# Presentation: 160856

## FDA’s Oncologic DrugsAdvisory Committee Meeting

**DASATINIB**(BMS-354825)

- FDA’s Oncologic DrugsAdvisory Committee Meeting

- 2 June 2006

## Introduction

**Donna Morgan Murray, PhD**
- Bristol-Myers SquibbGlobal Regulatory Sciences

## BMS Presentation

**Introduction**	.....................**	****Donna Morgan Murray, PhD****	****	**BMS,** **Global Regulatory Sciences
**Scientific Rationale****	**..........**	****Neil Shah, MD, PhD****	****	**UCSF School of Medicine
**Clinical Program****	**...............**	****Claude Nicaise, MD****	****	**BMS,** **Global Development
**Clinical Perspective****	**.........**	****Hagop Kantarjian, MD** 		MD Anderson Cancer Center
**Conclusion****	**......................**	****Donna Morgan Murray, PhD**

## Consultants Available to the Committee

**Neil Shah, MD, PhD**Assistant Professor	Division of Hematology/OncologyDepartment of MedicineUCSF School of MedicineSan Francisco, CA
**Hagop Kantarjian, MD** Chairman & ProfessorLeukemia DepartmentThe University of TexasMD Anderson Cancer CenterHouston, TX

## Medical Need for Therapeutic Options in CML

**Chronic**

**Accelerated**

**Blast**

**Chronic Myeloid Leukemia (CML) is usually treated with imatinib, although resistance and intolerance develops**
**After imatinib failure, therapeutic options are limited **(e.g., escalated doses of imatinib, hydroxyurea, interferon, investigational agents, stem cell transplants)
**Dasatinib offers a therapeutic option to patients****in all phases of CML after failure with imatinib**

## Proposed Indications for Dasatinib 

**Treatment of adults with chronic, accelerated, or blast phase chronic myeloid leukemia (CML) with resistance or intolerance to prior therapy including imatinib**
**Treatment of adults with Philadelphia chromosome‐positive (Ph+) acute lymphoblastic leukemia (ALL) and lymphoid blast chronic myeloid leukemia with resistance or intolerance to prior therapy **

## Scientific Rationale

**Neil Shah, MD, PhD**
- UCSF School of Medicine

## The Philadelphia (Ph) Chromosome Leads to CML

**Ph chromosome**

**BCR-ABL**** (****activated tyrosine kinase)**

**BCR**

**ABL**

**The Philadelphia (Ph) Chromosome ****Leads to CML**

## Loss of Response to Imatinib in CML

**Chronic Phase – Frontline****	****	****16%****	****(42 months)**
**Chronic Phase – IFN failure****	****	****26%**
**Accelerated Phase****	****	****	****73%      (48 months)**
**Blast Crisis****	****	****	****	****95%**

_**Rate of Relapse/Progression**_

**Silver et al, 2004; Guilhot et al, 2004; Bhatia et al, 2002; Graham et al, 2002 **

***For most imatinib-resistant or -intolerant patients, effective therapeutic options are severely limited***

## Clinical Resistance to Imatinib is Associatedwith Restoration of BCR-ABL Kinase Activity

**Mechanisms**
**Outgrowth of one or more clones harboring an imatinib-resistant BCR-ABL kinase domain mutation (most common)**
**Overproduction of BCR-ABL via genomic amplification**
**BCR-ABL-independent mechanisms**

## Map of BCR-ABL Kinase Domain Mutations Associated with Clinical Resistance to Imatinib

- E255K/V

- M244V

- M351T

- Y253H/F

- E279K

- F317L

- E355G/D

- F359C/V/D/I

- H396R/P

- Q252H/R

- E459K/Q

- F486S

- E450G/Q

- M388L

- G250E/A/F

- D276G

- T277A

- L387F/M

- V379I

- A397P

- E453G/K

- T315I/N

- F311L/I

- V289A

- L298V

- L248V

- E281A

- L364I

- G383D

- E292V

**x**

**Gorre et al, 2001; von Bubnoff et al, 2002; Branford et al, 2002; Hofmann et al, 2002; Roche-L’Estienne et al, 2002; Shah et al, 2002; Hochhaus et al, 2002; Al-Ali et al, 2004**

**P**

**C**

**A**

***Courtesy Tim Hughes***

**Map of *****BCR-ABL***** Kinase Domain Mutations Associated with Clinical Resistance to Imatinib**

- S417Y

## Dasatinib Inhibits Growth of 14/15 Imatinib-Resistant BCR-ABL-Expressing Ba/F3 Cell Lines in vitro

- Shah et al, Science, 2004

**Normalized cell number 48 hours of drug exposure**

**Concentration of dasatinib (nM)***

**0**

**0.2**

**0.4**

**0.6**

**0.8**

**1**

**1.2**

**0**

**0.5**

**2.5**

**5**

**25**

**50**

**T315I**

**Parental Ba/F3 cells**

****Dasatinib is 300-400x more potent than imatinib in vitro***

## Dasatinib Selectively Inhibits BCR-ABL-dependent Hematopoiesis in vitro

**imatinib-sensitive**
** ****(no mutation)**

**CML**
**imatinib-resistant**
** ****(BCR-ABL/M351T)**

**Normal**

**vehicle**

**5 **

**nM **

**BMS-354825**

**Dasatinib Selectively Inhibits BCR-ABL-dependent Hematopoiesis *****in vitro***

- Shah et al, Science 2004

**Normal**

**vehicle**

**5 nM dasatinib**

## Summary of Scientific Rationale: Dasatinib for Imatinib-resistant and -intolerant CML

**Imatinib resistance**
**Potently inhibits nearly all imatinib-resistant BCR-ABL kinase domain mutations**
**300-400x more potent than imatinib at inhibiting the activity of BCR-ABL**
**Imatinib intolerance**
**Structurally unrelated to imatinib, therefore, cross-intolerance not likely**
**Selectively inhibits the growth of BCR-ABL-positive hematopoietic progenitors**

## Clinical Program

**Claude Nicaise, MD**
- Bristol-Myers SquibbGlobal Development

## Clinical Program – Six Studies at 68 Centers

**One Phase I Study (002)**
**Dose escalation study**
**15 mg to 180 mg QD and 25 mg to 70 mg BID in chronic phase**
**35 mg to 120 mg BID in advanced disease**
**Intrapatient dose escalation / decrease to safe and effective dose**
**Four Phase II Studies (013, 005, 006 and 015)**
**Open label **
**Patients resistant or intolerant to imatinib**
**One Randomized Phase II Study (017)**
**Open label**
**Control group: imatinib 800 mg/day**
**Cross-over for lack of response or intolerance**

## Rationale for 70 mg BID Dose Selection

**Optimal drug exposure**
**Pharmacokinetic parameters**
**Cmax: 45 ng/mL (90 nM)**
**Pharmacodynamics and inhibition of pCRKL**
**≈**** ****100% at doses ******** 100 mg/day**
**BID > QD**
**Effective dose in Phase I study (002) 70 mg BID**
**Acceptable safety in Phase I study (002)**

## Imatinib Resistance

**Resistance at the maximum tolerated dose of imatinib**
**Primary resistance**
**No complete hematologic response at 3 months**
**No cytogenetic response at 6 months**
**No major cytogenetic response at 1 year**
**Secondary resistance**
**Loss of complete hematologic response**
**Loss of major cytogenetic response**
**Progression to accelerated / blast**

## Imatinib Intolerance

**Imatinib toxicities leading to intolerance**
**Grade 3-4 non-hematologic toxicity**
**Grade 4 hematologic toxicity lasting more than 7 days**
**Patients who responded to imatinib**
**Developed intolerance while in response**
**Unable to resume therapy**
**Patients who never responded to imatinib**
**Unable to tolerate imatinib at a dose of at least 400 mg**

## Response Criteria

|  | Chronic | Advanced |  |
| --- | --- | --- | --- |
| Hematologic Response | Complete | Complete | No Evidenceof Leukemia |
| WBC | ≤ ULN | ≤ ULN | ≤ ULN |
| Blasts/Promyelocytesin Peripheral Blood | 0 | 0 | 0 |
| Blasts in Bone Marrow | N/A | ≤ 5% | ≤ 5% |
| Basophils | < 20% | < 20% | < 20% |
| Myelocytes plus Metamyelocytesin Peripheral Blood | < 5% | < 5% | < 5% |
| Platelets x 109/L | < 450 | ≥ 100 | 20 – < 100 |
| Neutrophils x 109/L | N/A | ≥ 1 | 0.5 – < 1 |
| Extramedullary Disease | No | No | No |

**Cytogenetic Response**
**	**_**Complete (CCyR)**__**	**__**Partial (PCyR)**__**	**__**Major (MCyR)**_
**	****        ****0% Ph+****	****1% ****–**** 35% Ph+****	****CCyR + PCyR**

## Patients in Clinical Program

|  | No. of Patients in Phase I and II |  |  |  |  |  |
| --- | --- | --- | --- | --- | --- | --- |
|  | 002 | 005 | 006 | 013 | 015 | Total |
| Chronic | 40 | – | – | 186 | – | 226 |
| Accelerated | 11 | 107 | – | – | – | 118 |
| M. Blast | 23 | – | 74 | – | – | 97 |
| L. Blast / ALL | 10 | – | – | – | 78 | 88 |
| Total | 84 | 107 | 74 | 186 | 78 | 529 |

_**Randomized Trial: Study 017**_
**36 patients (22 dasatinib and 14 imatinib)**

## Baseline Characteristics

|  | n (%) of Patients |  |  |  |
| --- | --- | --- | --- | --- |
|  | Chronic
N = 226 | Accelerated
N = 118 | M. Blast
N = 97 | L. Blast/Ph+ ALL
N = 88 |
| Median Duration of CML (months) | 70 | 85 | 48 | 22 |
| Prior Imatinib |  |  |  |  |
|      Resistance | 159 (70) | 106 (90) | 90 (93) | 80 (91) |
|      Dose >600 mg/day | 123 (54) | 70 (59) | 49 (51) | 46 (52) |
|      Duration >3 years  | 122 (54) | 79 (67) | 44 (45) | 12 (14) |
| Prior Interferon  | 167 (74) | 89 (75) | 53 (55) | 25 (28) |
| Prior Chemotherapy | 101 (45) | 76 (64) | 64 (66) | 75 (85) |
| Prior Stem Cell Transplant | 19 (8) | 19 (16) | 14 (14) | 34 (39) |
| BCR-ABL Mutations  | 113 (50) | 64 (54) | 40 (41) | 43 (49) |
| Platelets <100 x 109/L |  16 (7) | 47 (40) | 70 (72) | 65 (74) |

## Efficacy in Chronic Phase CML

- Studies 002, 013 and 017

## Efficacy in Imatinib-resistant Patients

**Efficacy in Imatinib-resistant Patients**

|  | n (%) of Patients |  |
| --- | --- | --- |
|  | Study 002
N = 32 | Study 013
N = 127 |
| Hematologic Response |  |  |
|      Complete (CHR) | 29 (91) | 111 (87) |
| Cytogenetic Response |  |  |
|      Major (MCyR) | 12 (38) |   40 (31) |
|      Complete (CCyR) |   9 (28) |   28 (22) |
| Loss of CHR | 0 | 2 |
| Loss of MCyR | 0 | 0 |

## Major Cytogenetic Response Rate inImatinib-resistant Patients

**Percent Responders**

**29**

**25**

**98**

**92**

**60**

**28**

**32**

**127**

**N =**

**Chronic Phase CML**

**10/29**

**9/25**

**30/98**

**32/92**

**25/60**

**10/27**

**12/32**

**40/127**

**n/N =**

## Efficacy in Imatinib-intolerant Patients

|  | n (%) of Patients |  |
| --- | --- | --- |
|  | Study 002
N = 8 | Study 013
N = 59 |
| Hematologic Response |  |  |
|      Complete (CHR) | 8 (100) | 57 (97) |
| Cytogenetic Response |  |  |
|      Major (MCyR) | 6 (75) | 43 (73) |
|      Complete (CCyR) | 5 (63) | 33 (56) |
| Loss of CHR | 0 | 0 |
| Loss of MCyR | 0 | 0 |

**Chronic Phase CML**

## Major Cytogenetic Response inImatinib-intolerant Patients

**Percent Responders**

**8**

**N =**

**8**

**59**

**32**

**6/8**

**n/N =**

**6/8**

**43/59**

**22/32**

**Chronic Phase CML**

## Progression-free Survival 

**Progression-free Survival **

**Proportion Not Progressed**

**Months**

**002 Int**

**002 Res**

**013 Res**

**013 Int**

**Censored**

- + + + +

|  | 002 Intolerant | 002 Resistant | 013 Intolerant | 013 Resistant |
| --- | --- | --- | --- | --- |
| N | 8 | 32 | 59 | 127 |
| Number Progressed | 0 | 3 | 0 | 8 |

**Chronic Phase CML**

|  | Intolerant |  | Resistant |  |
| --- | --- | --- | --- | --- |
|  | N | Progression | N | Progression |
| Study 002 | 8 | 0 | 32 | 3 |
| Study 013 | 59 | 0 | 127 | 8 |

## Preliminary Data of the Randomized Study 017

|  | n (%) of Patients |  |
| --- | --- | --- |
|  | Dasatinib
N = 22 | Imatinib
N = 14 |
| Baseline Characteristics |  |  |
|     Prior Imatinib 600 mg/day | 16 (73) | 12 (86) |
|     Prior Interferon | 14 (64) | 11 (79) |
|     BCR-ABL Mutations | 10 (45) | 1 (7) |
| Efficacy |  |  |
|     Complete Hematologic Response | 21 (95) | 13 (93) |
|     Major Cytogenetic Response | 10 (45) | 3 (21) |
|     Complete Cytogenetic Response | 7 (32) | 1 (7) |
| Crossover | 2 (9) | 11 (79) |

**Chronic Phase CML**

## Efficacy in Accelerated Phase CML

- Studies 002 and 005

## Efficacy Results 

|  | n (%) of Patients |  |
| --- | --- | --- |
|  | Study 002
N = 11 | Study 005
N = 107 |
| Hematologic Response |  |  |
|      Major (MaHR) | 6 (55) | 63 (59)  |
|         Complete (CHR) | 5 (45) | 35 (33)  |
|         No Evidence of Leukemia | 1 (9) | 28 (26)  |
| Cytogenetic Response |  |  |
|      Major (MCyR) | 3 (27) | 33 (31) |
|      Complete (CCyR) | 2 (18) | 23 (22) |
| Loss of MaHR | 0  | 1  |
| Loss of MCyR | 0 | 2 |

**Accelerated Phase CML**

## Progression-free Survival

**Progression-free Survival**

|  | -002 | -005 |
| --- | --- | --- |
| N | 11 | 107 |
| Number Progressed | 4 | 15 |
| Median |  |  |
| 95% CI | 4.8 -   |   |

**Proportion Not Progressed**

**Months**

**Accelerated Phase CML**

|  | N | Progression |
| --- | --- | --- |
| Study 005 | 107 | 15 |
| Study 002 | 11 | 4 |

**002**

**005**

**Censored**

- + +

## Efficacy in Myeloid Blast Crisis

- Studies 002 and 006

## Efficacy Results 

|  | n (%) of Patients |  |
| --- | --- | --- |
|  | Study 002N = 23 | Study 006N = 74 |
| Hematologic Response |  |  |
|      Major (MaHR) | 7 (30) | 24 (32) |
|         Complete (CHR) | 3 (13) | 18 (24)  |
|         No Evidence of Leukemia | 4 (17) | 6 (8) |
| Cytogenetic Response |  |  |
|      Major (MCyR) | 8 (35) | 22 (30) |
|      Complete (CCyR) | 6 (26) | 20 (27) |
| Loss of MaHR | 2 | 0 |
| Loss of MCyR | 4 | 2 |

**Myeloid Blast Phase CML**

## Progression-free Survival

**Progression-free Survival**

|  | -002 | -006 |
| --- | --- | --- |
| N | 23 | 74 |
| Number Progressed | 16 | 35 |
| Median | 4.4 |  |
| 95% CI | 2.6 – 7.8  | 3.4 -   |

**Proportion Not Progressed**

**Months**

**002**

**006**

**Censored**

- + +

**Myeloid Blast Phase CML**

|  | N | Progression |
| --- | --- | --- |
| Study 002 | 23 | 16 |
| Study 006 | 74 | 35 |

## Efficacy in Lymphoid Blast Crisis and Ph+ ALL

- Studies 002 and 015

## Efficacy Results 

|  | n (%) of Patients |  |  |
| --- | --- | --- | --- |
|  | Study 002 | Study 015 |  |
|  | L. Blast/Ph+ ALL 
N = 10 | L. Blast
N = 42 | Ph+ ALL
N = 36 |
| Hematologic Response |  |  |  |
|      Major (MaHR) | 5 (50) | 13 (31) | 15 (42) |
|         Complete (CHR) | 3 (30) | 11 (26) | 11 (31) |
|         No Evidence of Leukemia | 2 (20) | 2 (5) | 4 (11) |
| Cytogenetic Response |  |  |  |
|      Major (MCyR) | 8 (80) | 21 (50) | 21 (58) |
|      Complete (CCyR) | 3 (30) | 18 (43) | 21 (58) |
| Loss of MaHR | 3 | 6 | 3 |
| Loss of MCyR | 6 | 10 | 8 |

**Lymphoid Blast Phase CML / Ph+ ALL**

## Progression-free Survival

**Progression-free Survival**

**Proportion Not Progressed**

**Months**

**002 LB/ALL**

**015 LB**

**015 ALL**

**Censored**

-  + + +

**Lymphoid Blast Phase CML / Ph+ ALL**

|  | N | Progression | Median | 95% CI |
| --- | --- | --- | --- | --- |
| Study 002 LB/ALL | 10 | 8 | 3.0 | 1.4 – 5.5 |
| Study 015 ALL | 36 | 22 | 3.3 | 1.1 – 7.2 |
| Study 015 LB | 42 | 30 | 2.8 | 2.0 – 4.3 |

## Hematologic Responses by Mutation Status

**F359C/I/V**

**E355G**

**M351T**

**T315I**

**E255K/V**

**Y253H/F**

**G250E**

**M244V**

**7/21**

**6/16**

**2/10**

**7/15**

**0/19**

**2/19**

**10/20**

**9/31**

**9/17**

_**MCyR**_

**14/21**

**8/16**

**6/10**

**12/15**

**0/19**

**8/19**

**15/20**

**19/31**

**13/17**

_**MaHR**_

**P**

**C**

**A**

**Hematologic Responses by Mutation Status**

**34 unique mutations**
**9 amino acid substitutions account for 68% of all BCR-ABL mutations**

## Summary of Efficacy

**Chronic Phase CML **
**High rate of major cytogenetic response in imatinib-resistant and imatinib-intolerant patients**
**Durable responses extending beyond 1 year**
**Progression-free survival at 6 months predictive of****long-term benefit**
**Advanced Disease (Accelerated, Blast, Ph+ ALL)**
**High rate of major hematologic responses**
**Durable, complete responses in Ph+ ALL**
**Long-term survivors identified at all stages including patients in blast transformation**

## Safety

## Safety Overview

**Safety Database**
**511 leukemic patients treated with dasatinib BID**
**Minimum 8 months of follow-up**
**Major Findings**
**Myelosuppression, mostly thrombocytopenia**
**Fluid retention, including pleural effusion**

## Myelosuppression

|  | n (%) of Patients |  |  |  |  |
| --- | --- | --- | --- | --- | --- |
|  | Chronic
N = 208 | Accelerated
N = 118 | M. Blast
N = 97 | L. Blast / Ph+ ALL
N = 88 | Solid Tumor
N = 32 |
| WBC <2.0 x 109/L | 50 (24) | 71 (60) | 65 (68) | 60 (68) | 0 |
| ANC <1.0 x 109/L | 103 (50) | 92 (78) | 83 (86) | 67 (79) | 0 |
| Platelets <50 x 109/L | 97 (47) | 97 (82) | 81 (84) | 72 (82) | 0 |

## Time to Severe Thrombocytopenia

**Percent (%)**

## Adverse Reactions Relatedto Myelosuppression

|  | n (%) of Patients |  |  |  |  |
| --- | --- | --- | --- | --- | --- |
|  | Chronic
N = 208 | Accelerated
N = 118 | M. Blast
N = 97 | L. Blast/Ph+ ALL
N = 88 | TotalN = 511 |
| GI Hemorrhage | 8 (4) | 22 (19) | 14 (14) | 8 (9) | 52 (10) |
| CNS Hemorrhage | 1 (<1) | 0 | 0 | 2 (2) | 3 (1) |
| Febrile Neutropenia | 3 (1) | 10 (8) | 5 (5) | 10 (11) | 28 (5) |
| Severe Infections | 5 (2) | 8 (7) | 6 (6) | 9 (10) | 28 (5) |
|     Pneumonia | 4 (2) | 5 (4) | 1 (1) | 4 (5) | 14 (3) |
|     Sepsis | 0 | 0 | 1 (1) | 1 (1) | 2 (<1) |
|     Aspergillosis | 0 | 1 (1) | 0 | 0 | 1 (<1) |

## Management of Myelosuppression

|  | n (%) of Patients |  |  |  |
| --- | --- | --- | --- | --- |
|  | Chronic
N = 208 | Accelerated
N = 118 | M. Blast
N = 97 | L. Blast/Ph+ ALL
N = 88 |
| Transient Dose Interruption | 106 (51) | 55 (47) | 26 (27) | 11 (13) |
| Median Duration (days) | 10 | 14 | 7 | 13 |
| Dose Reduction | 93 (45) | 44 (37) | 20 (21) | 5 (6) |
| Platelet Transfusion | 46 (22) | 71 (60) | 72 (74) | 54 (61) |
| Red Cell Transfusion
 | 63 (30) | 100 (85) | 87 (90) | 61 (69) |
| HematopoieticGrowth Factors | 32 (15) | 37 (31) | 26 (27) | 29 (33) |
| Discontinuation | 2 (1) | 1 (1) | 1 (1) | 1 (1) |

## Most Common Non-hematologicAdverse Reactions

|  | n (%) of Patients |  |
| --- | --- | --- |
|  | Grade 1-4 | Grade 3-4 |
| Fluid Retention | 223 (44) | 42 (8) |
| Diarrhea | 179 (35) | 20 (4) |
| Rash | 132 (26) | 7 (1) |
| Nausea | 103 (20) | 5 (1) |
| Headache | 121 (24) | 5 (1) |
| Fatigue | 108 (21) | 9 (2) |
| Dyspnea | 106 (21) | 19 (4) |
| Asthenia | 82 (16) | 13 (3) |
| Musculoskeletal pain | 77 (15) | 4 (1) |
| Vomiting | 68 (13) | 4 (1) |

## Fluid Retention

|  | n (%) of Patients |
| --- | --- |
|  | N = 511 |
| Any Fluid Retention | 223 (44) |
| Superficial Edema | 144 (28) |
| Pleural Effusion | 108 (21) |
| Others |  |
|    Pericardial Effusion | 14 (3) |
|    Congestive Heart Failure | 12 (2) |
|    Pulmonary Edema | 10 (2) |
|    Cardiac Dysfunction | 7 (1) |
|    Pulmonary Hypertension | 5 (1) |

## Pleural Effusion

|  | n (%) of Patients |  |  |  |
| --- | --- | --- | --- | --- |
|  | Chronic
N = 208 | Accelerated
N = 118 | M. Blast
N = 97 | L. Blast/Ph+ ALLN = 88 |
| Drug-related | 38 (18) | 26 (22) | 29 (30) | 15 (17) |
| Grade 3-4 | 7 (3) | 3 (3) | 13 (13) | 2 (2) |
| Time to Event (days) | 7-319 | 15-343 | 1-296 | 6-247 |

## Management of Pleural Effusion

|  | n (%) of Patientswith Events |
| --- | --- |
| All Drug-related Events | 108 |
| Medical Intervention |  |
| Diuretics | 83 (77) |
| Corticosteroids | 37 (34) |
| Dose Interruption | 48 (44) |
| Dose Reduction | 8 (7) |
| Invasive Procedures |  |
| Thoracentesis | 19 (18) |
| Pleurodesis | 1 (1) |
| Discontinuation | 4 (4) |

## Management of Other Events of Fluid Retention

|  | n (%) of Patientswith Events |
| --- | --- |
| All Drug-related Events | 44 |
| Medical Intervention |  |
| Diuretics | 34 (77) |
| Corticosteroids | 11 (25) |
| Dose Interruption | 17 (39) |
| Dose Reduction | 4 (9) |
| Invasive Procedures |  |
| Pericardial window | 2 (5) |
| Discontinuation | 6 (14) |

## Effect on Cardiac Repolarization

**Nonclinical evaluation**
**hERG IC****50****: 14,300 ****nM**
**No ECG change in telemetered monkeys**
**Clinical findings**
**Mean ∆ QTcF: 3–6 msec**
**QTc outlier analysis (serial ECGs in Phase II)**
**QTcF:  3/446 >500 msec on Day 8**
**∆ ****QTcF:  13/441 >60 msec on Day 8**
**Adverse events**
**9 AEs of QT prolongation**
**No arrhythmia associated with QT prolongation**

## Laboratory Abnormalities

|  | n (%) of Patients |  |
| --- | --- | --- |
|  | Grade 1-4 | Grade 3-4 |
| AST | 321 (63) | 17 (3) |
| ALT | 296 (58) | 26 (5) |
| Bilirubin | 131 (26) | 16 (3) |
| Creatinine | 175 (34) | 5 (1) |
| ↓ Ca++ | 313 (62) | 50 (10) |
| ↓ Mg++ | 175 (34) | 1 (<1) |

## Dasatinib in Imatinib-intolerant Patients

**94 intolerant patients**
**Similar safety profile to the entire population**
**Myelosuppression**
**Fluid retention**
**Minimal cross-intolerance with imatinib**
**No recurrent hepatotoxicity or skin toxicity**
**Three patients developed the same grade 3 toxicity on dasatinib (nausea, diarrhea, fatigue)**

## Safety Summary

**Myelosuppression **
**Predictable, frequently severe**
**Rarely complicated by severe bleeding or infection**
**Manageable by dose interruption, dose reduction and occasionally by transfusion**
**Fluid retention including pleural effusion**
**Common, likely related to PDGFR inhibition**
**Managed with diuretics, corticosteroids, dose interruptions and, occasionally, invasive procedures**
**Minimal hepatotoxicity**
**Other adverse events were usually mild to moderate**

## Clinical Perspective

**Hagop M. Kantarjian, MD**
- Chairman & Professor, Leukemia DepartmentMD Anderson

## Chronic Phase CML – Imatinib-resistant

**Poor prognosis after imatinib failure**
**Few cytogenetic responses **
**Poor survival: <2 years; <1 year with *****P*****-loop mutations**
**Limited treatment options: stem cell transplant, escalate imatinib, hydroxyurea, IFN-********, investigational agents**
**Major benefit with dasatinib:**
**CHR 87% and MCyR >30%**
**Duration of response > 1 year**

## Chronic Phase CML – Imatinib-intolerant

**Highest unmet medical need**
**No benefit from targeted therapy**
**Imatinib intolerance uncommon, but often associated with resistance**
**67 patients with intolerance, mostly****non-hematologic, treated**
**Hematologic and cytogenetic responses similar to those achieved with imatinib post-interferon**
**Responses durable; all patients progression-free  (follow-up 6 to 20 months)**
**Minimal cross-intolerance  **

## Accelerated Phase CML Post-imatinib Failure

**Initial diagnosis of accelerated phase uncommon; most patients progress from chronic phase and are imatinib-resistant**
**Poor prognosis: median survival <1 yr**
**Limited options: hydroxyurea,****intensive chemotherapy +/- stem cell transplant, investigational agents**
**No durable responses**
**Dasatinib highly effective**
**High rates of durable hematologic and cytogenetic response  **

## Blast Phase CML Post-imatinib Failure

**Almost all patients progressed to blast phase and were imatinib resistant**
**Very poor survival; rarely exceeds few months**
**Most had prior chemotherapy**
**Limited options: intensive chemotherapy, investigational therapy**
**Dasatinib induces durable responses unexpected with other therapeutic options**

## Ph+ ALL Post-imatinib Failure

**Worst prognosis **
**No treatment options due to failure of prior therapies including chemotherapy and stem cell transplant**
**Expected survival less than 3 months**
**Dasatinib highly effective**
**Durable complete hematologic and cytogenetic responses  **
**Duration of response > 4 months**

## Overall Safety 

**Most important safety issues myelosuppression and fluid retention**
**Potentially severe, but manageable with early interventions**
**Dose interruption**
**Dose reduction**
**Non-invasive interventions**
**Growth factors for myelosuppression**
**Diuretics and steroids for fluid retention**

## Dasatinib Benefit:Risk Potential

**Benefits patients with CML and Ph+ ALL who have no other treatment options**
**Highly effective in all CML phases post-imatinib failure**
**Minimal cross-intolerance with imatinib**
**Myelosuppression predictable and manageable**
**Other toxicities (including pleural effusion) manageable with early intervention**

## Conclusion

**Donna Morgan Murray, PhD**
- Bristol-Myers SquibbGlobal Regulatory Sciences

## Proposed Indications for Dasatinib 

**Treatment of adults with chronic, accelerated, or blast phase chronic myeloid leukemia (CML) with resistance or intolerance to prior therapy including imatinib**
**Treatment of adults with Philadelphia chromosome‐positive (Ph+) acute lymphoblastic leukemia (ALL) and lymphoid blast chronic myeloid leukemia with resistance or intolerance to prior therapy **