3160A4-3000

Pfizer Inc.

235 E 42nd Street, New York, United States, NY 10017

Pfizer ClinicalTrials.gov Call Center, Pfizer Inc., 001 800-718-1021, ClinicalTrials.gov_Inquiries@pfizer.com

Pfizer ClinicalTrials.gov Call Center, Pfizer Inc., 001 800-718-1021, ClinicalTrials.gov_Inquiries@pfizer.com

No

No

No

Final

27 May 2015

No

Yes

27 May 2015

Yes

This was a multinational, multicentre, randomized, open-label, parallel-arm Phase 3 study to compare the efficacy and safety of bosutinib alone to that of imatinib alone in subjects with newly diagnosed chronic phase chronic myelogenous leukemia.

This study was conducted in compliance with the ethical principles originating in or derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonisation Clinical Practice. In addition, all local regulatory requirements were followed, in particular, those affording greater protection to the safety of trial participants. The final protocol and any amendments were reviewed and approved by the Institutional Review Board(s)/or Independent Ethics Committee(s) each of the investigational centres participating in the study.

05 Feb 2008

Yes

Yes

Argentina: 4

Belgium: 7

Canada: 15

Chile: 3

Colombia: 7

Germany: 20

Spain: 12

France: 17

United Kingdom: 8

Hong Kong: 9

Hungary: 8

India: 54

Italy: 18

Japan: 27

Korea, Republic of: 19

Lithuania: 17

Latvia: 4

Mexico: 3

Poland: 30

Russian Federation: 54

Singapore: 15

South Africa: 2

Thailand: 10

Turkey: 7

Taiwan: 3

Ukraine: 58

United States: 41

Brazil: 12

China: 18

502

141

0

0

0

0

0

0

446

54

2

Overall Study (overall period)

Randomised - controlled

Yes

Bosutinib

Film-coated tablet

Oral use

Film-coated bosutinib tablets administered once daily at a dose of 500 mg with food (preferably in the morning) for up to 5 years or until treatment failure, unacceptable toxicity, death, withdrawal of consent. Dose adjustments, if needed, included an escalation to bosutinib 600 mg tablet orally once daily or a reduction to bosutinib 300 mg (<300 mg if deemed appropriate by the investigator and sponsor) tablet orally once daily.

Imatinib

Tablet

Oral use

Imatinib tablets administered once daily at a dose of 400 mg with food and a large glass of water for up to 5 years or until treatment failure, unacceptable toxicity, death, withdrawal of consent. Dose adjustments, if needed, included an escalation to imatinib 600 mg tablet orally once daily or a reduction to imatinib 300 mg tablet orally once daily.

Bosutinib

Imatinib

Bosutinib

Imatinib

Bosutinib

Bosutinib 500 milligram (mg) tablet orally once daily up to 5 years or until treatment failure, unacceptable toxicity, death, withdrawal of consent. Dose adjustments, if needed, included an escalation to bosutinib 600 mg tablet orally once daily or a reduction to bosutinib 300 mg tablet orally once daily.

Imatinib

Imatinib 400 mg tablet orally once daily up to 5 years or until treatment failure, unacceptable toxicity, death, withdrawal of consent. Dose adjustments, if needed, included an escalation to imatinib 600 mg tablet orally once daily or a reduction to imatinib 300 mg tablet orally once daily.

Cytogenetic Response (CyR) is based on the prevalence of Philadelphia chromosome positive (Ph+) metaphases among cells in metaphase on a bone marrow (BM) aspirate. CCyR was achieved when there was 0 percent (%) Ph+ metaphases among cells in a BM sample when at least 20 metaphases from a BM sample were analyzed, or less than (<) 1% breakpoint cluster region Abelson protooncogene (Bcr-Abl) fusion product among cells in a BM sample or peripheral blood sample when at least 200 cells were analyzed.

Primary

Year 1 (48 weeks)

Bosutinib v Imatinib

502

Pre-specified

Molecular response was assessed using Bcr-Abl transcript levels measured by reverse transcriptase polymerase chain reaction (RT-PCR) from peripheral blood. A MMR was defined as a ratio Bcr-Abl/Abl less than or equal to (≤) 0.1% on the international scale (greater than or equal to [≥] 3 log reduction from standardized baseline in ratio of Bcr-Abl to Abl transcripts) with at least 3000 Abl analyzed.

Secondary

Year 1 (48 weeks)

Bosutinib v Imatinib

502

Pre-specified

Duration of CCyR was measured from the first date of response until the first date of loss of response, objectively documented. Duration of response was calculated using only participants who responded to study medication. CyR is based on the prevalence of Ph+ metaphases among cells in metaphase on a bone marrow sample. CCyR was achieved when there was 0% Ph+ metaphases among cells in a bone marrow sample when at least 20 metaphases from a BM sample were analyzed, or <1% Bcr-Abl fusion product among cells in a BM sample or peripheral blood sample when at least 200 cells were analyzed. The medians have not been reached in either arm, as such, the premature estimated hazard ratio is provided. 4 year rates displayed since the majority of participants had first CCyR by Year 1.

Secondary

Every 12 weeks in Year 1, every 24 weeks in Years 2 and 3 and every 48 weeks for Year 4 through 5

Bosutinib v Imatinib

401

Pre-specified

0.64

2-sided

Duration of CHR was measured from the first date of response until the first date of loss of response, objectively documented. Duration of response was calculated using only participants who responded to study medication. CHR must have been of at least 4 weeks in duration confirmed by 2 assessments at least 4 weeks apart and was defined as follows: white blood cells ≤ institutional upper limit of normal [20*10^9 per liter (/L)], no peripheral blasts or promyelocytes, myelocytes + metamyelocytes <5% in blood, absolute neutrophil count ≥1.0*10^9/L, platelets ≥100 but <450*10^9/L unless related to therapy, <20% basophils in blood and no extramedually involvement (including hepato- or splenomegaly). The medians have not been reached in either arm; as such, the premature estimated hazard ratio is provided. 4 year rates displayed since the majority of participants had first CHR by Year 1.

Secondary

Every 4 weeks up to Week 20 thereafter every 12 weeks until 7 to 28 days after last dose of study medication

Bosutinib v Imatinib

461

Pre-specified

0.59

2-sided

Duration of MMR was measured from the first date of response until the first date loss of response, objectively documented. Duration of response was calculated using only participants who responded to study medication. Molecular response was assessed using Bcr-Abl transcript levels measured by RT-PCR from peripheral blood. MMR is defined as a ratio Bcr-Abl/Abl ≤ 0.1% on the international scale (≥ 3 log reduction from standardized baseline in ratio of Bcr-Abl to Abl transcripts) with at least 3000 Abl analyzed. The medians have not been reached in either arm; as such, the premature estimated hazard ratio is provided. 3 year rates displayed since the majority of imatinb participants had first MMR by Year 2.

Secondary

Every 12 weeks for Years 1 and 2 and every 24 weeks for Year 3 through 5

Bosutinib v Imatinib

338

Pre-specified

3.25

2-sided

Time to transformation to AP/BP was defined as the time from randomization to the first date of transformation to AP or BP while on study treatment adjusting for the competing risk of treatment discontinuation without transformation. Criteria for transformation to AP: 15 to 29% blasts; ≥30% blasts + promyelocytes; ≥20% basophils in blood or bone marrow; platelets <100*10^9/L (not related to therapy), in blood. Criteria for transformation to BP: ≥30% blasts in blood or bone marrow and extramedullary involvement other than liver or spleen (example: chloromas). Time to transformation was calculated as weeks = ([date of first documented occurrence of the event - date of randomization] + 1)/7. If transformation was not obtained, censoring was at the last hematologic assessment or death (whichever was earliest). Participants who were not treated contributed time=1 day/7. 95% confidence interval for the cumulative incidence is from Gray’s method.

Secondary

From date of randomization (Week 0) up to first transformation to AP/BP phase or 7 to 28 days after last dose of study medication

Bosutinib v Imatinib

502

Pre-specified

0.41

2-sided

Adverse events (AEs) were recorded from first dose of study treatment through last subject visit. Serious adverse events (SAE) were recorded from informed consent through and including 28 calendar days after last administration of study treatment.

The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.

18.0

Imatinib

Bosutinib