Abstract
Panobinostat (LBH589), a novel cinnamic hydroxamic acid analogue with potent pan deacetylase inhibitor activity, acetylates HSP90 and promotes degradation of its client proteins, such as BCR-ABL. Panobinostat induces degradation of wild-type BCR-ABL, as well as BCR-ABL with the T315I and the E255K mutations in BaF3 cells. It also induces apoptosis in primary patients CML-BC cells. Panobinostat was investigated for the first time in patients (pts) in AP or BC stage of a Ph1+ CML in this Phase II trial. Panobinostat was dosed orally, 20 mg, once-a-day, thrice weekly. Concomitant hydroxyurea was permitted for up to 7 days within 14 first days in Cycle 1. Primary objective was to assess hematologic response rate, ie, complete hematologic response (CHR) with no evidence of leukemia (NEL) or return to chronic phase (RTC). Response confirmation was required after 4 weeks. As per protocol, to avoid futility for pts, efficacy cut-off required to move to Stage 2 enrollment was of 3 or more major cytogenetic responders (MCyR) out of the first 25 treated pts in Stage 1. A total of 27 pts, 13 female/14 male, with Ph+ CML who had failed ≥2 prior BCR-ABL tyrosine kinase inhibitors (TKIs), were enrolled into Stage 1 cohort of the study. Median age at entry was 55 years (29–76). Patients entered with a disease stage of AP or BC of 17/10, respectively. Time since initial CML diagnosis was ≥5 years in 59% of pts. The majority of pts (55%) had evolved into their current disease stage (AP or BC) within the year prior to entry. Best response under TKIs, at any disease stage, had been cytogenetic response (CyR) in 8 pts, complete hematologic response (CHR) in 9 pts, and finally, no CHR in 10 pts. Median treatment duration with panobinostat was 17 days (1–76). Discontinuation from study was due to disease progression in 19 pts (70%) or new leukemia therapy in 1 pt (3%), and it was recorded as due to AE in 5 pts (18%) or to abnormal lab values in 2 pts (7%). CNS new involvement by leukemia occurred in 4 pts. The most common Grade 3/4 AEs were thrombocytopenia in 12 pts (44%) and anemia in 9 pts (33%). Gastrointestinal (GI) AEs were Grade 1/2 for 13 of the 14 events, including diarrhea in 10 pts. 1 pt presented Grade 3 abdominal pain. Atrial fibrillation recorded as possibly related to study drug was the AE cause for discontinuation in 1 pt. Out of 684 records of post baseline ECGs evaluable to date, 1 single QTcF prolongation >480 ms was recorded (Grade 2). Notable lab abnormalities were Grade 3 hyperkalemia in 2 pts, Grade 3 hypokalemia in 2 pts, and Grade 3 WBC count increased in 2 pts. Hematologic RTC response was reported for 4 pts, (in Cycle 1 for 1 pt, Cycle 2 for 2 pts, and Cycle 3 for 1 pt). However, these responses were not confirmed. Consistently, no MCyR was observed. No major molecular response was observed from BCR-ABL transcript analysis performed at a central lab from patients blood samples obtained at baseline and post treatment. BCR-ABL mutation analysis by direct sequencing at a central lab showed that in addition to T315I, which was most frequently observed, a spectrum of other mutations were also seen at baseline and at disease progression. Some patients harbored more than one mutation in BCR-ABL at baseline and/or disease progression, which will be presented in details. Single-agent, oral panobinostat at a dose of 20 mg/day, thrice weekly did not show any sustained clinical responses in AP or BC CML patients enrolled. Furthermore, disease progression was very rapidly determined with median therapy duration being less than 3 weeks. This could possibly be related to a too short interval of temporary co-administration of hydroxyurea, as per study protocol. In patients with AP/BC CML resistant to 2 TKIs, oral, single-agent panobinostat at a dose of 20 mg/day, thrice weekly was safe but did not show meaningful clinical activity precluding study continuation. Promising clinical activity of panobinostat has since been observed in various other hematological malignancies, such as CTCL, as well as HL, AML, and MDS — mostly at higher doses. In these and other indications, clinical investigation of the oral and i.v. formulations of panobinostat at different doses and in combination with established standard treatment regimens are planned or ongoing.
Continued Complete Hematologic Response