14 CLINICAL STUDIES

14.1 Newly Diagnosed Chronic Phase CML in Adults

DASISION (Dasatinib vs Imatinib Study in Treatment-Naive Chronic Myeloid Leukemia Patients) (NCT00481247) was an open-label, multicenter, international, randomized trial conducted in adult patients with newly diagnosed chronic phase CML. A total of 519 patients were randomized to receive either SPRYCEL 100 mg once daily or imatinib 400 mg once daily. Patients with a history of cardiac disease were included in this trial except those who had a myocardial infarction within 6 months, congestive heart failure within 3 months, significant arrhythmias, or QTc prolongation. The primary endpoint was the rate of confirmed complete cytogenetic response (CCyR) within 12 months. Confirmed CCyR was defined as a CCyR noted on two consecutive occasions (at least 28 days apart).

Median age was 46 years in the SPRYCEL group and 49 years in the imatinib groups, with 10% and 11% of patients ≥65 years of age, respectively. There were slightly more male than female patients in both groups (59% vs 41%). Fifty-three percent of all patients were Caucasian and 39% were Asian. At baseline, the distribution of Hasford scores was similar in the SPRYCEL and imatinib treatment groups (low risk: 33% and 34%; intermediate risk: 48% and 47%; high risk: 19% and 19%, respectively). With a minimum of 12 months follow-up, 85% of patients randomized to SPRYCEL and 81% of patients randomized to imatinib were still on study.

With a minimum of 24 months follow-up, 77% of patients randomized to SPRYCEL and 75% of patients randomized to imatinib were still on study and with a minimum of 60 months follow-up, 61% and 62% of patients, respectively, were still on treatment at the time of study closure.

Efficacy results are summarized in Table 16.

Table 16: Efficacy Results in a Randomized Newly Diagnosed Chronic Phase CML Trial
	SPRYCEL (n=259)	Imatinib (n=260)
a Confirmed CCyR is defined as a CCyR noted on two consecutive occasions at least 28 days apart. b Major molecular response (at any time) was defined as BCR-ABL ratios ≤0.1% by RQ-PCR in peripheral blood samples standardized on the International scale. These are cumulative rates representing minimum follow up for the time frame specified. * Adjusted for Hasford score and indicated statistical significance at a pre-defined nominal level of significance. CI = confidence interval.
Confirmed CCyRa
Within 12 months (95% CI)	76.8% (71.2–81.8)	66.2% (60.1–71.9)
P-value	0.007*
Major Molecular Responseb
12 months (95% CI)	52.1% (45.9–58.3)	33.8% (28.1–39.9)
P-value	<0.0001
60 months (95% CI)	76.4% (70.8–81.5)	64.2% (58.1–70.1)

The confirmed CCyR within 24, 36, and 60 months for SPRYCEL versus imatinib arms were 80% versus 74%, 83% versus 77%, and 83% versus 79%, respectively. The MMR at 24 and 36 months for SPRYCEL versus imatinib arms were 65% versus 50% and 69% versus 56%, respectively.

After 60 months follow-up, median time to confirmed CCyR was 3.1 months in 215 SPRYCEL responders and 5.8 months in 204 imatinib responders. Median time to MMR after 60 months follow-up was 9.3 months in 198 SPRYCEL responders and 15.0 months in 167 imatinib responders.

At 60 months, 8 patients (3%) on the dasatinib arm progressed to either accelerated phase or blast crisis while 15 patients (6%) on the imatinib arm progressed to either accelerated phase or blast crisis.

The estimated 60-month survival rates for SPRYCEL- and imatinib-treated patients were 90.9% (CI: 86.6%–93.8%) and 89.6% (CI: 85.2%–92.8%), respectively. Based on data 5 years after the last patient was enrolled in the trial, 83% and 77% of patients were known to be alive in the dasatinib and imatinib treatment groups, respectively, 10% were known to have died in both treatment groups, and 7% and 13% had unknown survival status in the dasatinib and imatinib treatment groups, respectively.

At 60 months follow-up in the SPRYCEL arm, the rate of MMR at any time in each risk group determined by Hasford score was 90% (low risk), 71% (intermediate risk) and 67% (high risk). In the imatinib arm, the rate of MMR at any time in each risk group determined by Hasford score was 69% (low risk), 65% (intermediate risk), and 54% (high risk).

BCR-ABL sequencing was performed on blood samples from patients in the newly diagnosed trial who discontinued dasatinib or imatinib therapy. Among dasatinib-treated patients the mutations detected were T315I, F317I/L, and V299L.

Dasatinib does not appear to be active against the T315I mutation, based on in vitro data.

14.2 Imatinib-Resistant or -Intolerant CML or Ph+ ALL in Adults

The efficacy and safety of SPRYCEL were investigated in adult patients with CML or Ph+ ALL whose disease was resistant to or who were intolerant to imatinib: 1158 patients had chronic phase CML, 858 patients had accelerated phase, myeloid blast phase, or lymphoid blast phase CML, and 130 patients had Ph+ ALL. In a clinical trial in chronic phase CML, resistance to imatinib was defined as failure to achieve a complete hematologic response (CHR; after 3 months), major cytogenetic response (MCyR; after 6 months), or complete cytogenetic response (CCyR; after 12 months); or loss of a previous molecular response (with concurrent ≥10% increase in Ph+ metaphases), cytogenetic response, or hematologic response. Imatinib intolerance was defined as inability to tolerate 400 mg or more of imatinib per day or discontinuation of imatinib because of toxicity.

Results described below are based on a minimum of 2 years follow-up after the start of SPRYCEL therapy in patients with a median time from initial diagnosis of approximately 5 years. Across all studies, 48% of patients were women, 81% were white, 15% were black or Asian, 25% were 65 years of age or older, and 5% were 75 years of age or older. Most patients had long disease histories with extensive prior treatment, including imatinib, cytotoxic chemotherapy, interferon, and stem cell transplant. Overall, 80% of patients had imatinib-resistant disease and 20% of patients were intolerant to imatinib. The maximum imatinib dose had been 400–600 mg/day in about 60% of the patients and >600 mg/day in 40% of the patients.

The primary efficacy endpoint in chronic phase CML was MCyR, defined as elimination (CCyR) or substantial diminution (by at least 65%, partial cytogenetic response) of Ph+ hematopoietic cells. The primary efficacy endpoint in accelerated phase, myeloid blast phase, lymphoid blast phase CML, and Ph+ ALL was major hematologic response (MaHR), defined as either a CHR or no evidence of leukemia (NEL).

Chronic Phase CML

Dose-Optimization Trial: A randomized, open-label trial (NCT00123474) was conducted in adult patients with chronic phase CML to evaluate the efficacy and safety of SPRYCEL administered once daily compared with SPRYCEL administered twice daily. Patients with significant cardiac diseases, including myocardial infarction within 6 months, congestive heart failure within 3 months, significant arrhythmias, or QTc prolongation were excluded from the trial. The primary efficacy endpoint was MCyR in patients with imatinib-resistant CML. A total of 670 patients, of whom 497 had imatinib-resistant disease, were randomized to the SPRYCEL 100 mg once-daily, 140 mg once-daily, 50 mg twice-daily, or 70 mg twice-daily group. Median duration of treatment was 22 months.

Efficacy was achieved across all SPRYCEL treatment groups with the once-daily schedule demonstrating comparable efficacy (non-inferiority) to the twice-daily schedule on the primary efficacy endpoint (difference in MCyR 1.9%; 95% CI [−6.8%–10.6%]); however, the 100-mg once-daily regimen demonstrated improved safety and tolerability.

Efficacy results are presented in Tables 17 and 18 for adult patients with chronic phase CML who received the recommended starting dose of 100 mg once daily.

Table 17: Efficacy of SPRYCEL in Adult Patients with Imatinib-Resistant or -Intolerant Chronic Phase CML (minimum of 24 months follow-up)
All Patients	100 mg Once Daily (n=167)
a CHR (response confirmed after 4 weeks): WBC ≤ institutional ULN, platelets <450,000/mm3, no blasts or promyelocytes in peripheral blood, <5% myelocytes plus metamyelocytes in peripheral blood, basophils in peripheral blood <20%, and no extramedullary involvement. b MCyR combines both complete (0% Ph+ metaphases) and partial (>0%–35%) responses.
Hematologic Response Rate % (95% CI)
CHRa	92% (86–95)
Cytogenetic Response Rate % (95% CI)
MCyRb	63% (56–71)
CCyR	50% (42–58)

Table 18: Long-Term MMR of SPRYCEL in the Dose Optimization Trial: Adult Patients with Imatinib-Resistant or -Intolerant Chronic Phase CMLa
	Minimum Follow-up Period
	2 Years	5 Years	7 Years
a Results reported in recommended starting dose of 100 mg once daily. b Major molecular response criteria: Defined as BCR-ABL/control transcripts ≤0.1% by RQ-PCR in peripheral blood samples.
Major Molecular Responseb % (n/N)
All Patients Randomized	34% (57/167)	43% (71/167)	44% (73/167)
Imatinib-Resistant Patients	33% (41/124)	40% (50/124)	41% (51/124)
Imatinib-Intolerant Patients	37% (16/43)	49% (21/43)	51% (22/43)

Based on data 7 years after the last patient was enrolled in the trial, 44% were known to be alive, 31% were known to have died, and 25% had an unknown survival status.

By 7 years, transformation to either accelerated or blast phase occurred in nine patients on treatment in the 100 mg once-daily treatment group.

Advanced Phase CML and Ph+ ALL

Dose-Optimization Trial: One randomized open-label trial (NCT00123487) was conducted in patients with advanced phase CML (accelerated phase CML, myeloid blast phase CML, or lymphoid blast phase CML) to evaluate the efficacy and safety of SPRYCEL administered once daily compared with SPRYCEL administered twice daily. The primary efficacy endpoint was MaHR. A total of 611 patients were randomized to either the SPRYCEL 140 mg once-daily or 70 mg twice-daily group. Median duration of treatment was approximately 6 months for both treatment groups. The once-daily schedule demonstrated comparable efficacy (non-inferiority) to the twice-daily schedule on the primary efficacy endpoint; however, the 140-mg once-daily regimen demonstrated improved safety and tolerability.

Response rates for patients in the 140 mg once-daily group are presented in Table 19.

Table 19: Efficacy of SPRYCEL in Imatinib-Resistant or -Intolerant Advanced Phase CML and Ph+ ALL (2-Year Results)
	140 mg Once Daily
	Accelerated (n=158)	Myeloid Blast (n=75)	Lymphoid Blast (n=33)	Ph+ ALL (n=40)
a Hematologic response criteria (all responses confirmed after 4 weeks): Major hematologic response: (MaHR) = complete hematologic response (CHR) + no evidence of leukemia (NEL). CHR: WBC ≤ institutional ULN, ANC ≥1000/mm3, platelets ≥100,000/mm3, no blasts or promyelocytes in peripheral blood, bone marrow blasts ≤5%, <5% myelocytes plus metamyelocytes in peripheral blood, basophils in peripheral blood <20%, and no extramedullary involvement. NEL: same criteria as for CHR but ANC ≥500/mm3 and <1000/mm3, or platelets ≥20,000/mm3 and ≤100,000/mm3. b MCyR combines both complete (0% Ph+ metaphases) and partial (>0%–35%) responses. CI = confidence interval ULN = upper limit of normal range.
MaHRa	66%	28%	42%	38%
(95% CI)	(59–74)	(18–40)	(26–61)	(23–54)
CHRa	47%	17%	21%	33%
(95% CI)	(40–56)	(10–28)	(9–39)	(19–49)
NELa	19%	11%	21%	5%
(95% CI)	(13–26)	(5–20)	(9–39)	(1–17)
MCyRb	39%	28%	52%	70%
(95% CI)	(31–47)	(18–40)	(34–69)	(54–83)
CCyR	32%	17%	39%	50%
(95% CI)	(25–40)	(10–28)	(23–58)	(34–66)

In the SPRYCEL 140 mg once-daily group, the median time to MaHR was 1.9 months (min-max: 0.7-14.5) for patients with accelerated phase CML, 1.9 months (min-max: 0.9-6.2) for patients with myeloid blast phase CML, and 1.8 months (min-max: 0.9-2.8) for patients with lymphoid blast phase CML.

In patients with myeloid blast phase CML, the median duration of MaHR was 8.1 months (min-max: 2.7-21.1) and 9.0 (min-max: 1.8-23.1) months for the 140 mg once-daily group and the 70 mg twice-daily group, respectively. In patients with lymphoid blast phase CML, the median duration of MaHR was 4.7 months (min-max: 3.0-9.0) and 7.9 months (min-max: 1.6-22.1) for the 140 mg once-daily group and the 70 mg twice-daily group, respectively. In patients with Ph+ ALL who were treated with SPRYCEL 140 mg once-daily, the median duration of MaHR was 4.6 months (min-max: 1.4-10.2). The medians of progression-free survival for patients with Ph+ ALL treated with SPRYCEL 140 mg once-daily and 70 mg twice-daily were 4.0 months (min-max: 0.4-11.1) and 3.1 months (min-max: 0.3-20.8), respectively.

14.3 CML in Pediatric Patients

The efficacy of SPRYCEL in pediatric patients was evaluated in two pediatric studies of 97 patients with chronic phase CML. Among 97 patients with chronic phase CML treated in two pediatric studies, an open-label, non-randomized dose-ranging trial (NCT00306202) and an open-label, non-randomized, single-arm trial (NCT00777036), 51 patients (exclusively from the single-arm trial) had newly diagnosed chronic phase CML and 46 patients (17 from the dose-ranging trial and 29 from the single-arm trial) were resistant or intolerant to previous treatment with imatinib. Ninety-one of the 97 pediatric patients were treated with SPRYCEL tablets 60 mg/m2 once daily (maximum dose of 100 mg once daily for patients with high BSA). Patients were treated until disease progression or unacceptable toxicity.

Baseline demographic characteristics of the 46 imatinib resistant or intolerant patients were: median age 13.5 years (range 2 to 20 years), 78.3% White, 15.2% Asian, 4.4% Black, 2.2% other, and 52% female. Baseline characteristics of the 51 newly diagnosed patients were: median age 12.8 years (range 1.9 to 17.8 years), 60.8% White, 31.4% Asian, 5.9% Black, 2% Other, and 49% female.

Median duration of follow-up was 5.2 years (range 0.5 to 9.3 years) for the imatinib resistant or intolerant patients and 4.5 years (range 1.3 to 6.4 years) for the newly diagnosed patients, respectively. Efficacy results for the two pediatric studies are summarized in Table 20.

Table 20 shows increasing trend for response for CCyR, MCyR, and MMR across time (3 months to 24 months). The increasing trend in response for all three endpoints is seen in both the newly diagnosed and imatinib resistant or intolerant patients.

Table 20: Efficacy of SPRYCEL in Pediatric Patients with CP-CML Cumulative Response Over Time by Minimum Follow-Up Period

	3 months	6 months	12 months	24 months
a Patients from pediatric study of newly diagnosed CP-CML receiving oral tablet formulation b Patients from pediatric studies of imatinib-resistant or -intolerant CP-CML receiving oral tablet formulation
CCyR (95% CI)
Newly diagnosed (N = 51)a	43.1% (29.3, 57.8)	66.7% (52.1, 79.2)	96.1% (86.5, 99.5)	96.1% (86.5, 99.5)
Prior imatinib (N = 46)b	45.7% (30.9, 61.0)	71.7% (56.5, 84.0)	78.3% (63.6, 89.1)	82.6% (68.6, 92.2)
MCyR (95% CI)
Newly diagnosed (N = 51)a	60.8% (46.1, 74.2)	90.2% (78.6, 96.7)	98.0% (89.6, 100)	98.0% (89.6, 100)
Prior imatinib (N = 46)b	60.9% (45.4, 74.9)	82.6% (68.6, 92.2)	89.1% (76.4, 96.4)	89.1% (76.4, 96.4)
MMR (95% CI)
Newly diagnosed (N = 51)a	7.8% (2.2, 18.9)	31.4% (19.1, 45.9)	56.9% (42.2, 70.7)	74.5% (60.4, 85.7)
Prior imatinib (N = 46)b	15.2% (6.3, 28.9)	26.1% (14.3, 41.1)	39.1% (25.1, 54.6)	52.2% (36.9, 67.1)

With a median follow-up of 4.5 years in newly diagnosed patients, the median durations of CCyR, MCyR, MMR could not be estimated as more than half of the responding patients had not progressed at the time of data cut-off. Range of duration of response was (2.5+ to 66.5+ months for CCyR), (1.4 to 66.5+ months for MCyR), and (5.4+ to 72.5+ months for subjects who achieved MMR by month 24 and 0.03+ to 72.5+ months for subjects who achieved MMR at any time), where ‘+’ indicates a censored observation.

With a median follow-up of 5.2 years in imatinib-resistant or - intolerant patients, the median durations of CCyR, MCyR, and MMR could not be estimated as more than half the responding patients had not progressed at the time of data cut-off. Range of duration of response was (2.4 to 86.9+ months for CCyR), (2.4 to 86.9+ months for MCyR), and (2.6+ to 73.6+ months for MMR), where ‘+’ indicates a censored observation.

The median time to response for MCyR was 2.9 months (95% CI: 2.8 months, 3.5 months) in the pooled imatinib-resistant/intolerant CP-CML patients. The median time to response for CCyR was 3.3 months (95% CI: 2.8 months, 4.7 months) in the pooled imatinib-resistant/intolerant CP-CML patients. The median time to response for MMR was 8.3 months (95% CI: 5.0 months, 11.8 months) in the pooled imatinib- resistant/intolerant CP-CML patients.

The median time to response for MCyR was 3.0 months (95% CI: 2.8 months, 4.3 months) in the newly diagnosed treatment-naïve CP-CML patients. The median time to response for CCyR was 5.5 months (95% CI: 3.0 months, 5.7 months) in the newly diagnosed treatment-naïve CP-CML patients. The median time to response for MMR was 8.9 months (95% CI: 6.2 months, 11.7 months) in the newly diagnosed treatment-naïve CP-CML patients.

In the Phase II pediatric study, 1 newly diagnosed patient and 2 imatinib-resistant or -intolerant patients progressed to blast phase CML.

14.4 Ph+ ALL in Pediatric Patients

The efficacy of SPRYCEL in combination with chemotherapy was evaluated in a single cohort (cohort 1) of Study CA180372 (NCT01460160), a multicenter, multiple-cohort study of pediatric patients with newly diagnosed B-cell precursor Ph+ ALL. The 78 patients in cohort 1 received SPRYCEL at a daily dose of 60 mg/m2 for up to 24 months, in combination with chemotherapy. The backbone chemotherapy regimen was the AIEOP-BFM ALL 2000 multi-agent chemotherapy protocol.

Patients had a median age of 10.4 years (range 2.6 to 17.9 years) and included 20 patients (25%) 2 to 6 years of age, 37 patients (46%) 7 to 12 years of age, and 24 patients (30%) 13 to 17 years of age. Eighty-two percent of patients were white, and 55% were male. Thirty-two patients (41%) had a white blood cell count (WBC) of ≥50,000 mcl at diagnosis, and 17 patients (22%) had extramedullary disease.

Efficacy was established on the basis of 3-year event-free survival (EFS), defined as the time from the start of SPRYCEL to lack of complete response at the end of the third high risk block, relapse, secondary malignancy, or death from any cause. The 3-year EFS binary rate for patients on Study CA180372 was 64.1% (95% CI: 52.4, 74.7). At the end of induction, 75 patients (96%) had a bone marrow with <5% lymphoblasts, and 76 patients (97%) achieved this by the end of consolidation.