Trial Information

A Phase 2 Multicenter Study of First-line Dasatinib Plus Conventional Chemotherapy in Adults With Newly Diagnosed Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia

Recent clinical trials on imatinib in combination with cytotoxic agents as a front-line
treatment, have demonstrated an improved complete remission (CR) rate and a better outcome
in adults with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-positive
ALL). Previously, we also demonstrated the positive impact of first-line imatinib interim
therapy on the outcome of allogeneic stem cell transplantation (SCT) in adults with
Ph-positive ALL. Nevertheless, a substantial proportion of patients continue to die as a
result of disease progression. Recently, we demonstrated that a reduction in BCR-ABL
transcript levels of at least 3 log after the completion of imatinib therapy was found to be
the most powerful predictor of lower relapse and better disease-free survival after
allogeneic SCT. In the light of disease aggressiveness and recurrence, mainly as a result of
the outgrowth of leukemic subclones with imatinib-resistant BCR-ABL mutations, an improved
strategy to induce more effective leukemic cell clearance during the pretransplantation
treatment course is clearly needed.

Dasatinib, a potent dual BCR-ABL/SRC family kinase inhibitor, demonstrated 325-fold greater
activity against native BCR-ABL compared with imatinib and has shown efficacy against all
imatinib-resistant BCR-ABL mutations with the exception of T315I. According to the START-L
(SRC/ABL Tyrosine Kinase Inhibition Activity: Research Trials of Dasatinib) trial, dasatinib
(70 mg twice daily) induced rapid hematologic and cytogenetic responses in a substantial
proportion of patients with imatinib-resistant or intolerant Ph-positive ALL (hematologic CR
rate, 33%; major cytogenetic response rate, 57%; cytogenetic CR rate, 54%). However, the
median duration of a major cytogenetic response was 6.9 months. Considering this kinetics of
resistance, it is felt likely that dasatinib monotherapy is not sufficient as a first-line
treatment for Ph-positive ALL.

Allogeneic SCT clearly benefits certain high-risk patients, such as those with Ph-positive
ALL or those that show a poor initial response to chemotherapy, and long-term survival rates
with SCT are markedly increased when patients are in CR. Recent studies suggest that among
adults with ALL, transplantation from a matched unrelated donor could yield results similar
to those achieved by matched related donor transplantation. While unrelated donor
transplants are generally associated with more transplant-related complications than matched
sibling transplants, a compensatory decrease in relapse rates due to a strong
graft-versus-leukemia effect has narrowed the gap between the two approaches. In addition,
reduced-intensity conditioning allogeneic SCT is increasingly being used for patients who
are considered poor candidates for myeloablative conditioning SCT because of their advanced
age or other concurrent medical conditions. Two recent reports of patients undergoing a
transplant using related or unrelated donor and a reduced-intensity conditioning regimen
(fludarabine plus melphalan) showed an optimistic outcome in a group of patients with ALL
either at high risk during first CR or who were transplanted after achieving a subsequent
CR. Recently, we also demonstrated an evidence of positive role of reduced-intensity
conditioning SCT for the management of high-risk adult ALL who are ineligible for
myeloablative transplantation with low leukemic cell burden (especially in first CR) through
a prospective analysis (phase 2 study). From this point of view, the role of first-line
dasatinib plus conventional chemotherapy followed by allogeneic SCT should be clarified in
the era of targeted drugs.

Recently, the results of the phase 3 study in patients with chronic phase-chronic myeloid
leukemia suggest that dasatinib (100 mg q.d.) offers the most favorable overall benefit-risk
assessment. On the basis of these results, dasatinib will be administered orally at 100 mg
once a day in this study.

Induction regimen: "Modified Hyper-CVAD"

- Cyclophosphamide 300 mg/m2, IV for 2 hours, every 12 hours x 6 doses, days 1-3

- Vincristine 1.4 mg/m2/day (maximum 2 mg/day), IV for 30 minutes, days 4 & 11

- Daunorubicin 45 mg/m2/day, IV for 1 hour, days 4 & 11

- Dexamethasone 40 mg/day, IV push, days 1~4 & days 11-14

First consolidation regimen: "Cytarabine and Mitoxantrone"

- Cytarabine 2 g/m2, IV for 3 hours, every 12 hours x 10 doses, days 1-5

- Mitoxantrone 12 mg/m2/day, IV for 30 minutes, days 1-2

Second consolidation regimen: "Modified Hyper-CVAD"

- Cyclophosphamide 300 mg/m2, IV over 2 hours, every 12 hours x 6 doses, days 1-3

- Vincristine 1.4 mg/m2/day (maximum 2 mg/day), IV for 30 minutes, days 4 & 11

- Daunorubicin 45 mg/m2/day, IV for 1 hour, days 4 & 11

- Dexamethasone 40 mg/day, IV push, days 1-4 & days 11-14

Dose of chemotherapeutic drugs (except vincristine, dexamethasone, and etoposide) will be
reduced by 25% in patients aged between 50 and 59 years; and by 50% in patients 60 years or
older. During the consolidation phase, serious toxicities (more than or equal to grade 3
non-hematologic toxicities) will require subsequent dose reductions of 25% to 50% at the
attending physician's discretion.

Central nervous system prophylaxis will be performed by intrathecally administering triple
agents (methotrexate 12 mg, cytarabine 40 mg, and hydrocortisone 50 mg; 6 times in total).

After the completion of each induction and consolidation chemotherapy with recovery of
leukocyte and platelet counts, dasatinib will be given as an alternative manner (100 mg once
daily by mouth for 4 weeks).

Dasatinib dose adjustment will be performed according to the guidelines for managing
hematologic and nonhematologic adverse events during dasatinib treatment. Briefly,

1. Dose escalation will be permitted in patients with no hematologic CR (to 140 mg daily;
140 mg q.d. or 70 mg b.i.d.).

2. Dose reduction (to 80 mg daily; 80 mg q.d. or 40 mg b.i.d.) and interruption will be
permitted after dasatinib-related grades 3-4 hematologic toxicity or grades 2-4
nonhematologic toxicity .

Dasatinib will be administered until disease progression or intolerable toxicity, as
determined by the treating physician.

Patients with an HLA-matched or suitable donor will undergo allogeneic SCT.

Patients without a donor will undergo continuous consolidation (up to 4 courses) and
maintenance therapy (dasatinib 100 mg once daily for up to 2 years as long as the patients
remain in hematologic CR with stable MRD level).

The number of dasatinib plus conventional chemotherapy will be dependent on the speed of
coordination process (for transplants) or the patient's tolerability (for non-transplants).

SCT from an HLA-matched sibling or a suitably matched (less than or equal to 2-allele
mismatched) family or unrelated donor will be performed according to the policies of the
participating institutions. A preparative regimen will be started 7 days after the last day
of the dasatinib treatment.

No prophylactic dasatinib maintenance therapy is planned after SCT.