Clinical trial NCT00390793
Conditions: Acute Lymphoblastic Leukemia BCR-ABL1 Fusion Protein Expression Blast Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive Philadelphia Chromosome Positive Recurrent Acute Lymphoblastic Leukemia t(9;22)
Sponsor: M.D. Anderson Cancer Center
Start date: 2006-09-28; Completion date: 2024-02-02
Enrollment: 107 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase II trial studies how well combination chemotherapy and dasatinib works in treating participants with Philadelphia-positive or B-cell receptor-ABL positive acute lymphoblastic leukemia. Drugs used in chemotherapy, such as cyclophosphamide, vincristine, doxorubicin, dexamethasone, methotrexate, and cytarabine, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Dasatinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving chemotherapy in combination with dasatinib may work better in treating participants with Philadelphia-positive or BCR-ABL positive acute lymphoblastic leukemia.

Detailed description:
PRIMARY OBJECTIVES:

I. To evaluate the clinical efficacy (event-free survival) of an intensive short-term chemotherapy regimen (Hyper- cyclophosphamide, vincristine, doxorubicin, dexamethasone \[CVAD\] program) given in combination with the tyrosine kinase inhibitor dasatinib for Philadelphia (Ph)-positive and/or B-cell receptor BCR-ABL-positive acute lymphoblastic leukemia (ALL).

II. To evaluate other clinical efficacy (overall response rate and survival) and safety of an intensive short-term chemotherapy regimen (Hyper-CVAD program) given in combination with the tyrosine kinase inhibitor dasatinib for Philadelphia (Ph)-positive and/or BCR-ABL-positive acute lymphoblastic leukemia (ALL).

OUTLINE:

HYPER-CVAD THERAPY: Participants receive cyclophosphamide intravenously (IV) twice daily (BID) over 3 hours on days 1-3, vincristine IV over 30 minutes on days 4 and 11, and doxorubicin IV over 24-48 hours on day 4. Participants also receive dexamethasone orally (PO) or IV over 30 minutes on days 1-4 and 11-14, and dasatinib PO once daily (QD) on days 1-14 of course 1 and on days 1-21 for subsequent courses. Courses repeat every 21 days for up to 4 odd courses (1, 3, 5, and 7) in the absence of disease progression or unacceptable toxicity.

METHOTREXATE PLUS CYTARABINE: Participants receive methotrexate IV over 24 hours on day 1, dasatinib PO on days 1-21, and cytarabine IV BID over 2 hours on days 2 and 3. Courses repeat every 21 days for up to 4 even courses (2, 4, 6, and 8) in the absence of disease progression or unacceptable toxicity.

MAINTENANCE THERAPY: Participants receive vincristine IV over 30 minutes on day 1, prednisone PO on days 1-5, and dasatinib PO BID. Courses repeat every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity. During courses 6 and 13, participants may receive an additional course of hyper-CVAD therapy.

After completion of study treatment, participants are followed for up to 12 months.

Arms: arm 1: See detailed description in outline.
Interventions: intervention 1: Cyclophosphamide intervention 2: Cytarabine intervention 3: Dasatinib intervention 4: Dexamethasone intervention 5: Doxorubicin intervention 6: Methotrexate intervention 7: Prednisone intervention 8: Vincristine
Intervention descriptions: intervention 1: Given IV intervention 2: Given IV or IT intervention 3: Given PO intervention 4: Given IV or PO intervention 5: Given IV intervention 6: Given IV or IT intervention 7: Given PO intervention 8: Given IV

Protocol documents:
Prot_SAP_000.pdf: 
Protocol No. 2006-0478 
June 23, 2009 
 
PHASE II STUDY OF COMBINATION OF HYPER-CVAD AND DASATINIB IN 
PATIENTS WITH PHILADELPHIA (PH) CHROMOSOME POSITIVE AND/OR 
BCR-ABL POSITIVE ACUTE LYMPHOBLASTIC LEUKEMIA (ALL)  
BMS PROTOCOL NUMBER CA180095 
 
 
 
 Investigator: 
Farhad Ravandi, MD 
 Department of Leukemia,  
University of Texas – M D Anderson Cancer Center 
Address: Unit 428 
1515 Holcombe Boulevard 
Houston, Texas 77030 
Tel – 713-745-0394 
Fax – 713-745-4612 
E-mail – fravandi@mdanderson.org 
 
Date: 6/23/09 
 
 
 


Protocol No. 2006-0478 
June 23, 2009 
 
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TABLE OF CONTENTS 
PROTOCOL SUMMARY .................................................................... 3 
1. 
INTRODUCTION ................................................................ 98 
2.  
STUDY OBJECTIVES ................................................... 1614 
3. 
SELECTION OF PATIENTS .......................................... 1614 
4. 
TREATMENT OF SUBJECTS ....................................... 1716 
5. 
CONCOMITTANT MEDICATIONS ................................ 2422 
6. 
STUDY PROCEDURES ................................................. 2523 
7. 
EFFICACY AND SAFETY ASSESSMENTS ................. 2624 
8. 
STUDY DRUG(S) ........................................................... 2725 
9. 
ADVERSE EVENTS ...................................................... 3331 
10. 
STATISTICAL METHODOLOGY .................................. 3634 
11. 
REFERENCES…………………...………………………. 
35 
 
 


Protocol No. 2006-0478 
June 23, 2009 
 
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PROTOCOL SUMMARY 
 
 
Objectives: 
 
1. To evaluate the clinical efficacy (event-free survival) of an intensive short-term chemotherapy 
regimen (Hyper-CVAD program) given in combination with the tyrosine kinase inhibitor dasatinib 
for Philadelphia (Ph)-positive and/or BCR-ABL-positive acute lymphoblastic leukemia-ALL). 
 
2. To evaluate other clinical efficacy (overall response rate and survival) and safety of an 
intensive short-term chemotherapy regimen (Hyper-CVAD program) given in combination with the 
tyrosine kinase inhibitor dasatinib for Philadelphia (Ph)-positive and/or BCR-ABL-positive acute 
lymphoblastic leukemia-ALL). 
 
Rationale:  
 
At least 70% of children with ALL can be cured. Adult ALL has a worse outcome, with 
expected CR rates of around 75%, and long-term event-free survival (EFS) rates ranging 
from 20% to 35%.The outcomeof patients with newly diagnosed Ph-positive ALL treated at 
MD Anderson Cancer Center who were treated with hyper-CVAD alone was recently 
reviewed. The CR rate was 90% with no induction deaths observed. The median survival was 
16 months, and median CR duration (CRD) was 10 months. When compared to VAD or other 
conventional chemotherapy programs,  hyper-CVAD was clearly superior in terms of CR rate 
(90% vs 55%, p=.002), failure rate (10% vs 37%, p=.014), and median disease-free survival 
(42 vs 29 weeks, p=.008). However, the event-free survival (EFS) rate was 14% and the 3-
year survival and DFS rates were both less than 10%. Combination of hyper-CVAD with the 
tyrosine kinase inhibitor, imatinib mesylate, in Ph+-ALL has been evaluated and appears to 
be highly effective. Dasatinib (BMS-354825) is a potent, broad spectrum ATP-competitive 
inhibitor of several tyrosine kinases including BCR-ABL and SRC. Dasatinib is ~500-fold 
more potent than imatinib in inhibiting BCR-ABL by binding to both active and inactive 
conformations of c-ABL, whereas imatinib only binds to the inactive state. In in vitro studies, 
dasatinib demonstrated curative efficacy against several advanced human CML xenografts in 
severe combined immunodeficiency (SCID) mice, including an imatinib “acquired-resistance” 
model completely insensitive to imatinib. Furthermore, early clinical studies of dasatinib have 
demonstrated its high activity and limited toxicity in treating patients with Ph+-leukemias 
including patients with refractory Ph+-ALL. As such, it is expected that combinations of 
chemotherapy regimens used to treat patients with ALL and dasatinib are likely to be 
associated with better response rates and higher likelihood of eradication of minimal residual 
leukemia than those reported with imatinib.  
 
Eligibility:  
 
Inclusion: 
 
1. Diagnosis of one of the following: 
 


Protocol No. 2006-0478 
June 23, 2009 
 
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I - Previously untreated Ph-positive ALL [either t(9;22) and/or bcr-abl positive] (includes patients 
initiated on first course of hyper-CVAD before cytogenetics known) 
 
II - After 1-2 courses of chemotherapy with or without imatinib mesylate (Gleevec) 
 
If they achieved CR, they are assessable only for event-free and overall survival, 
or 
 
If they failed to achieve CR, they are assessable for CR, event-free, and overall 
survival 
 
III – Patients with relapsed Ph-positive ALL [either t(9;22) and/or bcr-abl positive] or lymphoid 
blast phase of chronic myeloid leukemia failing any therapy other than dasatinib. 
 
These groups will be analyzed separately. 
 
 
2. Age  18 years.  
 
3. Zubrod performance status  2 (ECOG Scale, Appendix G). 
 
4. Adequate liver function (bilirubin  3.0 mg/dl, unless considered due to tumor), and renal 
function (creatinine  3.0 mg/dl, unless considered due to tumor). 
 
5. Adequate cardiac function as assessed clinically. 
 
6. Signed informed consent  
 
 
Exclusion: 
 
1. An active serious infection not controlled by oral or intravenous antibiotics.  
 
2. Treatment with any investigational antileukemic agents or chemotherapy agents in the 
last 7 days before study entry, unless full recovery from side effects has occurred or 
patient has rapidly progressive disease judged to be life-threatening by the investigator. 
 
3. Active secondary malignancy other than skin cancer (e.g., basal cell carcinoma or 
squamous cell carcinoma) that in the investigator’s opinion will shorten survival to less 
than 1 year. 
 
4. Active Grade III-V cardiac failure as defined by the New York Heart Association Criteria 
(Appendix H).  
Uncontrolled angina, or MI within 6 months 
Diagnosed or suspected congenital long QT syndrome 
Any history of clinically significant ventricular arrhythmias (such as ventricular 
tachycardia, ventricular fibrillation, or Torsades de pointes) 
Prolonged QTc interval on pre-entry electrocardiogram (> 470 msec) unless corrected 
after electrolyte replacement 
Patients currently taking drugs that are generally accepted to have a risk of causing 
Torsades de Pointes (unless these can be changed to acceptable alternatives)  
 
5. Prior history of treatment with dasatinib. 


Protocol No. 2006-0478 
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6. Pregnant and lactating women will not be eligible; women of childbearing potential should 
have a negative pregnancy test prior to entering on the study and be willing to practice 
methods of contraception. Women do not have childbearing potential if they have had a 
hysterectomy or are postmenopausal without menses for 12 months. In addition, men 
enrolled on this study should understand the risks to any sexual partner of childbearing 
potential and should practice an effective method of birth control. 
 
7. History of significant bleeding disorder unrelated to cancer, including: 
 
Diagnosed congenital bleeding disorders (e.g., von Willebrand’s disease) 
 
Diagnosed acquired bleeding disorder within one year (e.g., acquired anti-factor VIII 
antibodies) 
 
8.  Patients with documented significant pleural or pericardial effusions unless they are 
 
thought to be secondary to their leukemia 
 
 
Treatment/Study Plan: 
 
Hyper-CVAD plus dasatinib [Odd courses 1, 3, 5, 7]: 
Cyclophosphamide (CTX) 300 mg/m2 IV over 3 h every 12 hrs x 6 doses days 1,2,3 (total 
dose 1800 mg/m2). 
MESNA 600 mg/m2/d IV continuous infusion daily for 24 hrs, starting approximately 1 hour 
prior to CTX and completing by approximately 12 hrs after the last dose of CTX.  
Doxorubicin 50 mg/m2 IV over 24 hrs via central venous catheter on day 4 after last dose of 
CTX given (infuse over 48 hrs in patients with reduced ejection fractions < 50%). May be 
given by shorter infusion if difficulty with central venous access.  
Vincristine 2 mg IV on day 4 plus/minus 2 days and day 11 plus/minus 2 days.  
Dexamethasone 40 mg IV or p.o. daily on days 1-4 plus/minus 2 days and days 11-14 
plus/minus 2 days. 
Dasatinib 100 mg po daily days 1-14 for course 1 (may shift  +/- 4-5 days if therapy changed 
once results of cytogenetics known). For subsequent courses 3, 5, and 7 dasatinib 70 mg po 
daily continuously without interruptions unless due to toxicity. 
GCSF 10 mcg /kg (rounded) subcutaneously daily (or 5 mcg /kg twice daily) until post-nadir 
granulocytes > 1.0 x 109/L.  
For patients with CD20 expression (≥ 20% by flow cytometry) Rituximab 375 mg/m2 on days 
1 and 11 of cycles 1 and 3. 
CNS prophylaxis: Methotrexate 12 mg intrathecally (6 mg via Ommaya reservoir) on day 2 
plus/minus 2 days. Cytarabine 100 mg intrathecally on day 7 plus/minus 2 days.  
 
High-dose Methotrexate and cytarabine plus dasatinib [Even courses 2,4, 6, and 8]: 
Methotrexate (MTX) 200 mg/m2 IV over 2 hrs followed by 800 mg/m2 over 22 hrs on day 1. 
Solumedrol 50 mg IV approximately every 12 hrs for 6 doses days 1 to 3. 
Dasatinib 70 mg po daily continuously without interruptions unless due to toxicity in courses 
2, 4, 6, and 8. 
Cytarabine 3 g/m2 IV over 2 hrs every 12 hrs for 4 doses on days 2,3. 
Reduce to 1 g/m2 IV over 2 hrs every 12 hrs for 4 doses on days 2 and 3 for:  


Protocol No. 2006-0478 
June 23, 2009 
 
6 
Neurotoxicity  
Age 60 years or greater. 
Creatinine greater than or equal to 1.5 mg/dL. 
Citrovorum rescue 50 mg IV or PO followed by 15 mg IV every 6 hours for 8 doses beginning 
12 hrs  +/- 2 hrs post MTX completion, i.e. approximately 36 hours from start of MTX. 
GCSF 10 mcg/kg (rounded) subcutaneously daily (or 5 mcg /kg twice daily) until post-nadir 
granulocytes greater than or equal to 1.0 x 109/L.  
For patients with CD20 expression (≥ 20% by flow cytometry) Rituximab 375 mg/m2 on days 
1 and 8 of cycles 2 and 4. 
CNS prophylaxis: Methotrexate 12 mg intrathecally (6 mg via Ommaya reservoir) day 2 
plus/minus 2 days. Cytarabine 100 mg intrathecally day 7 plus/minus 2 days.  
 
Maintenance, Intensifications, and Post-Remission Therapy 
Maintenance therapy with dasatinib plus vincristine and steroids. 
Maintenance chemotherapy with vincristine, and prednisone for approximately 24 months 
beginning at level 0 or lower dose level if prior toxicity required dose reduction of agents 
(titrate to keep ANC > 0.5 x 109/L and platelet count ≥ 30 x 109/L): 
Vincristine 2 mg IV day 1 approximately every 28 days 
Prednisone 200 mg P.O. daily days 1 to 5 approximately every 28 days with vincristine 
dasatinib 100 mg po daily as tolerated. 
 
lntensifications interrupting maintenance phase as follows: 
1. Two intensifications with one course of hyper-CVAD plus dasatinib 100 mg po daily on 
days 1-14 or 70 mg po every day depending on tolerance, months 6 and 13 of maintenance.  
2. Intensifications may be eliminated if the bone marrow PCR for bcr-abl is negative, or prior 
toxicity with intensive chemotherapy prohibits administration, or for other reasons judged 
valid by the Principal Investigator. 
3. Dasatinib may be continued indefinitely after the 24 months of therapy at a dose tolerated 
by the patient. 
4. For patients with CD20 expression (≥ 20% by flow cytometry) Rituximab 375 mg/m2 on 
days 1 and 11 of the intensification cycles in months 6 and 13. If patients do not receive the 
intensification cycles (due to reasons specified in 2. above), they may receive Rituximab 
alone 375 mg/m2 on days 1 and 11 of maintenance cycle in months 6 and 13. 
 
Disease Group: Leukemia 
 
 
Treatment Agent: Adriamycin, Cyclophosphamide, Cytarabine, Dasatinib, Dexamethasone, 
Methotrexate, Vincristine, Prednisone, and Sulumedrol 
 
 
Statistical Considerations: 
 
1. The major study objective is to evaluate the event-free survival after hyper-CVAD plus 
dasatinib and achieve a 2-year EFS rate > 60% (based on reported data from hyperCVAD plus 
imatinib)21. The study is expected to accrue 115 patients (previously untreated, or after having 
received one or two prior course of chemotherapy, or relapsed) over approximately 2 years 
(referral pattern of 15 to 20 patients/year, accrual completed in 12 to 24 months), with an 
additional 12 months of follow-up. This will allow estimates of CR rates and disease-free 
survivals. Disease-free survival is the time from documented CR until relapse or death. Event-free 


Protocol No. 2006-0478 
June 23, 2009 
 
7 
survival is the time from treatment until any failure (resistant disease, relapse, or death). The 
results will be compared descriptively to historical controls in terms of response, survival, toxicity, 
etc. (recently published data). A 95% confidence interval width will be approximately 11% for the 
CR rate estimated with 115 patients. 
 
2. It is expected that the addition of dasatinib will achieve an efficacy superior to that obtained 
with the hyper-CVAD program alone and superior to hyper-CVAD plus imatinib mesylate. The trial 
will be monitored for possible early termination if there is evidence that the rate of response is not 
at least equivalent to that observed on the previous hyper-CVAD trial (26 CR of 29 patients). 
Observation of the following number of responses or fewer per number of patients evaluated will 
be regarded as evidence for termination: 2/5, 6/10, 10/15, 14/20, 18/25, 21/30, 25/35, 29/40, 
33/45, 37/50, 41/55, 45/60, 49/65, 53/70, 57/75, 61/80, 65/85, 69/90,73/95,77/100,81/105, 
85/110, or 89/115 on the basis that there is < 5% probability that efficacy is superior to that of 
hyper-CVAD. Using these guidelines, simulation results indicate the following expected results for 
several values of CR rate:  
 
True rate of CR 
Probability of early termination 
recommendation 
Expected median sample size 
(25%, 75%) 
0.6 
>0.99 
5 (5, 10) 
0.7 
0.98 
15 (10, 35) 
0.8 
0.50 
110 (20,115) 
0.85 
0.16 
115 (115, 115)  
0.9 
0.03 
115 (115, 115) 
0.95 
0.01 
115 (115, 115) 
 
 
The molecular CR rate with hyper-CVAD is not known. Quantification of bcr-abl will be measured 
prospectively and analyzed by descriptive statistics. 
 
3. Hyper-CVAD alone has very low toxicity (<5%). In this combination trial, if the toxicity rate is 
too high (Pr[Toxicity rate > 5%|Data] > 0.9), then the trial will be stopped (toxicity is defined at the 
beginning of this section). Specifically, the trial will be stopped if the number of patients 
experiencing unacceptable (as defined in section 9.0) toxicities /total number of patients is greater 
than or equal to 2/5, 3/12, 4/24, 5/37, 6/51, 7/65, 8/79, 9/100, or 10/109. The probability to stop 
the trial early is 0.02, 0.12, 0.73, 0.98 or >0.99 when the true toxicity rate is 0.03, 0.05, 0.10, 0.15 
or 0.20 respectively. 
 
4. A separate analysis will be carried out for previously treated patients (who have received one 
or two prior course of therapy). The historical number of Philadelphia-positive patients presenting 
after failure of one course of chemotherapy is one of 204 patients (< 1%). The historical rate of 
patients who achieved a CR after one course of chemotherapy continuing on hyper-CVAD at 
MDACC is 4 of 208 patients (2%). None were Ph-positive. Thus, the expected number of patients 
in this category is expected to be small. Patients who have failed one course of non-hyper-CVAD 
chemotherapy will be assessed for CR rate (historical CR rate for ALL overall is 5 of 6 [83%]) and 
disease-free survival.  Patients presenting in CR will be assessed for disease-free survival and 
toxicity only. 
 
5. A separate analysis will also be carried out for patients with relapsed disease, i.e. those with 
Ph-positive ALL or lymphoid blast phase of chronic myeloid leukemia who have failed (after 
achieving an initial response) prior therapy which does not include dasatinib. It is expected that 


Protocol No. 2006-0478 
June 23, 2009 
 
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40 patients will be enrolled in this category alone. Patients will be evaluated for response, toxicity, 
event-free survival and disease-free survival. 
 
6. Despite best efforts, the expected rate of allogeneic transplant is at best 20%, with failure due 
to lack of a suitable donor, age or performance status characteristics, comorbid conditions, or 
relapse of their disease prior to planned transplant. Patients who successfully undergo allogeneic 
transplant will be censored for disease-free survival at the time of transplant. Those patients who 
successfully complete allogeneic transplant prior to completion of the program will be replaced. 


Protocol No. 2006-0478 
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1. 
INTRODUCTION 
1.0 BACKGROUND 
 
1.1 Acute Lymphoblastic Leukemia (ALL) 
 
Significant improvements in outcome for childhood acute lymphoblastic leukemia (ALL) have 
been observed, with complete response (CR) rates exceeding 90% with modern chemotherapy 
regimens.1,2 At least 70% of children with ALL can be cured. Adult ALL has a worse outcome, 
with expected CR rates of around 75%, and long-term event-free survival (EFS) rates ranging 
from 20% to 35%.3-7 Prognosis is influenced by age, performance status, organ function, white 
blood cell count, ALL phenotype (CALLA, T-cell, B-cell, Burkitt's or Burkitt's-like), karyotype [t(1; 
19), t(4; 11), Philadelphia (Ph) chromosome], and time to achieve CR. 
 
TABLE I. OUTCOME OF ALL PATIENTS BY RISK CATEGORY 
Risk Category 
% patients  
% Event free survival 
Standard (good) 
25 
50-60 
Poor (WBC ≥ 5 x 109/L,  
≥ 1 course therapy until CR) 
75 
 20 
Ph (+) 
15 
 10 
 
Kantarjian et al reported the overall results of hyper-CVAD in adult ALL,8,9 with the subsets of 
Burkitt's type ALL and lymphoblastic lymphoma (LL) being detailed separately.10,11 The outcome 
in both these subtypes has been significantly improved with CR rates of 81% and 96% in Burkitt's 
and LL, respectively. Overall survival for the LL group was improved to 75% at 3 years, with two-
thirds of the patients remaining disease-free at 3 years compared to previously employed 
standard ALL regimens.11 
 
Overall, the group had a median age of 40 years (range 15-90 years); 20% of the patients were 
aged 60 or older.9 The majority of patients were considered high-risk for systemic relapse (74%) 
or CNS relapse (55%). Compared to the VAD (vincristine, doxorubicin, dexamethasone) program 
(DM85-43, DM88-015, DM88-150, DM89-123), the outcome with hyper-CVAD was significantly 
improved with respect to CR rate and overall survival.8,9 
 
The overall CR rate with hyper-CVAD for all subtypes of ALL (n=288) was 92% with an induction 
mortality of 5% (all due to infections). Eleven percent of the patients required 2 courses to 
achieve CR; only 3% of the patients failed to achieve a remission with persistence of the 
leukemia. Leukocytosis and karyotypic abnormalities were not prognostic for achieving CR with 
the hyper-CVAD. Patients with poor performance status, hypoalbuminemia, hyperbilirubinemia 
and hepatomegaly had lower CR rates (in the range of 68% to 82%)mostly because of high 
induction mortality rate.9 Side effects were similar to those reported in the recent update of the 
hyper-CVAD program in Burkitt's type ALL.9,10 
 
Multivariate analysis identified the following factors to be adverse independent factors for CR 
duration (P < 0.05): age 
45 years; leukocytosis 
50 × 109/L; poor performance (ECOG score of 
3-4); Ph-positive disease; FAB L2 morphology; > 1 course to CR; and bone marrow blasts > 5% 


Protocol No. 2006-0478 
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on Day 14. Central nervous system relapse was low, with a 7% incidence in low-risk patients 
(given 4 prophylactic intrathecal [IT] treatments), 1% in high-risk patients (I6 prophylactic ITs), 
and 6% in patients with unknown CNS relapse risk (8 prophylactic ITs).9 The 5-year continuous 
CR rate was 35% with a 5-year survival of 36%. On multivariate analysis, pre-treatment factors 
associated with a shorter survival included older age, poor performance status, presence of 
hepatomegaly, high leukocyte count ( 50 x 109/L), low platelet count, and presence of Ph+ 
disease. When compared to other published standard regimens of MSKCC,5 SWOG,6 Hoelzer et 
al,4 and Larson et al,7 the outcome was comparable even though the MDACC patients were older 
and prognostically less favorable. 
 
1.2 Hyper-CVAD in Ph-positive ALL 
 
The outcome with hyper-CVAD in newly diagnosed Ph-positive ALL was recently reviewed by 
Faderl et al.12 Twenty-nine patients were treated with the regimen 
from 1992 to 1997. Their median age was 41, and median leukocyte count was 23 x 109/L. The 
CR rate was 90% with no induction deaths observed. The median survival was 16 months, and 
median remission duration (CRD) was 10 months. When compared to VAD [n=32] (or other 
conventional chemotherapy programs, n=6), the hyper-CVAD was clearly superior in terms of CR 
rate (90% vs 55%, p=.002), failure rate (10% vs 37%, p=.014), and median disease-free survival 
(42 vs 29 weeks, p=.008). The event-free survival (EFS) rate was 14%. Despite improvements in 
CR rate and median CRD compared to earlier and other published conventional ALL programs, 
the 3-year survival and DFS rates were both less than 10%. 
 
1.3 Single Agent lmatinib Mesylate in Chronic Myelogenous Leukemia and Ph-positive ALL 
 
lmatinib mesylate is an inhibitor of a number of protein-tyrosine kinases including Bcr-Abl, the 
platelet-derived growth factor (PDGF) receptor and c-Kit, but not of other members of the Type Ill 
receptor kinase family, such as Flt-3 and Fms. Chronic myeloid leukemia (CML) represents an 
ideal disease for therapy with lmatinib mesylate given that the Bcr-Abl kinase plays a dominant 
role in the deregulated myeloid cell proliferation which is the hallmark of this disease. Inhibition of 
the Bcr-Abl kinase is most likely to have anti-leukemic effects during the chronic phase of CML 
since additional chromosomal abnormalities may drive the malignant process during accelerated 
phase and blast crisis. However, activity has already been observed during these later phases of 
the disease.  
 
lmatinib mesylate shows selectivity for the Abl protein-tyrosine kinase at the in vitro, cellular and 
in vivo level.13 The compound specifically inhibits proliferation of Bcr-Abl expressing cells. In 
colony forming assays using ex vivo peripheral blood and bone marrow samples, imatinib 
mesylate shows selective inhibition of Bcr-Abl positive colonies from CML patients13 and ALL 
patients.14 Beran et al also demonstrated significant suppression of phosphorylation of p190bcr-
abl.14 In animal models, the compound shows potent anti-tumor activity against Bcr-Abl and v-Abl 
expressing cells at tolerated doses.15 
 
Multiple studies have demonstrated the efficacy and safety of Imatinib mesylate in the treatment 
of all phases of chronic myeloid leukemia and have established it as the therapy of choice in this 
disease.16-19 
 
Although the single agent response rate with imatinib mesylate in relapsed or 
refractory Ph+ALL is encouraging, ongoing maintained responses (after short follow-up) were 
observed in only a small number of patients treated by Ottmann et al.20 They treated 56 patients 
with relapsed or refractory Ph(+) acute lymphoblastic leukemia (ALL; 48 patients) or chronic 


Protocol No. 2006-0478 
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myelogenous leukemia in lymphoid blast crisis (LyBC; 8 patients). Imatinib was given once daily 
at 400 mg or 600 mg. Imatinib induced complete hematologic responses (CHRs) and complete 
marrow responses (marrow-CRs) in 29% of ALL patients (CHR, 19%; marrow-CR, 10%), which 
were sustained for at least 4 weeks in 6% of patients. Median estimated time to progression and 
overall survival for ALL patients were 2.2 and 4.9 months, respectively. CHRs were reported for 3 
(38%) of the patients with LyBC (one sustained CHR). Grade 3 or 4 treatment-related 
nonhematologic toxicity was reported for 9% of patients; none of the patients discontinued 
therapy because of nonhematologic adverse reactions. Grade 4 neutropenia and 
thrombocytopenia occurred in 54% and 27% of patients, respectively. Imatinib therapy resulted in 
a clinically relevant hematologic response rate in relapsed or refractory Ph(+) acute lymphoid 
leukemia patients, but development of resistance and subsequent disease progression were 
rapid.20 
 
Several investigators have conducted in vitro assays to determine the effects of imatinib mesylate 
in combination with various antileukemic agents such as interferon-alpha, hydroxyurea, 
daunorubicin, and cytarabine. The combination of imatinib mesylate was additive or synergistic 
with interferon-alpha, daunorubicin, and cytarabine. Therefore, strategies such as combination 
imatinib with an effective ALL regimen such as hyper-CVAD have been evaluated.21,22 
 
1.4 HyperCVAD plus tyrosine kinase inhibitors 
 
Thomas et al have reported on the results of a phase II clinical trial of concurrent hyper-CVAD 
and imatinib to improve the above results of combination chemotherapy. The initial regimen of 
imatinib 400 mg orally daily days 1-14 of each course (fractionated cyclophosphamide, vincristine 
[VCR], doxorubicin and dexamethasone alternating with high dose methotrexate and cytarabine) 
was followed by imatinib, VCR and prednisone maintenance with intensifications months 6 and 
13. Allogeneic stem cell transplant (SCT) was performed in CR if feasible. Preliminary results of 
first 20 patients treated were encouraging.21 Recent modifications included increasing the dose of 
imatinib to 600 mg daily days 1-14 of course 1, then daily if tolerated with courses 2-8. 
Maintenance was extended to 24 months with imatinib indefinitely. At the time of the report, 43 
patients with Ph+ ALL had been treated from April 2004 to July 2005. Thirty-six patients had 
active disease, either untreated (n=31) or refractory (n=5) to one induction course without 
imatinib; 7 patients were in CR after one induction course without imatinib. Of 35 evaluable 
patients, 33 (94%) achieved CR (1 induction death, 1 failed to meet platelet criteria for CR). 
Median time to response was 21 days. 13 patients underwent allogeneic SCT within a median of 
3 months from start of therapy (range, 1-12). After a median follow-up of 3 years (range 1-48 
months), 1 primary refractory patient relapsed at 12 months, 1 de novo patient had isolated CNS 
relapse, 2 patients relapsed after allogeneic SCT (no post SCT imatinib) and 2 patients changed 
therapy for persistent Ph+ metaphases (1 relapsing). Deaths in CR included 5 older patients 
without allogeneic SCT (1 osteomyelitis, 1 mucormycosis, 1 C. difficile colitis, 1 sudden death, 1 
GNR sepsis) and 4 patients after allogeneic SCT (3 graft-versus-host disease, 1 GNR sepsis). 
Outcome with the hyper-CVAD and imatinib regimen continues to demonstrate favorable disease-
free survival rates compared with hyper-CVAD alone, particularly for the de novo group. Use of 
higher dose imatinib concurrently appears to be feasible. Molecular response rates appear to be 
improved with the higher dose imatinib. 
 
Dasatinib (BMS-354825) is a potent, broad spectrum ATP-competitive inhibitor of several tyrosine 
kinases including BCR-ABL and SRC. Dasatinib is ~260fold more potent than imatinib in 
inhibiting BCR-ABL by binding to both active and inactive conformations of c-ABL, whereas 
imatinib only binds to the inactive state. In in vitro studies, dasatinib demonstrated curative 
efficacy against several advanced human CML xenografts in severe combined immunodeficiency 


Protocol No. 2006-0478 
June 23, 2009 
 
12 
(SCID) mice, including an imatinib “acquired-resistance” model completely insensitive to imatinib. 
Furthermore, early clinical studies of dasatinib have demonstrated its high activity and limited 
toxicity in treating patients with Ph+-leukemias including patients with refractory Ph+-ALL. As 
such, it is expected that combinations of chemotherapy regimens used to treat patients with ALL 
and dasatinib are likely to be associated with better response rates and higher likelihood of 
eradication of minimal residual leukemia than those reported with imatinib. 
 
In a recently reported study (ASH 2005), a total of 78 patients with either Ph+ ALL (n=36) or CML 
in lymphoid blast phase (n=42) were treated with dasatinib. An overall hematological response 
rate of 73% including a complete hematological response rate of 52% was reported (31% in Ph+ 
ALL and 21% in CML lymphoid blast phase). Another 18% had no evidence of leukemia but with 
inadequate count recovery for a response. Complete cytogenetic responses were noted in 21 
(58%) of Ph+ ALL patients and 15 (43%) of patients with CML in lymphoid blast phase. 
Therefore, dasatinib appears to be highly active in this setting and merits further investigation in 
combination with standard chemotherapy. 
1.5   Summary of Results of Investigational Program for Dasatinib 
Dasatinib has been administered to over 2000 subjects; the majority with CML refractory or 
intolerant to imatinib.  Other target populations studied include Ph+ ALL and metastatic solid 
tumors. Additional background information on preclinical pharmacology, toxicology and 
pharmacokinetics may be found in the Investigator Brochure.38 
1.5.1 Preclinical Anti-tumor Activity 
1.5.1.1 In Vitro Molecular Studies 
Dasatinib competes with ATP for the ATP-binding site in the kinase domain of selected protein 
tyrosine kinases (PTKs) and has been shown to inhibit at least five protein tyrosine 
kinases/kinase families: SRC family kinases, BCR-ABL, c-KIT, EPHA2 and the PDGF receptor. 
Dasatinib is much more potent than imatinib mesylate. 
1.5.1.2. Cellular Studies 
Dasatinib inhibits the BCR-ABL kinase with an in vitro IC50 of 3 nM, a potency that was 260-fold 
greater than that of imatinib mesylate (IC50 = 790 nM). In cellular assays, dasatinib killed or 
inhibited the proliferation of all BCR-ABL dependent leukemic cell lines tested to date. Dasatinib 
also demonstrated undiminished antitumor activity against several preclinically- and clinically-
derived models of imatinib mesylate resistance. Evidence that SRC family kinase over expression 
may play a role in clinical resistance to imatinib mesylate was demonstrated in three CML cell 
lines established from patients who failed imatinib mesylate therapy. These cells remained highly 
sensitive to the cell-killing effects of dasatinib.38 
These results demonstrate that dasatinib is effective in reducing the proliferation or survival of 
both imatinib mesylate-sensitive and resistant cells, and its inhibitory activity is not solely 
dependent on BCR-ABL. 


Protocol No. 2006-0478 
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13 
1.5.2. In Vivo Studies 
The activity of dasatinib against CML cells in vitro was reproduced in vivo against several human 
CML xenograft models grown subcutaneously in SCID mice. Against the K562/imatinib 
mesylate/R CML model, dasatinib was curative in 100% of the treated animals. In contrast, at its 
optimal dose and schedule, imatinib mesylate was inactive. 
1.5.2.1.  Preclinical Toxicology 
Single or repeated oral administration of dasatinib principally affected the gastro-intestinal (GI) 
tract, including the liver, the hematopoietic and lymphoid systems in rats and monkeys. Other 
prominent effects after single oral administration of dasatinib included renal and cardiac toxicity in 
rats at lethal doses, and cutaneous hemorrhage in monkeys. Dasatinib can also affect the 
immune system and bone turnover. 
Dasatinib in vitro activity in the HERG/IKr and Purkinje-fiber assays indicated a moderate liability 
for prolongation of cardiac ventricular repolarization (QT interval) in the clinic. However, there 
were no dasatinib-related changes observed in electrocardiograms, nervous system function, 
respirations and heart rate, blood pressure, or arterial oxygen saturation in single-dose, 10-day, 
or 1-month oral toxicity studies in monkeys. 
Dasatinib was found to exhibit a profile of broad-spectrum platelet inhibition best typified by anti-
platelet agents such as the GPIIb/IIIa antagonists, integrelin and abciximab. 
Finally, modulation of SRC kinase activity could also affect osteoclast morphology and function 
and bone remodeling. This effect could potentially result in an increase in bone mineral density 
and a phenotype analogous to osteopetrosis.38 
 1.5.2.2. Clinical Pharmacokinetics 
The pharmacokinetics of oral dasatinib have been extensively studied in normal volunteers and in 
subjects with leukemia. Studies in subjects with solid tumors are currently in progress.  
After an oral dose of 70 mg, the recommended dose in recurrent CML, a peak level of 50 – 60 
ng/mL is attained at 1 – 1.5 hours followed by an mean plasma half-life of 4 – 5 hours. Good 
bioavailability of the clinical tablet formulation has been documented. No accumulation has been 
observed in any schedule. Dose proportionality was documented over the entire dose range from 
15 – 240 mg/day, although substantial interpatient variability has been observed. No significant 
effect of age, gender, race or disease state has been detected. No clinically-significant food effect 
was found, but antacid treatment markedly reduced exposure. Plasma protein binding has been 
estimated at 96% based on in vitro studies, and distributes freely into red blood cells 
(blood:plasma ratio ~1.8); estimated volume of distribution is approximately 9-fold greater than 
total body water.  
Metabolism is primarily via CYP3A4, followed by biliary excretion; renal excretion is minimal. 
Clinically-significant increases in dasatinib exposure were observed with concomitant 
ketoconazole (a CYP3A4 inhibitor) and decreases with concomitant rifampicin (a CYP3A4 
inducer). For additional detail, see the Investigator Brochure, Appendix I. 


Protocol No. 2006-0478 
June 23, 2009 
 
14 
1.5.3.  Experience in CML 
Clinical experience with dasatinib in chronic phase (CP) CML is considered more applicable to 
patients with solid tumors than that in advanced-phase CML or Ph+ ALL, and will be summarized 
briefly. 
One phase I study in CML, which included 40 subjects with progressive CP CML, was open for 
accrual from November, 2003, to April, 2005. Two Phase II studies in subjects with imatinib-
resistant or –intolerant CP CML were open from February to July, 2005 (CA180013; n=424) and 
February to September, 2005 (CA180017; n=150). A Phase III randomized study in CP CML 
(CA180034; n=670) was open for accrual from July, 2005 to March, 2006.  
In addition, over 1,000 subjects with recurrent advanced-phase CML or Ph+ ALL have been 
studied in Phase I (CA180002, n=44), Phase II (CA180005, CA180006, and CA180015, n=420), 
and Phase III (CA180035, n=613).39,40,41,42,43,44 
Myelosuppression is part of the natural history of most hematologic malignancies and is also a 
common side effect of most chemotherapeutic agents. Thus, the level of hematologic toxicity 
observed may partly be the result of the underlying leukemic diagnosis and the extensive prior 
therapies in these patient populations. 
Subsequently, two randomized phase III studies were launched (CA1800034 and CA1800035) to 
compare efficacy and safety of QD vs BID schedules in all phases of CML and of different daily 
dose in chronic phase CML. These studies have closed to accrual. 
Two Phase I trials are in progress in patients with recurrent or progressive solid tumors, one with 
a BID and one with a QD schedule. To date, the safety profile in solid tumor subjects has been 
similar to that in CP CML subjects with the exception that myelosuppression (attributable to 
suppression of the Bcr-Abl-driven clone) has not been observed in solid tumor patients. No MTD 
has been reached in these studies. 
1.5.4. Overall Risk/Benefit Assessment 
The most common side effects of dasatinib are skin rash, fluid retention including pleural effusion, 
headache, fever, fatigue or weakness, gastrointestinal symptoms including bloating or flatulence, 
diarrhea or nausea, and discomfort in muscles or joints. Less common side effects include 
pneumonitis, constipation or abdominal pain, hypocalcemia, shortness of breath, neurologic 
changes such as tingling, confusion or dizziness. Minimal myelosuppression has been observed 
in subjects with solid tumors treated with dasatinib. 
1.5.5.  Phase II Experience 
Subjects with AP CML, MyBP CML and LyBP CML or Ph+ ALL were enrolled in three Phase II 
studies using a dose of 70 mg BID. These studies are closed to enrollment. Data from 35 
subjects on the START-A Study for Accelerated Phase CML have been reported.38 Most patients 
were extensively treated with imatinib. Cytogenetic responses were documented in 13/24 
patients, including 4 complete and 2 partial responses. Molecular response data is not yet 
available. Profound myelosuppression (Grade 4 thrombocytopenia and Grade 4 neutropenia) 
were reported in 20 and 17 patients respectively. Non-hematologic toxicities included diarrhea 


Protocol No. 2006-0478 
June 23, 2009 
 
15 
(10 patients), nausea (5 patients), headache (5 patients), peripheral edema (3 patients) and 
pleural effusion (2 patients) all Grade 1 or 2.  
Data from the first 34 patients from the START-B Study for CML, Myeloid Blast Crisis have been 
reported.38  Major hematologic responses were seen in 16/29 (55%) of patients, with 7 complete 
hematologic responses and 9 with no evidence of leukemia. Cytogenetic responses were seen in 
13 (45%) [21% complete, 12% partial). Molecular response data is not yet available. Grade 4 
neutropenia occurred in 59% and grade 4 thrombocytopenia occurred in 56% of patients. Other 
non hematologic toxicity, usually Grade 1-2, included diarrhea (8 pts), rash (4 pts), nausea (3pts), 
peripheral edema (3pts) and pleural effusion (4 pts). 
Data from the first 28 (13 CML-LBC and 13 Ph+ ALL) patients accrued to the START-L Study for 
CML Lymphoid Blast Crisis or Ph+ ALL have been reported.38  Seventy seven patients were 
enrolled to the study. Thirteen patients had a MHR (7 CHR and 6 no evidence of leukemia). 
Twelve (12) patients had a cytogenetic response within 1-3 months (11 complete, 1 minor). The 
majority of patients had Grade 3 or 4 myelosuppression, in some cases pre-existing to study 
participation. Grade 4 hematologic toxicities include neutropenia (64%) and thrombocytopenia 
(71%), Non-hematologic toxicity included Grade 1-2 peripheral edema (3 pts), Grade 1 facial 
edema (2 pts), GI intolerance was infrequent. 
More recent trials have demonstrated that once daily dosing is associated with a lower toxicity 
and similar efficacy.45 
 
1.5.6 CD20 expression and rituximab 
 
Immunophenotypic classification of acute lymphoblastic leukemia (ALL) has well recognized 
prognostic implications. The significance of CD20 expression has been evaluated in childhood 
precursor B-lineage ALL with conflicting results. In a recently published report, our group  
retrospectively analyzed the influence of CD20 expression on outcome in 253 adults with de novo 
precursor B-lineage ALL treated with either conventional (VAD/CVAD) or intensive (hyper-CVAD) 
frontline regimens in the pre-rituximab era. Overall, CD20 positivity > 20% was associated with 
lower 3-year rates of complete remission duration (CRD) (20% vs 55%, p<.001) and overall 
survival (OS) (27% vs 40%, p=.03). In the CD20 negative subset, the 3-year rates for CRD (58% 
vs 42%, p=.04) and OS (60% vs 28%, p<.001) were superior for hyper-CVAD compared with 
VAD/CVAD; rates were particularly favourable for the CD20 negative younger age group (68% 
and 85%, respectively). In contrast, 3-year CRD and OS rates were uniformly poor for the CD20 
positive group regardless of therapy (27% or less). Multivariate analysis for event-free survival 
identified older age, leukocyte count >30 x 109/L, presence of Philadelphia chromosome, high 
systemic risk classification, and CD20 positivity as independent predictors of worse outcome. The 
authors concluded that CD20 expression in de novo adult precursor B-lineage ALL appears to be 
associated with a poor prognosis and suggested that the incorporation of monoclonal antibodies 
directed against CD20 into frontline chemotherapy regimens warrants investigation.46 Another 
report by our group has demonstrated that the addition of rituximab to hyper-CVAD may improve 
outcome in adult BL or B-ALL, particularly in elderly patients.47 Within our database we have seen 
that approximately 45% of patients with Ph+ ALL express the CD20 antigen. 
 


Protocol No. 2006-0478 
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16 
2.  
STUDY OBJECTIVES 
2.1. To evaluate the clinical efficacy (event-free survival) of an intensive short-term chemotherapy 
regimen (Hyper-CVAD program) given in combination with the tyrosine kinase inhibitor dasatinib 
for Philadelphia (Ph)-positive and/or BCR-ABL-positive acute lymphoblastic leukemia-ALL. 
 
2.2. To evaluate other clinical efficacy (overall response rate and survival) and safety of an 
intensive short-term chemotherapy regimen (Hyper-CVAD program) given in combination with the 
tyrosine kinase inhibitor dasatinib for Philadelphia (Ph)-positive and/or BCR-ABL-positive acute 
lymphoblastic leukemia-ALL. 
 
3. 
SELECTION OF PATIENTS 
Patients will be selected from those referred to the Leukemia department at M D Anderson 
Cancer Center through the normal of process of referral. Eligible patients will be registered after 
the process of consenting on the MD Anderson protocol and data monitoring system. 
3.1 
Inclusion Criteria 
1. Diagnosis of one of the following: 
 
I - Previously untreated Ph-positive ALL [either t(9;22) and/or bcr-abl positive] (includes patients 
initiated on first course of hyper-CVAD before cytogenetics known) 
II - After 1-2 courses of chemotherapy with or without imatinib mesylate (Gleevec) 
 
If they achieved CR, they are assessable only for event-free and overall survival, 
or 
 
If they failed to achieve CR, they are assessable for CR, event-free, and overall 
survival 
III – Patients with relapsed Ph-positive ALL [either t(9;22) and/or bcr-abl positive] or lymphoid 
blast phase of chronic myeloid leukemia failing any therapy other than dasatinib. 
 
These groups will be analyzed separately. 
 
2. Age  18 years.  
 
3. Zubrod performance status  2 (ECOG Scale, Appendix G). 
 
4. Adequate liver function (bilirubin  3.0 mg/dl, unless considered due to tumor), and renal 
function (creatinine  3.0 mg/dl, unless considered due to tumor). 
 
5. Adequate cardiac function as assessed clinically by physical examination. 
 
6. Signed informed consent  
 
 
3.2 
Exclusion Criteria 
1. Active serious infection not controlled by oral or intravenous antibiotics.  
 


Protocol No. 2006-0478 
June 23, 2009 
 
17 
2. Treatment with any investigational antileukemic agents or chemotherapy agents in the 
last 7 days before study entry, unless full recovery from side effects has occurred or 
patient has rapidly progressive disease judged to be life-threatening by the investigator. 
 
3. Active secondary malignancy other than skin cancer (e.g., basal cell carcinoma or 
squamous cell carcinoma) that in the investigator’s opinion will shorten survival to less 
than 1 year. 
 
4. Active Grade III-V cardiac failure as defined by the New York Heart Association Criteria 
(Appendix H).  
Uncontrolled angina, or MI within 6 months 
Diagnosed or suspected congenital long QT syndrome 
Any history of clinically significant ventricular arrhythmias (such as ventricular 
tachycardia, ventricular fibrillation, or Torsades de pointes) 
Prolonged QTc interval on pre-entry electrocardiogram (> 470 msec) unless corrected 
after electrolyte replacement 
Patients currently taking drugs that are generally accepted to have a risk of causing 
Torsades de Pointes (unless these can be changed to acceptable alternatives)  
 
5. Prior history of treatment with dasatinib. 
 
6. Pregnant and lactating women will not be eligible; women of childbearing potential should 
have a negative pregnancy test prior to entering on the study and be willing to practice 
methods of contraception. Women do not have childbearing potential if they have had a 
hysterectomy or are postmenopausal without menses for 12 months. In addition, men 
enrolled on this study should understand the risks to any sexual partner of childbearing 
potential and should practice an effective method of birth control. 
 
7, History of significant bleeding disorder unrelated to cancer, including: 
 
Diagnosed congenital bleeding disorders (e.g., von Willebrand’s disease) 
 
Diagnosed acquired bleeding disorder within one year (e.g., acquired anti-factor VIII 
antibodies) 
 
8.  Patients with documented significant pleural or pericardial effusions unless they are 
 
thought to be secondary to their leukemia. 
 
  
4. 
TREATMENT OF SUBJECTS 
4.1. Variations in dose reductions of the individual chemotherapy or the administration of 
dasatinib or supportive care dose schedules other than those suggested below are allowed in the 
best interest of patients. Such patients should be discussed with the principal investigator. Dose 
escalations for the intensive chemotherapy courses above those outlined in the protocol; 
however, are not allowed. 
 
4.2. General Considerations 
 


Protocol No. 2006-0478 
June 23, 2009 
 
18 
1. The hyper-CVAD (odd courses) will alternate with high dose methotrexate and cytarabine 
(even courses) administered on 21 or later day cycle (as count recovery allows), or 
earlier if count recovery allows.  
 
Anti-emetic therapy with each course of intensive chemotherapy as needed.  
 
G-CSF will be administered with each course after the completion of 
chemotherapy. 
 
Next course may be started when granulocytes > 1.0 x 109/L and platelets  50 x 
109/L, following discontinuation of G-CSF. Courses may be started with dose 
reductions prior to full platelet recovery, if the treatment is delayed (e.g., greater 
than 28 days from last course).   
 
Prophylactic antibiotics may be given with each course until neutrophil recovery 
to 500/L or greater (or other antibiotics if being treated for active infection). 
Suggestions include:  Levaquin 500 mg p.o. daily (or other quinolone) or 
trimethoprim-sulfamethoxazole double strength one tablet p.o. b.i.d. or other 
appropriate antibacterial agent. Fluconazole 200 mg p.o. daily or itraconazole 
200 mg p.o. bid. or other appropriate antifungal agent. Valacyclovir 500 mg p.o. 
daily or acyclovir 200 mg p.o. b.i.d. or other appropriate antiviral agent.  
 
Dasatinib 100 mg po daily will be given days 1 to 14 of the first course of 
intensive chemotherapy (course 1 doses may be adjusted  4-5 days if therapy 
changed from frontline protocol once cytogenetics known). For subsequent 
courses 2, 3, 4, 5, 6, and 7 dasatinib 70 mg po daily will be given continuously 
without interruptions unless due to toxicity. 
 
Patients who enter the program in CR or with partial response after one course of 
therapy may start this program either with course 1 or 2 depending on their prior 
therapy, with the decision made by the Principal Investigator at study entry. 
 
For patients with CD20 expression (≥ 20% by flow cytometry) Rituximab 375 
mg/m2 on days 1 and 11 of cycles 1 and 3, and days 1 and 8 of cycles 2 and 4. 
For patients with CD20 expression (≥ 20% by flow cytometry) Rituximab 375 
mg/m2 on days 1 and 11 of the intensification cycles in months 6 and 13. If 
patients do not receive the intensification cycles, they may receive Rituximab 
alone 375 mg/m2 on days 1 and 11 of maintenance cycle in months 6 and 13. 
 
In general 8 cycles of chemotherapy (4 hyperCVAD, 4 methotrexate plus 
cytarabine) will be administered in approximately 3 to 4 week intervals 
(depending on the recovery of blood counts). This will be followed by 
approximately 24 months of maintenance chemotherapy. Thereafter, dasatinib 
may be continued indefinitely. Modifications thought to be in the best interest of 
the patient are allowed after discussion with the principal investigator. Patients 
will be followed indefinitely for relapse and survival. 
 
All patients should have a chest radiograph before each course of methotrexate 
and cytarabine; methotrexate dose will be adjusted as indicated below for pleural 
effusions. 
 
2. Total number of prophylactic intrathecal treatments for newly diagnosed patients will be 
as follows (2 intrathecals of methotrexate on day 2  2 days and cytarabine day 7  2 
days with each course of chemotherapy until total number reached):  
 
Indeterminate or high-risk disease: 8 intrathecals Serum lactate dehydrogenase 
(LDH) > 1400 U/L; or Proliferative index %S + G2M ≥ 14%; or De novo LDH 
and/or proliferative index unknown  
 
Low-risk disease: 6 intrathecals  
None of the above features  


Protocol No. 2006-0478 
June 23, 2009 
 
19 
 
If the patient has been previously treated, and has had prior intrathecal therapy, 
or prior CNS disease, discuss management of CNS with the principal 
investigator.  
 
If active CNS disease: Consider methotrexate alternating with cytarabine (see 
sections 5.3 and 5.4) twice weekly until CSF clear; then once weekly for 4 weeks, 
then back to prophylactic schedule. Consider XRT to the base of the skull, 
particularly with cranial nerve root involvement (cranial nerve palsies). Alternative 
methods of treating CNS disease are allowed if appropriate for the patient (e.g., 
intrathecal liposomal cytarabine, or others). Modifications to the regimen thought 
to be necessary for administration of XRT are allowed after discussion with the 
principal investigator. 
 
CSF specimens obtained during therapeutic and diagnostic lumbar punctures will 
be evaluated for presence of minimal residual leukemia and β-2 microglobulin: 
(1) first spinal tap at M D Anderson, (2) first lumbar puncture after CR is 
documented (3) last spinal tap during the consolidation therapy. Variations in 
these time-points are permitted if felt to be appropriate by the treating physician. 
 
CSF specimens obtained during therapeutic and diagnostic lumbar punctures will 
be evaluated for dasatinib concentrations. Up to 3 specimens per patients will 
obtained during any of the scheduled lumbar punctures and sent to the 
laboratory of Dr Merrill Egorin, MD at the University of Pittsburg Cancer Institute. 
 
3. Maintenance phase chemotherapy will be given after completion of the 8 courses of 
intensive chemotherapy as outlined in Section 4.6. 
Patients may be moved from the intensive chemotherapy to the maintenance phase 
prior to completion of 8 cycles of chemotherapy (or for transitional treatment prior to 
allogeneic bone marrow transplant) if intolerant after discussion with the Principal 
Investigator. 
 
4.3. Hyper-CVAD plus dasatinib [Odd courses 1, 3, 5, 7]: 
 
 
Cyclophosphamide (CTX) 300 mg/m2 IV over 3 h every 12 hrs x 6 doses days 1,2,3 (total 
dose 1800 mg/m2). 
 
 
MESNA 600 mg/m2/d IV continuous infusion daily for 24 hrs, starting approximately 1 
hour prior to CTX and completing by approximately 12 hrs after the last dose of CTX.  
 
 
Doxorubicin 50 mg/m2 IV over 24 hrs via central venous catheter on day 4 after last dose 
of CTX given (infuse over 48 hrs in patients with reduced ejection fractions < 50%). May 
be given by shorter infusion if difficulty with central venous access. 
 
 
Vincristine 2 mg IV on day 4  2 days and day 11  2 days. Vincristine is not 
myelosuppressive and may be given while patients are receiving G-CSF; no known 
adverse effects have been observed with the 2 agents given together. 
 
 
Dexamethasone 40 mg IV or p.o. daily on days 1-4  2 days and days 11-14  2 days. 
 
 
Dasatinib 100 mg po daily days 1-14 for course 1, (may shift  4-5 days if therapy 
changed once results of cytogenetics known). ). For subsequent courses 3, 5, and 7 
dasatinib 70 mg po daily continuously without interruptions unless due to toxicity. 
 


Protocol No. 2006-0478 
June 23, 2009 
 
20 
 
GCSF 10 mcg /kg (rounded) subcutaneously daily (or 5 mcg /kg twice daily) until post-
nadir granulocytes > 1.0 x 109/L. G-CSF may be stopped earlier for bone pain or other 
related toxicity. Minimum time allowed between courses is 14 days.  
 
 
For patients with CD20 expression (≥ 20% by flow cytometry) Rituximab 375 mg/m2 on 
days 1 and 11 of cycles 1 and 3. 
 
 
CNS prophylaxis: Methotrexate 12 mg intrathecally (6 mg via Ommaya reservoir) on day 
2 ( 2 days). Cytarabine 100 mg intrathecally on day 7 ( 2 days). Administer in 3 to 5 cc 
of preservative-free normal saline. 
 
 
4.4. High-dose Methotrexate and cytarabine plus dasatinib [Even courses 2,4, 6, 
and 8]: 
 
 
Methotrexate (MTX) 200 mg/m2 IV over 2 hrs followed by 800 mg/m2 over 22 hrs on day 
1. Total duration of administration is 24 hours (2 plus 22 hours). 
 
 
Solumedrol 50 mg IV approximately every 12 hrs for 6 doses days 1 to 3. 
 
 
 
Dasatinib 70 mg po daily continuously without interruptions unless due to toxicity in 
courses 2, 4, 6, and 8. 
 
 
Cytarabine 3 g/m2 IV over 2 hrs every 12 hrs for 4 doses on days 2,3. 
Reduce to 1 g/m2 IV over 2 hrs every 12 hrs for 4 doses on days 2 and 3 for:  
 
Neurotoxicity (≥ grade 2 cerebellar or other cytarabine-related CNS 
toxicity as per Appendix F), or 
 
Age 60 years old or greater. 
 
Creatinine ≥1.5 mg/dL. 
 
 
Citrovorum rescue 50 mg IV or PO followed by 15 mg IV or PO every 6 hours for 8 doses 
beginning 12 hrs  2 hrs post MTX completion, i.e. approximately 36 hours from start of 
MTX. 
 
 
Check MTX levels around time 0h, 24h and 48h post completion of MTX unless 
methotrexate cleared: 
1. if > 20 M at time 0, hold cytarabine and repeat level; if continues to be > 20 M 
reduce cytarabine to 1 g/m2 IV over 2 hours every 12 hours for 4 doses on days 
2,3. Begin citrovorum rescue as described above. 
 
2. if > 1 M at 24hrs or > 0.1 M at 48 hours, increase citrovorum rescue to 50 mg 
IV or PO every 6 hrs until serum methotrexate level is < 0.1 M. Clearance to 
levels 0.15 M or less is acceptable in patients with normal renal function. 
 
3. Citrovorum rescue may be increased further for elevated methotrexate levels or 
delayed clearance 
 


Protocol No. 2006-0478 
June 23, 2009 
 
21 
 
GCSF 10 mcg/kg (rounded) subcutaneously daily (or 5 mcg /kg twice daily) until post-
nadir granulocytes ≥ 1.0 x 109/L. G-CSF may be stopped earlier for bone pain or other 
related toxicity. Minimum time allowed between courses is 14 days (e.g., day 14). 
 
 
For patients with CD20 expression (≥ 20% by flow cytometry) Rituximab 375 mg/m2 on 
days 1 and 8 of cycles 2 and 4. 
 
 
CNS prophylaxis: Methotrexate 12 mg intrathecally (6 mg via Ommaya reservoir) day 2  
2 days. Cytarabine 100 mg intrathecally day 7  2 days. Administer in 3 to 5 cc of 
preservative-free normal saline. 
 
4.5. Suggested Standard Dose Reductions/modifications: 
 
1. Cytarabine 1 g/m2 IV over 2 hrs every 12 hrs for 4 doses on days 2 and 3. 
 
 
Creatinine > 1.5 g/dL. 
 
Time “0” MTX level > 20 M (on repeat level).  Follow the directions outlined in 
section 4.4, Bullet #4. 
 
Age ≥ 60 years. 
 
Grade 2 or greater CNS toxicity. 
 
2. Vincristine 1 mg IV days 4 and 11 (50% reduction). 
 
 
Bilirubin > 2.0 g/dl and  3.0 g/dl 
 
Clinically significant grade 2 peripheral neuropathy persisting greater than 2 
weeks. 
 
Eliminate vincristine for grade 3-4 peripheral neuropathy, including grade 3-4 
ileus suspected to be related to vincristine, bilirubin > 3.0 g/dL. 
 
3. Doxorubicin: 
 
 
Reduce by 50% for bilirubin 2 to 3 g/dl, by 75% for bilirubin 3 to 5 g/dl. Eliminate 
if bilirubin > 5 g/dL. 
 
Administer over 48 hours in patients with borderline reduced (< 50%) ejection 
fractions. 
 
Contraindicated in patients with prior history of known Type I 
hypersensitivity or anaphylactic reactions to doxorubicin. 
 
4. Methotrexate: 
 
 
Consider reduction by 25%-50% for grade 3 or worse mucositis with previous 
methotrexate course. 
 
Reduce by 50% for calculated creatinine clearance 10-50 ml/min, if < 10 ml/min, 
hold methotrexate. 
 
Reduce by 25% to 75% for delayed excretion and/or nephrotoxicity with previous 
methotrexate course. 
 
Reduce by 50% for pleural effusion or ascites (drain effusion if possible). All 
patients should have a chest radiograph prior to each course of methotrexate 
and cytarabine. 
 


Protocol No. 2006-0478 
June 23, 2009 
 
22 
5. Dasatinib 
 
 
Grade Ill-IV non-hematological toxicity: 
Consider holding until grade I or less. 
May consider resuming at 70 mg po daily (if the patient is receiving 100 mg po 
daily in the first cycle) or resuming at 50 mg po daily (if the patient is receiving 70 
mg po daily in the subsequent cycles) for grade Ill or IV non-hematological 
toxicity; consider discontinuing if grade III or IV non-hematological toxicity recurs. 
 
Other modifications should be discussed with the Principal Investigator 
 
 
During intensive phase of chemotherapy, consider holding dasatinib if ANC not > 
1.0 x 109/L or if platelet count not > 30,000 by day 21 of the cycle. Resume 
dasatinib upon recovery to ANC > 1.0 x 109/L and platelet count ≥ 50,000 
(without need for G-CSF or platelet transfusions) if able to tolerate. Resume 
dasatinib at the dose of 70 mg po daily if time to recovery < 1 week. Resume 
dasatinib at 50 mg po daily if time to recovery > 1 week. 
 
 
If there is inadequate response to dasatinib  70 mg po daily and in the absence 
of significant (grade III or IV toxicity) may consider increasing the dose of 
dasatinib to 100 mg po daily or 70 mg twice daily or 140 mg po daily. 
 
 
Dasatinib may be administered once or twice daily if felt to be in the patient’s 
best interest; once daily is likely to be associated with reduced toxicity. 
 
6. Dose reductions exceeding those above or in other agents, e.g., citrovorum, antibiotics, 
antiemetics, etc., are allowed after discussion with the Principal Investigator. 
 
4.6. Maintenance, Intensifications, and Post-Remission Therapy 
 
 
Maintenance therapy with dasatinib plus vincristine and steroids. 
 
Maintenance chemotherapy with vincristine, and prednisone for approximately 24 months 
beginning at Dose level 0 or lower dose level if prior toxicity required dose reduction of agents 
(titrate to keep ANC > 0.5 x 109/L and platelet count ≥ 30 x 109/L) (See table below): 
 
Vincristine 2 mg IV day 1 approximately every 28 days 
Prednisone 200 mg P.O. daily days 1 to 5 approximately every 28 days with vincristine 
dasatinib 100 mg po daily as tolerated. 
 
 
Suggested maintenance chemotherapy dose adjustments are as below: 
 
Level 
VCR (mg) 
Prednisone (mg) 
Dasatinib (mg) 
+1 
2 
200 
70 bid or 140 po daily 
 0 
2 
200 
100 po daily 
-1 
1 
100 
70 po daily 
-2 
0 
50 
50 po daily 
 
1. Prednisone 
Dose should remain at 200 mg unless steroid myopathy or other significant 
toxicity occurs. 


Protocol No. 2006-0478 
June 23, 2009 
 
23 
Prednisone not required to be dose adjusted for hyperglycemia. 
 
2. Vincristine 
Decrease by one dose level for grade 2 peripheral neuropathy persisting longer 
than 2 weeks. 
Discontinue for grade 3 or greater peripheral neuropathy persisting longer than 2 
weeks. 
3. Dasatinib 
Grade Ill-IV non-hematological toxicity: 
Consider holding until grade I or less. 
May resume at dose of 70 mg po daily for grade III or IV non-
hematological toxicity; consider discontinuing if toxicity recurs. 
Other modifications should be discussed with the principal investigator. 
If ANC < 0.5 x 109/L or platelets < 30 x 109/L: 
Hold until ANC > 1 x 109/L and platelet count > 50 x 109/L, and wait for 
recovery. 
If recovery occurs in < 2 weeks, resume at same dose. 
If recovery occurs > 2 weeks, resume at 80 mg po daily level. 
Recurrent neutropenia may be managed with dose modifications after 
discussion with the Principal Investigator. 
If there is inadequate cytogenetic/molecular response, the dose of dasatinib may 
be increased to 70 mg twice daily or 140 mg po daily. 
 
 
lntensifications interrupting maintenance phase as follows: 
 
1. Two intensifications with one course of hyper-CVAD plus dasatinib 100 mg po daily on days 1-
14 or 70 mg po every day depending on tolerance, months 6 and 13 of maintenance.  
 
2. Intensifications may be eliminated if the bone marrow PCR for bcr-abl is negative, or prior 
toxicity with intensive chemotherapy prohibits administration, or for other reasons judged valid by 
the Principal Investigator. 
 
3.  Dasatinib may be continued indefinitely after the 24 months of therapy. 
 
4.7. Monitoring Plan 
 
The hyper-CVAD regimens have been conducted since 1992, and have accrued over 500 
patients on similar induction-consolidation-maintenance phases. The treatment-associated side-
effects, both myelosuppressive and extramedullary are well-known, and have been described and 
reported. Known and anticipated side effects of this regimen (Appendix E) will not be reported as 
individual ADRs, according to the Code of Federal Regulations and ICH guidelines BCGP Section 
4.1 I. I,p. 24. This also complies with the NCI CTEP-CTC guidelines which state that for expected 
events grade 4 myelosuppression or other grade 4 events that do not require expedited reporting 
will be specified in the protocol (Section 12.0). 
The trial will be closely monitored for any adverse effect of dasatinib on the expected toxicity and 
CR rate for the first 10 patients. An accrual rate of 1 to 2 patients per month is expected. The first 
10 patients will receive their entire 8 courses of chemotherapy treatment in Houston in order to be 
closely monitored. Early stopping for excessive toxicity will be considered if early induction 
mortality exceeds 20%. Thus the study will be stopped if deaths/treated patients is >1/5 or >2/10. 
The trial will also be stopped if the number of patients experiencing unacceptable toxicities (as 


Protocol No. 2006-0478 
June 23, 2009 
 
24 
defined in section 9.0)/total number of patients is greater than or equal to 2/5, 3/12, 4/24, or 5/37. 
The continuation of study at the above doses will be dependent on clear evidence that the 
addition of dasatinib will not adversely affect these parameters as compared to previous regimens 
including hyperCVAD and hyperCVAD plus gleevec. 
. 
Recognizing there will be instances where patient cannot receive all of their therapy at M.D. 
Anderson, the following monitoring plan will be implemented as feasible: 
 
All patients who enter therapy with active disease will receive their first course of therapy at M. D. 
Anderson, and will be monitored until CR or failure to respond.  
 
Subsequent courses of therapy may be given by a local physician under direction of the M. D. 
Anderson Cancer Center treating physician or the principal investigator (The first 10 patients will 
receive their entire 8 courses of therapy at M D Anderson). The patient will be given a copy of the 
protocol, instructions, and the M. D. Anderson contact numbers for the principal investigator and 
research nurse, with telephone and fascimile numbers. The referring physician will be identified, 
contacted and the protocol details discussed. It will be detailed that therapy should not be 
administered unless carrying out handwritten chemotherapy orders compiled by the principal 
investigator or treating physician at M. D. Anderson. A recent weight to calculate BSA, review of 
laboratory data, review of compliance with dasatinib, and review of toxicities will be performed. 
Orders will be written by M. D. Anderson treating physician or the principal investigator after 
discussion of the patient's status with the treating physician. 
 
Physicians will be requested to sign a letter stipulating these items, and indicating their 
willingness to defer all decisions regarding the chemotherapy and dasatinib to MDACC. 
Documentation will be requested from outside physicians, including drug administration records 
to ensure that the orders were followed. Outside physicians will be asked to contact MDACC for 
prior approval of any decisions or changes related to the chemotherapy or dasatinib 
administration. 
 
5. 
CONCOMITTANT MEDICATIONS 
Short-acting antacid agents may be taken, but it is recommended that these not be taken from 2 
hours before to 2 hours after dosing of dasatinib.  
Dasatinib may be taken with meals. The dosing time may be adjusted as required (for bid 
schedules recommend skipping doses that are missed by 6 hours, for qd dosing recommend 
skipping doses that are missed by more than 12 hours). If doses are missed for toxicity, they 
should not be replaced. If vomiting occurs within 30 minutes of intake, that dose may be 
repeated. If needed, tablets should be dissolved in strong juice rather than crushed. 
Patients currently taking drugs that are generally accepted to have a risk of causing Torsades de 
Pointes (including: quinidine, procainamide, disopyramide, amiodarone, sotalol, ibutilide, 
dofetilide, erythromycins, clarithromycin, chlorpromazine, haloperidol, mesoridazine, thioridazine, 
pimozide, cisapride, bepridil, droperidol, methadone, arsenic, chloroquine, domperidone, 
halofantrine, levomethadyl, pentamidine, sparfloxacin, lidoflazine) should change these to 
acceptable alternatives. 
 
Medications that inhibit platelet function (i.e., aspirin, dipyridamole, epoprostenol, eptifibatide, 
clopidogrel, cilostazol, abciximab, ticlopidine, and any non-steroidal anti-inflammatory drug) or 


Protocol No. 2006-0478 
June 23, 2009 
 
25 
Anticoagulants (warfarin, heparin/low molecular weight heparin [e.g., danaparoid, dalteparin, 
tinzaparin, enoxaparin]) should be avoided as much as possible. 
Exceptions include low-dose warfarin for prophylaxis to prevent catheter thrombosis, and for 
heparin-flushes for IV lines. If patients develop deep vein thrombosis during the course of therapy 
or are receiving anticoagulation for indications such as recent thrombosis or artificial heart valves 
these drugs may be continued with close monitoring of the patients. 
 
When used concomitantly with drugs known to be CYP3A4 inducers such as rifampin, consider 
increasing the dose of dasatinib with careful monitoring for toxicity. When used concomitantly with 
strong CYP3A4 inhibitors, such as ketoconazole, consider decreasing the dasatinib dose. 
 
Proton pump inhibitors may be administered concomitantly with dasatinib if felt to be in the 
patient’s best interest. 
6. 
STUDY PROCEDURES  
6.0. PRETREATMENT EVALUATION 
 
1. History and physical examination, documentation of disease. 
2. CBC, platelet count, differential, total bilirubin, creatinine, SGPT, uric acid. 
3. Bone marrow aspirate and cytogenetics. Quick Philadelphia screen is acceptable. 
4. EKG 
5. Pregnancy test in patients of appropriate age and menopausal state 
6. Echocardiogram or MUGA scan to assess cardiac function 
 
 
6.1. EVALUATION DURING STUDY 
 
1. 1-2 times weekly CBC, platelet count and differential for course 1 (if in CR at study entry every 
1-3 weeks), then every 1-3 weeks during 8 cycles of chemotherapy then every 4-6 weeks during 
maintenance. 
2. Total bilirubin, SGPT, creatinine weekly for course 1, then every 1-4 weeks during intensive 
chemotherapy cycles, then every 4-8 weeks during maintenance. 
3. Bone marrow aspiration for course 1 (in patients enrolled with active marrow disease) on day 
14  5 days and day 21  5 days (or at the time of hematologic recovery) if day 14 bone marrow 
with residual leukemia. 
4. Evaluate for toxicity assessment 
5. EKG – Recommended at baseline and week 4 
6. A chest radiograph should be performed at baseline and before each course of methotrexate to 
evaluate for the presence of pleural effusions 
 
 
 
 
 
 
 
 
 
 


Protocol No. 2006-0478 
June 23, 2009 
 
26 
 
 
 
Intensive treatment plus dasatinib 
Odd: hyperCVAD 
Even: 
MTX/Cytarabine 
Dasatinib days 1-14 
Pre-Rx 
1 
2 
3 
4 
5 
6 
7 
8 
Informed consent 
X 
 
 
 
 
 
 
 
 
EKG 
X 
 
X 
 
 
 
 
 
 
History + physical 
X 
 
 
 
 
 
 
 
 
CBC/Diff/Platelet 
X 
X 
X 
X 
X 
X 
X 
X 
X 
SGPT, Bili, creat 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Marrow, CG 
X 
 
 
 
 
 
 
 
 
Pregnancy test (If 
indicated) 
X 
 
 
 
 
 
 
 
 
Chest X-ray 
X 
 
X 
 
X 
 
X 
 
X 
Toxicity assessment 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
7. 
EFFICACY AND SAFETY ASSESSMENTS 
7.0. CRITERIA FOR RESPONSE 
 
1. Complete Remission (CR): Normalization of the peripheral blood and bone marrow with 5% or 
less blasts in normocellular or hypercellular marrow with a granulocyte count of 1 x 109/L or 
above, and platelet count of 100 x 109/L. Complete resolution of all sites of extramedullary 
disease is required for CR. 
2. Molecular CR: Same as for CR with RT-PCR negativity for bcr-abl. 
3. Partial Response (PR): As above for CR except for the presence of 6-25% marrow blasts. 
4. Relapse and resistant disease will be defined based on morphological assessment of bone 
marrow and peripheral blood. 
 
7.1. EVALUATION OF TOXICITY 
 
1. Toxicities will be graded according to the NCI Common Toxicity Criteria for Adverse 
Event Reporting Version 3.0 (Appendix B). The toxicity of the regimen will be monitored 
continuously during the course of the study. 
 
 
7.2. CRITERIA FOR REMOVAL FROM THE STUDY 
 
1. Unacceptable toxicity judged to be related to therapy by the investigator, as defined by the NCI 
Common Toxicity Criteria (Appendix B). (Irreversible or prolonged (greater than 42 days) grade 4 
hematological toxicity or grade 4 non-hematological toxicity thought to be related to dasatinib). 
2. Non-compliance by the patient with protocol requirements or patient's request to be removed 
from the study. 
 
 


Protocol No. 2006-0478 
June 23, 2009 
 
27 
 
 
7.3 DEFINITION OF STUDY END-POINTS 
 
1. Disease-free survival is the time from documented complete response until relapse or death. 
 
2. Event-free survival is the time from the first day of treatment until any failure (resistant 
disease, relapse, or death). 
 
3. Overall response rate is defined as the percentage of patients achieving complete remission 
and partial remission as defined above. 
 
4. Overall survival is defined as the time from the first day of treatment to time of death from any 
cause. 
 
8. 
STUDY DRUG(S) 
8.0 The background drug information for the following agents is attached as an appendix to the 
back of this protocol (Appendix F). 
 
Vincristine 
doxorubicin 
G-CSF 
cyclophosphamide 
methotrexate 
cytarabine 
Mesna 
 
8.1.  Dasatinib 
8.1.1. Introduction  
 
Dasatinib (BMS-354825) is a potent, broad spectrum ATP-competitive inhibitor of 5 critical 
oncogenic tyrosine kinases/kinase families: BCR-ABL, SRC, c-KIT, PDGFR, and ephrin (EPH) 
receptor kinases, each of which has been strongly linked to multiple forms of human 
malignancies. BCR-ABL is a constitutively active protein tyrosine kinase (PTK) present in >90% 
of patients with CML and 15-30% of adult patients with ALL. Numerous studies have 
demonstrated that BCR-ABL activity is required for the transforming ability of this protein.23,24 With 
the approvals of imatinib mesylate (Gleevec
®
, Glivec
®
, STI-571), inhibition of BCR-ABL has 
proven effective in management of CML, particularly chronic phase where the hematologic 
response rate is >90%. However, patients with advanced disease are much less sensitive to 
imatinib, and experience less frequent and transient responses.16 Clinical refractoriness to 
imatinib has been associated with the development of multiple mechanisms of drug resistance, 
including BCR-ABL gene mutation/over-expression and activation of selected SRC kinases.25,26 
Dasatinib is ~260fold more potent than imatinib in inhibiting BCR-ABL by binding to both active 
and inactive conformations of c-ABL, whereas imatinib only binds to the inactive state.
 
This 
difference in binding may be responsible for the vastly increased potency of dasatinib over 
imatinib.  


Protocol No. 2006-0478 
June 23, 2009 
 
28 
Dysregulation of SRC function has been strongly linked to the pathogenesis of human cancers. 
Tumor cells with increased metastatic potentials have been shown to have activated SRC kinase, 
providing strong evidence linking SRC activation with tumor progression and metastasis.27
 
In 
epithelial cancers, SRC promotes metastasis by disrupting and/or weakening the normally strong 
cell-cell adhesions. At the same time, SRC increases the cell-matrix interaction and enhances cell 
migration.28,29
 
 
c-KIT is the receptor for stem-cell factor (SCF).30
 
Binding of SCF to the KIT receptor results in 
autophosphorylation and activation of its kinase activity. These initial events trigger several down-
stream signaling cascades that regulate cellular activities such as proliferation, apoptosis, and 
motility.31 Specific somatic mutations in c-KIT resulting in kinase activation have been shown to 
cause certain forms of cancer and have been strongly implicated in the pathogenesis of 
gastrointestinal stromal tumors (GIST).32,33
 
Imatinib, which inhibits mutant forms of c-KIT found in 
GIST, has been effective in the treatment of GIST.34 Another type of mutation, involving the 
receptor kinase domain, is found in most cases of adult sporadic mastocytosis, germ cell tumors, 
acute myelogenous leukemia (AML), and sinonasal natural killer/T-cell lymphoma.35 This latter 
form of mutant KIT has been shown to be insensitive to imatinib. Other types of tumors in which 
c-KIT dysregulation has been implicated include small cell lung cancer (SCLC), neuroblastoma, 
melanoma, ovarian carcinoma, and breast carcinoma.35
 
 
Dysregulations of PDGF and PDGFR expression and function have been implicated in many 
forms of solid tumors, including glioblastoma, meningiomas, melanomas, neuroendocrine tumors, 
ovarian, pancreatic, gastric, lung, and prostate cancer.36 There is strong evidence supporting 
autocrine PDGF stimulation of tumor cell growth and paracrine PDGF stimulation of tumor 
angiogenesis as the underlying drivers of the oncogenic potential of PDGF and its receptors.37
  
 
 
 
8.1.2. Nonclinical Studies  
 
Dasatinib has been extensively studied in vivo and in vitro.  In vivo, at doses well below maximum 
tolerated dose (MTD), dasatinib demonstrated curative efficacy against several advanced human 
chronic myelogenous leukemia (CML) xenografts in severe combined immunodeficiency (SCID) 
mice, including an imatinib “acquired-resistance” model completely insensitive to imatinib. 
Dasatinib also demonstrated antitumor efficacy against several susceptible cancer models in 
nude mice, and is a potent inhibitor of vascular endothelial growth factor (VEGF)-stimulated 
proliferation and migration in human umbilical vein endothelial cells (HUVECs). In cellular assays, 
dasatinib killed BCR-ABL dependent leukemic cell lines, including a number that are resistant to 
imatinib whether due to mutations that affect drug binding or through overexpression of SRC 
kinases. Against 4 imatinib naive CML cell lines, cytotoxicity potency was 300-655 times higher 
for dasatinib than for imatinib. Dasatinib inhibited cellular proliferation of numerous cancer cell 
lines that express activated SRC or c-KIT.  
 
8.1.3. Effects in Humans  
 
Bristol-Myers Squibb Company (BMS) began Phase 1 clinical development of dasatinib in 
November 2003.  Since then, dasatinib has been studied in more than 900 patients with CML and 
Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL) resistant or 
intolerant to imatinib, and a number of solid tumors. Preliminary clinical pharmacokinetic (PK) 
data indicate that dasatinib has good oral absorption, is >90% protein bound and is predicted to 
have a large volume of distribution.  Comparable dosing interval exposures are seen regardless 
of whether dasatinib is administered once daily (QD) or twice daily (BID).  Dasatinib’s overall 


Protocol No. 2006-0478 
June 23, 2009 
 
29 
mean terminal half-life is around 4 hours in patients and it is expected to be eliminated mainly 
through metabolism.  
Dasatinib has an acceptable safety profile.  None of the patients who were intolerant to imatinib 
became intolerant to dasatinib or developed adverse events similar to those that precluded 
treatment with imatinib. Most chronic phase CML patients had some degree of myelosuppression, 
most importantly, severe thrombocytopenia.  In cases of severe myelosuppression, recovery 
generally occurred following short dose interruptions. Other severe hematologic toxicities were 
uncommon.  In advanced CML and Ph+ ALL, severe myelosuppression was noted in most 
patients. In solid tumor patients, however, there was no clinically important myelosuppression.  
Nonhematologic toxicities consisted primarily of gastrointestinal (GI) intolerance, which typically 
was mild and easily manageable in chronic phase CML patients and mild to moderate in patients 
with advanced disease. In patients with advanced disease, especially blast phase, there was 
evidence of fluid retention, pleural and pericardial effusion. In all CML and Ph+ ALL patients, 
there were very few changes in blood chemistries and there were no instances of severe drug-
related hepatic dysfunction.  ECG measurements suggest a moderate QTc prolongation (4 
chronic, 2 advanced patients had >60 msec increase from baseline in QTc).  
Major cytogenetic response and complete hematologic response have been observed in a large 
number of imatinib resistant and intolerant patients in all phases of disease. The complete 
hematologic response rate in chronic phase CML was 90% (36/40) and was similar with QD and 
BID schedules. The major hematologic response rate was 71% (30/42) in patients with CML and 
Ph+ ALL.  Cytogenetic responses were documented in 52% (22/42), including major cytogenetic 
responses in 7 of 21 with BCR/ABL mutations reported to confer resistance to imatinib.    
Recently Sawyers et al presented an update of a Phase I dose-escalating study, initiated in 
November 2003, of dasatinib in imatinib-resistant/intolerant patients with CML in late chronic 
phase (CP) or advanced disease (accelerated phase [AP], myeloid blast crisis [MBC] or lymphoid 
blast crisis [LBC]) or with Ph+ ALL. Data were available for 84 patients (40 CP, 10 AP, 23 MBC, 
11 LBC/Ph+ ALL). At the time of the report, 40 CP patients, with 8 years median duration of CML 
(range: 1–17 yrs), had been treated with dasatinib (15–180 mg/day, once-daily [QD] or twice daily 
[BID]) for a median of 13 months. The rate of complete hematologic response (CHR) in CP was 
88% (35/40). Major cytogenetic responses (MCyR) were observed in 40% (16/40), with complete 
CyR (CCyR) in 33% (13/40). In advanced disease, 44 patients have been treated with dasatinib 
(70–240 mg/day, BID) for a median of 3–7 months; 2 patients (1 MBC and 1 LBC) were not 
evaluable for response, but were included in the analysis of time to progression. The rate of major 
hematologic response (MHR) (bone marrow blasts <5%) was 80% (8/10) in AP, 77% (17/22) in 
MBC and 60% (6/10) in LBC/Ph+ ALL. The CHR rate (<5% bone marrow blasts, with recovery of 
peripheral blood counts) is 50% (5/10) in AP, 18% (4/22) in MBC and 50% (5/10) in LBC/Ph+ 
ALL. The overall rates of MCyR and CCyR in advanced disease were 36% (15/42) and 21% 
(9/42), respectively. Cytogenetic responses were seen in patients with a wide spectrum of BCR-
ABL mutations, as well as in patients with minimal or no prior CyR with imatinib. Treatment was 
well tolerated. Reversible grade 3–4 myelosuppression was observed in all cohorts [CP (38%); 
AP (70%); MBC and LBC/ Ph+ ALL (91%)]. 8 patients developed unexplained pleural effusions (2 
CP; 6 BC), which were easily managed without treatment discontinuation. No patients have gone 
off study for toxicity. Responses were durable in CP and AP patients, but relapses had occurred 
in the MBC and LBC/Ph+ ALL cohorts, often due to dasatinib-resistant BCR-ABL mutations. Their 
data support the therapeutic potential of dasatinib in patients with imatinib-resistant or -intolerant 
CML/Ph+ ALL. In summary, dasatinib has an acceptable safety profile and demonstrated 
evidence of activity in all phases of CML and Ph+ ALL. 
Talpaz et al also reported the preliminary results from a Phase II trial in CML patients in myeloid 
blast crisis (MBC), which was initiated in December 2004. This open-label study was carried out 
in 37 centers worldwide between December 2004 and May 2005. A total of 74 imatinib-resistant 
(IM-R) or imatinib intolerant (IM-I) MBC pts were accrued (41 male, median age 56 years [range 


Protocol No. 2006-0478 
June 23, 2009 
 
30 
21-71]). Preliminary data were available on the first 34 patients (29 IM-R and 5 IM-I). Dasatinib 
was administered orally, at a dose of 70 mg twice daily (BID) in a continuous daily dosing 
schedule; dose escalation to 100 mg BID was permitted for patients who did not achieve 
hematologic response and dose reduction to 50 mg and 40 mg BID was allowed in the presence 
of persistent toxicity. Complete blood counts were performed weekly and bone marrow 
assessment, including cytogenetic analysis, was performed monthly. Mutations in the BCR-ABL 
domain were assessed in all patients. Pretreatment characteristics of these 34 patients included: 
71% male, median age 54 years (range 21 – 71). Median duration of CML from first diagnosis 
was 49.3 months (range 5.6 – 215.5). Prior therapy included bone marrow transplant (5 pts, 15%) 
and interferon (18 pts, 53%). In 44% of pts, the highest IM dose was >600 mg/day and 41% of pts 
received IM for >3 years. Best responses to IM were complete hematologic response (CHR) in 
82% of patients and major cytogenetic response in 39% of patients (complete in 27%, and partial 
in 12%). At baseline, 35% of pts had a WBC count ≥20 x 103/mm3, 71% had a platelet count <100 
x 103/mm3 and 24% had ≥50% bone marrow blasts. BCR-ABL mutations were documented in 
4/10 patients. Dasatinib doses were increased in 32% of patients while dose reductions were 
required in 21% of patients, mostly due to persistent thrombocytopenia. Major hematologic 
responses were documented in 16/29 (55%) patients with 7 CHR and 9 no evidence of leukemia 
(CHR without complete recovery of PMN or platelets). There were 13 (45%) cytogenetic 
responses, including 6 (21%) complete (0% Ph+) and 5 (17%) partial (1 – 35% Ph+). Dasatinib 
therapy was associated with rapid and profound myelosuppression. PMN <500/l occurred in 
59% of patients and platelets <25 x 103 /l in 56% of pts. Non-hematologic toxicities were 
uncommon and usually grade 1 or 2, with diarrhea in 8 patients, rash in 4 patients, nausea in 3 
patients (1 grade 3) and peripheral edema in 3 patients. 4 patients had pleural effusion. This 
preliminary data provided further evidence of the activity of dasatinib in CML patients with MBC 
and of its acceptable safety profile. 
 
 
8.1.4. Formulation and chemical properties 
 
Dasatinib is supplied for clinical research as 20 mg and 50 mg film-coated tablets and 
commercially as 70 mg film-coated tablets containing dasatinib with lactose monohydrate, 
microcrystalline cellulose, croscarmellose sodium, hydroxypropyl cellulose, magnesium stearate.  
The tablet coating consists of hydromellose, titanium dioxide, and polyethylene glycol. Tablets for 
clinical studiesare supplied in high-density polyethylene bottles containing a desiccant and cotton; 
the bottles are heat-induction sealed with child-resistant caps. The recommended storage 
condition is 15°C - 25°C.  The tablet descriptions are as follows:  
20 mg tablet - white to off-white, biconvex, round, film-coated with “20” debossed on one side and 
“527” on the other side  
50 mg tablet -white to off-white, biconvex, oval, film-coated with “50” debossed on one side and 
“528” on the other side  
70 mg tablet (commercial tablet) - is white to off-white, biconvex, round, film-coated with “BMS” 
debossed on one side and “524” on the other side  
 
The chemical name for dasatinib is N-(2-Chloro-6-methylphenyl)-2-[[6-[4-(2hydroxyethyl)-1-
piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazolecarboxamide, monohydrate. The molecular 
formula is C22H26ClN7O2S • H2O. The formula weight for the monohydrate is 506.02 and for the 
anhydrous free base is 488.01. 
Dasatinib is a white to off-white powder, which may contain lumps, and has a melting point of 
280°C - 286°C. The drug substance is insoluble (United States Pharmacopeia [USP] definition) in 
water (0.008 mg/mL) at 24 ± 4°C. The pH of a saturated solution of dasatinib in water is about 
6.0. Two basic ionization constants (pKa) (6.8 and 3.1) and one weakly acidic pKa (10.8) were 


Protocol No. 2006-0478 
June 23, 2009 
 
31 
determined. The solubility (USP definition) of dasatinib in various solvents at 24 ± 4°C are as 
follows: slightly soluble in ethanol (USP), methanol, polyethylene glycol 400, and propylene 
glycol; very slightly soluble in acetone and acetonitrile, and practically insoluble in corn oil. 
 
Clinical experience in more than 900 patients has identified several safety concerns with 
dasatinib.  There is a potential for myelosupression (in addition to that produced by the underlying 
disease), fluid retention, pleural and pericardial effusion, QTc prolongation, skin rashes, 
respiratory events, GI/CNS hemorrhage and tumor lysis syndrome. Due to these events, patients 
are prohibited from taking anticoagulants or medications that inhibit platelet function while on 
dasatinib therapy.  An exception to this may be the use of anagrelide for CML patients with 
significantly elevated platelet counts.  
 
8.1.5 
Dasatinib Product Identification 
The following investigational product, BMS-354825-03 (dasatinib), will be supplied by 
Bristol-Myers Squibb Pharmaceutical Research Institute in two different strengths: 
BMS-354825-03 20 mg film coated tablets, biconvex, round, white to off-white in appearance with 
“BMS” or  “20” debossed on one side and “527” on the other side. 
BMS-354825-03 50 mg film coated tablets, biconvex, oval, and white to off-white in appearance 
with “BMS” or  “50” debossed on one side and “528” on the other side. 
8.1.6 
Packaging and Labeling  
Dasatinib will be labeled in open-label fashion. Each bottle will be labeled with a two-panel label. 
Description of the contents, batch number, container number, storage conditions and caution 
statements required by country regulations will be on the label. The second panel will have batch 
number, container number. 
8.1.7 
Handling and Dispensing of Investigational Product  
Investigational product should be stored in a secure area according to local regulations.  It is the 
responsibility of the Investigator to ensure that investigational product is only dispensed to study 
subjects. The investigational product must be dispensed only from official study sites by 
authorized personnel according to local regulations. 
It is recommended that investigational product should only be handled by the subject.  While the 
risk for dermal exposure is considered minimal, it is recommended that only the study subject 
handle the study medication.  In particular, pregnant women or women who are breastfeeding 
should not handle the study drug.  Also children who are not study participants should not handle 
the drug.  If caregivers must handle or come in contact with the drug, it is advised that protective 
gloves be worn. 
Dasatinib should be administered as an oral dose as per the protocol. Subjects do not require 
fasting at the time of dasatinib consumption. Grapefruit juice should not be consumed during 
study drug therapy, as P450 enzyme inhibition may increase drug exposure.  


Protocol No. 2006-0478 
June 23, 2009 
 
32 
If a scheduled dose is missed by more than 6 hours, this dose should be omitted. Missed 
doses should not be made up.  Subjects should be provided with a diary in which to record any 
changes in dosing of study drug. 
Bristol-Myers Squibb will be responsible for assuring that the quality of BMS-354825-03 is 
adequate for the duration of the trial. 
Investigational product should be stored in a secure area, at 59°F to 77°F (15°C to 25°C). 
The Investigator (or assigned designee, i.e., study pharmacist) will dispense the proper number of 
each strength tablet to the subject to satisfy dosing requirements for the study.  The containers 
provided to the subject should be labeled with proper instructions for use.  Subjects should be 
instructed to return all unused drug to the site in the same container.  Re-supplies can be 
obtained by completing the SRC re-supply request form and fax to 203-677-6489 or submit the 
electronic copy to srcsupply@bms.com.  Re-supply requests need to be submitted at-least 2 
weeks before the expected delivery date. 
The lot numbers, dosing start dates and the number of tablets for each dosage strength must be 
recorded on the drug accountability pages of record for the site.  The subject must be instructed 
to return all unused study medications in the provided packaging at each subsequent visit. 
The Investigator must be satisfied the subject returned or accounted for all unused medication 
before additional medication is dispensed.  If the number of tablets used is substantially different 
from the number of tablets dispensed, the subject must be counseled on how study therapy 
should be taken.  If such deviations persist, the Investigator may consider discontinuing the 
subject for non-compliance. 
Investigational product should be stored in a secure area according to local regulations.  It is the 
responsibility of the Investigator to ensure that investigational product is only dispensed to study 
subjects.  The investigational product must be dispensed only from official study sites by 
authorized personnel according to local regulations. 
The Investigator should ensure that the investigational product is stored in accordance with the 
environmental conditions (temperature, light and humidity) as determined by the Sponsor and 
defined in the Investigator Brochure or SmPC/reference label. 
8.1.8 
Investigational Product Records at Investigational Site(s) 
It is the responsibility of the Investigator to ensure that a current record of investigational product 
disposition is maintained at each study site where investigational product is inventoried and 
disposed.  Records or logs must comply with applicable regulations and guidelines, and should 
include: 
Amount received and placed in storage area.  
Amount currently in storage area. 
Label ID number or batch number and use date or expiry date. 
Dates and initials of person responsible for each investigational product inventory 
entry/movement. 
Amount dispensed to and returned by each subject, including unique subject identifiers. 
Amount transferred to another area/site for dispensing or storage. 


Protocol No. 2006-0478 
June 23, 2009 
 
33 
Non-study disposition (e.g., lost, wasted, broken). 
Amount returned to Sponsor. 
Amount destroyed at study site, if applicable. 
Retain samples sent to third party for bioavailability/bioequivalence, if applicable. 
Investigational product dispensing record/inventory logs and copies of signed packing lists must 
be maintained at the investigational site.  Batch numbers for BMS-354825-03 must be recorded in 
the drug accountability records. 
8.1.9 
Return and Destruction of Investigational Product 
8.1.10 Return of Investigational Product 
Upon completion or termination of the study, all unused and/or partially used investigational 
product must be returned to BMS, if not authorized by BMS to be destroyed at the site. 
All investigational products returned to BMS must be accompanied by the appropriate 
documentation and be clearly identified by protocol number and study site number on the 
outermost shipping container.  Returned supplies should be in the original containers.  Empty 
containers should not be returned to BMS.  It is the Investigator’s responsibility to arrange for 
disposal of all empty containers, provided that procedures for proper disposal have been 
established according to applicable federal, state, local, and institutional guidelines and 
procedures, and provided that appropriate records of disposal are kept.  The return of unused 
investigational product(s) should be arranged by the responsible Investigator at the site.  
8.1.11 Destruction of Investigational Product 
If investigational products are to be destroyed on site, it is the Investigator’s responsibility to 
ensure that arrangements have been made for disposal and written authorization has been 
granted by BMS, and that procedures for proper disposal have been established according to 
applicable regulations, guidelines, and institutional procedures.  Appropriate records of the 
disposal must be maintained.  The unused investigational products can only be destroyed after 
appropriate instruction by BMS. 
9. 
ADVERSE EVENTS  
1. See Appendices A and E for guidelines for reporting ADR's. 
2. Adverse Events Requiring Expedited Reporting: Serious unexpected adverse events (SAEs) 
considered associated therapy should be reported to the Principal 
Investigator [Farhad Ravandi, MD, Telephone (71 3) 745-0394 within 48 hours of observing or 
learning of the event.  
3. Expected therapy-related events include those known toxicities or side effects related to the 
components of the chemotherapy as indicated in the Guidelines for AE Reporting for Leukemia 
Phase 2/3 studies (Appendix E). These grade 4 or less events will not be reported as individual 
SAEs, but will be summarized in the annual report to the IRB: Hyperglycemia Electrolyte 
abnormalities, changes in serum lactate dehydrogenase. Renal failure related to tumor lysis 
syndrome, methotrexate, or antibiotic therapy (e.g, AmBisome, aminoglycosides) Cytarabine 
related central nervous system toxicity Catheter-related deep venous thrombosis Coagulation 


Protocol No. 2006-0478 
June 23, 2009 
 
34 
abnormalities during induction chemotherapy (e.g. chemical DIC or hypofibrinogenemia) lleus 
related to vincristine Hepatotoxicity related to methotrexate Post lumbar puncture headaches 
All serious, unusual, life-threatening, or lethal experience which may be due to dasatinib drug 
toxicity will be reported within 24 hrs by telephone to Bristol-Myers Squibb and must be followed 
by a written report which must be received within 10 business days. Information about all serious 
adverse events will be collected and recorded on the Bristol Myers Serious Adverse Event Report 
Form. To ensure patient safety, each serious adverse event must also be reported to Bristol 
Myers within 24 hours of learning of its occurrence.  
Events not considered to be serious events are hospitalizations for the routine treatment or 
monitoring of the studied indication, not associated with any deterioration in condition. Treatment, 
which was elective or pre-planned, for a pre-existing condition that did not worsen. Treatment on 
an emergency, outpatient basis for an event not fulfilling any of the definitions of serious given 
above and not resulting in hospital admission.  
Pregnancy, although itself not a serious adverse event, should also be reported on a serious 
adverse event form or pregnancy form and be followed up to determine outcome, including 
spontaneous or voluntary termination, details of birth, and the presence or absence of any birth 
defects or congenital abnormalities. Any serious adverse event occurring in a patient after 
providing informed consent, while receiving study drug and until 30 days after stopping study drug 
must be reported on the Medwatch Form. The period after discontinuing study drug may be 
extended if there is a strong suspicion that the drug has not yet been eliminated. All serious 
adverse events must also be reported for the period in which the study protocol interferes with the 
standard medical treatment given to a patient (e.g. treatment withdrawal during washout period, 
change in treatment to a fixed dose of concomitant medication. 
 
A serious AE is any untoward medical occurrence that at any dose:   
results in death,  
is life-threatening (defined as an event in which the patient was at risk of death at the time of the 
event; it does not refer to an event which hypothetically might have caused death if it were more 
severe),  
requires inpatient hospitalization or causes prolongation of existing hospitalization,  
results in persistent or significant disability/incapacity,  
is a congenital anomaly/birth defect,  
results in the development of drug dependency or drug abuse,  
is an important medical event (defined as a medical event(s) that may not be immediately life-
threatening or result in death or hospitalization but, based upon appropriate medical and scientific 
judgment, may jeopardize the patient or may require intervention (e.g., medical, surgical) to 
prevent one of the other serious outcomes listed in the definition above.)  Examples of such 
events include, but are not limited to, intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization.) For 
reporting purposes, also consider the occurrences of pregnancy or overdose (regardless 
of adverse outcome) as events which must be reported as important medical events. 
 
Adverse events classified as “serious” require expeditious handling and reporting to BMS 
to comply with regulatory requirements.  
 
All serious AEs whether related or unrelated to investigational product, must be 
immediately reported to BMS (or designee) by confirmed facsimile transmission.  If only 


Protocol No. 2006-0478 
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35 
limited information is initially available, follow-up reports are required.  The original SAE 
form must be kept on file at the study site. 
 
For studies that are IND Exempt, any event that is both serious and unexpected must be 
reported to BMS as soon as possible and, in no event, later than 7 days (death or life-
threatening event) or 15 days (all other SAEs) after the investigator’s or institution’s initial 
receipt of the information.   
 
All SAEs should be faxed to Bristol-Myers Squibb at: 
Global Pharmacovigilance & Epidemiology 
Bristol-Myers Squibb Company 
Fax Number:  609-818-3804 
 
 
For studies conducted under an Investigator IND, any event that is both serious and 
unexpected must be reported to the FDA as soon as possible and, in no event, later than 
7 days (death or life-threatening event) or 15 days (all other SAEs) after the investigator’s 
or institution’s initial receipt of the information.  Bristol-Myers Squibb will be provided with 
a simultaneous copy via facsimile of all adverse events filed with the FDA.  SAEs should 
be reported on the MedWatch Form 3500A, or other institutional or group form. 
SAEs should be sent to the FDA at: 
MEDWATCH 
5600 Fishers Lane 
Rockville, MD  20852-9787 
Fax:  1-800-FDA-0178 (1-800-332-0178) 
All SAEs should simultaneously be faxed to Bristol-Myers Squibb at: 
Global Pharmacovigilance & Epidemiology 
Bristol-Myers Squibb Company 
Fax Number:  609-818-3804 
 
 
Collection of complete information concerning SAEs is extremely important.  Full 
descriptions of each event will be followed by BMS. Thus, follow-up information which 
becomes available as the SAE evolves, as well as supporting documentation (e.g., 
hospital discharge summaries and autopsy reports), should be collected 
subsequently, if not available at the time of the initial report, and immediately sent 
using the same procedure as the initial SAE report. 
 
An overdose is defined as the accidental or intentional ingestion of any dose of a 
product that is considered both excessive and medically important.  For reporting 


Protocol No. 2006-0478 
June 23, 2009 
 
36 
purposes, BMS considers an overdose, regardless of adverse outcome, as an 
important medical event (see Serious Adverse Events). 
 
In BMS supported trials, all SAEs must be collected which occur within 30 days of 
discontinuation of dosing or completion of the patient’s participation in the study if the 
last scheduled visit occurs at a later time.  In addition, the Investigator should notify 
BMS of any SAE that may occur after this time period which they believe to be 
certainly, probably or possibly related to investigational product. 
10. 
STATISTICAL METHODOLOGY 
1. The major study objective is to evaluate the event-free survival after hyper-CVAD plus 
dasatinib and achieve a 2-year EFS rate > 60% (based on reported data from hyperCVAD plus 
imatinib)21. The study is expected to accrue 115 patients (previously untreated, or after having 
received one or two prior course of chemotherapy, or relapsed) over approximately 2 years 
(referral pattern of 15 to 20 patients/year, accrual completed in 12 to 24 months), with an 
additional 12 months of follow-up. This will allow estimates of CR rates and disease-free 
survivals. Disease-free survival is the time from documented CR until relapse or death. Event-free 
survival is the time from treatment until any failure (resistant disease, relapse, or death). The 
results will be compared descriptively to historical controls in terms of response, survival, toxicity, 
etc. (recently published data). A 95% confidence interval width will be approximately 11% for the 
CR rate estimated with 115 patients. 
 
2. It is expected that the addition of dasatinib will achieve an efficacy superior to that obtained 
with the hyper-CVAD program alone and superior to hyper-CVAD plus imatinib mesylate. The trial 
will be monitored for possible early termination if there is evidence that the rate of response is not 
at least equivalent to that observed on the previous hyper-CVAD trial (26 CR of 29 patients). 
Observation of the following number of responses or fewer per number of patients evaluated will 
be regarded as evidence for termination: 2/5, 6/10, 10/15, 14/20, 18/25, 21/30, 25/35, 29/40, 
33/45, 37/50, 41/55, 45/60, 49/65, 53/70, 57/75, 61/80, 65/85, 69/90,73/95,77/100,81/105, 
85/110, or 89/115 on the basis that there is < 5% probability that efficacy is superior to that of 
hyper-CVAD. Using these guidelines, simulation results indicate the following expected results for 
several values of CR rate:  
 
True rate of CR 
Probability of early termination 
recommendation 
Expected median sample size 
(25%, 75%) 
0.6 
>0.99 
5 (5, 10) 
0.7 
0.98 
15 (10, 35) 
0.8 
0.50 
110 (20,115) 
0.85 
0.16 
115 (115, 115)  
0.9 
0.03 
115 (115, 115) 
0.95 
0.01 
115 (115, 115) 
 
 
The molecular CR rate with hyper-CVAD is not known. Quantification of bcr-abl will be measured 
prospectively and analyzed by descriptive statistics. 
 
3. Hyper-CVAD alone has very low toxicity (<5%). In this combination trial, if the toxicity rate is 
too high (Pr[Toxicity rate > 5%|Data] > 0.9), then the trial will be stopped (toxicity is defined at the 


Protocol No. 2006-0478 
June 23, 2009 
 
37 
beginning of this section). Specifically, the trial will be stopped if the number of patients 
experiencing unacceptable (as defined in section 9.0) toxicities /total number of patients is greater 
than or equal to 2/5, 3/12, 4/24, 5/37, 6/51, 7/65, 8/79, 9/100, or 10/109. The probability to stop 
the trial early is 0.02, 0.12, 0.73, 0.98 or >0.99 when the true toxicity rate is 0.03, 0.05, 0.10, 0.15 
or 0.20 respectively. 
 
 
4. A separate analysis will be carried out for previously treated patients (who have received one 
or two prior course of therapy). The historical number of Philadelphia-positive patients presenting 
after failure of one course of chemotherapy is one of 204 patients (< 1%). The historical rate of 
patients who achieved a CR after one course of chemotherapy continuing on hyper-CVAD at 
MDACC is 4 of 208 patients (2%). None were Ph-positive. Thus, the expected number of patients 
in this category is expected to be small. Patients who have failed one course of non-hyper-CVAD 
chemotherapy will be assessed for CR rate (historical CR rate for ALL overall is 5 of 6 [83%]) and 
disease-free survival.  Patients presenting in CR will be assessed for disease-free survival and 
toxicity only. 
 
5. A separate analysis will also be carried out for patients with relapsed disease, i.e. those with 
Ph-positive ALL or lymphoid blast phase of chronic myeloid leukemia who have failed (after 
achieving an initial response) prior therapy which does not include dasatinib. It is expected that 
40 patients will be enrolled in this category alone. Patients will be evaluated for response, toxicity, 
event-free survival and disease-free survival. 
 
6.Despite best efforts, the expected rate of allogeneic transplant is at best 20%, with failure due 
to lack of a suitable donor, age or performance status characteristics, comorbid conditions, or 
relapse of their disease prior to planned transplant. Patients who successfully undergo allogeneic 
transplant will be censored for disease-free survival at the time of transplant. Those patients who 
successfully complete allogeneic transplant prior to completion of the program will be replaced. 
 
10A. Data Confidentiality Plan 
Data from this clinical trial will be shared with which is a retrospective data analysis study.  
2006-0478 new testing will be undertaken on any specimen. (See Waiver of Informed Consent.) 
 
 
11. 
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46.       Thomas DA, Faderl S, O’Brien S, et al. Chemoimmunotherapy with hyper-CVAD plus 
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