# Presentation: 215334

## FDA Review of DASATINIB

**Oncology Drug Advisory Committee (ODAC)**
**June 2, 2006**

**Notes:**
Good Morning!
I am Dr. Kaminskas. 

## 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.

**Notes:**
This is the team that is reviewing the dasatinib application. I will be presenting some aspects of efficacy and Dr. Goodman will describe the safety portion. 

## Overview

- Regulatory Background
- Clinical Studies
- Dose Finding
- Populations Studied and Efficacy Results
- Safety Issues
- Conclusions
- Questions for the Committee

**Notes:**
I will briefly mention some regulatory aspects that pertain to this application, the clinical studies supporting the proposed indications, the dose finding study, the populations studied and the efficacy results. 

## 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.

**Notes:**
The proposed indication for dasatinib is 
     treatment of adults with chronic, accelerated or blast phase chronic  myeloid leukemia with resistance to or intolerance of prior therapy, including imatinib,
and with
Philadelphia chromosome-positive Acute Lymphoblastic Leukemia or lymphoid blast CML with resistance to or intolerance of prior therapy.

## 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.

**Notes:**
Since the application is for treatment of CML and for imatinib resistant or intolerant patients, it is worthwhile to review briefly the approval history for imatinib mesylate, that is Gleevec.

Accelerated approval was granted for Gleevec on the basis of 3 single-arm studies of CML patients in blast crisis, accelerated phase or in chronic phase after failure of interferon-alfa therapy. A total of 1027 patients were enrolled in these studies. Efficacy was assessed by the rate of hematologic responses and by cytogenetic responses. The median duration of responses in the blast phase patients was about 6 months. In chronic phase and accelerated phase patients, median response durations could not be defined, because the  follow-up period was not long enough. 

Full approval for Gleevec was granted on longer follow-up of the above Phase 2 studies.

## 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.

**Notes:**
I shall also briefly define imatinib resistance and imatinib intolerance in a simplified manner. 

Basically, primary resistance is defined as failure to achieve a cytogenetic or a  hematologic response with imatinib therapy. Acquired resistance is defined as progression of disease after having achieved a cytogenetic or a hematologic response.

Intolerance is defined as 1) discontinuation because of toxicity (such as grade 3 or 4 non-hematologic toxicity or grade 4 hematological toxicity lasting > 7 days) or 2) inability to tolerate 400 mg or more of imatinib per day.  

## FDA Issues with the NDA

- Whether a lower starting dose should be further evaluated.
- Whether sufficient data (magnitude/ duration) have been provided for the imatinib intolerant population.

**Notes:**
FDA reviewers have not detected major issues with this application. Two issues are shown above. 

The sponsor recommends a starting dose of 70 mg twice a day on a continuous basis; we think lower starting doses should be evaluated.

The second issue is whether the data for imatinib intolerant population are sufficient in magnitude, since relatively few such patients were enrolled in all but one study.

## 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 |

**Notes:**
The submission contains the results of 4 single-arm studies of dasatinib in 

Chronic phase CML, in which 186 patients were treated, 
in Accelerated Phase CML, in which 107 patients were treated, 
in Myeloid Blast CML, in which 74 patients were treated, 
and in lymphoid blast CML and Philadelphia chromosome-positive Acute Lymphoblastic Leukemia, in which 78 patients were treated. 

## 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 |

**Notes:**
In addition, the submission contains the results of a Phase 1 dose-finding study  with 84 treated patients, 40 with chronic phase CML and 44 with advanced phase CML and Philadelphia chromosome-positive ALL.

In a randomized study, chronic phase patients were randomized for treatment with dasatinib or with high dose imatinib.

## 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.

**Notes:**
The 4 Phase 2  single arm trials were large, multicenter, international trials. The data cutoff for this submission was 6 months after the start of dasatinib therapy. The trials are ongoing and will be completed after 24 month data have been collected.
The primary efficacy endpoint in chronic phase CML patients is Major cytogenetic response, which includes both 
	Complete Response with no Philadelphia chromosome positive  
                     cells and 
	Partial response with up to 35% of cells being Philadelphia
                      chromosome positive.

## 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.

**Notes:**
In advanced phases of CML and in Philadelphia chromosome-positive ALL the primary efficacy endpoint is Major hematologic response, which includes 
	Complete Hematologic Response, basically, a normalization of
                      blood counts and bone marrows, and 
	No Evidence of Leukemia, which permits cytopenias due to
                      incomplete marrow recovery.

These response criteria were used in the Gleevec application.

## 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).

**Notes:**
Now, to the dose Finding Study.
The recommended dose for the Phase 2 studies was determined on the basis of primary efficacy parameters, not on the basis of dose limiting toxicities and maximally tolerated dose. 
The following two slides show the data from the Phase 1 dose finding study. 

## 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% |

**Notes:**
In chronic phase CML patients, dasatinib was administered daily either as a single dose or in two divided doses. The results were similar with both dosing schedules; therefore, they are combined in this slide. 

Major cytogenetic responses occurred in patients treated with as little as 30 mg per day to as much as 180 mg per day. The highest percentages of responses occurred in patients treated with 100 mg and with 140 mg total daily doses. 

## 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% |

**Notes:**
Advanced phase CML and ALL patients were treated with higher starting doses than chronic phase CML patients, from a total daily dose of 70 mg to 240 mg. 

Again, the highest percentages of responses occurred in patients treated with 50 mg twice a day and 70 mg twice a day schedules.

## 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.

**Notes:**
These response data suggest that 50 mg BID may result in similar response rates as 70 mg BID in both chronic phase and in advanced phase patients.

## 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% |

**Notes:**
I will now turn to the efficacy results in the 4 single arm trials. 
These trials enrolled patients with a long history of disease and with extensive prior therapy. 
Patients with the longest history of disease were CML patients with chronic phase, accelerated phase and myeloid blast phase CML. The median times from the time of diagnosis ranged from 49 months to 91 months. 
They had been treated for  long periods with imatinib (over one-half of the patients for longer than 3 years), had extensive chemotherapy, most had prior interferon treatment, and about 10-20 % had prior bone marrow transplants.
Patients with acute lymphoblastic leukemia and with lymphoid blast CML had shorter histories of disease, shorter exposures to imatinib, less interferon, and about 30-40% had prior bone marrow transplants.

## 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)

**Notes:**
The starting dose of dasatinib for all patients was 70 mg BID. The durations of treatment at the time of data cut-off for this submission are shown above.

The median durations of treatment were longest in the chronic phase and accelerated phase CML patient populations (about 5.5 months) and shortest in the myeloid and lymphoid blast phase CML and in ALL populations (about 3 months). 

## 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.

**Notes:**
About 45% of patients with chronic phase CML had a major cytogenetic response. Most of the responses occurred after 12 weeks of treatment, at the first cytogenetic analysis per protocol. 
The responses were durable. All of the responders remained in response at the 6 month follow-up data cut-off.
About 90% of patients had a complete hematologic response, a secondary endpoint. 

## 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

**Notes:**
In advanced phases of CML and in ALL, major hematologic response was the primary efficacy endpoint

The highest response rate was in accelerated phase CML at 59%, patients in other phases had response rates of 30 – 40 %.

The responses were durable. Median duration could not be determined in accelerated phase and myeloid blast phase patients, as all responders except one remained in response at the 6 month follow-up data cut-off time.

Median durations of responses were 3.7 months in Lymphoid blast CML patients and 4.8 months in Philadelphia chromosome-positive ALL patients, according to FDA reviewers.

Major cytogenetic responses, a secondary efficacy endpoint, occurred in 30 - 58% of the advanced phase CML and ALL patients. 

## 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%) |

**Notes:**
Lastly, I will present the response rates in imatinib resistant and imatinib intolerant populations. All the patients in the single-arm Phase 2 studies, the randomized study and the dose-finding study are included. 
The only disease category with substantial enrollment of imatinib intolerant patients was chronic phase CML. About one-quarter of the patients were imatinib intolerant, and they had about twice the response rate of the resistant patients (73% vs. 34%). 

In all the other disease categories, the imatinib intolerant patients comprised less than 10% of each patient population. Responses occurred in these patients, but the numbers were too small for quantitation of response rates.

## 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.

**Notes:**
Efficacy findings may be summarized in the following conclusions: 
Dasatinib treatment results in major hematologic and cytogenetic responses
in patients with all phases of CML and with Philadelphia chromosome positive Acute Lymphoblastic Leukemia who are resistant to imatinib or who have limited tolerance for imatinib. 

The proportions of patients with responses ranged from 30% to about 60%, depending on the disease phase and the efficacy endpoint measured.

Responses occur within the first 3 months of treatment and appear to be durable. 
The median durations of responses were about 4 to 5 months in Acute Lymphoblastic Leukemia patients and in Lymphoid Blast CML patients. 

Median response durations in chronic phase, accelerated phase and myeloid blast phase CML are longer but cannot be estimated during this length of follow-up. 

## 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.

**Notes:**
70 mg twice a day is an effective dose, but lower doses also result in responses.
Among chronic phase CML patients, imatinib intolerant patients have higher response rates than imatinib resistant patients.

Imatinib intolerant patients with other phases of CML and with ALL also had responses, but too few of them were enrolled to provide valid estimates of response rates.

I will now ask Dr. Goodman to present the safety data and overall conclusions.

## 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

**Notes:**
I will now summarize the safety findings.
The safety population consists of all patients who initiated treatment with dasatinib at a dose of 70 mg bid, the starting dose on the phase 2 studies.
This population therefore includes all patients treated on the four single arm phase 2 studies, all patients initially treated with dasatinib on the randomized phase 2 study, and patients on the dose escalation study who received an initial dose of 70 mg bid.
Patients initially receiving imatinib who crossed over to dasatinib on the randomized study are not included in the safety population.  Patients who initially received dasatinib and who crossed over to imatinib on the randomized trial were evaluated for events occurring prior to the date of crossover.

## 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

**Notes:**
There are 489 patients in this safety population including 214 patients with chronic phase CML, 110 patients with AP CML, 84 patients with MB CML, and 81 patients with LB CML or Ph + ALL.

## Duration of Exposure

- < 3 months: 32%
- 3 months to 6 months: 57%
- > 6 months: 11%

**Notes:**
Overall, 57% of patients had a duration of 3-6 months of exposure to dasatinib, while 32% were treated for three months or less and 11% were treated for more than 6 months. The longest durations of exposure were seen in the phase 1 study, where nearly one-third of patients received 6 months or more of dasatinib.  This is also the only study in which any patient had 12 months or more of exposure. 

A 120 day safety update was recently submitted and is still under review; the data are therefore not included in this safety analysis.

## Dose Adjustments

| Disease Phase | Dose Reduction | Interruption |
| --- | --- | --- |
| CP | 50% | 82% |
| AP | 45% | 73% |
| MB | 35% | 74% |
| LB | 11% | 57% |
| Ph + ALL | 30% | 68% |

**Notes:**
The percent of patients by disease phase who required dose reduction or dosing interruption for any reason is shown here.
Dose interruptions were required in 68-82% of patients.  The median length of the first dose interruption was 12-14 days.  Dose reductions occurred in 11-50% of patients, more commonly those with earlier stage disease.  

## 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

**Notes:**
Patients were queried for adverse events at each visit.  Adverse events were graded according to NCI Common Terminology Criteria for Adverse Events v.3.   The next 3 slides describe, in order of decreasing frequency, the common adverse events, defined as those with an incidence of 10% or greater in the safety population.

The most commonly reported events included gastrointestinal events such as diarrhea, nausea, abdominal pain, and vomiting; constitutional symptoms such as fever, headache, fatigue, asthenia and anorexia; and fluid retention events such as peripheral edema and pleural effusion.

## 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 |

**Notes:**
While neutropenia, thrombocytopenia and anemia are listed in this table because they were reported in more than 10% of patients, these events were not universally reported as AEs.  A more accurate picture of treatment-emergent cytopenias  based on laboratory data will be shown in a later slide.

## 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 |

**Notes:**
Bleeding events were common on all the leukemia studies.  Epistaxis, the single most common bleeding event, occurred in 11% of all patients.  Other bleeding events are described in a later slide.
Neutropenic fever occurred in 10% of patients in the overall population, most commonly those with more advanced disease.  Neutropenic fever was relatively uncommon in patients with CP disease, occurred in 11-12% of patients with either AP or MB CML, and in 27% of those with LB CML  or Ph + ALL.

## 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

**Notes:**
Hypocalcemia was the most common non-hematologic laboratory abnormality.  8-30% of patients on the leukemia studies had baseline hypocalcemia of any grade and less than or equal to 1% had grade 3 or 4 hypocalcemia.  While on study, the incidence of any grade hypocalcemia increased to 46-80%, and the incidence of grade 3 or 4 hypocalemia was 4-22%.
These abnormalities were least common in CP patients and more common in patients with advanced disease.
There were no reports of tetany or muscle spasm associated with hypocalcemia.  A seizure occurred in one patient with grade 3 hypocalcemia; this patient also had documented leukemic involvement of the CNS.
Patients who experienced hypocalcemia were treated with calcium supplementation as clinically indicated.
The mechanism of hypocalcemia with dasatinib use is unclear.  However, in non-clinical studies, dasatinib inhibited parathyroid hormone-stimulated release of calcium dose-dependently and blocked bone resorption.

## 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% |

**Notes:**
Treatment-emergent grade 3 and 4 hematologic abnormalities were common among patients receiving dasatinib.  Baseline grade 3 and 4 cytopenias were uncommon in CP CML and more common in advanced phases of disease.  The percentage of patients with grade 3 and 4 cytopenias while receiving dasatinib increased substantially from baseline in all populations studied.  

On treatment grade 3 or 4 thrombocytopenia and neutropenia were more common than grade 3 and 4 anemia for all populations studied.

## 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% |

**Notes:**
Dasatinib has been observed to cause platelet dysfunction in in vitro assays as well as thrombocytopenia.  Bleeding complications are also a well-recognized complication of leukemia.
Bleeding events of any grade were reported in approximately one-third of patients, while grade 3 and 4 events occurred in 10% and fatal events in 1%.  Fatal bleeding was primarily intracranial, accounting for 5 out of 6 events with a fatal outcome.  The final fatality was a pulmonary hemorrhage.
Epistaxis was the most common bleeding event, followed by gastrointestinal bleeding. Other sites of bleeding included gingival, conjunctival, CNS, vaginal, urinary tract, eye, and respiratory tract.

## 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

**Notes:**
Most of the CNS hemorrhages occurred in patients with advanced disease, with 5 of the 6 events occurring in patients with blast phase CML or with Ph + ALL.  The remaining patient was in chronic phase.
While most of the cases were in patients with severe thrombocytopenia, one patient had a platelet count of 21,000 and another had a platelet count of 56,000 prior to the event.  One event occurred following a head injury; the remainder had no known precipitating factors.
The single non-fatal event was a subdural hematoma which resolved following surgical intervention.

## 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

**Notes:**
Preclinical studies suggested that dasatinib has the potential to cause QT prolongation. Prolonged QT, listed as either an adverse event or based on ECG data, was examined in all the CML trials.
 Nine patients or 1.8% of the safety population,  had at least one episode of QT prolongation reported as an adverse event while receiving dasatinib and 7 additional patients or 1.4%,  were found to have QTc prolongation of > or equal to 500 msec on ECG as assessed by a central laboratory reading.  Two patients were reported to have 5 beat runs of NSVT; there were no reports of torsades. 
Two patients had recurrent QTc prolongation following resumption of the drug, in one case after a dose reduction.  However, this patient continued on the lower dose and had no further episodes of QTc prolongation.

## 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)

**Notes:**
Preclinical studies in both rats and monkeys demonstrated a potential for dasatinib to cause cardiac toxicity.  Multifocal cardiac necrosis, hemorrhage, fibrosis and cardiac hypertrophy were seen in rats, and hypertrophy and inflammation were noted in monkeys.
Twenty patients or 4% of the safety population had an event classified as CHF, ventricular dysfunction or cardiac decompensation.  Among the 20 subjects, twelve had some cardiac history, primarily hypertension.
One patient died due to CHF: a 28 year old man heavily pretreated for CML including prior anthracyclines who had baseline mitral valve insufficiency but a normal baseline ejection fraction.  One week before death, his EF was 30%.  Cause of death was reported as global cardiac insufficiency and febrile pancytopenia.
Action taken with respect to study drug for cardiac failure events was dose interruption in 9 patients, discontinuation in 4 patients, dose reduction in 1 patient and no action in 6 patients.

## 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 |

**Notes:**
Forty percent of patients experienced edema of any type and 19% experienced pleural or pericardial effusions. 
Peripheral edema was the most common event, occurring in 26% of patients, followed by pleural effusion in 17%, and periorbital edema in 7%.  Facial edema, pericardial effusion, pulmonary edema and edema of other types were less common.
Grade 3 or 4 fluid retention events were uncommon with the exception of pleural effusion, with a 5% incidence of grade 3 or 4 severity.

## 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

**Notes:**
In summary, gastrointestinal events were common across all phases of disease, and included diarrhea, nausea, vomiting and abdominal pain.  Fluid retention events including edema and effusions were also common, with edema of any type affecting 40% of all patients.
Grade 3 and 4 hematologic laboratory abnormalities increased substantially from baseline in patients receiving dasatinib.
Cardiac failure events occurred in 4% of patients; death due to CHF occurred in one patient.
3% of patients had QTc prolongation reported either as an adverse event or determined by central laboratory ECG reading.
Approximately one-third of all patients had bleeding of any type, with epistaxis and gastrointestinal bleeding the most common.  There were six fatal bleeding events including 5 CNS hemorrhages and one pulmonary hemorrhage.

## 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

**Notes:**
I would now like to summarize the findings of the FDA clinical review of this application for dasatinib.
31-59% of all patients treated with 70 mg bid of dasatinib achieved a response in the primary response endpoint.  Responses were also seen at lower doses in a limited number of phase 1 patients.
Median duration of response has not been reached for most of the studies due to the limited duration of follow-up.  In CP, AP, and MB patients, nearly all patients who achieved a response remain in response at 6 months’ follow-up..  In LB CML, the median duration of response was 3.7 months and in Ph + ALL, the median duration of response was 4.8 months.
The most common adverse events include gastrointestinal events, constitutional events, fluid retention and bleeding.  Grade 3 and 4 hematologic laboratory abnormalities were also very common and occurred with a higher incidence on dasatinib than at baseline.
Most patients required dose interruptions or reductions due to toxicity.
Due to clear evidence of activity in CML and Ph + ALL, on February 6, 2006 an expanded access program was initiated on a treatment protocol for patients with advanced disease.