A Phase 1/2 Study Of Bosutinib (SKI-606) In Japanese Adults With Philadelphia Chromosome-Positive (Ph+) Chronic Myeloid Leukemia (CML)

Bosutinib (BOS), an oral dual Src/Abl tyrosine kinase inhibitor, has demonstrated efficacy and acceptable safety in patients (pts) with chronic phase (CP)-CML resistant/intolerant to imatinib (IM). This ongoing open-label, 2-part, phase 1/2 study evaluated the safety, pharmacokinetics (PK), and efficacy of BOS in Japanese pts with Ph+ CML.

In this study, Part 1 was designed to confirm the safety of BOS up to 600 mg/d (or establish a maximum tolerated dose <600 mg/d) and evaluate PK parameters in IM-resistant/intolerant CP-CML pts. In Part 1, BOS (400 mg, 500 mg, and 600 mg) was administered to successive cohorts of pts aged ≥20 to <75 y as a single daily dose on d 1 and as a continuous once-daily dose from d 3, with each cohort (3-6 pts) evaluated for 28 d before enrolling the next dosing cohort. Part 2 evaluated the efficacy and safety of BOS in CP-CML or advanced (ADV) CML pts after resistance/intolerance to IM (second-line [2L]) or to IM plus dasatinib or nilotinib (third-line [3L]; exploratory cohort). In Part 2, BOS (starting dose: 500 mg/d) was administered to pts aged ≥20 y, with dose escalation to 600 mg/d allowed for lack of efficacy. The primary efficacy endpoint was the cumulative major cytogenetic response (MCyR) rate by wk 24 in CP-CML 2L pts (primary cohort).

In Part 1, 17 pts received BOS (400 mg, n=7, 500 mg, n=7; 600 mg, n=3); 1 pt each in the 400 mg and 500 mg dose groups was not evaluable for dose limiting toxicities (DLTs) due to early study discontinuation (disease progression and pt request, respectively). DLTs during the first 28 d of treatment occurred in 1/6 pt receiving BOS 400 mg (grade 3 liver injury) and 1/6 pt receiving BOS 500 mg (grade 4 abnormal hepatic function); no DLTs occurred in the 3 BOS 600-mg pts. BOS 500 mg was chosen as starting dose for Part 2 based on DLTs and previous results (Cortes et al. Blood. 2011;118:4567-76). PK analyses indicated relatively slow absorption, with a median T_max of ∼4 h after single or multiple doses of BOS 400–600 mg. BOS exposure (C_max and AUC) generally increased with increasing dose after single and multiple doses.

In Part 2, 46 additional pts were enrolled (2L, n=35 [28 CP-CML, 7 ADV]; 3L, n=11 [10 CP-CML, 1 accelerated-phase (AP)]); 63 pts were treated with BOS (median [range] age: 55 [20-78] y; 62% male; entry diagnosis: CP-CML, n=58; AP-CML, n=3; blast phase [BP]-CML, n=2). Median follow-up was 132 wk for 2L pts and 37 wk for 3L pts.

In the CP-CML 2L cohort in Part 2 (n=28), the MCyR rate by wk 24 was 36% (10/28 pts; complete [CCyR], n=8; partial [PCyR], n=2) (primary endpoint); maintained MCyR at wk 24 was 64% (18/28 pts; CCyR, n=16; PCyR, n=2); median time to MCyR was 12.3 wk. Only 1 of 13 CP-CML 2L pts who attained MCyR at any point during the study lost it. Cumulative major molecular response (MMR) rate through the study was 43% (12/28 pts). AP/BP transformation occurred in 1 CP-CML 2L pt; at wks 48 and 96, progression-free survival (PFS) rates were 100% and 94%, respectively, and overall survival (OS) rate was 96% (both). Of 7 ADV 2L pts, 1 had confirmed complete hematologic response (cCHR) at wk 84 with duration of 95 wk (cCHR lost). AP/BP transformation occurred in 1 ADV 2L pt; at wks 48 and 96, PFS rate was 21% (both), and OS rate was 43% (both). In the 3L cohort, the cumulative MCyR rate by wk 24 and maintained MCyR rate at wk 24 were 18% (2/11 pts) and 64% (7/11 pts [CCyR, n=6; PCyR, n=1]); cumulative MMR rate through the study was 18% (2/11 pts). The only 3L pt with AP-CML attained cCHR at 12 wk with a duration of 24 wk as of the date of this analysis (censored due to data cutoff). No AP/BP transformation occurred in the 3L cohort; treatment duration was inadequate for assessment of PFS and OS.

Overall, the most common treatment-emergent AEs (TEAEs) were diarrhea (95%), rash (57%), nasopharyngitis (51%), nausea (38%), vomiting (38%), increased alanine aminotransferase (ALT; 38%), lymphopenia (35%), thrombocytopenia (30%), and increased aspartate aminotransferase (30%). Grade 3/4 TEAEs were reported in 54 (86%) pts, most commonly lymphopenia (21%), increased lipase (19%), neutropenia (18%), thrombocytopenia (18%), and increased ALT (18%). 16 (25%) pts discontinued treatment due to AEs. No deaths occurred within 30 d of last BOS dose.

The safety and PK profiles of BOS up to 600 mg/d was confirmed in Japanese pts with Ph+ CML resistant/intolerant to IM. BOS 500 mg/d demonstrated clinical activity and an acceptable safety profile in this population.

Kobayashi:Ariad: Research Funding; Boehringer Ingelheim: Research Funding; Novartis: Research Funding; Ohtsuka: Research Funding; Onconova: Research Funding. Shibata:Pfizer Japan Inc: Employment. Fujii:Pfizer Japan Inc: Employment. Ono:Pfizer Japan Inc: Employment.