LY317615 Enzastaurin was limited to patients with CML CP. In the 17 patients treated with 240 mg BID, transaminase elevations were still observed but were less severe. No patients had drug related grade 3 AST elevations and only 1 patient had a drug related grade 3 ALT elevation. Drug related grade 2 ALT elevations occurred at the 240 mg BID dose level in 9 patients, and a grade 2 AST elevation developed in 1 patient. The elevated transaminase levels observed at 240 mg BID resolved when INNO 406 dosing was withheld temporarily and then resumed at a lower dose. Based on these results, an INNO 406 dose of 240 mg BID is proposed for phase 2 studies. In addition to elevated transaminases, the other most common drug related grade 3/4 adverse event noted was thrombocytopenia.
When both drug and non drugrelated thrombocytopenic events were considered, BMY 7378 2 and 3 patients experienced grade 3 and 4 thrombocytopenia, respectively, including 1 patient who initiated INNO 406 treatment with preexisting grade 4 thrombocytopenia. Platelet counts recovered when INNO 406 was withheld and then resumed at a lower dose. This study incorporated a planned central evaluation of electrocardiograms during the first cycle of therapy to assess for QT prolongation. During this period of intense monitoring, the QTcB increased to grade 2 in 4 patients and the QTcF increased to grade 2 in 1 patient. Only 1 patient, who entered the study with a waiver due to a prolonged QTc, developed a QTc 500 msec during this routine monitoring after cycle 1.
The patient experienced no further events after discontinuing INNO 406. The NCI categories of adverse events that were experienced by 10% of patients were metabolic/laboratory, gastrointestinal, pain, constitutional symptoms, infection, dermatology/skin, blood/bone marrow, lymphatics, neurology, pulmonary/upper respiratory, cardiac general, hemorrhage/bleeding, and musculoskeletal/soft tissue. Five patients have died since beginning treatment, all deaths were related to leukemia progression. Four deaths were among 16 patients in CML blastic phase or Ph positive ALL, 1 death was among 8 patients in CML accelerated phase, no deaths so far have been recorded among 31 patients in chronic phase. The 5 deaths did not appear to be correlated to dosing regimen: 1 at 30 mg daily, 2 at 120 mg daily, 1 at 480 mg BID, 1 at 360 mg BID.
No cases of pleural or pericardial effusions were noted. Efficacy Table 3 provides a detailed summary of cytogenetic responses. All of the patients who achieved a cytogenetic response had CML CP. No responses were observed in patients with CML AP, CML BP, or Ph positive ALL. Major cytogenetic responses were noted in 6 patients with CML CP. Three patients had a complete cytogenetic response, one at each of the INNO 406 dose schedules of 120 mg QD, 120 mg BID, and 240 mg BID. The remaining3 patients had a partial cytogenetic response: 2 patients at 240 mg BID and 1 patient at 480 mg BID. None of the six major cytogenetic responders had baseline cytogenetic clonal evolution. Thus, 4 of the major cytogenetic responses occurred in patients treated with INNO 406 doses of 240 mg BID or greater. This represents a major cytogenetic responses rate of 11% for all patients enrolled, and a rate of 19%