Phase I Study of Dasatinib in Recipients of Allogeneic Stem Cell Transplantation for Hematologic Malignancies.
Phase: PHASE1
Conditions: Non-Hodgkin's Lymphoma, Hodgkin's Lymphoma, Myeloid Leukemia, Multiple Myeloma, Myelodysplastic Syndrome, Lymphoid Leukemia
Sponsor: Barbara Ann Karmanos Cancer Institute

 
2011-204:  Phase I/II Study of Dasatinib in Recipients of Allogeneic Stem Cell 
Transplantation for Hematologic Malignancies. 
 
BMS Protocol Number:  
CA-180-384 
 
Principal Investigator: 
Abhinav Deol, MD 
Email: deola@karmanos.org 
Phone: (313) 576-8093 
Fax: (313) 576-8766 
 
Co-Investigators: 
Charles Schiffer, MD 
Email: schiffer@karmanos.org 
Phone: (313) 576-8730 
Fax: (313) 576-8766 
 
Voravit Ratanatharathorn, MD 
Email: ratanath@karmanos.org 
Phone: (313) 576-8787 
Fax: (313) 576-8766 
 
 
Joseph P. Uberti, MD, PhD 
Email: ubertij@karmanos.org 
Phone: (313) 576-8754 
Fax: (313) 576-8766 
 
Lois J. Ayash, M.D. 
Email: ayashl@karmanos.org 
Phone: (313) 576-8711 
Fax: (313) 576-8766 
 
Divaya Bhutani, M.D. 
Email: bhutanid@karmanos.org 
Phone: (313) 576-8724 
Fax: (313) 576-8766 
 
Lawrence G. Lum, M.D., D.Sc. 
Email: luml@karmanos.org 
Phone: (313) 576-8326 
Fax: (313) 576-8939 
 
Statistics: 
Judith Abrams, PhD 
Email: abramsj@karmanos.org 
Phone: (313) 576 8651 
Fax: (313) 576- 8766 
 
Barbara Ann Karmanos Cancer Institute 

 
Wayne State University School of Medicine 
Detroit, Michigan 48201 
 
 
Version:  Amendment 2.0 30-September-2015 
 
Original 27-October-2011 
Revised 14-December-2011 
15-February-2012 
         26-April-2012 
         15-May-2012 
         30-September-2015 
2 
 

 
Table of Contents 
 
1. OBJECTIVES………………….……………………………………………………………… 1 
2. BACKGROUND……………………………………………………………………………… 
1 
3. ELIGIBILITY CRITERIA………………………......………………………………………… 
3 
 
3.1 Inclusion Criteria………………………………………………………………….. 
3 
 
3.2 Exclusion Criteria…………………………………………………………………. 
4 
4. DRUG INFORMATION……………………………………………………………………… 
5 
 
4.1 Product Description………………………………………………………………. 
5 
 
4.2 Pharmacokinetics…………………………………………………………………. 
5 
 
4.3 Drug Interaction…………………………………………………………………… 
6 
 
4.4 Common Adverse Effects………………………………………………………... 
9 
 
4.5 Lab Anomalies with Dasatinib…………………………………………………… 
13 
 
4.6 Warning and Precautions…………………………………………………………. 14 
5. DRUG SUPPLY……………………………………………………………………….. ……. 
15 
 
5.1 Packaging and Labeling…………………………………………………………. 
15 
 
5.2 Storage……………………………………………………………………………. 
16 
 
5.3 Handling and Dispensing………………………………………………………… 
16 
 
5.4 Drug Ordering……………………………………………………………………… 16 
 
5.5 Drug Accountability……………………………………………………………….. 
16 
6. TREATMENT SCHEMA……………………………………………………………………… 17 
7. REGISTRATION, DEFINITIONS, ENDPOINTS AND STATISTICAL ANALYSIS………. 18 
 
7.1 Protocol Registration……………………………………………………………… 18 
7.2 Definition of Dose-Limiting Toxicity…………………………………………….... 18 
 
7.3 Large Granular Lymphocytosis- Definition……………………………………… 19 
7.4 Dose Escalation – Rules and Definitions………………………………………...  19 
             7.5 Stopping Rules……………………………………………………………………... 19 
7.6 Discontinuation of Subjects from Treatment…………………………………….. 20 
7.7 Estimation of Probability of LGL …………………………………………………. 20 
8. STUDY MONITORING……………………………………………………………………….. 21 
 
8.1 Pre-Enrollment Clinical and Laboratory Requirements………………………… 21 
 
8.2 Clinical Monitoring………………………………………………………………….. 21 
 
8.3 Laboratory Monitoring……………………………………………………………... 21 
 
8.4 Sample Collection for Correlative studies………………………………………... 22 
 
8.5 Study Calendar……………………………………………………………………... 22 
9. DATA COLLECTION AND REPORTING....................................................................... 23 
 
9.1 Outcomes…………………………………………………………………………… 23 
9.2 Assignment of Adverse Event Intensity and Relationship to Dasatinib………. 23 
 
9.3 Collection and Reporting Adverse Events………………………………………. 24 
 
 
9.3.1 Serious Adverse Events………………………………………………. 24 
 
 
9.3.2 Non Serious Adverse Events………………………………………… 
25 
 
 
9.3.3 Overdose………………………………………………………………. 
25 
 
 
9.3.4 Pregnancy……………………………………………………………… 
25 
 
 
9.3.5 Handling of Expedited Safety Reports……………………………… 
26 
10. ETHICAL CONSIDERATION……………………………………………………………… 
27 
 
10.1 Good Clinical Practice…………………………………………………………… 27 
 
10.2 Protocol Review/IRB…………………………………………………………….. 27 
 
10.3 Informed Consent………………………………………………………………… 27 
11. DATA SAFETY AND MONITORING……………………………………………………… 27 
12. REFERENCES……………………………………………………………………………… 
29
3 
 

1. OBJECTIVES 
 
PRIMARY: 
 
To establish the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of dasatinib 
in the recipient of allogeneic stem cell transplantation (ASCT) for hematologic malignancies. 
 
SECONDARY 
 
1. To estimate the non-DLTs associated with administration of dasatinib in ASCT recipients 
 
2. To estimate the incidence of large granular lymphocytosis (LGL) and its clinical course in 
recipients of ASCT 
 
3. To perform correlative in vitro studies to see if the large granular lymphocytes show 
enhanced cytotoxicity to leukemia/ lymphoma cell lines 
 
2. BACKGROUND 
 
Immune reconstitution after ASCT follows the developmental ontogeny of the immune system.  
Regardless of the sources of the stem cell, natural killer (NK) cells usually recover within the 
first month after stem cell transplant1-4. The pattern of T-cell immune recovery is similar in both 
autologous and allogeneic transplantation at least in the pediatric populations.  Prompt 
recovery of NK cells might decrease the risk of viral infections as well as enhance the graft-
versus-malignancy effect 5.  In 1995, Dolstra et al reported the expansion of CD8+/CD57+ 
cells in 46% of the recipients of T-depleted stem cell transplant6. Importantly, recipients with 
an expanded population of CD8+/CD57+ T cells showed a lower incidence of leukemic 
relapse than those without LGL. The 3-year probability of relapse was 19% versus 64% (P = 
0.03), respectively.  Subsequently, Mohty et al reported the first case of large granular 
lymphocyte expansion in a patient who received non-myeloablative conditioning regimen7.  
Further studies by the same investigators reported 6 cases of LGL expansion that occurred 
among 201 consecutive patients.  The LGL expansion was seen more frequently following 
fludarabine and anti-T lymphocyte globulin-based preparative regimens (4 cases/49), than 
after a conventional myeloablative regimen (2 cases/152).  Expansion of LGL was seen 
between 3 and 15 months following ASCT.  These patients had mild to severe cytopenia and 
other autoimmune manifestations including polyarthritis and hypergammaglobulinemia were 
also observed.   
We reported our own experience with LGL in recipients of ASCT in 2009 8. This retrospective 
study was done on all adult patients who underwent ASCT at the Karmanos Cancer Institute 
(KCI) between January 1, 2004 and June 30, 2009. In patients with persistent lymphocytosis 
(≥ 3000 cells/mm3) post ASCT, expansion of LGL phenotype was identified by flow cytometry 
(CD2, CD3, CD5, CD7, CD8 and CD57 positive) and clonality was confirmed by T cell 
receptor beta and/or gamma gene rearrangement (TCR-GR) using southern blot analysis and 
polymerase chain reaction (PCR).   We identified LGL in 24 patients with persistent 
lymphocytosis using flow cytometry. The median age of patients with LGL expansion was 50 
years (range 24-68 years); with a median time to detection of 275 days post HSCT (range 69-
1454 days) and median duration of follow-up was 811 days (range 85-1701 days). All 24 
patients achieved full donor chimerism post transplantation by short tandem repeat (STR) 
analysis. Fourteen of 24 patients with T-LGL expansion had positive TCR-GR; in 2 patients 
 
 
1 
Revised: 09/30/15 
 
 

 
TCR-GR was not done and in the remainder was negative. Twenty of 24 patients had 
cytomegalovirus (CMV) viremia confirmed by PCR before the onset of T-LGL; the remainder 
had no CMV viremia. In all patients with LGL there was no subsequent recurrence of CMV 
viremia or infection. All 24 patients had documented graft versus host disease (GvHD). In the 
group with LGL only 2 patients relapsed with primary disease and only one patient died (due 
to a cardiac event). The cumulative incidence of LGL was estimated at 4.4%.  
We have now extended our series to 46 patients, with estimated incidence of LGL of 8% (95% 
CI, 6%-10%) (Unpublished): 17 of 250 patients who received allogeneic grafts from family-
related donors (6.8%; 95% CI, 4%-11%), and 29 of 359 patients who received allogeneic 
grafts from unrelated donor (8%; 95% CI, 5%-11%) (P = 0.44, Fisher’s exact test) developed 
LGL. Using a landmark analysis at 6 months, patients who developed LGL expansion had a 
significantly better survival than those who did not develop LGL expansion (p=0.046).  
  
Recently, several investigators reported that one of the immunomodulatory effects of dasatinib 
in patients treated for CML may include an expansion of LGL9-11.  A study by Kreutzman et al 
observed that 10 of 20 patients with CML treated with dasatinib developed a clonal expansion 
of lymphocytes with T/NK cell phenotypes.  A similar group of patients treated with imatinib did 
not show the same clonal expansion.   In addition this clonal expansion of T/NK cells was 
associated with favorable treatment response and survival compared to patients without clonal 
expansion.  
At Karmanos, we observed 4 cases of LGL among 15 patients treated with dasatinib (26.6%); 
2 of these patients were treated for blast crisis with dasatinib alone and remain in molecular 
remission12, 13. Subsequently, Schiffer et al analyzed the data on 1897 patients who were 
treated in phase II and phase III studies of dasatinib after 2 years of treatment 14. 
Lymphocytosis was observed in a large proportion of dasatinib-treated patients in chronic 
(31%), accelerated (39%), and myeloid blast (34%) phase, also the incidence of 
lymphocytosis was similar in patients in chronic phase receiving total doses of 100 or 140 mg 
p = 0.046
LGL
No LGL
0.00
0.25
0.50
0.75
1.00
Overall Survival
46
42
31
20
13
5
0
LGL
343
268
176
122
79
38
14
No LGL
Number at risk
0
12
24
36
48
60
72
Follow-up Time (mos)
 
 
 
2 
Revised: 09/30/15 

 
of dasatinib. The same authors then evaluated the occurrence of lymphocytosis in patients 
participating in a phase III randomized study comparing 12-month therapy with dasatinib vs. 
imatinib 15.  Patients who received dasatinib developed lymphocytosis more frequently (24% 
vs. 5%) and earlier (3 months vs. 4.7 months) than patients who received imatinib.  
Furthermore, in dasatinib treated patients, lymphocytosis was associated with a higher 
complete cytogenetic response (CCyR) rate (84% with vs. 75% without). In both studies, the 
incidence of pleural effusions was higher in patients who developed lymphocytosis.  
Unfortunately flow cytometry data is not available form these large muticenter studies to 
confirm that the lymphocytosis in these patients was indeed LGL. These observations 
suggested that lymphocytosis associated with dasatinib therapy might confer 
immunomodulatory and antitumor activity.  Further elucidation of the biology of TKI-induced 
lymphocytosis is needed.   
 
Combining the observations of spontaneous LGL expansion in allogeneic transplant setting 
with the dasatinib associated LGL expansion, we hypothesize that dasatinib therapy in 
recipients of allogeneic transplantation might favor the expansion of LGL, which may confer 
antitumor effects.  In this proposal, we want to explore the tolerance and dose-limiting toxicity 
of dasatinib in recipients of allogeneic transplantation and to estimate the frequency of 
development of expansion of LGL at the optimal dose 
 
3. ELIGIBILITY CRITERIA 
 
3.1. Inclusion Criteria 
 
1. Recipients of first ASCT from related or unrelated donor for the treatment of 
hematologic malignancies (Acute myeloid leukemia, Chronic Myeloid leukemia, 
Acute Lymphoblastic leukemia, Chronic Lymphocytic Leukemia, Myelodysplastic 
syndrome Hodgkins and Non Hodgkin Lymphoma) who are 1-antigen or 1-allele 
mismatched or fully matched at HLA-A, -B, -C and –DR as defined by high resolution 
typing. 
2. Patients must be ≥18 years of age. 
3. Patients must be between 100 - 200 days after allogeneic stem cell transplantation. 
4. Dasatinib use prior to ASCT is allowed 
5. Performance Status ≥60% 
6. Presence of LGL clone prior to enrollment will not be an exclusion criterion if the LGL 
clone is < 25% of T cell population 
7. Adequate Organ Function 
a. Total bilirubin < 2.0 times the institutional Upper Limit of Normal (ULN) 
b. Hepatic enzymes (AST, ALT ) ≤ 2.5 times the institutional ULN  
c. Serum Creatinine < 1.5 time the institutional ULN 
d. Hemoglobin ≥8 g/dL, absolute neutrophil count ≥1,500 cells per µL and 
platelets ≥ 75,000 per µL. 
8. Patient should be able to provide signed Written Informed Consent 
a. Before any  s tudy pr ocedures a re pe rformed, s ubjects w ill ha ve t he 
details of the study described to them, and they will be given a written 
informed c onsent doc ument t o r ead. Then, i f s ubjects c onsent t o 
participate in t he study, they will indicate t hat consent by signing and 
dating the informed consent document in the presence of study 
personnel. 
 
 
3 
Revised: 09/30/15 

 
b. Written consent will include a HIPAA form according to institutional 
guidelines 
9. Patient should be able to take oral medication (dasatinib must be swallowed whole) 
 
3.2.  Exclusion Criteria 
 
1. Recipient of mismatched (allele or antigen level) graft in more than one loci of HLA-
A, -B, -C or –DR loci will not be eligible, i.e. recipients of 2-antigen or 2-allelele 
mismatched graft 
2. Patients on investigational therapy for GVHD 
3. Patients with uncontrolled acute or chronic GVHD or refractory disease not 
responding to conventional therapy 
4. Patients who have evidence of disease progression before day 100 after ASCT 
5. Sex and Reproductive Status 
a. WOCBP who are unwilling or unable to use an acceptable method to 
avoid pregnancy for the entire study period and f or at least 4 weeks 
after the last dose of study drug.  
b. Women who are pregnant or breastfeeding. 
c. Women with a positive pregnancy test. 
d. Sexually active fertile men not  using effective bi rth control if their 
partners are WOCBP 
6. Medical history and concurrent diseases 
a. No m alignancy [ other than for which patient underwent t ransplant] 
which r equired r adiotherapy or  s ystemic t reatment w ithin t he pas t 5 
years. 
b. Concurrent medical condition which may increase the risk of toxicity, 
including: 
I. Pleural or pericardial effusion of any grade at the time of screening 
for study 
II. Cardiac S ymptoms; any  o f the following s hould be c onsidered for 
exclusion:   
 Uncontrolled angina, c ongestive heart failure or  MI within (6 
months) 
 Diagnosed congenital long QT syndrome 
 Any history of clinically significant ventricular arrhythmias 
(such as ventricular tachycardia, ventricular fibrillation, or 
Torsades de pointes) 
c. History of significant bleeding disorder unrelated to cancer, including: 
 
Diagnosed c ongenital bl eeding di sorders ( e.g., von Willebrand’s 
disease) 
 
Diagnosed acquired bl eeding disorder within one year (e.g., 
acquired anti-factor VIII antibodies) 
 
Ongoing or recent (≤ 3 months) significant gastrointestinal 
bleeding 
7. Any previous history of ≥ grade 3 toxicity to Dasatinib 
8. Prohibited treatments and or therapies  
 
 
4 
Revised: 09/30/15 

 
a. Category I drugs that are generally accepted to have a risk of causing 
Torsades de P ointes including: (Patients must discontinue drug 7 days 
prior to starting dasatinib) 
 
quinidine, procainamide, disopyramide 
 
amiodarone, sotalol, ibutilide, dofetilide 
 
erythromycin, clarithromycin 
 
chlorpromazine, haloperidol, mesoridazine, thioridazine, pimozide 
 
cisapride, bepridil, droperidol, methadone, arsenic, chloroquine, 
domperidone, halofantrine, levomethadyl, pentamidine, 
sparfloxacin, lidoflazine. 
b. Patient agrees to discontinue St. Johns Wort while receiving dasatinib 
therapy (discontinue St. Johns Wort at least 5 days before starting 
dasatinib) 
c. Patient agrees that I V bisphosphonates will be withheld f or t he first 8 
weeks of dasatinib therapy due to risk of hypocalcemia 
9. Other exclusion criteria 
a. Prisoners or subjects who are involuntarily incarcerated. 
b. Subjects w ho ar e c ompulsorily det ained f or treatment o f ei ther a 
psychiatric or physical (egg, infectious disease) illness. 
 
4. DRUG INFORMATION  
 
4.1 Product  Description 
 
SPRYCEL® 16 (dasatinib, Bristol-Myers Squibb [BMS]-354825) is a potent, broad 
spectrum inhibitor of 5 critical oncogenic tyrosine kinases/kinase families (BCR-ABL, 
SRC, c-KIT, PDGF receptor β [PDGFRβ], and ephrin [EPH] receptor kinases), each of 
which is linked to multiple forms of human malignancies, and was discovered and 
developed by BMS. SPRYCEL is approved in the United States (US), Europe (EU), and 
several other countries for the treatment of adults in all phases of chronic myeloid 
leukemia (CML) with resistance or intolerance to prior therapy including imatinib, and 
Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL) who are 
resistant or intolerant to prior therapy17.  
The recommended starting dosage for subjects with chronic phase CML is 100 mg 
administered orally once daily (QD). The recommended starting dosage for accelerated 
phase CML, myeloid or lymphoid blast phase CML, or Ph+ ALL is 140 mg/day 
administered orally once daily. In clinical studies of adult CML and Ph+ ALL patients, 
dose escalation to 140 mg once daily (chronic phase CML) or 180 mg once daily 
(advanced phase CML and Ph+ ALL) was allowed in patients who did not achieve a 
hematologic or cytogenetic response at the recommended starting dosage. 
 
4.2 Pharmacokinetics 
 
Dasatinib is rapidly absorbed following oral administration in subjects with leukemia.18  
Across all treatment regimens, disease status, and study days; mean Cmax values were 
attained at median Tmax values that ranged from 0.45 to 3.18 hours postdose. The 
overall median Tmax value was approximately 1 hour. There was no influence of 
treatment regimens, disease status, or study days on the half-life (T-HALF) of dasatinib. 
 
 
5 
Revised: 09/30/15 

 
The overall mean T-HALF value was approximately 3 to 5 hours. Dasatinib has an 
apparent volume of distribution of 2505 L, suggesting that the drug is extensively 
distributed in the extravascular space. There were no clinically meaningful relationships 
between steady state CLo and body weight or body surface area. Statistical linear 
regression analyses were performed on log (AUC) versus log (DOSE) to assess dose 
proportionality. The AUC of dasatinib is approximately dose proportional in the dose 
range of 15 to 240 mg/day, suggesting that the drug exhibited linear kinetics over the 
entire dose range. However, the 90% CIs are wide, indicating that the variability in AUC 
is high. There was no marked effect of disease state, age, gender, and race on the PK 
parameters CLo, Vz/F, and T-HALF, suggesting that dose adjustment in these 
subpopulations may not be necessary.19 The geometric mean accumulation index (AI) 
ranged from 1.01 to 1.61 between days 5/8 and 26/29 and no consistent dose-related 
trends were observed in the accumulation of dasatinib after repeated administration. 
Data from a study of 54 healthy subjects administered a single, 100 mg dose of 
dasatinib 30 minutes following consumption of a high-fat meal resulted in a 14% 
increase in the mean AUC of dasatinib.20 The observed food effects were not clinically 
relevant.  
Dasatinib is extensively metabolized in humans. Unchanged dasatinib represented 29% 
of circulating radioactivity in plasma after a 100 mg dose of [14C]-labeled dasatinib was 
administered to 8 healthy subjects in study CA180019.21 Elimination is predominantly in 
the feces, mostly as metabolites. Following a single oral dose of [14C]-labeled dasatinib, 
approximately 85% of the dose was recovered in the feces within 10 days, and 
approximately 4% of the administered radioactivity was recovered in the urine. 
The cytochrome p450 enzyme CYP3A4 plays a major role in the metabolism of dasatinib 
in the humans. Dasatinib has little potential to induce CYP3A4 and, at concentrations 
≤ 25 μM (1 μM = 488 ng/mL), dasatinib did not induce CYP1A2, CYP2B6, CYP2C9, and 
CYP3A4 in primary cultures of human hepatocytes.22 Based on these data and plasma 
concentrations observed in vivo, dasatinib is unlikely to decrease the exposure of co-
administered drugs that are metabolized by CYP1A2, CYP2B6, CYP2C9, or CYP3A4. In 
human liver microsomes, dasatinib did not inhibit CYP1A2, CYP2B6, CYP2C19, 
CYP2D6, or CYP2E1 at concentrations up to 50 μM.22 It inhibited CYP2A6 
(IC50 = 35 μM), CYP2C8 (IC50 = 12 μM), CYP2C9 (IC50 = 50 μM), and CYP3A4 (IC50 
values of 18 and 10 μM for midazolam and testosterone substrates, respectively).22  
 
4.3 Drug Interactions 
 
4.3.1 Drugs That May Increase Dasatinib Plasma Concentrations 
CYP3A4 Inhibitors:  Dasatinib is a CYP3A4 substrate. In a study of 18 patients 
with solid tumors, 20-mg SPRYCEL once daily co administered with 200 mg of 
ketoconazole twice daily increased the dasatinib Cmax and AUC by four- and 
five-fold, respectively. Concomitant use of SPRYCEL and drugs that inhibit 
CYP3A4 may increase exposure to dasatinib and should be avoided. In patients 
receiving treatment with SPRYCEL, close monitoring for toxicity and a SPRYCEL 
dose reduction should be considered if systemic administration of a potent 
CYP3A4 inhibitor cannot be avoided. 
 
4.3.2 Drugs That May Decrease Dasatinib Plasma Concentrations 
CYP3A4 Inducers: When a single morning dose of SPRYCEL was administered 
following 8 days of continuous evening administration of 600 mg of rifampin, a 
potent CYP3A4 inducer, the mean Cmax and AUC of dasatinib were decreased 
by 81% and 82%, respectively. Alternative agents with less enzyme induction 
 
 
6 
Revised: 09/30/15 

 
potential should be considered. If SPRYCEL must be administered with a 
CYP3A4 inducer, a dose increase in SPRYCEL should be considered.  
 
4.3.3 Antacids: Nonclinical data demonstrate that the solubility of dasatinib is pH 
dependent. In a study of 24 healthy subjects, administration of 30 mL of 
aluminum hydroxide/magnesium hydroxide 2 hours prior to a single 50-mg dose 
of SPRYCEL was associated with no relevant change in dasatinib AUC; 
however, the dasatinib Cmax increased 26%. When 30 mL of aluminum 
hydroxide/magnesium hydroxide was administered to the same subjects 
concomitantly with a 50-mg dose of SPRYCEL, a 55% reduction in dasatinib 
AUC and a 58% reduction in Cmax were observed. Simultaneous administration 
of SPRYCEL with antacids should be avoided. If antacid therapy is needed, the 
antacid dose should be administered at least 2 hours prior to or 2 hours after the 
dose of SPRYCEL.  
 
4.3.4 H2 Antagonists/Proton Pump Inhibitors: Long-term suppression of gastric acid 
secretion by H2 antagonists or proton pump inhibitors (egg, famotidine and 
omeprazole) is likely to reduce dasatinib exposure. In a study of 24 healthy 
subjects, administration of a single 50-mg dose of SPRYCEL 10 hours following 
famotidine reduced the AUC and Cmax of dasatinib by 61% and 63%, 
respectively. In a study of 14 healthy subjects, administration of a single 100-mg 
dose of SPRYCEL 22 hours following a 40-mg omeprazole dose at steady state 
reduced the AUC and Cmax of dasatinib by 43% and 42%, respectively. The 
concomitant use of H2 antagonists or proton pump inhibitors with SPRYCEL is 
not recommended. The use of antacids (at least 2 hours prior to or 2 hours after 
the dose of SPRYCEL) should be considered in place of H2 antagonists or 
proton pump inhibitors in patients receiving SPRYCEL therapy.  
 
4.3.5 Drugs That May Have Their Plasma Concentration Altered By Dasatinib 
CYP3A4 Substrates: Single-dose data from a study of 54 healthy subjects 
indicate that the mean Cmax and AUC of simvastatin, a CYP3A4 substrate, were 
increased by 37% and 20%, respectively, when simvastatin was administered in 
combination with a single 100-mg dose of SPRYCEL. Therefore, CYP3A4 
substrates known to have a narrow therapeutic index such as alfentanil, 
astemizole, terfenadine, cisapride, cyclosporine, fentanyl, pimozide, quinidine, 
sirolimus, tacrolimus, or ergot alkaloids (ergotamine, dihydroergotamine) should 
be administered with caution in patients receiving SPRYCEL. 
 
4.3.6 Drugs That May Prolong QT Interval:  Dasatinib may prolong QT interval and 
caution is need when used with other drugs that prolonged QT interval e.g. 
amiodarone, disopyramide, quinidine and procainamide; or conditions that 
prolonged QT interval such as hypokalemia and hypomagnesemia. 
4.3.7 Medications that Inhibit Platelet Function and Anticoagulants: Src-family kinase 
inhibition potentially reduces platelet aggregation. Caution should thus be 
exercised if subjects are required to take medications that inhibit platelet function 
or anticoagulants. Such medications include: 
a. aspirin or aspirin-containing combinations, clopidogrel, dipyridamole 
b. tirofiban, di pyridamole, epoprostenol, ept ifibatide, c ilostazol, abc iximab, 
ticlopidine, cilostazol 
 
 
7 
Revised: 09/30/15 

 
c. warfarin, heparin/low molecular weight heparin [eg, danaparoid, 
dalteparin, tinzaparin, enoxaparin] 
d. exceptions ar e low-dose warfarin for p rophylaxis t o prevent c atheter 
thrombosis and heparin for flushes of intravenous lines. 
 
4.3.8 Commonly Used Drugs in Allogeneic Transplantation and Interaction 
 
Immunosuppressants 
Cyclosporine  
Increase cyclosporine exposure 
Increase dasatinib exposure 
Tacrolimus 
Increase tacrolimus exposure 
Increase dasatinib exposure 
Sirolimus 
Increase sirolimus exposure 
Mycophenolate mofetil 
No interaction 
Methotrexate 
No interaction 
 
SSRI 
Fluoxetine 
Increase QT by additive effect 
Paroxetine 
No interaction 
Citalopram 
Increase citalopram exposure 
Sertraline 
Increase sertraline exposure 
 
Benzodiazepines/Psychotropic and other CNS drugs 
Lorazepam 
No interaction 
Clonazepam 
Increase clonazepam exposure 
Alprazolam 
Increase alprazolam exposure 
Zolpidem  
Increase zolpidem exposure 
Bupropion 
No interaction 
Gabapentin 
No interaction 
Sumatryptan 
No interaction 
 
Opioids  
Tramadol 
Increase tramadol exposure 
Methadone 
Increase QT interval 
Increase methadone exposure 
Increase dasatinib exposure 
Oxycodone 
Increase oxycodone exposure 
Morphine 
No interaction 
Hydromorphone 
No interaction 
 
Anti-infectives 
Penicillins 
No interaction 
Cephalosporins 
No interaction 
Azithromycin 
No interaction 
Doxycycline 
No interaction 
Erythromycin 
Increase dasatinib exposure 
Norfloxacin  
Increase QT interval 
Ciprofloxacin 
Increase QT interval 
Increase dasatinib exposure 
 
 
8 
Revised: 09/30/15 

 
Levofloxacin 
Increase QT interval 
Increase dasatinib exposure 
Co-trimoxazole 
No interaction 
Itraconazole 
Increase dasatinib exposure 
Fluconazole 
Increase QT interval 
Increase dasatinib exposure 
Voriconazole 
Increase QT interval 
Increase dasatinib exposure 
Rifampin 
Increase dasatinib exposure 
Acyclovir 
No interaction 
Valciclovir 
No interaction 
Valganciclovir 
No interaction 
Ganciclovir 
No interaction 
Lamivudine 
No interaction 
 
 
For Drugs not included in the table above please refer to article by Haouala et 
al23 
 
4.4 Common Adverse Drug Reactions (ADRs):  
 
The data presented in Table below reflect exposure to dasatinib in 2182 patients 
with leukemia in clinical studies (starting dosage 100 mg once daily, 140 mg 
once daily, 50 mg twice daily, or 70 mg twice daily). The median duration of 
therapy was 11 months (range 0.03–26 months).  
The majority of dasatinib-treated patients (1,864 [85%]) experienced at least 
1 drug-related adverse reaction at some time. Drug was discontinued for adverse 
reactions in 14% (296/2182) of subjects. Drug related AEs leading to 
discontinuation in any 1 category occurred in ≤1% of the subjects with the 
exception of pleural effusion (85/2182; 4%). In subjects with chronic phase CML, 
drug-related pleural effusion accounted for discontinuation in 52 of the 1150 
subjects. Only 1 subject in the 100 mg QD group had discontinuation due to 
drug-related pleural effusion compared with 35 subjects in the 70 mg BID group. 
In subjects with advanced phase CML or Ph+ ALL, drug-related pleural effusion 
accounted for discontinuation in 33 of the 1032 subjects. Six subjects in the 
140 mg QD group had discontinuation due to drug-related pleural effusion 
compared with 27 subjects in the 70 mg BID group. 
Overall, 59% (1287/2182) of subjects across all disease phases reported SAEs 
(any grade). Drug-related SAEs were reported in 53% (681/2182) of subjects. In 
subjects with chronic phase CML, notable common drug-related AEs included 
dyspnea, pleural effusion, congestive heart failure, febrile neutropenia, and 
thrombocytopenia. In most cases, a lower proportion of subjects in the 100 mg 
QD group reported drug-related SAEs than subjects in the 70 mg BID or other 
dose groups. In subjects with advanced phase CML or Ph+ ALL, notable 
common drug-related AEs included dyspnea, pleural effusion, diarrhea, and 
hematological toxicities. In most cases, there was little difference in these SAEs 
between the 140 mg QD and 70 mg BID groups. Rates of severe drug-related 
pleural effusion were lower in the 140 mg QD group (3%) vs. the 70 mg BID 
(6%). 
The most frequently reported ADRs are shown in Table below. 
 
 
9 
Revised: 09/30/15 

 
 
Very Common and Common ADRs Reported in Subjects in Clinical Studies 
 
All Subjects 
(N = 2182) 
Percent (%) of 
Subjects 
All 
Grades 
Grades 
3/4 
Nervous system disorders 
Very common: headache 
25 
1 
Common: neuropathy (including peripheral neuropathy) 
7 
<1 
 
dizziness 
5 
<1 
 
dysgeusia  
2 
0 
 
somnolence 
2 
<1 
Respiratory, thoracic and mediastinal disorders 
Very common: pleural effusion 
27 
7 
 
dyspnea 
24 
5 
 
cough 
10 
<1 
Common: pulmonary edema  
2 
<1 
 
lung infiltration  
2 
<1 
 
pneumonitis  
2 
<1 
 
pulmonary hypertension 
1 
<1 
Gastrointestinal disorders 
Very common: diarrhea 
33 
4 
 
nausea 
23 
1 
 
vomiting 
13 
1 
 
abdominal pain 
11 
<1 
Common: gastrointestinal bleeding 
8 
4 
 
mucosal inflammation (including mucositis/stomatitis) 
7 
<1 
 
dyspepsia 
6 
0 
 
abdominal distension 
5 
0 
 
constipation 
5 
<1 
 
gastritis  
2 
<1 
 
colitis (including neutropenic colitis), 
2 
<1 
 
oral soft tissue disorder 
2 
0 
Skin and subcutaneous tissue disorders 
Very common: skin rasha 
23 
<1 
Common: pruritus 
7 
<1 
 
acne  
5 
<1 
 
alopecia  
5 
0 
 
 
10 
Revised: 09/30/15 

 
Very Common and Common ADRs Reported in Subjects in Clinical Studies 
 
All Subjects 
(N = 2182) 
Percent (%) of 
Subjects 
All 
Grades 
Grades 
3/4 
 
dry skin 
3 
0 
 
hyperhidrosis 
2 
0 
 
urticaria  
1 
<1 
 
dermatitis (including eczema) 
1 
0 
Musculoskeletal and connective tissue disorders 
Very common: musculoskeletal pain 
15 
1 
Common: arthralgia 
9 
<1 
 
myalgia 
8 
<1 
 
muscle inflammation  
3 
<1 
 
muscular weakness 
1 
<1 
 
musculoskeletal stiffness 
1 
0 
Metabolism and nutrition disorders 
Common: anorexia  
9 
<1 
 
appetite disturbances  
2 
<1 
 
hyperuricaemia 
1 
<1 
Infections and infestations 
Very Common: infection (including bacterial, viral, fungal, 
 
nonspecific) 
11 
3 
Common: pneumonia  (including bacterial, viral, fungal) 
5 
3 
 
upper respiratory tract infection/inflammation  
5 
<1 
 
herpes viral infection 
1 
<1 
 
enterocolitis infection 
1 
<1 
 
sepsis (including fatal outcome) 
1 
<1 
Cardiac Disorders 
Common: pericardial effusion 
5 
1 
 
arrhythmia (including tachycardia) 
3 
<1 
 
congestive heart failure/cardiac dysfunctionb  
3 
2 
 
palpitations 
2 
0 
Vascular disorders 
Very common: hemorrhagec 
16 
2 
Common: flushing  
4 
0 
 
hypertension 
2 
<1 
Blood and lymphatic system disorders 
Common: febrile neutropenia, 
5 
5 
 
 
11 
Revised: 09/30/15 

 
Very Common and Common ADRs Reported in Subjects in Clinical Studies 
 
All Subjects 
(N = 2182) 
Percent (%) of 
Subjects 
All 
Grades 
Grades 
3/4 
 
pancytopenia 
1 
<1 
General disorders and administration site conditions 
Very common: fatigue 
23 
2 
 
superficial edemad  
22 
1 
 
pyrexia 
14 
1 
Common: asthenia 
9 
<1 
 
pain 
8 
<1 
 
chest pain 
6 
<1 
 
generalized edema 
4 
<1 
 
chills 
3 
<1 
Psychiatric disorders 
Common: insomnia 
2 
0 
 
depression 
2 
<1 
Eye disorders 
Common: visual disorder (including visual disturbance, vision blurred, 
and visual acuity reduced)  
2 
<1 
 
dry eye 
1 
<1 
Ear and labyrinth disorders 
Common: tinnitus 
1 
0 
Investigations 
Common: weight increased 
5 
<1 
 
weight decreased 
5 
<1 
Injury, poisoning, and procedural complications 
Common: contusion 
2 
<1 
Note: Frequencies are defined as: very common (≥ 1/10) and common (1/100 to < 1/10)  
Source: Dasatinib Investigator Brochure24 
a 
Includes drug eruption, er ythema, er ythema multiforme, er ythrosis, ex foliative r ash, 
fungal r ash, ge neralized er ythema, geni tal r ash, heat  r ash, m ilia, r ash, r ash 
erythematous, rash follicular, rash generalized, rash macular, rash maculo-papular, rash 
papular, r ash pr uritic, r ash pus tular, r ash v esicular, s kin ex foliation, s kin i rritation, an d 
urticaria vesiculosa. 
b 
Includes v entricular dysfunction, c ardiac f ailure c hronic, c ardiac f ailure c ongestive, 
cardiomyopathy, c ongestive c ardiomyopathy, d iastolic d ysfunction, ej ection f raction 
decreased, and ventricular failure. 
c 
Excludes gastrointestinal bleeding and CNS bleeding; these adverse drug reactions 
are r eported u nder t he g astrointestinal d isorders s ystem or gan c lass and t he nervous 
system disorders system organ class, respectively. 
 
 
12 
Revised: 09/30/15 

 
d 
Includes aur icular s welling, c onjunctival edema, e ye edem a, eye s welling, e yelid 
edema, face edema, gravitational edema, lip edema, localized edema, mascular edema, 
edema genital, edema mouth, edema peripheral, orbital edema, penile edema, periorbital 
edema, pitting edema, scrotal edema, swelling face, and tongue edema. 
 
4.5 Laboratory Abnormalities with Dasatinib 
Myelosuppression was commonly reported in all patient populations. The 
frequency of  Grade 3 or 4 neutropenia, thrombocytopenia, and anemia was 
higher in patients with advanced CML or Ph+ ALL than in chronic phase CML. 
Myelosuppression was reported in patients with normal baseline laboratory 
values as well as in patients with pre-existing laboratory abnormalities.  
In patients who experienced severe myelosuppression, recovery generally 
occurred following dose interruption and/or reduction; permanent discontinuation 
of treatment occurred in 1% of patients. Grade 3 or 4 elevations of transaminase 
or bilirubin and Grade 3 or 4 hypocalcemia and hypophosphatemia were reported 
in patients with all phases of CML but were reported with an increased frequency 
in patients with myeloid or lymphoid blast phase CML and Ph+ ALL. Elevations in 
transaminase or bilirubin were usually managed with dose reduction or 
interruption.  
Patients developing Grade 3 or 4 hypocalcemia during the course of dasatinib 
therapy often had recovery with oral calcium supplementation.  In the Phase 2 
randomized  study,  the frequency of Grade 3 or 4 neutropenia, 
thrombocytopenia, and anemia was  63%, 56%, and 19%, respectively, in the 
dasatinib group and 39%, 14%, and 8%, respectively, in the imatinib group.  The 
frequency of Grade 3 or 4 hypocalcemia was 4% in the dasatinib group and 0% 
in the imatinib group. Laboratory abnormalities reported in the Phase 3 dose-
optimization study in patients with chronic phase CML are shown in the 
table below. 
 
CTC Grades 3/4 Laboratory Abnormalities in Clinical Studies 
 
Chronic Phasea 
 
(n=1150) 
Accelerated 
Phase 
 
 (n=502) 
Myeloid Blast 
Phase 
  
(n=280) 
Lymphoid Blast 
Phase and 
Ph+ ALL  
(n=250) 
Percent (%) of Patients 
Hematology Parameters 
 
Neutropenia  
47 
69 
80 
78 
 
Thrombocytopenia 
41 
72 
82 
78 
 
Anemia 
19 
55 
75 
46 
Biochemistry Parameters 
 
Hypophosphatemia 
10 
12 
19 
20 
 
Hypocalcemia 
2 
7 
16 
11 
 
Elevated SGPT 
(ALT) 
1 
3 
6 
7 
 
 
13 
Revised: 09/30/15 

 
CTC Grades 3/4 Laboratory Abnormalities in Clinical Studies 
 
Chronic Phasea 
 
(n=1150) 
Accelerated 
Phase 
 
 (n=502) 
Myeloid Blast 
Phase 
  
(n=280) 
Lymphoid Blast 
Phase and 
Ph+ ALL  
(n=250) 
Percent (%) of Patients 
 
Elevated SGOT 
(AST) 
1 
1 
4 
5 
 
Elevated Bilirubin 
1 
1 
4 
5 
 
Elevated Creatinine 
1 
2 
3 
1 
 
 
 
a 
The chronic phase data include patients prescribed any dose of dasatinib. 
 
 
 
 
CTC grades: neutropenia (Grade 3 ≥0.5–1.0 × 109/L, Grade 4 < 0.5 × 109/L);   
 
 
 
thrombocytopenia (Grade 3 ≥10–50 × 109/L, Grade 4 < 10 × 109/L); anemia  
 
 
 
 
(hemoglobin ≥65–80 g/L, Grade 4 < 65 g/L); elevated creatinine (Grade 3 > 3–6 × upper  
 
 
 
limit of normal range (ULN), Grade 4 > 6 × ULN); elevated bilirubin (Grade 3 > 3–10 ×  
 
 
 
ULN, Grade 4 > 10 x ULN); elevated SGOT or SGPT (Grade 3 > 5-20 x ULN, Grade 4 > 
 
 
 
20 x ULN); hypocalcemia (Grade 3 < 7.0-6.0 mg/dL, Grade 4 < 6.0 mg/dL);  
 
 
 
 
hypophosphatemia (Grade 3 < 2.0-1.0 mg/dL, Grade 4 < 1.0 mg/dL). 
 
4.6 Warnings and Precautions 
4.6.1 Myelosuppression: Treatment with dasatinib is associated with severe (NCI 
CTCAE Grade 3 or 4) thrombocytopenia, neutropenia, and anemia. Their occurrence 
is more frequent in patients with advanced CML or Ph+ ALL than in chronic phase 
CML. Complete blood counts should be performed weekly for the first 2 months and 
then monthly thereafter, or as clinically indicated. Myelosuppression was generally 
reversible and usually managed by withholding dasatinib temporarily or dose 
reduction.1 In a Phase 3 dose-optimization study in patients with chronic phase 
CML, Grade 3 or 4 myelosuppression was reported less frequently in patients treated 
with 100 mg once daily than in patients treated with 70 mg twice daily. 
 
4.6.2 Bleeding Related Events: Severe CNS hemorrhages, including fatalities, 
occurred in ≤ 1% of patients receiving dasatinib. Severe gastrointestinal hemorrhage 
occurred in 4% of patients and generally required treatment interruptions and 
transfusions. Other cases of severe hemorrhage occurred in 2% of patients. Most 
bleeding events were associated with severe thrombocytopenia. (Incidences in this 
paragraph reflect drug-related adverse reactions based on investigator’s attribution.) 
Patients were excluded from participation in dasatinib clinical studies if they took 
medications that inhibit platelet function or anticoagulants. In some trials, the use of 
anticoagulants, aspirin, and non-steroidal anti-inflammatory drugs (NSAIDs) was 
allowed concurrently with dasatinib if the platelet count was 50,000 to 75,000. 
Caution should be exercised if patients are required to take medications that inhibit 
platelet function or anticoagulants 
 
4.6.3 Fluid Retention: Dasatinib is associated with fluid retention. In all clinical 
studies, severe fluid retention was reported in 10% of patients, including pleural and 
pericardial effusion reported in 7% and 1% of patients, respectively. Severe ascites 
 
 
14 
Revised: 09/30/15 

 
and generalized edema were each reported in < 1% of patients. Severe pulmonary 
edema was reported in 1% of patients. Patients who develop symptoms suggestive 
of pleural effusion such as dyspnea or dry cough should be evaluated by chest X-
ray. Severe pleural effusion may require thoracentesis and oxygen therapy. Fluid 
retention events were typically managed by supportive care measures that include 
diuretics or short courses of steroids. (Incidences in this paragraph reflect drug-
related adverse reactions based on investigator’s attribution) 
In the Phase 3 dose-optimization study in patients with chronic phase CML, fluid 
retention events were reported less frequently in patients treated with 100 mg once 
daily than in patients treated with 70 mg twice daily 
.  
4.6.4 QT Prolongation A comprehensive evaluation of data from Phase 2 studies 
(N = 865) examined the possible effect of dasatinib on ECG parameters, particularly 
the QTc interval. The mean QTc interval changes from baseline using Fridericia’s 
method (QTcF) were 4 to 6 msec; the upper 95% confidence intervals for all mean 
changes from baseline were < 7 msec. On-study, a total of 5 subjects (< 1%) 
reported a QTcF > 500 msec; 1 of these 5 subjects reported a QTcF > 500 msec on 
both Day 1 and Day 8. No events of torsade de pointes were reported. Nine of the 
1150 subjects with chronic phase CML had QTc prolongation reported as an adverse 
event. Of these 9 subjects, 7 were considered related to drug. None of the 9 subjects 
who reported QTc prolongation were from the 100 mg QD group compared with 8 
subjects from the 70 mg BID group. Ten of the 1032 subjects with advanced disease 
had QTc prolongation reported as an adverse event. Of these 10 subjects, 7 were 
considered drug-related. All 10 of the subjects who reported QTc prolongation were 
from the 70 mg BID group. Overall, of the 2182 subjects treated with dasatinib, 21 
(1%) subjects across the studies reported a QTcF > 500 msec. 
 
 
5. Drug Supply 
5.1 Packaging and Labeling 
Dasatinib is supplied as 5 mg, 20 mg, and 50 mg film coated tablets containing 
dasatinib with lactose monohydrate, microcrystalline cellulose, croscarmellose 
sodium, hydroxypropyl cellulose, and magnesium stearate. The tablet coating 
contains hydroxypropyl methylcellulose, titanium dioxide, and polyethylene glycol 
(triacetin in the 5 mg film coated tablet). Tablets for clinical studies are supplied 
in high-density polyethylene bottles containing a desiccant and cotton. The 
bottles are heat-induction sealed with child resistant caps.  
 
Each bottle is labeled in an open label manner. Labels contain, at a minimum, 
the following information: product name, tablet strength, batch number, directions 
for use, storage conditions, and appropriate caution statements. 
 
 
Strength Description 
5 mg 
white, round, film coated tablet 
20 mg 
white to off-white, biconvex, round, film coated tablet with either “20” or 
“BMS” debossed on one side and “527” on the other side 
 
 
15 
Revised: 09/30/15 

 
Strength Description 
50 mg 
white to off-white, biconvex, oval, film coated tablet with either “50” or 
“BMS” debossed on one side and “528” on the other side 
 
5.2 Storage 
Bottles containing dasatinib tablets should be stored at 15° - 25°C.  
Dasatinib will be stored in a secure area in the pharmacy supervised by 
investigational drug pharmacist who is responsible for dispensing investigational 
drug to study subjects. 
5.3 Handling and Dispensing 
Procedures for proper handling of anticancer drugs will be followed according to 
the institutional policies and procedures.  
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. 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 dasatinib in the provided packaging at each subsequent visit. 
 
5.4 Drug Ordering 
Initial Orders of dasatinib should be requested by completing the Dasatinib 
(Sprycel®) Drug Supply Form for Investigator Sponsored Studies and submitting 
the request form electronically via e-mail at least 5-7 business days before the 
expected delivery date. Deliveries will be made Tuesday through Friday.  The 
drug supply form will be sent to srcsupply@bms.com.  
Initial drug supply will be provided for a 12-week treatment period per subject. 
Re-supply requests will be sent to the same email address.  Please check “Re-
supply” on the drug supply form. Re-supply requests should be submitted at least 
5-7 business days before the expected delivery date. Deliveries will be made 
Tuesday through Friday. 
 
5.5 Drug Accountability 
Investigational drug pharmacist will ensure that a current record of disposition of 
investigational product is maintained where the investigational product is 
inventoried and disposed. Records or logs must comply with applicable 
regulations and guidelines and should include: 
a. amount received and placed in storage area 
b. amount currently in storage area 
c. label identification number or batch number and use date or expiry 
date 
d. dates and initials of person responsible for each inventory 
entry/movement 
e. amount dispensed to and returned by each subject, including 
unique subject identifiers 
 
 
16 
Revised: 09/30/15 

 
f. amount transferred to another area/site for dispensing or storage 
g. non-study disposition (eg, lost, wasted, broken) 
h. amount destroyed at study site, if applicable, and 
i. 
retain samples sent to third party for bioavailability/bioequivalence, 
if applicable. 
j. 
Dasatinib dispensing record/inventory logs and copies of signed 
packing lists must be maintained at the investigational site.   
k. Batch numbers for dasatinib must be recorded in the drug 
accountability records. 
 
If dasatinib is to be destroyed on site, it is the investigator’s responsibility to 
ensure that arrangements have been made for disposal, and that procedures for 
proper disposal have been established according to applicable regulations, 
guidelines, and institutional procedures. Appropriate records of the disposal will 
be maintained. 
 
 
6. Treatment Schema 
 
This is a phase 1 dose escalation study, using a standard 3+3 design.  Dasatinib 
is administered orally once daily in the outpatient setting. Patients who are day 
100-180 post transplant will be eligible. The treatment will be started as close to 
day 100 as possible. The range of days is provided to ensure that patients have 
recovered from toxicities associated with ASCT and are not deemed ineligible if 
they were recovering from any toxicity associated with ASCT at day 100.The 
starting dose of dasatinib is 20 mg daily.  The increment of dose escalation is 20 
mg per dose level.  Thus, there will be 5 dose levels (20 mg, 40 mg, 60 mg, 80 
mg and 100 mg, respectively) with 3 patients in each cohort.  Patients will 
continue on dasatinib for 6 months.   
 
Dose Level 
Dasatinib Dose 
L1 
20 mg PO q 24 hrs 
L2 
40 mg PO q 24 hrs 
L3 
60 mg PO q 24 hrs 
L4 
80 mg PO q 24 hrs 
L5 
100 mg PO q 24 hrs 
 
The dosing time may be adjusted as required. If doses are missed for toxicity, 
they should not be replaced. If a dose is not taken due to an error, it may be 
taken up to 12 hours later. If vomiting occurs within 30 minutes of intake, that 
dose may be repeated. Adverse events not related to dasatinib will be managed 
per standard of care for and use of growth factors is allowed at the discretion of 
treating physician.  
 
 
17 
Revised: 09/30/15 

 
 
 
 
 
 
7. Registration and Definitions 
 
7.1 Protocol Registration 
The Investigators will consider the patient for the study.  All patient information will be 
forwarded to the Data Management office (313-576-9277)) for determination of eligibility.  
Upon informed consent and eligibility confirmation, the patient will be registered to the 
study.  
  
7.2 Definition of Dose-Limiting Toxicity 
Toxicities will be graded according to the NCI Common Toxicity Criteria for Adverse 
Events CTCAE version 425.  The following treatment-related adverse events are 
considered dose-limiting toxicities (DLT) if related to dasatinib therapy and occur within 2 
months of starting treatment: 
 
 
 
18 
Revised: 09/30/15 

 
a. Grade 4 neutropenia 
b. Grade 4 thrombocytopenia 
c. Grade 3 nausea and vomiting if it occurs despite maximal (5HT3 
antagonist and corticosteroid) antiemetic therapy, and if hydration is 
required for >24 hours. 
d. Grade 3 diarrhea despite patient compliance with anti-diarrheal therapy. 
e. Grade 3 bleeding/hemorrhage (Requiring Transfusion) 
f. Grade 4 hypertension 
g. Grade 3 pericardial effusion (effusion with physiologic consequence) 
h. Grade 2 pleural effusion (symptomatic and requires therapeutic 
intervention). 
 
7.3 Large Granular Lymphocytosis- Definition 
Lymphocytosis will be defined as absolute lymphocyte count of ≥ 2000 cells/mm3 post 
ASCT with LGL phenotype identified by flow cytometry (CD3, CD8, CD16 and CD57) 
which constitutes ≥ 25% of T cell population or when LGL phenotype identified by flow 
cytometry (CD3, CD8, CD16 and CD57) constitutes ≥ 25% of T cell population without 
absolute lymphocyte count of ≥ 2000 cells/mm3 .    
    
 
7.4 Dose Escalation – Rules and Definitions 
Patients who experienced DLT will discontinue treatment until toxicity improves at least by 
one grade. Treatment can be resumed with dose reduction by one level.  There will be no 
intra-individual dose escalation.  Dose escalation for the subsequent cohort will follow the 
guideline listed below: 
a. As toxicity for other causes is very high in transplant patients, only DLTs 
that occur during the first 2 month of treatment will be used to guide dose 
escalation.   
b. Patients who are not evaluable for DLT will be replaced. 
c. If one patient experiences a DLT, an additional 3 patients will be entered 
at the same dose level to a maximum of 6 patients.  If an additional DLT 
is encountered there will be no further dose escalation.  Three patients 
will then be enrolled onto the next lower level.  If there is no further 
toxicity noted, then this will be the MTD.  If 6 patients were previously 
entered into the lower dose level, there would be no further patient 
entered to the lower dose level and the lower dose level will be declared 
MTD. 
d. MTD is the highest dose at which no more than one of DLT is observed 
(among the first 6 patients treated and evaluable for toxicity for the 
purpose of cohort dose escalation decisions). 
 
7.5 Stopping Rules 
The stopping rule for dose escalation is determined by MTD as well as the occurrence of 
the desirable biological effect, i.e. lymphocytosis.   
a. If MTD has not been reached but lymphocytosis was attained in the entire 
cohort of three patients, dose escalation will be terminated.  Then, 
additional patients will be entered to a total of 12 patients to complete the 
phase II portion of this study. 
b. If lymphocytosis was not observed in all 3 patients in the cohort, then 
dose escalation will continue until the MTD is reached.   
c. Once the MTD had been reached, the phase II portion of the study will 
 
 
19 
Revised: 09/30/15 

 
commence with additional patient to be enrolled at the MTD dose to a 
total of 12 patients. 
d. If MTD was not reached after completion of all 5 levels of the dose-
escalation schema, then additional patients will be enrolled at the highest 
level to a total of 12 patients.  
 
Drug will be discontinued after 6 months in all patients. For patients who develop LGL, 
blood counts will be followed as standard of care.  
 
 
7.6 Discontinuation of Participants from Treatment 
Participants MUST discontinue study treatment and withdraw from the study if any of the 
following occurs: 
1. Withdrawal of informed consent (subject’s decision to withdraw for any 
reason) 
2. Progressive disease or recurrence of underlying malignancy at any time 
3. Excessive toxicity despite dose reduction 
4. Any clinical adverse event (AE), laboratory abnormality, or intercurrent 
illness which, in the opinion of the investigator, indicates that continued 
participation in the study is not in the best interest of the subject 
5. Pregnancy 
 Instruct WOCBP to contact the investigator or study staff 
immediately if they suspect they might be pregnant (eg, missed or 
late menstrual period) at any time during study participation.  
 The investigator must immediately notify BMS if a study subject 
becomes pregnant. 
6. Termination of the study by BMS.  
7. Loss of ability to freely provide consent through imprisonment or 
involuntarily incarceration for treatment of either a psychiatric or physical 
(eg, infectious disease) illness. 
7.7 Statistical Considerations 
7.7.1 Estimation of Probability of LGL Lymphocytosis: Estimation of the probability of 
LGL among 12 patients treated on MTD is as follows: 
 
LGL Lymphocytosis Observed 
in a Cohort of Size 12 
N 
Proportion 
95% C.I. 
3 
0.25 
0.09, 0.53 
4 
0.33 
0.14, 0.61 
5 
0.42 
0.19, 0.68 
6 
0.50 
0.25, 0.75 
7 
0.58 
0.32, 0.81 
8 
0.67 
0.39, 0.86 
9 
0.75 
0.47, 0.91 
10 
0.83 
0.55, 0.95 
11 
0.92 
0.65, 0.99 
12 
1.00 
0.75, 1.00 
 
 
 
20 
Revised: 09/30/15 

 
With the information derived from this cohort of 12 patients, we will determine whether 
treatment with dasatinib is associated with the development of LGL lymphocytosis.  
According to our estimate based on the spontaneous LGL lymphocytosis in 46 out of 636 
allograft recipients, if at least 3 of 12 patients in this study develop lymphocytosis then it is 
likely that dasatinib is associated with incidence of LGL lymphocytosis (upper 95% 
confidence limit greater than 0.50).  This finding would provide the basis to proceed with 
larger clinical trials. 
 
We estimate there would be a maximum of 30 patients enrolled in this entire study. 
In 2011, 114 allogeneic SCT and 158 autologous transplants were performed at KCC.  
With large number of patients available, we should be able to recruit 15-20 patients on the 
trial / yr with accrual duration being 2 years. The total study duration will be at the most 2-3 
years 
 
 
8. Study Monitoring 
 
8.1 Pre-Enrollment Clinical and Laboratory Requirements (Within 1 week prior to 
enrollment on the protocol)  
1. Baseline symptoms and signs of residual regimen-related toxicity or GVHD. 
2. Pregnancy test in woman of child-bearing potential (WOCBP): urine or serum to 
be done within 72 hours of initiation of dasatinib. 
3. Laboratory studies: CBC with differential, Electrolytes, BUN, creatinine, ALT, 
AST, T bilirubin,  magnesium, phosphorus, PTT, PT,  INR, peripheral blood flow 
cytometry to determine and enumerate mononuclear cells expressing CD3, CD8, 
CD16 and CD57 
4. EKG 
 
8.2 Clinical Monitoring 
Patient will be seen every 2 weeks for first 2 months after starting dasatinib and once a 
month, thereafter or as clinically indicated.  They will be evaluated for the development 
of GVHD at each visit and grading will be done according to the standard of care using 
consensus criteria for acute GVHD and NIH criteria for chronic GVHD.  Development 
of GVHD is not included in the evaluation of dose-limiting toxicity of dasatinib, although 
it may be an important biologic phenomenon associated with the dasatinib 
administration because of the inhibitory effects of dasatinib on T-cell activation.  The 
administration of dasatinib should not influence the decision on management of 
GVHD, e.g. initiation of steroids or secondary therapy for GVHD.  The final visit should 
be conducted 30 days (+/- 7 days) after the last dose of study drug. 
 
8.3 Laboratory Monitoring 
1. CBC with differential weekly for the first month after starting dasatinib 
2. CBC with differential, Electrolytes, BUN, creatinine, ALT, AST, T bilirubin, 
magnesium, phosphorus and will be obtained at each visit.   
3. EKG once a month for first 2 months and then as clinically indicated. 
4. Therapeutic drug monitoring such as immunosuppressives, antibiotics and IgG 
will be obtained as clinically indicated.   
5. Tumor imaging studies, bone marrow aspiration and associated studies will be 
done according to standard of care. 
6. Flow cytometry of peripheral blood will be obtained every 4 weeks till 
confirmation of LGL.  Peripheral blood mononuclear cells will be examined for the 
 
 
21 
Revised: 09/30/15 

 
expressions of the following antigens: CD3, CD8, CD16 and CD57. 
7. T-cell receptor gene rearrangement in patients who develop LGL expansion.  
 
8.4 Sample Collection for Correlative studies: Peripheral blood mononuclear cells 
(PBMC) and serum will be collected from peripheral blood of participants (approximately 
20 ml in 3 green top tubes and 1 red top tube) if they consent to collection and use of their 
cells. The PBMC will be separated by Ficoll Hypaque separation. They will be washed and 
stored in liquid nitrogen. Samples will be collected prior to initiation of dasatinib and at any 
time after development of LGL. These cells will be used in the future to provide preliminary 
data about the mechanism by which dasatinib may cause LGL. And also to test 
cytotoxicity of these cells against leukemia/ lymphoma cell lines. Serum will be stored for 
future correlative studies.   
 
8.5 Study Calendar 
Time and Events Schedule for Protocol  
Procedure 
Screening/ 
Baseline 
Day 1 
Day 
15 (± 
5 
days) 
Day 30 
(± 5 
days) 
Day 
45 (± 
5 
days) 
Day 
60 (± 
5 
days) 
Once 
a 
month 
(± 7 
days) 
Final 
Visit 
(+/- 7 
days) 
 
Eligibility 
Assessments 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
Inclusion/Exclusion 
Criteria 
X 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
Safety 
Assessments 
 
 
 
 
 
 
 
 
Physical 
Examination 
X 
 
 
 
 
 
 
 
Targeted Physical 
Examination 
 
X 
X 
X 
X 
X 
X 
X 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
Assessment of 
Signs and 
Symptoms 
 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
Assessment 
 
X 
X 
X 
X 
X 
X 
X 
Laboratory 
Monitoring 
X 
X 
X 
X 
X 
X 
X 
X 
Electrocardiogram 
X 
 
 
X 
 
X 
 
 
Chest X-ray 
X 
 
 
 
 
 
 
 
Pregnancy Test 
X 
 
 
 
 
 
 
 
 
 
22 
Revised: 09/30/15 

 
Time and Events Schedule for Protocol  
Procedure 
Screening/ 
Baseline 
Day 1 
Day 
15 (± 
5 
days) 
Day 30 
(± 5 
days) 
Day 
45 (± 
5 
days) 
Day 
60 (± 
5 
days) 
Once 
a 
month 
(± 7 
days) 
Final 
Visit 
(+/- 7 
days) 
 
Immune 
Correlative Blood 
Draw 
X 
 
 
 
 
 
 
 
 
 
9. Data Collection and Reporting 
 
9.1 Outcomes: All the transplant essential data are collected and reported to CIBMTR.  
The data management team of the BMT program also maintains an ACCESS Database 
which mirrors the data field collected for the CIBMTR.  Additional data field will be created 
to capture the pertinent data pertaining to this study to include lymphocyte count, results of 
flow cytometry data (till LGL is confirmed) and t cell gene rearrangement analysis 
(performed after LGL is confirmed).  Laboratory results will be monitored clinically by the 
treating physician but will not be transcribed into the CRF.  If abnormal values are 
considered an AE, then they will be entered into the AE log.   
 
9.2 Assignment of Adverse Event Intensity and Relationship to Dasatinib: All adverse 
events, including those that are serious, will be graded according to the National Cancer 
Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), Version 4.0. 
 
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening 
of a pre-existing medical condition in a patient or clinical investigation subject administered 
an investigational (medicinal) product and that does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and unintended 
sign (including an abnormal laboratory finding, for example), symptom, or disease 
temporally associated with the use of investigational product, whether or not considered 
related to the investigational product. 
 
Serious Adverse Events 
A Serious Adverse Event (SAE) is any untoward medical occurrence that at any 
dose:  
 results in death 
 is life-threatening (defined as an event in which the subject 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 (see note below for exceptions) 
 results in persistent or significant disability/incapacity 
 is a congenital anomaly/birth defect 
 is an important medical event, defined as a medical event that may not be 
immediately life-threatening or result in death or hospitalization but, based on 
appropriate medical and scientific judgment, may jeopardize the subject or 
may require intervention (eg, medical, surgical) to prevent one of the other 
 
 
23 
Revised: 09/30/15 

 
serious outcomes listed above. Examples of such events include but are not 
limited to intensive treatment in an emergency department or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization. 
 All pregnancies, regardless of outcome, must be reported to BMS, including 
pregnancies that occur in the female partner of a male study subject. All 
pregnancies must be followed to outcome.  
 Although overdose and cancer are not always serious by regulatory 
definition, these events should also be reported in an expedited manner 
 
NOTE: The following hospitalizations are not considered SAEs: 
 a visit to the emergency room or other hospital department lasting less than 
24 hours that does not result in admission (unless considered an “important 
medical event” or a life-threatening event) 
 elective surgery planned before signing consent 
 admissions as per protocol for a planned medical/surgical procedure 
 routine health assessment requiring admission for baseline/trending of health 
status (eg, routine colonoscopy) 
 medical/surgical admission for purpose other than remedying ill health state 
that was planned before study entry. Appropriate documentation is required 
in these cases. 
 admission encountered for another life circumstance that carries no bearing 
on health status and requires no medical/surgical intervention (eg, lack of 
housing, economic inadequacy, caregiver respite, family circumstances, 
administrative). 
 
Nonserious Adverse Events 
Nonserious adverse events are all adverse events that are not classified as SAEs. 
The following categories and definitions of causal relationship to investigational product as 
determined by a physician should be used: 
 Related: There is a reasonable causal relationship to 
investigational product administration and the adverse event. 
 Not Related: There is not a reasonable causal relationship to 
investigational product administration and the adverse event. 
 
The expression “reasonable causal relationship” is meant to convey in general that there 
are facts (eg, evidence such as de-challenge/re-challenge) or other arguments to suggest 
a positive causal relationship. 
 
9.3 Collection and Reporting Adverse Events: Adverse events can be spontaneously 
reported or elicited during open-ended questioning, examination, or evaluation of a 
subject. To prevent reporting bias, subjects should not be questioned regarding the 
specific occurrence of one or more adverse events. 
If known, the diagnosis of the underlying illness or disorder should be recorded, rather 
than its individual symptoms. The following information should be captured for all AEs: 
onset, duration, intensity, seriousness, relationship to investigational product, action taken, 
and treatment required. If treatment for the event was administered, it should be recorded 
in the medical record. The investigator must supply BMS and the IRB/IEC with any 
additional information requested, notably for reported deaths of subjects. 
 
 
24 
Revised: 09/30/15 

 
 
9.3.1 Serious Adverse Events: Following the subject’s written consent to participate 
in the study, all SAEs must be collected, including those thought to be associated with 
protocol-specified procedures. Collection of all SAEs must continue for 30 days after 
the last administration of the investigational product. If applicable, SAEs must be 
collected that relate to any later protocol-specified procedure (eg, a follow-up skin 
biopsy). The investigator should notify BMS of any SAE occurring after this time period 
that is believed to be related to the investigational product or protocol-specified 
procedure. 
All SAEs, whether considered related or unrelated to dasatinib, must be reported to 
BMS (by the investigator or designee) within 24 hours of study personnel becoming 
aware of the event. If only limited information is initially available, follow-up reports are 
required. The original SAE form must be kept on file at the study site. 
All SAEs should be faxed or emailed to BMS at: 
Global Pharmacovigilance & Epidemiology 
Bristol-Myers Squibb Company 
Fax Number: 609-818-3804 
Email: Worldwide.safety@bms.com 
For studies conducted under an Investigator IND, any event that is both serious and 
unexpected must be reported to the Food and Drug Administration (FDA) as soon as 
possible and no later than 7 days (for a death or life-threatening event) or 15 days 
(for all other SAEs) after the investigator’s or institution’s initial receipt of the 
information. BMS will be provided with a simultaneous copy of all adverse events filed 
with the FDA. SAEs should be reported on MedWatch Form 3500A, which can be 
accessed at: http://www.accessdata.fda.gov/scripts/medwatch/. 
MedWatch SAE forms should be sent to the FDA at: 
MEDWATCH 
5600 Fishers Lane 
Rockville, MD 20852-9787 
Fax: 1-800-FDA-0178 (1-800-332-0178) 
http://www.accessdata.fda.gov/scripts/medwatch/ 
All SAEs should simultaneously be e-mailed to BMS at: 
Global Pharmacovigilance & Epidemiology 
Bristol-Myers Squibb Company 
Email: Worldwide.safety@bms.com 
If the investigator believes that an SAE is not related to the investigational product but 
is potentially related to the conditions of the study (such as withdrawal of previous 
therapy, or a complication of a study procedure), the potential relationship should be 
specified in the narrative section of the SAE report. 
If an ongoing SAE changes in its intensity or relationship to the investigational product, 
a follow-up SAE report should be sent within 24 hours to BMS. As follow-up 
information becomes available it should be sent within 24 hours using the same 
procedure used for transmitting the initial SAE report. All SAEs should be followed to 
resolution or stabilization. 
 
9.3.2 Nonserious Adverse Events: The investigator will begin collecting nonserious 
adverse event (NSAE) information once administration of the investigational product is 
initiated.  
All identified NSAEs must be recorded and described in the medical record. If an 
ongoing NSAE worsens in its intensity, or if its relationship to the investigational 
product changes, a new NSAE entry for the event should be completed. NSAEs 
 
 
25 
Revised: 09/30/15 

 
should be followed to resolution or stabilization, or reported as SAEs if they become 
serious. Follow-up is also required for NSAEs that cause interruption or discontinuation 
of investigational product, or those that are present at the end of study participation. 
Subjects with NSAEs at study completion should receive post-treatment follow-up as 
appropriate. 
 
9.3.3 Overdose: An overdose is defined as the accidental or intentional ingestion or 
infusion of any dose of a product that is considered both excessive and medically 
important. All occurrences of overdose must be reported as an SAE. 
 
9.3.4 Pregnancy: Sexually active WOCBP must use an effective method of birth 
control during the course of the study, in such a manner that the risk of failure is 
minimized. Before enrolling WOCBP in this study, investigators must review the BMS-
provided information about study participation for WOCBP. The topics include the 
following:  
General Information 
Informed Consent Form 
Pregnancy Prevention Information Sheet 
Drug Interactions with Hormonal Contraceptives 
Contraceptives in Current Use 
Guidelines for the Follow-up of a Reported Pregnancy. 
 
Before study enrollment, WOCBP must be advised of the importance of avoiding 
pregnancy during study participation and of the potential risk factors for an 
unintentional pregnancy. The subject must sign an informed consent form 
documenting this discussion.  
All WOCBP MUST have a negative pregnancy test within 72 hours before 
receiving dasatinib. The minimum sensitivity of the pregnancy test must be 25 IU/L or 
equivalent units of HCG. If the pregnancy test is positive, the subject must not receive 
dasatinib and must not continue in the study. 
In addition, all WOCBP must be instructed to contact the investigator and/or 
other study personnel immediately if they suspect they might be pregnant (eg, 
missed or late menstrual period) at any time during study participation. 
Instruct WOCBP to contact the investigator or study staff immediately if they suspect 
they might be pregnant (eg, missed or late menstrual period) at any time during study 
participation.  
The investigator must immediately notify BMS if a study subject becomes pregnant. 
 
If, following initiation of the investigational product, it is subsequently discovered that a 
study subject is pregnant or may have been pregnant at the time of investigational 
product exposure, including during at least 6 half-lives after administration, the 
investigational product will be permanently discontinued in an appropriate manner (eg, 
dose tapering if necessary for subject safety). The investigator must immediately notify 
BMS of this event and record the pregnancy on the Pregnancy Surveillance Form (not 
on an SAE form). Initial information on a pregnancy must be reported immediately to 
BMS, and information on the outcome provided once it is available. Completed 
Pregnancy Surveillance Forms must be forwarded to BMS according to SAE reporting 
procedures.  
Note: Any pregnancy that occurs in a female partner of a male study subject must be 
reported to BMS using the Pregnancy Surveillance Form. 
 
 
26 
Revised: 09/30/15 

 
Protocol-required procedures for study discontinuation and follow-up must be 
performed for the subject unless contraindicated by pregnancy (eg, x-ray studies). 
Other appropriate pregnancy follow-up procedures should be considered if indicated. 
Information regarding the course of the pregnancy, including perinatal and neonatal 
outcome, must be reported to BMS on the Pregnancy Surveillance Form.  
 
9.3.5 Handling of Expedited Safety Reports: In accordance with local regulations, 
BMS will notify investigators of all SAEs that are suspected (related to the 
investigational product) and unexpected (ie, not previously described in the 
Investigator Brochure). In the European Union, an event meeting these criteria is 
termed a Suspected Unexpected Serious Adverse Reaction (SUSAR). BMS will send 
investigators an expedited safety report (ESR) to notify them of such an event. 
Other important findings that BMS may report as ESRs include increased frequency of 
a clinically significant expected SAE, an SAE considered associated with study 
procedures that could modify the conduct of the study, lack of efficacy that poses 
significant hazard to study subjects, clinically significant safety findings from a 
nonclinical (eg, animal) study, important safety recommendations from a study data 
monitoring committee, or the decision by BMS to end or temporarily halt a clinical 
study for safety reasons. 
Upon receiving an ESR from BMS, the investigator must review and retain the ESR 
with the Investigator Brochure. Where required by local regulations or when there is a 
central IRB/IEC for the study, BMS will submit the ESR to the appropriate IRB/IEC. 
The investigator and IRB/IEC will determine if the informed consent requires revision. 
When BMS has a written agreement with a local IRB/IEC, BMS will directly submit 
ESR(s). The investigator should also comply with the IRB/IEC procedures for reporting 
any other safety information. 
In addition, BMS will report suspected serious adverse reactions (whether expected or 
unexpected) to the relevant health authorities in all concerned countries according to 
local regulations (either as expedited and/or in aggregate reports). 
 
10. Ethical Consideration 
 
10.1 Good Clinical Practice: This study will be conducted in accordance with Good 
Clinical Practice (GCP), as defined by the International Conference on Harmonization 
(ICH) and in accordance with the ethical principles underlying European Union 
Directive 2001/20/EC and the United States Code of Federal Regulations, Title 21, 
Part 50 (21CFR50). 
The study will be conducted in compliance with the protocol. The protocol, any 
amendments, and the subject informed consent will receive Institutional Review 
Board/Independent Ethics Committee (IRB/IEC) approval/favorable opinion before 
initiation of the study. 
All potential serious breaches must be reported to Bristol-Myers Squibb (BMS) 
immediately. A serious breach is a breach of the conditions and principles of GCP in 
connection with the study or the protocol, which is likely to affect, to a significant 
degree, the safety or physical or mental integrity of the subjects of the study or the 
scientific value of the study. 
 
10.2 Protocol Review/IRB: This protocol is to be reviewed by peer medical review 
committee (PMRC) of Karmanos Cancer Institute and the institutional review board 
(IRB) of WSU.  Informed consent is to be signed by the participating subjects. 
 
 
 
27 
Revised: 09/30/15 

 
10.3 Informed Consent: Investigators will ensure that subjects (or, in those situations 
where consent cannot be given by subjects, the legally acceptable representative) are 
clearly and fully informed about the purpose, potential risks, and other critical issues 
regarding clinical studies in which they volunteer to participate. Freely given written 
informed consent must be obtained from every subject (or, in those situations where 
consent cannot be given by subjects, the legally acceptable representative) before 
clinical study participation, including informed consent for any screening procedures 
conducted to establish subject eligibility for the study. 
The rights, safety, and well-being of the study subjects are the most important 
considerations and should prevail over interests of science and society 
 
11. DATA AND SAFETY MONITORING 
 
Monitoring and Personnel Responsible for Monitoring 
The Bone Marrow Transplant Research Team consisting of the PI, Collaborating 
Investigators, CRA, protocol nurse, and statistician is responsible for monitoring the data 
and safety of this study, including implementation of any stopping rules for safety and 
efficacy.  
 
Scheduled meetings will occur monthly once patients are registered to the protocol. 
These meetings will include the Principal Investigator, co-investigators, research nurse, 
data managers, and anybody deemed important to attend by the Principal Investigator.  
 
During these meetings following points will be reviewed and discussed: 
 
1. 
Safety of protocol participants (AE reporting). 
2. 
Validity and integrity of the data. 
3. 
Enrollment rate relative to expectations and the characteristics of participants. 
4. 
Retention of participants and adherence to the protocol (potential or real protocol 
violations). 
5. 
Completeness of collected data. 
 
 
 
 
Reports of these Data and Safety Monitoring meetings will be kept on file in the Clinical 
Trials Office of the Karmanos Cancer Institute/Wayne State University. The Principal 
Investigator or one of the Co-Investigators will sign these reports. Quarterly, the monthly 
reports will be provided to the Karmanos Cancer Institute Data and Safety Monitoring 
Committee for independent oversight monitoring of the protocol as well to determine 
whether significant benefits or risks are occurring that would warrant study closure or 
continuation.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
28 
Revised: 09/30/15 

 
 
 
11. References 
 
 
1. 
Petersen SL, Ryder LP, Bjork P, Madsen HO, Heilmann C, Jacobsen N et al. A 
comparison of T-, B- and NK-cell reconstitution following conventional or 
nonmyeloablative conditioning and transplantation with bone marrow or peripheral blood 
stem cells from human leucocyte antigen identical sibling donors. Bone Marrow 
Transplant 2003; 32(1): 65-72. 
 
2. 
Kalwak K, Gorczynska E, Toporski J, Turkiewicz D, Slociak M, Ussowicz M et al. 
Immune reconstitution after haematopoietic cell transplantation in children: 
immunophenotype analysis with regard to factors affecting the speed of recovery. Br J 
Haematol 2002; 118(1): 74-89. 
 
3. 
Eyrich M, Lang P, Lal S, Bader P, Handgretinger R, Klingebiel T et al. A prospective 
analysis of the pattern of immune reconstitution in a paediatric cohort following 
transplantation of positively selected human leucocyte antigen-disparate haematopoietic 
stem cells from parental donors. Br J Haematol 2001; 114(2): 422-32. 
 
4. 
Niehues T, Rocha V, Filipovich AH, Chan KW, Porcher R, Michel G et al. Factors 
affecting lymphocyte subset reconstitution after either related or unrelated cord blood 
transplantation in children -- a Eurocord analysis. Br J Haematol 2001; 114(1): 42-8. 
 
5. 
Etzioni A, Eidenschenk C, Katz R, Beck R, Casanova JL, Pollack S. Fatal varicella 
associated with selective natural killer cell deficiency. J Pediatr 2005; 146(3): 423-5. 
 
6. 
Dolstra H, Preijers F, Van de Wiel-van Kemenade E, Schattenberg A, Galama J, de Witte 
T. Expansion of CD8+CD57+ T cells after allogeneic BMT is related with a low 
incidence of relapse and with cytomegalovirus infection. Br J Haematol 1995; 90(2): 
300-7. 
 
7. 
Mohty M, Faucher C, Gaugler B, Vey N, Sainty D, Arnoulet C et al. Large granular 
lymphocytes (LGL) following non-myeloablative allogeneic bone marrow 
transplantation: a case report. Bone Marrow Transplant 2001; 28(12): 1157-60. 
 
8. 
Ramesh MS, Al-Kadhimi Z, Mellon-Reppens S, Valent J, Lum LG, Ayash L et al. T-Cell 
Large Granular Lymphocyte (T-LGL) Expansion Post Adult Allogeneic Hematopoietic 
Stem Cell Transplantation (HSCT) - 'A Prognostic Indicator for Improved Overall 
Survival'. ASH Annual Meeting Abstracts 2009; 114(22): 2241-. 
 
9. 
Kim DH, Kamel-Reid S, Chang H, Sutherland R, Jung CW, Kim HJ et al. Natural killer 
or natural killer/T cell lineage large granular lymphocytosis associated with dasatinib 
therapy for Philadelphia chromosome positive leukemia. Haematologica 2009; 94(1): 
135-9. 
 
 
 
29 
Revised: 09/30/15 

 
10. 
Mustjoki S, Ekblom M, Arstila TP, Dybedal I, Epling-Burnette PK, Guilhot F et al. 
Clonal expansion of T/NK-cells during tyrosine kinase inhibitor dasatinib therapy. 
Leukemia 2009; 23(8): 1398-405. 
 
11. 
Kreutzman A, Juvonen V, Kairisto V, Ekblom M, Stenke L, Seggewiss R et al. 
Mono/oligoclonal T and NK cells are common in chronic myeloid leukemia patients at 
diagnosis and expand during dasatinib therapy. Blood 2010; 116(5): 772-82. 
 
12. 
Valent J, Schiffer CA. Prevalence of Large Granular Lymphocyte Proliferation in 
Chronic Myeloid Leukemia (CML) Patients Treated with Dasatinib. ASH Annual 
Meeting Abstracts 2009; 114(22): 1111-. 
 
13. 
Valent JN, Schiffer CA. Prevalence of large granular lymphocytosis in patients with 
chronic myelogenous leukemia (CML) treated with dasatinib. Leuk Res 2011; 35(1): e1-
3. 
 
14. 
Schiffer CAC, J. E.;Saglio, G.;  le Coutre,P; Bahceci E.;Dejardin D.and N. P. Shah, N. P. 
. Association of lymphocytosis following treatment with dasatinib with response and 
outcome. . Journal of Clinical Oncology 2010; 2010 ASCO Annual Meeting 
Proceedings (Post-Meeting Edition).Vol 28, No 15_suppl (May 20 Supplement), 
2010: 6553 
 
15. 
Schiffer CA, Cortes JE, Saglio G, Coutre Pl, Guilhot F, Bahceci E et al. Lymphocytosis 
Following First-Line Treatment for CML In Chronic Phase with Dasatinib Is Associated 
with Improved Responses: A Comparison with Imatinib. ASH Annual Meeting Abstracts 
2010; 116(21): 358-. 
 
16. 
Approved SPRYCEL (dasatinib) United States Package Insert, May 2009 Accessed 3-
June-2009. 
 
17. 
Approved SPRYCEL (dasatinib) Summary of Product Characteristics. Accessed 11-Dec-
2008. 
 
18. 
BMS-354825. Final PK and PD Clinical Study Report for Study CA180002: A Phase I 
Dose Escalation Study to Determine the Safety, Pharmacokinetics and 
Pharmacodynamics of BMS-354825 in the Treatment of Patients with Chronic, 
Accelerated, or Blast Phase Chronic Myelogenous Leukemia, or Philadelphia 
Chromosome Positive Acute Lymobhoblastic Leukemia Who Have Hematologic 
Resistance to Imatinib Mesylate (Gleevec): Pharmacodynamic and Pharmacodynamic 
Study Report. . BMS Document Control Number 930019090,Bristol-Myers Squibb 
Pharmaceutical Research Institute 2007. 
 
19. 
Bristol-Myers Squibb Pharmaceutical Research Institute. Dasatinib Population 
Pharmacokinetic Analysis in Subjects with Chronic Myeloid Leukemia and Philadelphia 
Chromosome Positive Acute Lymphoblastic Leukemia and Exposure-Response Analysis 
 
 
30 
Revised: 09/30/15 

 
for Efficacy and Safety in Subjects with Chronic Phase Chronic Myeloid Leukemia. 
Document Control No 930027195 2008. 
 
20. 
CA180009. The Effect of a Light Fat and a High Fat Meal on the Pharmacokinetics of 
BMS-354825 in Healthy Subjects. Bristol-Myers Squibb Pharmaceutical Research 
Institute. 2005. Bristol-Myers Squibb Pharmaceutical Research Institute. 2005.Document 
Control No. 930012202. 
 
21. 
Institute. B-MSPR. CA180019.  Mass Balance, Pharmacokinetics and Metabolism of 
[14C]BMS-354825 in Healthy Male Subjects. Document Control No. 930012551 2005. 
 
22. 
Bristol-Myers Squibb Pharmaceutical Research Institute. In vitro assessment of BMS-
354825 as an inducer of human cytochrome P450 expression in cultured human 
hepatocytes. BMS Document Control No. 930011325 2005. 
 
23. 
Haouala A, Widmer N, Duchosal MA, Montemurro M, Buclin T, Decosterd LA. Drug 
interactions with the tyrosine kinase inhibitors imatinib, dasatinib, and nilotinib. Blood 
2011; 117(8): e75-87. 
 
24. 
Bristol-Myers Squibb. SPRYCEL(dasatinib) BMS-354825 Investigator Brochure, 
Version 8, 2008 
 
 
25. 
NCI/NIH CTCAE v 4. 2009. 
 
 
 
 
 
31 
Revised: 09/30/15