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FDA Review of DASATINIB

Oncology Drug Advisory Committee (ODAC)June 2, 2006

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Review teams

Clinical - Michael Brave, M.D., Vicki Goodman, M.D., Edvardas Kaminskas, M.D., Ann T. Farrell, M.D. , and Robert Justice, M.D.

Statistical - Janet Jiang, Ph.D., and Raji Sridhara, Ph.D.Chemistry- William Timmer, Ph. D., Ravi Haranpanalli,

Ph.D., and Richard Lostritto, Ph.D.Pharmacology/Toxicology- Haleh Saber-Mahloogi Ph.D.,

and David Morse, Ph.D.Clinical Pharmacology- Angela Men, Ph.D., Leslie Kenna,

Pharm. D., Julia Bullock, Ph.D., and Brian Booth, Ph.D.Project Management- Amy Baird, B.A.

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Overview

• Regulatory Background

• Clinical Studies

• Dose Finding

• Populations Studied and Efficacy Results

• Safety Issues

• Conclusions

• Questions for the Committee

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Proposed Indication for Dasatinib

Treatment of adults with

chronic, accelerated, or blast phase CML with resistance to or intolerance of prior therapy including imatinib, and with

Philadelphia chromosome-positive ALL or lymphoid blast CML with resistance to or intolerance of prior therapy.

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Gleevec® Approval History

• Accelerated approval was granted on the basis of 3 single-arm trials of CML patients in blast crisis, accelerated phase, or in chronic phase after failure of interferon-therapy.

• Full approval was granted after a longer follow-up of the above Phase 2 studies.

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Imatinib Resistance or Intolerance in CML

• Imatinib resistance: • Primary: Imatinib treatment is ineffective - no

cytogenetic or hematologic response.• Acquired: Progression of disease after a

cytogenetic or hematologic response.

• Imatinib intolerance: • Discontinuation of imatinib because of toxicity.• Intolerance of ≥ 400 mg/day.

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FDA Issues with the NDA

1) Whether a lower starting dose should be further evaluated.

2) Whether sufficient data (magnitude/ duration) have been provided for the imatinib intolerant population.

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Clinical Studies Submitted - 1

Phase Population No. of Patients

Treated

Phase 2, Single-arm

Chronic Phase CML

(CP CML)

186

Phase 2, Single-arm

Accelerated Phase CML (AP CML)

107

Phase 2, Single-arm

Myeloid Blast Phase CML (MB CML)

74

Phase 2, Single-arm

Lymphoid Blast CML (LB CML) or Ph+ ALL

78

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Clinical Studies Submitted - 2

Phase Population No. of Patients

Treated

Phase 1 All phases of CML; Ph+ ALL

84

Phase 2, Two-arm, randomized

CP CML 36

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Study Design - 1

• The 4 multicenter , international, Phase 2 trials to evaluate efficacy and safety were single-arm. Minimum follow-up is 6 months after the start of therapy, but patients will be followed for 24 months.

• Primary efficacy endpoint in CP CML is major cytogenetic response (MCyR),defined as

CCyR (0% Ph+ cells) + PCyR (1-35% Ph+ cells) at 12 weeks.

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Study Design - 2

• Primary efficacy endpoint in advanced phases of CML and in ALL is major hematologic response (MaHR), defined as– Complete Hematologic Response, or – No Evidence of Leukemia.

• Secondary endpoints include median durations of responses.

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Dose Finding

Sponsor’s recommended dose for Phase 2 studies of 70 mg b.i.d. was determined on the basis of cytogenetic and hematologic responses, not on the basis of maximally tolerated dose (MTD).

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Dose Response in CP CML - MCyR

Total Daily Dose No. responses/

No. treated

% with Responses

15 mg 0/3 0%

30 mg 1/3 33%

50 mg 1/6 17%

70 - 75 mg 3/10 30%

100 - 105 mg 6/6 100%

140 mg 6/9 67%

180 mg 1/3 33%

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Dose Response in Advanced Phases of CML and Ph+ ALL - MaHR

Total Daily Dose No. responses/

No. treated

% with Responses

35 mg b.i.d. 0/1 0%

50 mg b.i.d. 3/8 38%

70 mg b.i.d. 5/17 29%

90 mg b.i.d. 2/11 18%

120 mg b.i.d. 1/7 14%

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Comment on Recommended Dose

These response data suggest that 50 mg b.i.d. may result in similar response rates as 70 mg b.i.d. in both chronic phase and advanced phases patients.

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Populations Studied in Single-Arm Trials

CP CML

N = 186

AP CML

N = 107

MB CML

N = 74

LB CML

N = 42

Ph+ ALL

N = 36

Median time since

Dx

64 months 91 months 49 months 28 months 20 months

Imatinib

>3 yr

>1 yr

54%

80%

68%

92%

47%

85%

24%

52%

3%

56%

% Bone marrow

transplant

9% 18% 12% 33% 42%

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Dasatinib treatment

• Starting dose: 70 mg b.i.d.• Duration of treatment in months, median (range), at the

time of data cut-off.– CP CML 5.6 (0.03 – 8.3)– AP CML 5.5 (0.2 – 10.1)– MB CML 3.5 (0.03 – 9.2)– LB CML 2.8 (0.1 – 6.4)– Ph+ ALL 3.2 (0.2 – 8.1)

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Response Rates in CP CML

Endpoint CP CML

MCyR rate

(95% CI)

45%

(37% - 52%)

Median duration

(months)

Not reached*

CHR rate

(95% CI)

90%

(85% - 94%)

*100% of responders in response at F/U.

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Response Rates in Advanced Phases of CML and in Ph+ ALL

Endpoint AP CML MB CML LB CML Ph+ ALL

MaHR rate

(95% CI)

59%

(49% - 68%)

32%

(22% - 44%)

31%

(18% - 47%)

42%

(26% - 59%)

Median duration

(95% CI)

Not

reached *

Not

reached*

3.7 months

(2.8, not reached)

4.8 months

(2.9, not reached)

MCyR rate

(95% CI)

31%

(22% - 41%)

30%

(20% - 42%)

50%

(34% - 66%)

58%

(41% - 75%)

*98-100% of responders in response at F/U

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Responses in Imatinib Resistant and Imatinib Intolerant Populations

Disease Phase

(endpoint)

Resistant Intolerant

Chronic (MCyR) 62/181 (34%) 49/67 (73%)

Accelerated (MaHR) 62/106 (58%) 7/12 (58%)

Myeloid Blast CML

(MaHR)

30/90 (33%) 1/7 (14%)

Lymphoid Blast CML

(MaHR)

14/41 (34%) 2/6 (33%)

Ph+ ALL

(MaHR)

14/39 (36%) 2/2 (100%)

Total (all phases) 182/457 (40%) 61/94 (65%)

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Efficacy Conclusions - 1

• Dasatinib treatment results in major hematologic and cytogenetic responses in patients with all phases of CML and with Ph+ ALL who are imatinib resistant or intolerant.

• Responses occur within the first 3 months and appear to be durable. Median durations of responses are 4-5 months in LB CML and Ph+ ALL. Median durations are longer in CP, AP, and MB CML, but the F/U is too short for estimates.

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Efficacy Conclusions - 2

• 70 mg b.i.d. is an effective dose, but lower doses also result in responses.

• Among CP CML patients, imatinib intolerant patients have higher response rates than imatinib resistant patients. Too few imatinib intolerant patients with other phases of CML and with ALL were enrolled to make a comparison.

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Safety Population

• Patients who received a starting dose of 70 mg b.i.d.

• All patients treated on the four single-arm phase 2 studies

• All patients initially treated with dasatinib on the randomized phase 2 study

• All patients who received a starting dose of 70 mg bid on the phase 1 study

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Safety Population

• 214 chronic phase (CP) patients

• 110 accelerated phase (AP) patients

• 84 myeloid blast phase (MB) patients

• 81 lymphoid blast phase (LB) and Ph + ALL patients

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Duration of Exposure

• < 3 months: 32%

• 3 months to 6 months: 57%

• > 6 months: 11%

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Dose Adjustments

Disease Phase Dose Reduction Interruption

CP 50% 82%

AP 45% 73%

MB 35% 74%

LB 11% 57%

Ph + ALL 30% 68%

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Common Treatment-Emergent Adverse Events

Adverse Event All Grades (%) Grade 3/4 (%)

Diarrhea 47 5

Pyrexia 39 7

Headache 38 3

Fatigue 34 3

Nausea 31 2

Dyspnea 29 6

Rash/Exanthem 29 1

Peripheral Edema 26 0.2

Abdominal Pain 25 2

NCI CTCAE v. 3.0

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Common Treatment-Emergent Adverse Events

Adverse Event All Grades (%) Grade 3/4 (%)

Cough 24 1

Asthenia 22 4

Vomiting 22 1

Thrombocytopenia 18 17

Pleural Effusion 17 4

Anorexia 15 1

Weight Decreased 14 1

Bone Pain 13 2

Pain in Extremity 12 0.4

Constipation 12 0.2

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Common Treatment-Emergent Adverse Events

Adverse Event All Grades (%) Grade 3/4 (%)

Epistaxis 11 1

Arthralgia 11 1

Anemia 11 7

Dizziness 11 0.2

Myalgia 11 1

Neutropenia 11 10

Neutropenic Fever 10 10

Petechiae 10 0.2

Weight Increased 10 0

Chills 10 0.2

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Hypocalcemia

• Hypocalcemia– Baseline 8-30%; Grade 3/4 ≤ 1%– On treatment 46-80%; Grade 3/4 4-22%

• No muscle spasms attributable to hypocalcemia

• One seizure in a patient w/ grade 3 hypocalcemia, documented CNS disease

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Grade 3/4 Hematologic Laboratory Abnormalities

Disease Phase Neutropenia Thrombocytopenia Anemia

Chronic

--At Baseline

--On Treatment

2%

45%

2%

46%

2%

18%

Accelerated

--At Baseline

--On Treatment

7%

76%

23%

79%

5%

66%

Myeloid Blast

--At Baseline

--On Treatment

24%

79%

45%

82%

15%

66%

LB/ Ph + ALL

--At Baseline

--On Treatment

33%

76%

58%

78%

3%

49%

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Bleeding Events

Any Grade

Grade 3/4 Grade 5

Any 34% 10% 1%

Epistaxis 11% 1% 0%

Gastrointestinal 10% 6% 0%

CNS 1% 0.2% 1%

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CNS Hemorrhage

• 5/6 in blast phase/ALL

• 1/6 in CP

• Platelet counts ranged from 1,000-56,000

• One event associated with a head injury

• One subdural hematoma resolved following surgical intervention

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QTc prolongation

• QTc prolongation reported as an AE in 9 patients

• An additional 7 had treatment-emergent QTcB ≥ 500 msec

• Two patients were reported to have non-sustained ventricular tachycardia

• There were no reports of torsades de pointes

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Cardiac Failure

• 20 patients (4%) had an event

• 12/20 (60%) had a prior cardiac history

• One death was attributed to cardiac failure

• Action:– Dose interruption (9)– Drug discontinuation (4)– Dose reduction (1)– None (6)

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Fluid Retention Other Than CHF

Event All Grades (%) Grade 3/4 (%)

Peripheral Edema 26 0.2

Pleural Effusion 17 5

Periorbital Edema 7 0

Face Edema 4 0

Pericardial Effusion

4 0.4

Pulmonary Edema 3 0.4

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Safety Summary

• GI toxicity was common across all phases of disease

• Fluid retention events including edema and effusions were common

• Grade 3/4 myelosuppression increased with dasatinib use

• 4% experienced cardiac failure • 3% had treatment-emergent QTc prolongation as

an AE or on ECG• Approximately one-third had bleeding events of

any type; 5 of 6 fatal events were intracranial

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FDA Summary of Dasatinib NDA

• 31-59% achieved responses in CML/ Ph + ALL• Responses also seen at lower doses in a limited number

of phase 1 patients• Median response duration has not been reached for

most studies due to limited follow-up• Common adverse events include GI, fluid retention,

bleeding; myelosuppression was also common• Most patients required dose interruptions and/or

reductions• Due to clear evidence of activity, on February 6, 2006,

an expanded access program was initiated