Conditions: Waldenstrom Macroglobulinemia DASATINIB
Keywords: Waldenstrom Macroglobulinemia DASATINIB
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 3
Healthy volunteers: no

Brief summary:
This is Phase I pilot, single center study designed to explore the safety of Dasatinib in symptomatic Waldenström Macroglobulinemia participants who are progressing on ibrutinib therapy with BTK Cys481 or PLCG2 mutations

Detailed description:
This research study is a Pilot Study, which is the first time investigators are examining this drug in patients with Waldenström Macroglobulinemia who have progressed on ibrutinib.

Patients who fulfill eligibility criteria will be entered into the trial to receive Dasatinib

After the screening procedures confirm participation in the research study:

The participant will be given a study drug-dosing calendar for each treatment cycle. In this research study, the investigators are planning to give Dasatinib, which is a targeted therapy intended to treat cancer by binding to the target protein called BTK.

* BTK is believed to be an important target for treatment of patients with specific gene mutations. Some patients who have disease progression after taking ibrutinib have these gene mutations.
* Making treatment decisions based on genetic testing is investigational, and the FDA has not approved this genetic testing.

The U.S. Food and Drug Administration (FDA) has not approved Dasatinib for Waldenström Macroglobulinemia but it has been approved for other uses.

Dasatinib is produced by Bristol-Myers Squibb.

Arms:
arm 1: \-- After the screening procedures confirm participation in the research study: The participant will be given a study drug-dosing calendar for each treatment cycle.

Dasatinib: Oral Study Drug(s):

* Each study treatment cycle lasts 4 weeks during which time you will be taking the study drug one time per day.
* This will continue for up to 24 cycles.

Interventions: intervention 1: Dasatinib
Intervention descriptions: intervention 1: Oral, daily, dosing per protocol, once a day for cycle

Protocol document:
Prot_SAP_000.pdf: 
1 
 
NCI Protocol #: 
N/a 
 
DF/HCC Protocol #: 19-305  
 
BMS Protocol #: CA180-703 
 
TITLE:  Dasatinib in patients with Waldenström Macroglobulinemia (WM) progressing on 
Ibrutinib 
 
Coordinating Center: 
 
 
Dana-Farber Cancer Institute 
 
 
 
 
 
 
 
 
 
450 Brookline Avenue  
 
 
 
 
 
 
 
 
 
Boston, MA 02215 USA 
 
Principal Investigator (PI): 
Jorge J. Castillo, MD 
 
Dana-Farber Cancer Institute 
 
Jorgej_castillo@dfci.harvard.edu 
 
 
 
 
 
 
Agent(s):  Dasatinib 
 
 
 
IND: 143803 
IND Sponsor:  Jorge J. Castillo, MD 
 
 
Protocol Type / Version # / Version Date: 
Revised/ Version #5/ 1.21.2021 


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SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Screening 
Registration 
Dasatinib Administration 
 
Maximum 24  
Four-week cycles 
Response Evaluation 
Stop Dasatinib 
Event Monitoring for 2 
years 
Stop Dasatinib after 24 
cycles 
Progressive Disease 
(PD), Unacceptable 
Toxicity, No Response 
Stable Disease or Response 
Event Monitoring for 2 
years 


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TABLE OF CONTENTS 
 
SCHEMA .........................................................................................................................................2 
1. 
OBJECTIVES ......................................................................................................................1 
1.1 
Study Design ............................................................................................................1 
1.2 
Primary Objectives ...................................................................................................1 
1.3 
Secondary Objectives ...............................................................................................1 
2. 
BACKGROUND .................................................................................................................2 
2.1 
Study Disease(s).......................................................................................................2 
2.2 
IND Agent Dasatinib ...............................................................................................3 
2.3 
Rationale ..................................................................................................................9 
2.4 
Correlative Studies Background ............................................................................11 
3. 
PARTICIPANT SELECTION ...........................................................................................11 
3.1 
Eligibility Criteria ..................................................................................................11 
3.2 
Exclusion Criteria ..................................................................................................13 
3.3 
Inclusion of Women and Minorities ......................................................................14 
4. 
REGISTRATION ..............................................................................................................14 
4.1 
General Guidelines for DF/HCC Institutions ........................................................14 
4.1 
Registration Process for DF/HCC Institutions .......................................................14 
5. 
TREATMENT PLAN ........................................................................................................14 
5.1 
Treatment Regimen ................................................................................................14 
5.2 
Pre-Treatment Criteria ...........................................................................................15 
5.3 
Agent Administration .............................................................................................15 
5.4 
Definition of Dose-Limiting Toxicity (DLT) ........................................................15 
5.5 
General Concomitant Medication and Supportive Care Guidelines ......................16 
5.6 
Criteria for Taking a Participant Off Protocol Therapy .........................................17 
5.7 
Duration of Follow Up ...........................................................................................18 
5.8 
Criteria for Taking a Participant Off Study ...........................................................18 
6. 
DOSING DELAYS/DOSE MODIFICATIONS................................................................18 
6.1 
Dasatinib Dose Adjustments for AEs ....................................................................19 
7. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................20 
7.2 
Adverse Event Characteristics ...............................................................................26 
7.3 
Adverse Event Reporting .......................................................................................26 
7.4 
Reporting to the Food and Drug Administration (FDA) .......................................26 
7.5 
Expedited Reporting to BMS Worldwide Safety ...................................................27 
7.6 
Reporting to Hospital Risk Management ...............................................................28 
7.7 
Routine Adverse Event Reporting .........................................................................28 
8. 
PHARMACEUTICAL INFORMATION ..........................................................................28 
8.1 
IND Agent #1 Dasatinib.........................................................................................28 


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9. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ........................................30 
9.1 
Laboratory Correlative Studies ..............................................................................30 
10. 
STUDY CALENDAR .......................................................................................................31 
11. 
MEASUREMENT OF EFFECT........................................................................................33 
12. 
DATA REPORTING / REGULATORY REQUIREMENTS ...........................................34 
12.1 
Data Reporting .......................................................................................................34 
12.2 
Data Safety Monitoring ..........................................................................................35 
13. 
STATISTICAL CONSIDERATIONS...............................................................................35 
13.1 
Study Design/Endpoints.........................................................................................35 
Primary Objectives .............................................................................................................36 
13.2 
Secondary Objectives .............................................................................................36 
13.3 
Sample Size, Accrual Rate and Study Duration ....................................................36 
13.4 
Stratification Factors ..............................................................................................36 
13.5 
Interim Monitoring Plan ........................................................................................36 
13.6 
Analysis of Primary Endpoints ..............................................................................37 
13.7 
Analysis of Secondary Endpoints ..........................................................................37 
13.8 
Reporting and Exclusions ......................................................................................37 
14. 
PUBLICATION PLAN .....................................................................................................37 
REFERENCES ..............................................................................................................................38 
APPENDIX A 
PERFORMANCE STATUS CRITERIA ..................................................41 
 


1 
 
1. OBJECTIVES 
1.1 
Study Design 
 
This is a Phase I Pilot, single center study designed to explore the safety of dasatinib, a 
pleiotropic kinase inhibitor that non-covalently blocks HCK and BTK, both downstream 
mediators of survival signaling in MYD88 mutated WM patients (Yang et al, 2013; 2016). The 
study will examine the safety of dasatinib, a non-covalent inhibitor of BTK and HCK in 
symptomatic MYD88 mutated WM participants who are progressing on the covalent BTK-
inhibitor ibrutinib, an FDA approved treatment for symptomatic WM.  Unlike ibrutinib that 
binds to BTK Cys 481, a frequent site of acquired resistance in WM (Xu et al, 2017),  dasatinib 
binds at BTK Thr 474  (Hantschel et al, PNAS 2007). Dasatinib is FDA approved for Chronic 
Myelogenous Leukemia (CML), and we plan to use the FDA approved dose (100mg PO QD) in 
this study.  Treatment will be comprised of dasatinib administered orally starting day 1 of cycle 1 
for up to 24 cycles. 
 
 At the Screening visit, a medical history will be obtained and a complete physical examination 
will be performed including vital signs and an ECOG performance status.  Bone marrow biopsy 
and aspirate and CT scanning of the chest, abdomen, and pelvis must be performed within 90 
days prior to Cycle 1 Day 1.  Clinical laboratory tests are required per section 10 Study Calendar. 
 
Participants who meet the eligibility requirements will be enrolled on study and initiated on 
study drug.  Participants will be seen in clinic and have routine laboratory studies prior to each 
cycle of dasatinib for the first 3 cycles and every 3 cycles there after until study completion.  
Participants will be evaluated for tolerance and response at each visit for the duration of the trial. 
The participants will be followed for 2 additional years after completion of study drug. 
Participants will be eligible to continue on therapy for up to 2 years as long as they do not have 
unacceptable toxicity or demonstrate progressive disease.  Response criteria updated at the Sixth 
International Workshop on Waldenström’s macroglobulinemia (Owen et al, BJH 2013) will be 
used to assess response, stable disease, and progressive disease.  Response outcomes to be 
determined will include: ORR and major response rates (including VGPR and CR rates); median 
PFS and TTNT. 
 
1.2 
Primary Objectives 
 
• To evaluate the toxicity profile of dasatinib in WM patients who progressed on ibrutinib  
1.3 
Secondary Objectives 
 
• To evaluate the ORR of dasatinib in WM patients who are progressed on ibrutinib.  
• To evaluate the rate of CR, very good partial response (VGPR), partial response (PR), 
minimal response (MR), stable disease (SD) and progressive disease (PD) to dasatinib in 
WM patients who progressed on ibrutinib.  
• To evaluate progression-free survival, time to next therapy (TTNT), and overall survival to 
dasatinib in WM patients who progressed on ibrutinib.  
• To evaluate the impact of MYD88 and CXCR4 mutations on response to dasatinib in WM 
patients who progressed on ibrutinib. 
 


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2. BACKGROUND 
 
2.1 
Study Disease(s) 
 
WM is a rare B-cell lymphoproliferative disorder characterized by the uncontrolled accumulation 
of IgM-producing lymphoplasmacytic cells (Swerdlow et al, 2008) Such malignant cells 
accumulate in the bone marrow, liver, spleen and lymph nodes. WM is diagnosed by the 
presence of lymphoplasmacytic cells in the bone marrow and an IgM monoclonal spike (M-
spike) identified in a serum protein electrophoresis (SPEP). The incidence of WM in the United 
States (US) is approximately 3 per million persons per year accounting for 1500 new cases per 
year (Sekhar et al, 2012). The clinical course of WM is variable and although patients might 
experience an overall survival (OS) measured in decades(Castillo et al, 2014; 2015), WM 
remains incurable with current therapeutic regimens. Hence, the disease course is characterized 
by continual relapses, each harder to treat than the previous one. Additionally, many of the 
disabling symptoms associated with the disease, such as hyperviscosity, fatigue, anemia or 
neuropathy, can be exacerbated by our therapy (Treon et al, 2015a). Hence, the careful 
evaluation of agents with novel mechanisms of action is needed to improve the quality of life 
(QOL), and response and survival rates in patients with WM. 
 
Previously, our group identified a recurrent mutation in the MYD88 gene (MYD88 L265P), 
which is seen in over 90% of cases with WM (Treon et al, 2012). The occurrence of this 
mutation in WM has since been validated in several independent cohorts (Jimenez et al, 2013; 
Mori et al, 2013; Poulain et al, 2013; Varettoni et al, 2013). . In contrast, the MYD88 L265P 
gene mutation was not detected in patients with IgM myeloma and was detected in less than 10% 
of patients with marginal zone lymphoma. The high specificity and sensitivity of the MYD88 
L265P gene mutation has obvious diagnostic implications in patients in whom a diagnosis of 
WM is suspected but uncertain. The MYD88 L265P gene mutation has shown to support growth 
and survival of WM cells in several studies. A knockdown model of MYD88 showed decreased 
survival of MYD88 L265P expressing WM cells, whereas survival was more enhanced by 
knock-in of mutant versus wild-type MYD88 (Yang et al, 2013). MYD88 acts as an adaptor 
molecule in toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) signaling Waters et al, 
2007). Following stimulation of TLR or IL-1R, MYD88 is recruited to the activated receptor 
complex as a homodimer which complexes with IL-1R-associated kinase 4 (IRAK4) and 
subsequently activates IRAK1 and IRAK2 (Lin et al, 2010). IRAK1 activation then leads to NF-
κB activation via IκBα phosphorylation (Kawagoe et al, 2008). Previously, our study showed 
that MYD88 L265P triggered the Bruton’s Tyrosine Kinase (BTK) pathway (Yang et al, 2013). 
In this pre-clinical study, the activation of BTK by MYD88 could be abrogated by the use of the 
covalent BTK kinase inhibitor ibrutinib that binds BTK at Cys481 . 
 
We subsequently reported the occurrence of recurrent somatic CXCR4 gene mutations in 
approximately 30-40% of WM patients (Hunter et al, 2014). The somatic mutations occur in the 
C-terminal domain,and are similar to those observed in patients with WHIM (Warts, 
Hypogammaglobulinemia, Infections, and Myelokathexis) syndrome. These mutations regulate 
signaling of CXCR4 by its ligand SDF-1a  In WM patients, two classes of CXCR4 mutations 
occur: non-sense (CXCR4WHIM/NS) and frameshift (CXCR4WHIM/FS) mutations (Hunter et al, 
2014; Treon et al, 2014) Non-sense and frameshift mutations are almost equally divided among 
WM patients, and over 30 different types of CXCR4 mutations have been identified. Preclinical 


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studies with the most common CXCR4 S338X mutation in WM have shown sustained signaling 
of AKT, ERK and BTK following SDF-1a binding in comparison with wild-type CXCR4, as 
well increased cell growth and survival of WM cells (Cao et al, 2014; Rocarro et al, 2014) 
 
In early 2015, following a prospective study led by our group, the U.S. FDA and the EMA 
approved the use of the oral BTK ibrutinib for the treatment of patients with symptomatic WM. 
The approval was based on the results of a phase II study in 63 patients with relapsed and/or 
refractory WM, in which ibrutinib induced an overall response rate (ORR) of 91% and a major 
response rate of 77%, as well as 5-year progression-free (PFS) and overall survival (OS) of 54% 
and 87%, respectively (Treon et al, 2020). Despite these exceptional results and the ease of 
administration, ibrutinib therapy is associated with toxicity, and response rates are affected by 
the MYD88/CXCR4 mutational status. Among other minor adverse events, ibrutinib therapy has 
been associated with an increased risk of bleeding with procedures prompting temporary hold of 
ibrutinib to minimize risk. Also, atrial fibrillation can occur on ibrutinib therapy in up to 10% of 
patients with WM. WM patients who carry MYD88 and CXCR4 mutations experience lower 
rates of ORR and major response rates than patients with MYD88 only disease. WM patients 
who are wild type for MYD88 and CXCR4, the no major response rates were observed.  
 
Progression on ibrutinib has been observed in patients with WM, and it has been associated with 
the development of mutations in BTK, including BTK C481S mutation, those downstream of 
BTK such as PLCG2 mutations, and more recently through whole exome sequencing 6q and 8p 
deletions encompassing regulators of BTK, MYD88/NFKB, and apoptosis. (Xu et al, 2017; Cen 
et al, 2018; Jimenez et al, 2020).WM patients who become resistant to ibrutinib experienced 
difficult-to-control disease progression and has been associated with an increased risk of death 
(Gustine et al, 2018). 
 
Therefore, there is an unmet need for highly effective, well-tolerated therapies in WM patients 
who are progressing on ibrutinib that would be indifferent to the genomic profile of WM 
patients. 
 
2.2 
IND Agent Dasatinib 
Dasatinib (BMS-354825) is a potent, broad-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.  Overexpression or activation of these kinases plays a 
critical role in the etiology of various cancer types, as well as in the malignant behavior 
associated with these diseases, such as unregulated proliferation and metastasis. Dasatinib 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 therapy. In a randomized trial, dasatinib at a 
dose of 100 mg PO QD showed to be more effective than imatinib 400 mg PO QD on inducing 
responses in patients with chronic phase CML. Therapy continued to disease progression or 
unacceptable toxicity. With regard to safety, grade 3 or 4 neutropenia, thrombocytopenia and 
anemia were seen in 21%, 19% and 10% of CML patients. Most of the adverse events were 
grade 1 or 2 and included anemia (90%), thrombocytopenia (70%), neutropenia (65%), fluid 


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retention (19%), diarrhea (17%), headache (12%), musculoskeletal pain (11%), rash (11%) and 
pleural effusion (10%).  
 
Unlike ibrutinib that binds to BTK Cys 481, a frequent site of acquired resistance in WM (Xu et 
al, 2017),  dasatinib binds at BTK Thr 474  (Hantschel et al, PNAS 2007). Based on preclinical 
data, dasatinib also inhibits hematopoietic cell kinase (HCK),. Both HCK and BTK are inhibited 
at a nanomolar concentration (0.35 nM and 1.4 nM, respectively) (Karaman et al, 2008). HCK is 
a member of the SRC family of protein tyrosine kinases, and one of the most aberrantly 
upregulated genes in WM cells (Gutierrez et al, 2007). In myeloma cells, HCK is activated by 
IL-6 through the IL-6 coreceptor IL-6ST. IL-6 is also a potent growth and survival factor in WM. 
HCK is an important mediator of WM cells survival, and HCK transcription and activation are 
enhanced in MYD88 mutated WM cells, also mediated by IL-6 (Yang et al, 2016). HCK 
expression was significantly higher on primary WM cells when compared to normal non-
memory or memory B-cells. 
 
Figure 1. HCK transcription using TaqMan Gene Expression Assay in primary LPCs (CD19+) from MYD88 L265P 
expressing WM patients, and HD-derived non-memory (CD19+CD27-) and memory (CD19+CD27+) B cells. 
P<0.01 for comparison of WM LPC vs. either HD non-memory or memory B-cells. 
 
Knockdown of HCK reduced the survival of and attenuated BTK, PI3K/AKT and MAPK/ERK 
signaling in mutated MYD88 WM cells. Specifically, dasatinib induced apoptosis in mutated 
MYD88 WM and DLBCL cell lines. 


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Figure 2. Dose-dependent survival determined by CellTiter-Glo Luminescent Cell Viability Assay for mutated 
(BCWM.1, MWCL-1, TMD-8, HBL-1, and OCI-LY3) and WT (OCI-LY7, OCI-LY19, Ramos, and RPMI 8226) 
MYD88 cells following treatment with dasatinib for 72 hours. 
 
Figure 3. Phosflow analysis showing changes in pHCKTyr411 following treatment of MYD88-mutated primary 
WM cells with 0.1 mM and 0.5 mM of ibrutinib or dasatinib for 30 minutes. 
 


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Of specific interest is the preclinical efficacy of dasatinib in BTK mutated WM cell lines. 
 
 
Figure 4. Dose-dependent survival determined by Cell Titer-Glo Luminescent Cell Viability Assay for BTK-
mutated and BTK WT cells following treatment with dasatinib for 72 hours. 
 
2.2.1 
Nonclinical Studies of Dasatinib 
Drug discovery and nonclinical pharmacology studies showed that dasatinib: 
• Kills BCR-ABL dependent leukemic cell lines, including those resistant to imatinib due to 
kinase domain mutations or overexpression of SRC family kinases 
• Is effective against all imatinib-resistant kinase domain mutations tested to date, except 
T315I 
• Has average cytotoxic potency 380-fold higher than imatinib in 4 imatinib naive CML cell 
lines 
• Inhibited proliferation of numerous cancer cell lines that express activated SRC or c KIT 
• Is active against several human CML xenografts in SCID mice at doses below MTD  
• Is active against several susceptible human solid cancer models in nude mice 
• Potently inhibits VEGF-stimulated proliferation and migration in HUVECs 
• Has potent bone anti-resorptive activity 
• Non-covalent inhibitor of BTK at Thr 474, different that BTK Cys 481 that ibrutinib binds 
• Blocks SRC family members including HCK, FYN 
• Triggers killing of MYD88 mutated ABC DLBCL cells, including ibrutinib resistant BTK 
Cys481 mutant expressing cells in vitro and in xenograft models independent of BTK 
itself (Scuoppo et al, 2019). 
Dasatinib was 260-, 8-, 60-, and >1000-fold more potent than imatinib versus BCR-ABL, c-KIT, 
PDGF receptor β, and SRC kinases, respectively. 


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Dasatinib inhibited cellular SRC autophosphorylation in several solid tumor cell lines that highly 
express c-SRC. These include P815 for mastocytoma; PC3, PC3/M, MDA PCa 2b, DU145 for 
prostate cancer; WiDr, LOVO, SW 480, 2C8, GEO for colon cancer; MDA MB 231 for breast 
cancer; RD1 for rhabdomyosarcoma, and A549 for lung cancer.1 Assays in SCLC cell lines 
demonstrated that dasatinib inhibited stem cell factor (SCF)-driven proliferation with a potency 
range of 110 nM to 220 nM. The concentration range of dasatinib required to inhibit c-KIT 
phosphorylation was in range with that needed to inhibit cellular proliferation.1  
Dasatinib exhibited in vivo antitumor activity in a broad spectrum of solid tumor types in nude 
mice. In mice, twice daily (BID) regimens 5-days-on and 2-days-off for 14 to 25 days were well-
tolerated with no sign of overt toxicity at doses up to 50 mpk/adm and were equally efficacious 
as continuous dosing regimens.1 
Nonclinical Toxicology 
The toxicity of dasatinib was evaluated in a spectrum of nonclinical safety studies, including 
single- and repeat-dose oral toxicity studies in mice, rats, dogs, and monkeys; a battery of in 
vitro and in vivo genotoxicity studies; a 2-year rat carcinogenicity study; reproductive and 
development toxicity studies in rats and rabbits; and a range-finding study that evaluated the 
feasibility of conducting a definitive perinatal and postnatal development study in rats. Based on 
these nonclinical evaluations, there were no findings that would preclude the administration of 
dasatinib to humans. However, women of childbearing potential should be advised to avoid 
becoming pregnant while taking dasatinib.  
 
Clinical Pharmacokinetics 
 
Dasatinib is rapidly absorbed following oral administration in subjects with leukemia. The 
median time to reach the maximum observed concentration (Cmax) ranged from 0.45 to 3.2 
hours postdose (overall median = 1 hour). The observed food effects were not clinically relevant. 
Dasatinib has an apparent volume of distribution of 2,505 L, suggesting extensive distribution to 
the extravascular space.  
 
Dasatinib is extensively metabolized in humans by cytochrome P450 3A4. Unchanged dasatinib 
represented 29% of circulating radioactivity in plasma after a 100-mg dose of [14C]-labeled 
dasatinib was administered to 8 healthy subjects. 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. Unchanged dasatinib accounted for 19% 
and 0.1% of the administered dose in feces and urine, respectively, with the remainder of the 
dose being metabolites. 
 
The overall mean half-life of dasatinib was approximately 3 to 5 hours and was not affected by 
dose administration interval (ie, QD or BID), disease status (ie, CP, AP, or CML), or duration of 
dosing (ie, PK evaluated on various study days following the initiation of dosing). The dasatinib 
dose-exposure (AUC) relationship is approximately proportional in the dose range of 15 to 240 
mg/day, suggesting linear PK. However, the 90% confidence intervals (CIs) are wide, indicating 
that the variability in the AUC is high. The geometric mean accumulation index ranged from 


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1.01 to 1.6 between Days 5/8 and 26/29, and no consistent dose-related trends were observed in 
the accumulation of dasatinib after repeated administration. 
 
Population PK analyses indicated that dasatinib can be administered without dose adjustment for 
body weight, age, gender, or race. The clearance of dasatinib did not change with time, and no 
evidence of autoinhibition or autoinduction was observed. There were no statistically significant 
or clinically relevant differences in dasatinib PK between subjects with newly diagnosed CP 
CML and subjects with CP CML who had been previously treated with 
imatinib. 
2.2.2 
Clinical Safety 
The data presented in Table 2 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%). 
2.2.3 
Clinical Efficacy with Dasatinib 
 
Efficacy data with a minimum of 5 years of follow-up for dasatinib are presented in the 
SPRYCEL USPI and SmPC as the representative product labels for the adult indications of CP 
and 2 years for AP and BP CML and Ph+ ALL with resistance to or intolerance of 
imatinib. Efficacy data with 7 and 5 years of follow-up for  Studies CA180034   and  
CA180035, respectively, are presented in this IB. (Efficacy results for Studies CA180034 and 
CA180035 are presented by randomized treatment group.) 
Efficacy in Subjects with Chronic Phase CML 
Data from the Phase 3 Study CA180056 (dasatinib showed statistically significant improvement 
in cCCyR at 12 months compared to imatinib) led to the approval of dasatinib in the treatment 


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of naive CP CML in USPI and SmPC. Long-term efficacy after 5 years of follow-up supports 
the durability of the high response rates of dasatinib demonstrated in the primary.  After a 
minimum of 5 years of follow-up, a similar percentage of treated subjects discontinued study 
treatment for reasons other than study closure (100/258 [38.8%] in the dasatinib group and 
96/258 [37.2%] in the imatinib group). 
Efficacy in Subjects with Advanced Phase CML and PH+ ALL Resistant to or Intolerant of 
Imatinib 
StudyCA180034 
In Study CA180034 (a randomized 2 × 2 Phase 3 study in subjects with CP CML who 
were resistant to or intolerant of imatinib), dasatinib demonstrated efficacy with both BID 
and QD dosing; however, the 100-mg QD dosing schedule showed improved tolerability and a 
reduced incidence of key side effects such as myelosuppression and pleural effusion.  This 
efficacy result was confirmed at the 7-year follow-up 
 
Based on these preclinical findings, dasatinib as a single agent can prove to be safe and effective 
in patients with symptomatic WM. 
 
Study CA180035 
 
In Study CA180035 (a randomized Phase 3 study in subjects with AP CML, BP CML 
[myeloid or  lymphoid],  or  Ph+  ALL  who  were  resistant  to  or  intolerant  of  imatinib),  
dasatinib demonstrated efficacy with both BID and QD dosing; however, the QD dosing 
schedule was associated with fewer dose reductions and interruptions and had fewer subjects 
reporting fluid retention-related AEs of all grades (including pleural effusion, pulmonary 
edema, pericardial effusion,  and  congestive  heart  failure  [CHF])  as  compared  with  the  
70-mg  BID  dosing schedule.  This result was confirmed at the 5-year follow-up. 
 
2.3 
Rationale 
 
Dasatinib inhibits BTK, which is the main substrate of ibrutinib. Ibrutinib is already approved by 
the US FDA and the EMA for its use in patients with symptomatic WM. In a preclinical 
comparative study, nanomolar concentrations of dasatinib induced higher cell killing levels than 
ibrutinib in primary WM cells. 
 
The binding of dasatinib to BTK is likely non-covalent and occurs at a different location than 
C481S, a hot spot associated with ibrutinib resistance in patients with CLL, MCL and WM. 
Therefore, dasatinib might prove to be effective in patients who would otherwise be resistant to 
ibrutinib. Preclinical data from our laboratory supports that dasatinib overcomes ibrutinib 
resistance associated with BTK C481S mutations in WM cell lines. About 50% of participants 
progressing on ibrutinib have the BTK Cys 481 mutation, and 5-10% have the PLCG2 mutation, 
which can be subclonal to the BTKCys 481 mutations (27, 28, 29). Other mutation and structural 
losses have recently been described in WM patients, including 6q and 8p deletions encompassing 
regulators of BTK, MYD88/NFKB, and apoptosis. Dasatinib is a known inhibitor of SRC family 
members including HCK, a key driver of growth and survival of mutated MYD88 through 
multiple growth pathways including BTK, AKT, ERK and SYK (Yang et al, 2016; Munshi et al, 
2020). Therefore, dasatinib may block MYD88 tiggered growth through non-covalent binding to 


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BTK but also by inhibition of SRC family members (Yang et al, 2016; Scuoppo et al, 2019); see 
Figure 5 below.  
 
 
 
 
 
 
 
 
 
 
 


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Hypothesis 
 
Single agent dasatinib is associated with a high overall response rate in WM patients who are 
progressing on ibrutinib. 
 
 
 
2.4 
Correlative Studies Background 
 
MYD88 L265P is a recently identified somatic mutation present in >90% of WM patients but in 
<5% of patients with other related processes such as CLL or MZL with plasmacytic 
differentiation or IgM myeloma (Treon 2012). Many groups have now validated the presence of 
this somatic mutation in WM patients. MYD88 L265P supports growth and survival of WM cells 
through both IRAK1 and IRAK4 (Treon 2012) as well as by activation of Bruton tyrosine kinase 
(BTK) (Yang 2013). Based on these findings, we conducted a clinical trial using the BTK 
inhibitor ibrutinib in 63 patients with relapsed/refractory WM (Treon 2015; 2020). In this study, 
ibrutinib was well tolerated and effective. Median hemoglobin improved from 10.5 g/dl to 14.2 
g/dl and IgM decreased from 3520 mg/dl to 821 mg/dl. Bone marrow involvement decreased 
from 70% to20% with a best ORR of 91% and a major response rate of 77%. The major response 
rate was 97% for patients with wild-type CXCR4 vs. 68% in those with WHIM-like CXCR4 
mutations. Decreases in serum IgM as well as improvements in hemoglobin were greater in 
patients with wild-type CXCR4. 
In recent studies, the MYD88 and CXCR4 mutational status are predictive of clinical status, 
response to therapy and survival outcomes (Treon et al, 2014; 2020). Activating MYD88 as well 
as nonsense and frameshift WHIM-like CXCR4 somatic mutations are common in Waldenström 
macroglobulinemia. CXCR4 nonsense mutations are present in aggressive cases including 
hyperviscosity syndrome, and MYD88 status is a determinant of survival (Treon et al, 2018). 
The MYD88 L265P mutational analysis by allele-specific PCR and CXCR4 mutational analysis 
by Sanger sequencing will be performed by the Bing Center for Waldenström 
Macroglobulinemia in Boston, MA for research purposes.  Eligibility for the study includes 
known MYD88 mutation and will be based on testing at a CLIA certified laboratory.  If the 
participant has had MYD88 mutation testing previously performed by a CLIA accredited testing 
facility, with results determined to be acceptable by the Investigator, those results may be used 
for eligibility determination. 
3. PARTICIPANT SELECTION 
 
3.1 
Eligibility Criteria  
 
Participants must meet the following criteria on screening examination to be eligible to 
participate.  Screening evaluations including consent, physical exam, and laboratory 


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assessments will be done within 30 days prior to Cycle 1 Day 1.  Bone marrow biopsy & 
aspirate, and CT C/A/P will be done within 90 days prior to Cycle 1 Day 1. 
 
3.1.1 Clinicopathological diagnosis of Waldenstrom’s Macroglobulinemia  
 
3.1.2 Known tumor expression of mutated MYD88 performed by a CLIA certified laboratory.  
 
 
3.1.3 At least one previous therapy, with ibrutinib as the most recent treatment.  Participants 
may remain on ibrutinib therapy during screening. A 1 day washout before starting 
dasatinib is required. 
 
3.1.4 Documented disease progression on last regimen (ibrutinib) per the Sixth International 
Workshop on WM (Owen et al, 2013).  One or more of the following: 
3.1.4.1 
25% increase in serum IgM level with at least 500 mg/dL absolute increase from 
nadir with re-confirmation 
3.1.4.2 
Progression of clinically significant disease related symptoms 
 
3.1.5 Symptomatic disease meeting criteria for treatment using consensus panel criteria from 
the Second International Workshop on WM (Kyle et al, 2003). One or more of the 
following: 
3.1.5.1 
Constitutional symptoms 
3.1.5.2 
Progressive or symptomatic lymphadenopathy or splenomegaly 
3.1.5.3 
Hemoglobin <10 g/dL 
3.1.5.4 
Platelet count <100 k/uL 
3.1.5.5 
Symptomatic peripheral neuropathy 
3.1.5.6 
Systemic amyloidosis 
3.1.5.7 
Renal insufficiency 
3.1.5.8 
Symptomatic cryoglobulinemia 
 
3.1.6 Age 18 years or older 
 
3.1.7 Measurable disease, defined as presence of immunoglobulin M (IgM) paraprotein with a 
minimum serum IgM level of > 2 times the upper limit normal.   
 
3.1.8 ECOG performance status ≤2 (Karnofsky ≥60%, see Appendix A) 
 
3.1.9 Women of childbearing potential: Females of childbearing potential (FCBP) must agree 
to use two reliable forms of contraception simultaneously or have or will have complete 
abstinence from heterosexual intercourse during the following time periods related to this 
study:  1) while participating in the study; and 2) for at least 28 days after discontinuation 
from the study. FCBP must be referred to a qualified provider of contraceptive methods if 
needed. 
 
3.1.10 Men must agree to use a latex condom during sexual contact with a female of 
childbearing potential (FCBP) even if they have had a successful vasectomy. 
 


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3.1.11 Participants must have normal organ and marrow function as defined below: 
− 
Absolute neutrophil count 
≥500/ uL (Growth factor not permitted) 
− 
Platelets 
≥50,000/ uL (Platelet transfusion not permitted) 
− 
Hemoglobin 
≥ 7 g/dL (RBC transfusion permitted) 
− 
Total bilirubin 
≤ 2 mg/dL 
− 
Potassium  
≥ LLN 
− 
Magnesium  
≥ LLN 
− 
AST(SGOT)/ALT(SGPT) 
≤2.5 × institutional upper limit of normal 
− 
Estimated GFR 
≥ 30 ml/min 
 
3.1.12 Able to swallow pills. 
 
3.1.13 Able to adhere to the study visit schedule and other protocol requirements. 
 
3.1.14 Ability to understand and the willingness to sign a written informed consent document. 
 
3.2 
Exclusion Criteria 
 
Participants who exhibit any of the following conditions at screening will not be eligible for 
admission into the study: 
 
3.2.1 Lactating or pregnant women. 
 
3.2.2 Participants who are receiving any other investigational agents. 
 
3.2.3 Prior therapy with BCR-ABL inhibitors. 
 
3.2.4 Known CNS lymphoma. 
 
3.2.6    Symptomatic hyperviscosity requiring urgent therapy. 
 
3.2.5 Human Immunodeficiency Virus (HIV), active infection with Hepatitis B Virus (HBV), 
and/or Hepatitis C Virus (HCV). 
  
3.2.6 Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, pleural or pericardial effusion, unstable angina 
pectoris, cardiac arrhythmia, QT Prolongation, or psychiatric illness/social situations that 
would limit compliance with study requirements. 
 
3.2.7 Prolonged QTc interval on pre-entry electrocardiogram (> 450 msec)  
 
3.2.8 History clinically significant ventricular arrhythmias such as ventricular tachycardia, 
ventricular fibrillation, or Torsades de pointes 
 
3.2.9 Known history of alcohol or drug abuse 
 


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3.2.10 On any active therapy for other malignancies with the exception of topical therapies for 
basal cell or squamous cell cancers of the skin. 
 
3.2.11 History of non-compliance to medical regimens. 
 
3.2.12 Treatment with strong CYP3A4/5 inhibitors or inducers 
 
3.2.13 Participants who are taking St. Johns Wort must discontinue at least 5 days before 
starting dasatinib. 
 
3.2.14 Treatment with H2 Antagonists and proton pump inhibitors 
 
3.3 
Inclusion of Women and Minorities 
 
Both men and women of all races and ethnic groups are eligible for this trial. 
 
4. REGISTRATION  
 
4.1 
General Guidelines for DF/HCC Institutions 
 
Institutions will register eligible participants in the Clinical Trials Management System (CTMS) 
OnCore. Registrations must occur prior to the initiation of any protocol-specific therapy or 
intervention. Any participant not registered to the protocol before protocol-specific therapy or 
intervention begins will be considered ineligible and registration will be denied. 
 
An investigator will confirm eligibility criteria and a member of the study team will complete the 
protocol-specific eligibility checklist. 
 
Following registration, participants may begin protocol-specific therapy and/or intervention. 
Issues that would cause treatment delays should be discussed with the Overall Principal 
Investigator (PI). If the subject does not receive protocol therapy following registration, the 
subject must be taken off-study in the CTMS (OnCore) with an appropriate date and reason 
entered.   
 
4.1 Registration Process for DF/HCC Institutions 
 
Applicable DF/HCC policy (REGIST-101) must be followed.   
 
5. TREATMENT PLAN 
 
5.1 
Treatment Regimen 
 
Dasatinib treatment will be administered daily in four-week cycles for up to 24 cycles.   
Treatment will be administered on an outpatient basis.  Reported adverse events and potential 
risks are described in Section 7.  Appropriate dose modifications are described in Section 6.  No 
investigational or commercial agents or therapies other than those described below may be 
administered with the intent to treat the participant's malignancy. 


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Regimen Description 
Agent 
Premedications; Precautions 
Dose 
Route 
Schedule 
Cycle 
Length 
Dasatinib 
Premedications: n/a 
 
Precautions:  Avoid simultaneous 
administration with antacids.  
Adminster antacid at least 2 hours 
prior to or 2 hours after dasatinib 
100mg PO 
Daily (QD) 
28 days  
(4 weeks) 
 
 
 
Up to 24 cycles 
 
5.2 
Pre-Treatment Criteria 
 
C1D1 results do not need to meet eligibility parameters. Day 1 chemistry and hematology 
laboratories must be reviewed prior to treatment. 
 
Participants must meet the following criteria on Day 1 of all cycles with clinic visits: 
• No grade 3 nausea, vomiting, or diarrhea (if persistent despite optimal antiemetic and/or 
antidiarrheal therapy) 
• No non-hematologic grade 3 toxicities 
• Neutrophil count > 500/uL (growth factor permitted to retreat) 
• Platelet count  
o > 25,000 uL in the absence of bleeding (platelet transfusion permitted to retreat)  
o > 50,000 uL in the presence of bleeding (platelet transfusion permitted to retreat) 
 
5.3 
Agent Administration 
 
Participants will self-administer dasatinib 100 mg orally once daily.  The tablets should be taken 
consistently either in the morning or the evening, swallowed whole.  The tablets must not be 
crushed or cut.  Dasatinib can be taken with or without a meal.  Participants will be instructed not 
to take antacids within two hours of a dose of dasatinib.  Dasatinib will be self-administered, and 
participants will be instructed to write in a diary daily, documenting that the drug was taken.   
 
If a dose of dasatinib is not taken at the scheduled time, it can be taken as soon as possible within 
6 hours, with a return to the normal schedule the following day.  The participant should not take 
extra tablets to make up a missed dose.   
 
If vomiting occurs within 30 minutes of taking dasatinib, that dose may be repeated. 
 
Dose reductions due to toxicity will be permitted on information seen in Section 6. 
 
5.4 
Definition of Dose-Limiting Toxicity (DLT)  
 


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The following will be considered a DLT if occurring during the 1st Cycle of Therapy: 
• > Grade 4 hematologic toxicity (anemia, neutropenia, or thrombocytopenia) 
• Any grade 5 hematologic or non-hematologic toxicity 
• Any grade 4 non-hematologic toxicity, including vomiting or diarrhea 
• Any other > Grade 3 adverse event not due to underlying disease, except for Grade 3 
infection, easily reversible asymptomatic laboratory abnormalities, and nausea, 
vomiting, or diarrhea controlled by medications.   
o Grade 3 vomiting or diarrhea can only be excluded if the participant does not 
require total parenteral nutrition (TPN), tube feeding, or hospitalization, and the 
toxicity resolves to less than grade 3 within 72 hours. 
o Reversible asymptomatic laboratory abnormalities may be excluded only if they 
are correctable to <grade 3 within 72 hours. 
 
Management and dose modifications associated with the above adverse events attributed to 
dasatinib are outlined in Section 6. 
 
If two participants experience a DLT or if any participant has a grade 5 treatment-related DLT 
enrollment will be stopped. 
 
5.5 
General Concomitant Medication and Supportive Care Guidelines 
 
Participants will be instructed not to take any additional medications (including over-the-counter 
products) during the course of the study without prior consultation with the investigator. At each 
visit, the investigator will ask the participant about any new medications he/she is or has taken 
after the start of the study drug. 
 
Anti-emetics are permitted if clinically indicated. Standard supportive care medications are 
permitted. All Concomitant medications/Significant non-drug therapies taken ≤ 30 days prior to 
start and after start of study drug, including physical therapy and blood transfusions, should be 
recorded.  
 
The following restrictions apply during the entire duration of the study: 
• 
No other investigational therapy should be given to participants. 
• 
No anticancer agents other than the study medication should be given to participants. If 
such agents are required for a patient, then the patient must first be withdrawn from the 
study. 
• 
Growth factors (i.e. G-CSF, GM-CSF, erythropoietin, platelets growth factors etc.) can 
be administered prophylactically, except to confirm eligibility, and may be prescribed at 
the discretion of the treating physician for treatment-related hematologic events in 
accordance with ASCO guidelines, and to meet re-treatment criteria. 
• 
Transfusions (red blood cells, platelets) can be administered for treatment-related 
hematologic events in accordance with ASCO guidelines, and to meet re-treatment 
criteria.  Transfusions of RBCs can be administered to meet eligibility criteria, but 
platelet transfusions are not permitted to meet eligibility criteria. 
• 
Use of H2 Antagonists and Proton Pump Inhibitors (PPIs) is prohibited.  These drugs 
may decrease dasatinib drug levels.  Consider antacids instead. 


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• 
Avoid grapefruit and Seville oranges. 
• 
Concurrent administration of dasatinib and strong CYP3A4/5 inhibitors and inducers is 
prohibited.  Examples of Strong inhibitors/inducers of CYP3A4/5 are in Table 5-1. 
 
Table 5-1 Strong Inhibitors and Inducers of CYP3A4/5 
Inhibitors of CYP3A4/5 
Inducers of CYP3A4/5 
Strong inhibitors: 
Strong CYP3A inducers: 
Boceprevir 
Clarithromycin 
Cobicistat 
Conivaptan 
Danoprevir/ritonavir 
Elvitegravir/ritonavir 
Idelalisib 
Indinavir 
Itraconazole 
Ketoconazole 
Mibefradil  
Lopinavir/ritonavir 
Nefazodone 
Nelfinavir 
Ritonavir 
Paritaprevir/ritonavir 
combinations 
Posaconazle 
Squinavir 
Telaprevir 
Telithromycin 
Tipranavir/ritonavir 
Voriconazole 
Avasimibe 
Carbamazepine 
Enzalutamine 
Mitotane 
Phenytoin 
Rifampin 
St. John’s wort 
 
 
Note that this is not an exhaustive list. For an updated list, see the following link: 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm080499
.htm  
 
5.6 
Criteria for Taking a Participant Off Protocol Therapy 
 
Duration of therapy will depend on individual response, evidence of disease progression and 
tolerance. In the absence of treatment delays due to adverse event(s), treatment may continue for 
24 cycles or until one of the following criteria applies: 
 
• 
Disease progression 
• 
Intercurrent illness that prevents further administration of treatment 
• 
Unacceptable adverse event(s) 
• 
Participant demonstrates an inability or unwillingness to comply with the oral 
medication regimen and/or documentation requirements 
• 
Participant decides to withdraw from the protocol therapy 
• 
General or specific changes in the participant's condition render the participant 
unacceptable for further treatment in the judgment of the treating investigator 
 
Special mentions: 
 
For participants meeting criteria for disease progression (based on consensus panel criteria for IgM 
response) but are deemed by the investigator to be clinically benefiting from dasatinib, these 
individuals will be permitted to continue on protocol therapy at the principal investigator’s 
discretion. Documentation describing the rationale for continuing benefit shall be entered into the 
medical record. Clinical benefit will be determined by considering clinical data, such as overall 
participant performance and disposition, complete blood counts, and when necessary, results from 


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bone marrow biopsies and/or CT scans. In such instances, any new nadir that may result with 
continued therapy will be used as the study nadir point for this patient. Patients must be on >2 
consecutive weeks of therapy for determination of a reliable IgM reading for response assessment 
purposes. 
 
Participants will be removed from the protocol therapy when any of these criteria apply.  The 
reason for removal from protocol therapy, and the date the participant was removed, must be 
documented in the case report form (CRF). Alternative care options will be discussed with the 
participant. 
 
When a participant is removed from protocol therapy and/or is off of the study, the relevant Off-
Treatment/Off-Study information will be updated in OnCore. 
 
5.7 
Duration of Follow Up 
 
Participants will be followed for 2 years after removal from protocol therapy, or until death, 
whichever occurs first.  Participants removed from protocol therapy for unacceptable adverse 
event(s) will be followed until resolution or stabilization of the adverse event. 
 
5.8 
Criteria for Taking a Participant Off Study 
 
Participants will be removed from study when any of the following criteria apply: 
• Lost to follow-up 
• Withdrawal of consent for data submission 
• Death 
 
The reason for taking a participant off study, and the date the participant was removed, must be 
documented in the case report form (CRF). In addition, the study team will ensure Off 
Treatment/Off Study information is updated in OnCore in accordance with DF/HCC policy 
REGIST-101. 
 
6. DOSING DELAYS/DOSE MODIFICATIONS 
 
Dose delays and modifications will be made as indicated in the following table(s). The 
descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 5.0 will be utilized for dose delays and dose modifications. A 
copy of the CTCAE version 5.0 can be downloaded from the CTEP website 
 http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.  
 
In the event of a non-hematological grade 3 or 4 toxicity such as chest pain, pleural effusion, or 
pericardial effusion the study drug should be stopped until appropriate diagnostic and therapeutic 
procedures have been undertaken.  Following the resolution of these events to <grade 1 dasatinib 
may be restarted a reduced dose (see Table 6-1 below). 
 
Dose re-escalation is not allowed for dose reduction triggered treatment related toxicities. 
 
Participants with any one of the following must permanently discontinue dasatinib therapy: 


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• An acute myocardial infarction or any other clinically significant arterial thromboembolic 
complication 
• Patients with confirmed pulmonary artery hypertension 
• Any treatment-related Grade 4 non-hematologic toxicity.  However, if the patient is 
deriving clinical benefit from dasatinib, and the toxicity resolves to Grade <1, the 
participant can re-start at a reduced dose after approval by the PI. 
• Women who become pregnant or are breast feeding 
 
If a participant requires a dose delay of >28 days, then the participant must be discontinued from 
the study, unless permitted to resume after discussion with the PI. 
 
Table 6-1 Dasatinib Dose Modification Guidelines 
Dose Level 
Dasatinib Dose 
 0 
100 mg PO QD 
-1 
70 mg PO QD 
-2 
50 mg PO QD 
 
6.1 
Dasatinib Dose Adjustments for AEs 
 
Neutropenia 
Management/Next Dose for Dasatinib 
≤ Grade 1 
No change in dose 
Grade 2 
No change in dose 
Grade 3 
No change in dose.  Hold until <Grade 2 if infection and/or fever 
present.  Resume at the same dose. 
Grade 4 
Hold if grade 4 until < Grade 3.  Resume at the same dose unless this is 
a recurring event or takes >7 days to recover at which time the dose 
should be reduced. 
*Administer G-CSF or growth factors for neutropenia as indicated. 
 
Thrombocytopenia 
Management/Next Dose for Dasatinib 
≤ Grade 1 
No change in dose 
Grade 2 
No change in dose 
Grade 3 
Hold until < Grade 2 if bleeding present.  No change in dose in the 
absence of bleeding.  Resume at the same dose. 
Grade 4 
Hold if grade 4 until < Grade 3.  Resume at the same dose unless this is 
a recurring event or takes >7 days to recover at which time the dose 
should be reduced. 
*Platelet transfusions for thrombocytopenia permitted. 
 
Non-Hematological 
Toxicities related to 
Dasatinib 
Management/Next Dose for Dasatinib 
≤ Grade 1 
• Add supportive care as indicated.  Continue dasatinib at the 
current dose level. 
Grade 2 
• Add supportive care as indicated.  Continue dasatinib at the 


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Non-Hematological 
Toxicities related to 
Dasatinib 
Management/Next Dose for Dasatinib 
current dose level. 
Grade 3 without 
optimal prophylaxis or 
which are easily 
managed by medical 
intervention or 
resolved quickly 
• Interrupt dasatinib and add supportive care as indicated 
• For AEs that are easily managed (e.g., correction of electrolytes) 
with resolution to baseline or Grade ≤ 1 within 24 hours, 
dasatinib may be resumed at either the same dose or with a dose 
reduction at the discretion of the investigator unless this is a 
recurring event at which time the dose should be reduced 
• For AEs that require supportive care, the dose should be held 
while supportive care is initiated and optimized. Then upon 
resolution of the AE to baseline or Grade ≤ 1, dasatinib may be 
resumed at either the same dose or with a dose reduction at the 
discretion of the investigator unless this is a recurring event at 
which time the dose should be reduced 
Grade 3 that occurred 
despite optimal 
prophylaxis or is not 
easily managed by 
medical intervention 
• Interrupt study treatment until recovery to ≤ Grade 1 or baseline, 
and resume treatment with a dose reduction 
Grade 4 
• Permanently discontinue study treatment unless determined that 
the subject is unequivocally deriving clinical benefit. In this 
case, upon recovery to Grade ≤ 1 or baseline, the subject may be 
re-treated at a reduced dose that is to be determined by the 
investigator 
 
7. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
following list of reported and/or potential AEs (Section 7.1) and the characteristics of an 
observed AE (Section 7.2) will determine whether the event requires expedited reporting in 
addition to routine reporting. 
 
7.1.1 
Adverse Events List 
 
7.1.1.1 
Adverse Event List(s) for Dasatinib 
 
Infections and infestations 
Very common 
infection (including bacterial, viral, fungal, non-specified) 
Common 
pneumonia (including bacterial, viral, and fungal), upper respiratory tract 
infection/inflammation,  herpes virus infection, enterocolitis infection, sepsis 
(including uncommon cases with fatal outcomes) 
Blood and lymphatic system disorders 
Very Common 
myelosuppression  (including anemia, neutropenia, thrombocytopenia) 
Common 
febrile neutropenia 
Uncommon 
lymphadenopathy,  lymphopenia 
Rare 
aplasia pure red cell 


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Immune system disorders 
Uncommon 
hypersensitivity (including erythema nodosum) 
Endocrine Disorders 
Uncommon 
hypothyroidism 
Rare 
hyperthyroidism, thyroiditis 
Metabolism and nutrition disorders 
Common 
appetite disturbancesa, hyperuricaemia 
Uncommon 
tumour lysis syndrome, dehydration, hypoalbuminemia, hypercholesterolemia 
Rare 
diabetes mellitus 
Psychiatric disorders 
Common 
depression, insomnia 
Uncommon 
anxiety, confusional state, affect lability, libido decreased 
Nervous system disorders 
Very common 
headache 
Common 
neuropathy (including peripheral neuropathy), dizziness, dysgeusia, somnolence 
Uncommon 
CNS bleeding*b, syncope, tremor, amnesia, balance disorder 
Rare 
cerebrovascular accident, transient ischaemic attack, convulsion, optic neuritis, VIIth 
nerve paralysis, dementia, ataxia 
Eye disorders 
Common 
visual disorder (including visual disturbance, vision blurred, and visual acuity 
reduced), dry eye 
Uncommon 
visual impairment, conjunctivitis, photophobia, lacrimation increased 
Ear and labyrinth disorders 
Common 
tinnitus 
Uncommon 
hearing loss, vertigo 
Cardiac disorders 
Common 
congestive heart failure/cardiac dysfunction*c, pericardial effusion*, arrhythmia 
(including tachycardia), palpitations 
Uncommon 
myocardial infarction (including fatal outcome)*, electrocardiogram QT prolonged*, 
pericarditis, ventricular arrhythmia (including ventricular tachycardia), angina 
pectoris, cardiomegaly, electrocardiogram T wave abnormal, troponin increased 
Rare 
cor pulmonale, myocarditis, acute coronary syndrome, cardiac arrest, 
electrocardiogram PR prolongation, coronary artery disease, pleuropericarditis 
Not known 
atrial fibrillation/atrial flutter 
Vascular disorders 
Very common 
haemorrhage*d 
Common 
hypertension, flushing 
Uncommon 
hypotension, thrombophlebitis 
Rare 
deep vein thrombosis, embolism, livedo reticularis 
Respiratory, thoracic and mediastinal disorders 
Very common 
pleural effusion*, dyspnoea 
Common 
pulmonary oedema*, pulmonary hypertension*, lung infiltration, pneumonitis, cough 
Uncommon 
pulmonary arterial hypertension, bronchospasm, asthma 
Rare 
pulmonary embolism, acute respiratory distress syndrome 
Not known 
interstitial lung disease 
Gastrointestinal disorders 
Very common 
diarrhoea, vomiting, nausea, abdominal pain 
Common 
gastrointestinal bleeding*, colitis (including neutropenic colitis), gastritis, mucosal 
inflammation (including mucositis/stomatitis),  dyspepsia, abdominal distension, 
constipation, oral soft tissue disorder 
Uncommon 
pancreatitis (including acute pancreatitis), upper gastrointestinal ulcer, oesophagitis, 
ascites*, anal fissure, dysphagia, gastroesophageal reflux disease 
Rare 
protein-losing gastroenteropathy, ileus, anal fistula 


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Not known 
fatal gastrointestinal haemorrhage* 
Hepatobiliary disorders 
Uncommon 
hepatitis, cholecystitis, cholestasis 
Skin and subcutaneous tissue disorders 
Very common 
skin rashe 
Common 
alopecia, dermatitis (including eczema), pruritus, acne, dry skin, urticaria, 
hyperhidrosis 
Uncommon 
neutrophilic dermatosis, photosensitivity, pigmentation disorder, panniculitis, skin 
ulcer, bullous conditions, nail disorder, palmar-plantar erythrodysesthesia syndrome, 
hair disorder 
Rare 
leukocytoclastic vasculitis, skin fibrosis 
Not known 
Stevens-Johnson Syndromef 
Musculoskeletal and connective tissue disorders 
Very common 
musculoskeletal pain 
Common 
arthralgia, myalgia, muscular weakness, musculoskeletal stiffness, muscle spasm 
Uncommon 
rhabdomyolysis, osteonecrosis, muscle inflammation, tendonitis, arthritis 
Renal and urinary disorders 
Uncommon 
renal impairment (including renal failure), urinary frequency, proteinuria 
Pregnancy, puerperium and perinatal conditions 
Rare 
abortion 
Reproductive system and breast disorders 
Uncommon 
gynecomastia, menstrual disorder 
General disorders and administration site conditions 
Very common 
peripheral oedemag, fatigue, pyrexia, face oedemah 
Common 
asthenia, pain, chest pain, generalised oedema*i, chills 
Uncommon 
malaise, other superficial oedemaj 
Rare 
gait disturbance 
Investigations 
Common 
weight decreased, weight increased 
Uncommon 
blood creatine phosphokinase increased, gamma-glutamyltransferase increased 
Injury, poisoning, and procedural complications 
Common 
contusion 
a. 
Includes decreased appetite, early satiety, increased appetite. 
 
b. Includes central nervous system haemorrhage, cerebral haematoma, cerebral 
haemorrhage, extradural haematoma, haemorrhage intracranial, haemorrhagic 
stroke, subarachnoid haemorrhage, subdural haematoma, and subdural 
haemorrhage. 
 
c. 
Includes brain natriuretic peptide increased, ventricular dysfunction, left ventricular 
dysfunction, right ventricular dysfunction, cardiac failure, cardiac failure acute, 
cardiac failure chronic, cardiac failure congestive, cardiomyopathy, congestive 
cardiomyopathy, diastolic dysfunction, ejection fraction decreased and ventricular 
failure, left ventricular failure, right ventricular failure, and ventricular hypokinesia. 
 
d. Excludes gastrointestinal bleeding and CNS bleeding; these adverse reactions are 
reported under the gastrointestinal disorders system organ class and the nervous 
system disorders system organ class, respectively. 
 
e. 
Includes drug eruption, erythema, erythema multiforme, erythrosis, exfoliative rash, 
generalised erythema, genital rash, heat rash, milia, miliaria, pustular psoriaisis, rash, 
rash erythematous, rash follicular, rash generalised, rash macular, rash maculo-papular, 
rash papular, rash pruritic, rash pustular, rash vesicular, skin exfoliation, skin irritation, 
toxic skin eruption, urticaria vesiculosa, and vasculitic rash. 
 


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f. 
In the post-marketing setting, individual cases of Stevens-Johnson syndrome have been 
reported.  It could not be determined whether these mucocutaneous adverse reactions 
were directly related to SPRYCEL or to concomitant medications. 
g. Gravitational oedema, localised oedema, oedema peripheral. 
 
h. Conjunctival oedema,  eye oedema,  eye swelling,  eyelid oedema,  face oedema,  lip oedema,  
macular oedema,  oedema mouth, orbital oedema,  periorbitalo edema, swelling face. 
 
i. 
Fluid overload, fluid retention, gastrointestinal oedema, generalised oedema, oedema, 
oedema due to cardiac disease, perinephric effusion, post procedural oedema, 
visceral oedema. 
 
j. 
Genital swelling, incision site oedema, oedema genital, penile oedema, penile 
swelling, scrotal oedema, skin swelling, testicular swelling, vulvovaginal swelling. 
 
7.1.1.1.1 Warnings and Precautions 
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. 
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.1 
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 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 


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short courses of steroids. (Incidences in this paragraph reflect drug-related adverse reactions 
based on investigator’s attribution).24 
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.  
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. 
 
7.1.1.1.2 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 Table 4. 


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Table 3: 
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 
 
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). 
7.1.1.1.3 Drug-Related Serious Adverse Events 
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 
(N = 1150), 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 (N = 1032), 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%). 
7.1.1.1.4 Drug-Related Deaths 
A total of 577 (26%) deaths at any time after the last dasatinib dose occurred in the cohort of 
2182 subjects pooled across disease phases. Disease accounted for 304 of the 577 deaths. 
In subjects with chronic phase CML (N = 1150), a total of 86 (7%) subjects died. Of these 86 
deaths, deaths due to study drug toxicity occurred in 2 subjects (1 due to pulmonary edema, 


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CHF, neck pain, pleural effusion and 1 due to necrosis of the colon). Both subjects were in the 
70 mg BID group. 
In subjects with advanced phase CML or Ph+ ALL, a total of 491 (48%) subjects died. Death 
due to study drug toxicity occurred in 8 subjects.  
 
7.2 
Adverse Event Characteristics 
 
• CTCAE term (AE description) and grade:  The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
5.0 will be utilized for AE reporting.  All appropriate treatment areas should have access 
to a copy of the CTCAE version 5.0.  A copy of the CTCAE version 5.0 can be 
downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
• For expedited reporting purposes only:   
- 
AEs for the agent(s) that are listed above should be reported only if the adverse event 
varies in nature, intensity or frequency from the expected toxicity information which 
is provided. 
- 
Other AEs for the protocol that do not require expedited reporting are outlined in the 
next section (Expedited Adverse Event Reporting) under the sub-heading of Protocol-
Specific Expedited Adverse Event Reporting Exclusions. 
 
• Attribution of the AE: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
7.3 
Adverse Event Reporting  
 
7.3.1 In the event of an unanticipated problem or life-threatening complications treating 
investigators must immediately notify the Overall PI. 
 
7.3.2 Investigators must report to the Overall PI any adverse event (AE) that occurs after the 
initial dose of study treatment, during treatment, or within 30 days of the last dose of 
treatment on the local institutional SAE form.  
 
7.3.3 
DF/HCC Adverse Event Reporting Guidelines 
 
Investigative sites within DF/HCC will report AEs directly to the DFCI Office for 
Human Research Studies (OHRS) per the DFCI IRB reporting policy.  
 
7.4 
Reporting to the Food and Drug Administration (FDA) 
 
The Overall PI, as study sponsor, will be responsible for all communications with the FDA. The 


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Overall PI will report to the FDA, regardless of the site of occurrence, any serious adverse event 
that meets the FDA’s criteria for expedited reporting following the reporting requirements and 
timelines set by the FDA. 
 
7.5 
Expedited Reporting to BMS Worldwide Safety 
 
All Serious Adverse Events (SAEs) that occur following the subject’s written consent to 
participate in the study through 30 days of discontinuation of dosing must be reported to BMS 
Worldwide Safety. 
• Following the subject’s written consent to participate in the study, all SAEs, whether 
related or not related to study drug, are collected, including those thought to be associated 
with protocol-specified procedures. The investigator should report any SAE occurring 
after these time periods that is believed to be related to study drug or protocol-specified 
procedure.  
SAEs and pregnancies must be reported to BMS within 24 hours of learning of the event 
regardless of causality. SAEs must be recorded on BMS or an approved form; pregnancies must 
be reported on a Pregnancy Surveillance Form. 
A serious AE (SAE) is any untoward medical occurrence that at any dose: 
a) results in death 
b) 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) 
c) requires inpatient hospitalization or causes prolongation of existing hospitalization (see 
NOTE below) 
d) results in persistent or significant disability/incapacity 
e) is a congenital anomaly/birth defect 
f) 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 subject 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.)  
g) Suspected transmission of an infectious agent (eg, any organism, virus or infectious 
particle, pathogenic or non-pathogenic) via the study drug is an SAE. 
h) Although pregnancy, overdose and cancer are not always serious by regulatory definition, 
these events must be handled as SAEs. 
NOTE: 
The following hospitalizations are not considered SAEs in BMS clinical studies: 
• a visit to the emergency room or other hospital department < 24 hours, that does not 
result in admission (unless considered "important medical event" or event life 
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• elective surgery, planned prior to 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 and was 
planned prior to entry into the study. 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, care-giver respite, family circumstances, administrative). 
SAE Email Address:  Worldwide.Safety@BMS.com 
SAE Facsimile Number:  609-818-3804 
If only limited information is initially available, follow-up reports are required. (Note: Follow-up 
SAE reports should include the same investigator term(s) initially reported.)  
If an ongoing SAE changes in its intensity or relationship to study drug or if new information 
becomes available, a follow-up SAE report should be sent within 24 hours to the BMS (or 
designee) using the same procedure used for transmitting the initial SAE report.  
All SAEs should be followed to resolution or stabilization. 
 
7.6 
Reporting to Hospital Risk Management 
 
Participating investigators will report to their local Risk Management office any participant 
safety reports, sentinel events or unanticipated problems that require reporting per institutional 
policy.  
 
7.7 
Routine Adverse Event Reporting 
 
All Adverse Events must be reported in routine study data submissions to the Overall PI on the 
toxicity case report forms.  AEs reported through expedited processes (e.g., reported to the 
IRB, FDA, etc.) must also be reported in routine study data submissions. 
 
8. PHARMACEUTICAL INFORMATION 
 
A list of the adverse events and potential risks associated with the investigational agent 
administered in this study can be found in Section 7.1. 
 
8.1 
IND Agent #1 Dasatinib 
 
8.1.1 
Description 
 
SPRYCEL (dasatinib) is a kinase inhibitor. The chemical name for dasatinib is N-(2-chloro-6-
methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-
thiazolecarboxamide, monohydrate. The molecular formula is C22H26ClN7O2S • H2O, which 
corresponds to a formula weight of 506.02 (monohydrate). The anhydrous free base has a 
molecular weight of 488.01. Dasatinib has the following chemical structure: 


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Dasatinib is a white to off-white powder. The drug substance is insoluble in water and slightly 
soluble in ethanol and methanol. SPRYCEL tablets are white to off-white, biconvex, film-coated 
tablets containing dasatinib, with the following inactive ingredients: lactose monohydrate, 
microcrystalline cellulose, croscarmellose sodium, hydroxypropyl cellulose, and magnesium 
stearate. The tablet coating consists of hypromellose, titanium dioxide, and polyethylene glycol. 
8.1.2 
Form 
 
Dasatinib is available as 20 mg, 50 mg, 70 mg, 80 mg, 100 mg film-coated tablets. 
 
8.1.3 
Storage and Stability 
 
Bottles containing dasatinib tablets should be stored at 20° - 25°C.  Excursions permitted 
between 15° and 30°. 
 
8.1.4 
Compatibility 
 
N/a. 
 
8.1.5 
Handling 
 
Dasatinib tablets consist of a core tablet (containing the active drug substance), surrounded by a 
film coating to prevent exposure of pharmacy and clinical personnel to the active drug substance. 
However, if tablets are inadvertently crushed or broken, pharmacy and clinical personnel should 
wear disposable chemotherapy gloves. Personnel who are pregnant should avoid exposure to 
crushed or broken tablets. 
 
8.1.6 
Availability 
 
Dasatinib is provided by Bristol-Myers Squibb.  The study drug will be labeled and handled as 
open-label material, and packaging labels will fulfill all requirements specified by governing 
regulations. 
8.1.7 
Preparation 
 
N/a. 
 
8.1.8 
Administration 
 
Dasatinib should be self-administered daily by the participant at approximately the same time 
(morning or evening).  Tablets should not be crushed or cut; they should be swallowed whole.  
Dasatinib may be taken on an empty or full stomach.  Participants will be instructed not to take 


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antacids within two hours of a dose of dasatinib.  The dosing time may be adjusted as required.  
If a participant forgets to take a dose, it may be taken up to 6 hours later.  If vomiting occurs 
within 30 minutes of intake, that dose may be repeated.   
 
8.1.9 
Ordering 
 
In this protocol, investigational product is Dasatinib, which will be supplied by BMS.  
 
The process for ordering study drug from BMS for the initial shipment and resupply shipments 
will be managed by the site through completion of a drug shipment request form, which will be 
provided by BMS. 
 
BMS contact details for drug ordering: 
Please email the drug supply form with the subject heading “Dasatinib Supply Request” to the 
following: 
Email: SRCSupply@bms.com 
Fax (to Wallingford, Connecticut USA): 866-227-7229 
 
 
 
            203-677-6489 
 
8.1.10 Accountability 
 
The investigator, or a responsible party designated by the investigator, should maintain a careful 
record of the inventory and disposition of the agent using the NCI Drug Accountability Record 
Form (DARF) or another comparable drug accountability form.  (See the NCI Investigator’s 
Handbook for Procedures for Drug Accountability and Storage.) 
 
8.1.11 Destruction and Return 
 
Unused dasatinib tablets will be returned by the participant, collected and counted at each study 
visit, and then returned to pharmacy for destruction.  Unused supplies of dasatinib should be 
destroyed according to institutional policies.  Destruction will be documented in the Drug 
Accountability Record Form. 
 
 
 
 
 
9. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 
9.1 
Laboratory Correlative Studies 
 
9.1.1 
Assessment of MYD88 L265P and CXCR4 WHIM genotyping. 
 
An allele-specific polymerase-chain-reaction (PCR) assay will be used to detect MYD88L265P, 
CXCR4WHIM mutation status will be determined by means of Sanger sequencing, and allele-
specific PCR will be used to detect CXCR4S338X C→G and C→A mutations in CD19-selected 
bone marrow cells (Xu et al, 2013; Hunter et al,2014; Treon et al, 2014). Bone marrow aspirate 


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(approximately 30 cc in 2 heparinized syringes & 1 purple top) will be collected at the screening 
bone marrow biopsy. 
 
At baseline, the samples will be genotyped for MYD88 and CXCR4 mutations by the Bing 
Center for WM laboratory.  Whole exome sequencing of BM samples will be performed as before 
to characterize variants including BTK Cys481 mutations associated with ibrutinib resistance 
(Jimenez et al, 2020). The samples will be used until depletion.   
 
Bing Center address: 
450 Brookline Avenue Mayer 5 
Boston, MA 02215 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
10. STUDY CALENDAR 
Assessments must be performed prior to administration of any study agent. Study assessments 
and agents should be administered within + 3 days of the protocol-specified date, unless 
otherwise noted. 
 
  
Screening* 
 
≤ 30days 
from study 
entry 
Treatment Phase7 
48- four week cycles (4 years) 
Off Treatment 
Assessment 
Follow-Up 
Phase  
Cycles 1*, 
2 
(4 weeks 
± 3 days) 
Cycles 3, 6, 9, 
etc. until 24 four 
week cycles 
completed 
(12 weeks± 2 
weeks) 
Within 4 weeks 
of completion 
of entire 
treatment plan 
or removal from 
study ± 2 weeks 
Post 
Treatment; 
Every 12 
weeks ± 2 
weeks for 2 
years 
Physical exams1, vital signs, 
weight 
X 
X 
X 
X 
X 
Medical History 
X 
 
 
 
 
ECOG performance status 
(see Appendix A) 
X 
 
 
 
 


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CT of the chest & abdomen 
/ pelvis2 
X 
 
X2 
 
X (if 
applicable) 
Bone marrow biopsy and 
aspiration3 
X 
 
X3 
 
X  (if 
applicable) 
Quantitative serum IgM, 
IgG, IgA, free light chain 
assays   
X 
X 
X 
X 
X 
ECG 
X 
 
 
 
 
Serum immuno-
electropheresis 
X 
X 
X 
X 
X 
Complete Blood Count plus 
differential1,4 
X 
X 
X 
X 
X 
Coagulation profile: PT, 
PTT, PT-INR5 
X 
 
 
 
 
Chemistry/ Comprehensive 
Metabolic Panel including: 
Electrolytes, Renal (BUN, 
Creatinine, eGFR) and 
Hepatic function testing 
[ALT (SGPT), AST 
(SGOT), Alk phos, total 
Bilirubin, albumin, and total 
protein], Magnesium, 
Phosphorus, Uric acid 
X 
X 
X 
X 
X 
LDH 
X 
 
 
 
 
Pregnancy Test6 
X 
 
 
 
 
Beta-2 microglobulin test 
X 
 
 
 
 
Review patient diary  
 
X 
X 
 
 
HBsAG, HBsAb, HBcAB, 
HCV, HIV Ab 
X 
 
 
 
 
Adverse event monitoring 
(see section 6) 
 
X 
X 
X 
* Labs, Physical exam, vital signs, and weight do not need to be repeated if Cycle 1, Day 1 is 
within 28 days of Screening. Cycle 1, Day 1 labs, if drawn, do not need to re-confirm eligibility 
prior to administering first dose. 
 
1More frequent visits may be required at the discretion of the treating physician.  
 
2If CT scans of the chest, abdomen and pelvis have been collected and done within 90 days 
of Cycle 1 Day 1 they will not be required at the screening visit. Scans will be repeated at 
cycle 6, 12, and EOT, for participants with extramedullary disease at baseline defined as 
adenopathy >1.5 cm in any axis, and splenomegaly >15 cm in the craniocaudal axis. Scans 
will also be repeated to confirm a complete response if the participant has no detectable 
monoclonal protein and had extramedullary disease at baseline, and at the discretion of the 
investigator.  
 
3Bone marrow biopsy and aspirations are required at baseline within 90 days of Cycle 1 Day 
1, and at cycle 6, 12, and EOT, or at time of progression Bone marrow biopsy and aspiration 
may also be done at the investigator’s discretion, and at any time to confirm a complete response 
if the participant has no detectable monoclonal protein. MYD88 and CXCR4 mutation status will 


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be assessed at baseline only.  10 mL of aspirate will be sent to the Treon Laboratory for whole 
exome sequencing for variants associated with ibrutinib resistance at baseline. 
 
4For patients who demonstrate therapy related hematological toxicity, more frequent CBC 
evaluations are strongly recommended. 
 
5Coagulation profile. Prothrombin time (PT) will be performed at screening and repeated as 
clinically indicated. PT will be reported as well as the international normalized ratio (INR).  
 
6For women of child-bearing potential only, a serum pregnancy test will be required at screening. 
 
7Please refer to Section 6 for Dose Modifications. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
11. MEASUREMENT OF EFFECT 
 
11.1.1 Definitions 
 
Evaluable for toxicity: All participants who receive at least one dose of study treatment will 
be evaluable for toxicity from the time of their first treatment. 
 
Evaluable for objective response: Only those participants who have measurable disease 
present at baseline, have received at least one cycle of therapy, and have had their disease 
re-evaluated will be considered evaluable for response. These participants will have their 
response classified according to the definitions stated below. (Note: Participants who 
exhibit objective disease progression or die prior to the end of cycle 1 will also be considered 
evaluable.) 
 
11.1.2 Response Criteria  
 
Complete Response (CR): A complete response (CR) is defined as having resolution of WM 


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related symptoms, normalization of serum IgM levels with complete disappearance of IgM 
paraprotein by immunofixation, and resolution of any adenopathy or splenomegaly. A complete 
response requires reconfirmation demonstrating normal serum IgM levels, and absence of IgM 
paraprotein by immunofixation by a measurement repeated at least 2 weeks later. 
 
Very Good Partial Response (VGPR): is defined as > 90% reduction in serum IgM levels, or 
normalization of serum IgM levels. 
 
Partial Response (PR): Partial response (PR) is defined as achieving a > 50% reduction in 
serum IgM levels. 
 
Minor Response (MR): A minor response (MR) is defined 25-49% reduction in serum IgM 
levels. 
 
Progressive Disease (PD): Progressive disease (PD) is defined as occurring when a greater than 
25% increase in serum IgM level occurs with an absolute increase of at least 500 mg/dL from the 
lowest attained response value, or progression of clinically significant disease related 
symptom(s). Reconfirmation of the initial IgM increase is required when IgM is the sole criterion 
for progressive disease confirmation.  Death from any cause or initiation of a new anti-neoplastic 
therapy will also be considered a progression event. An increase of 1 cm in any axis for 
adenopathy, or 2 cm in the craniocaudal axis of the spleen will be considered evidence of 
progression of extramedullary disease. Development of Bing Neel syndrome, or other 
extramedullary disease manifestations, as well as disease transformation will be considered as 
progressive events. 
 
Stable Disease (SD): Stable disease is defined as having < 25% change in serum IgM levels, in 
the absence of new or increasing adenopathy or splenomegaly and/or other progressive signs or 
symptoms of WM. 
 
Overall Response Rate (ORR): Includes patients who achieved MR, PR, VGPR and CR. 
11.1.2.1 
Time-to-event definition 
 
Progression-Free Survival (PFS) is defined as the duration of time from start of treatment to 
time of objective disease progression (including initiation of new therapy or death).  
 
12. DATA REPORTING / REGULATORY REQUIREMENTS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 
(Adverse Events: List and Reporting Requirements). 
 
12.1 
Data Reporting 
 
12.1.1 Method 
 
The Office of Data Quality (ODQ) will collect, manage, and perform quality checks on 
the data for this study. 
 


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12.1.2 Responsibility for Data Submission 
 
Investigative sites within DF/HCC or DF/PCC are responsible for submitting data and/or 
data forms to the Office of Data Quality (ODQ) in accordance with DF/HCC policies. 
 
12.2 
Data Safety Monitoring 
 
The DF/HCC Data and Safety Monitoring Committee (DSMC) will review and monitor toxicity 
and accrual data from this study. The committee is composed of medical oncologists, research 
nurses, pharmacists and biostatisticians with direct experience in cancer clinical research.  
Information that raises any questions about participant safety will be addressed with the Overall 
PI and study team. 
 
The DSMC will review each protocol up to four times a year with the frequency determined by 
the outcome of previous reviews. Information to be provided to the committee may include: up-
to-date participant accrual; current dose level information; DLT information; all grade 2 or 
higher unexpected adverse events that have been reported; summary of all deaths occurring 
within 30 days of intervention for Phase I or II protocols; for gene therapy protocols, summary of 
all deaths while being treated and during active follow-up; any response information; audit 
results, and a summary provided by the study team. Other information (e.g. scans, laboratory 
values) will be provided upon request.  
13. STATISTICAL CONSIDERATIONS 
 
Patients’ clinical and pathological characteristics and response to therapy will be presented using 
descriptive statistics. Median PFS, TTNT and OS times as well as 2-year and 4-year PFS, TTNT 
and OS rates will be estimated using the Kaplan-Meier method for incomplete observations. 
Predictive factors for response will be evaluated using logistic and linear regression, when 
appropriate. Prognostic factors for survival will be evaluated by fitting Cox proportional hazard 
regression models. Updates on response and survival will be evaluated and presented yearly. 
13.1 
Study Design/Endpoints 
 
This is a pilot study, aimed to assess the safety and possible efficacy of dasatinib as a salvage 
therapy after progression on ibrutinib for participants with Waldenstrom Macroglobulinemia. 
WM patients who progress on ibrutinib have a median of overall survival of 21 months, and new 
therapeutic strategies are needed to address this.  Given the small sample size of this trial, this 
study is not powered on disease outcomes, but we will collect and descriptively analyze many 
study elements. 
 
The maximum accrual for this study will be 6 participants.  If two participants experience DLTs 
or any participants have a grade 5 treatment-related DLT then enrollment will be stopped early 
and the study will be permanently closed.  
 
The following will be considered a DLT if occurring during the 1st Cycle of Therapy: 
• > Grade 4 hematologic toxicity (anemia, neutropenia, or thrombocytopenia) 
• Any grade 5 hematologic or non-hematologic toxicity 


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• Any grade 4 non-hematologic toxicity, including vomiting or diarrhea 
• Any other > Grade 3 adverse event not due to underlying disease, except for Grade 3 
infection, easily reversible asymptomatic laboratory abnormalities, and nausea, 
vomiting, or diarrhea controlled by medications.   
o Grade 3 vomiting or diarrhea can only be excluded if the participant does not 
require total parenteral nutrition (TPN), tube feeding, or hospitalization, and the 
toxicity resolves to less than grade 3 within 72 hours. 
o Reversible asymptomatic laboratory abnormalities may be excluded only if they 
are correctable to <grade 3 within 72 hours. 
 
Primary Objectives 
 
• To evaluate the toxicity profile of dasatinib in WM patients who progressed on ibrutinib with 
BTK or PLCG2 mutations. 
 
13.2 
Secondary Objectives 
 
• To evaluate the ORR of dasatinib in WM patients who are progressed . 
• To evaluate the rate of CR, very good partial response (VGPR), partial response (PR), 
minimal response (MR), stable disease (SD) and progressive disease (PD) to dasatinib in 
WM patients who progressed on ibrutinib. 
• To evaluate progression-free survival, time to next therapy (TTNT), and overall survival to 
dasatinib in WM patients who progressed on ibrutinib. 
• To evaluate the impact of MYD88 and CXCR4 mutations on response to dasatinib in WM 
patients who progressed on ibrutinib. 
 
13.3 
Sample Size, Accrual Rate and Study Duration 
 
The present pilot study will accrue 6 patients. The total study duration will be approximately 3.5 
years, which include 18 months of accrual, 2 years of treatment and 2 years of follow-up. 
 
13.4 
Stratification Factors 
 
No stratification factors will be applied for the study. 
 
13.5 
Interim Monitoring Plan 
 
The study will be monitored by the DFCI Data Safety Monitoring Committee (DSMC). The 
DSMC will meet at least two times a year and more often if needed (e.g., for safety review). For 
each meeting, the study will be reviewed for safety and progress toward completion. Copies of 
the toxicity reports prepared by the DSMC meetings will be distributed to the Principal 
Investigator. The Principal Investigator will then distribute to sub-investigators. Any DSMC 
recommendations for changes to the study will be distributed to the Principal Investigator and 
then circulated to sub- investigators by the Principal Investigator. No interim analysis of the 
outcome data is planned.  


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13.6 
Analysis of Primary Endpoints 
 
Primary analyses will be performed in FAS population and will include calculating the 
proportion of patients having a major response (PR or better).  Confidence intervals (95%) 
around these point estimates will be presented.   
 
13.7 
Analysis of Secondary Endpoints 
 
The Per-Protocol Analysis Set (PPS) is defined as all participants from the FAS set who 
complete the study and are deemed to be protocol-compliant.  To be protocol-compiant, a 
participant must not have any major protocol deviations during the study period.  Protocol 
deviations will be identified prior to database lock and will be listed in the clniical study report.  
The PPS will be used for secondary assessment of efficacy endpoints. 
 
Secondary analyses will be performed in both the FAS and PPS populations.  The time to 
response, both major (PR or better) and minor response will be estimated using Kaplan Meier 
methodology with median time plus 25th and 75th percentile time to response along with 95% 
confidence intervals being provided, as appropriate.  Time to progression (TTP) will also be 
estimated using Kaplan Meier methodology.  Best overall response and Very Good Partial 
Response (>90% reduction in disease burden)/ CR (complete response) will be estimated in both 
the FAS and PPS populations involving calculating the proportion of patients having an overall 
response (MR or better).  Confidence intervals (95%) around these point estimates will be 
presented. 
 
13.8 
Reporting and Exclusions 
 
13.8.1 Evaluation of Toxicity 
 
All participants who receive at least one dose of any test material during the study will be 
included in the safety analysis. 
 
13.8.2 Evaluation of the Primary Efficacy Endpoint 
 
All participants who have received at least one cycle of therapy are eligible for response 
assessment. Inevaluable patients for response will be replaced. All conclusions will be based on 
evaluable participants.  
 
 
14. PUBLICATION PLAN 
 
Interim study results may be presented at a major scientific meeting (American Society of 
Hematology, the International Workshop on WM or the International Conference on Malignant 
Lymphoma). 
 
A full report that will include primary and secondary endpoints will be published in a peer-
reviewed journal that meets the requirements of the International Committee of Medical Journal 
Editors within 24 months of reaching the end of the study. 


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APPENDIX A 
PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
40 
Disabled, requires special care and 


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of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead.