (positive HCG) or lactating.

- Karnofsky <60% or Lansky <60% if less than 16 years of age

- Age >30 years of age

- Any patient with uncontrolled infection prior to study entry

- Patients with evidence of active disease.

- Patients with Down syndrome are excluded