Abstract
Background: Panobinostat (LBH589) is a novel, high potent pan-deacetylase inhibitor, which acetylates HSP90 and promotes degradation of its client proteins, such as BCR-ABL. It induces degradation of wild-type, as well as BCR-ABL with the T315i and E255K mutations in BaF3 cells. Based on this encouraging data, we initiated a Phase II trial to investigate the efficacy and safety of oral panobinostat in patients (pts) with chronic phase (CP) CML who had received at least 2 prior BCR-ABL tyrosine kinase inhibitors (TKI).Methods: This was a single arm, 3-stage, open-label, multicenter, Phase II study. The primary objective was to estimate the proportion of pts attaining major cytogenetic response (MCyR). Complete hematologic response (CHR) was one secondary objective. All patients received panobinostat orally 20 mg/day on a thrice weekly, consecutive weekly schedule. If ≥3 confirmed MCyRs were observed among 25 pts in Stage 1, Stage 2 was planned to be opened with a total of 32 pts. Dose reduction to 10 and 5 mg/day for toxicity and re-escalation to 20 mg/day was allowed. Dose escalation beyond 20 mg/day for poor response was not foreseen.Results: 29 pts were enrolled in Stage 1 between February and November 2007. Median age was 56 years (yrs) (range 31–75). Time since diagnosis of CML was ≥5 yrs in 69% and <2 yrs in 3%. All pts met the study criteria for TKI resistance. Best cytogenetic response to any prior TKIs was evaluable in 26 pts: MCyR in 7 pts, minor in 6 pts, and no response in 13 pts. Median time since last treatment of any kind, including hydroxyurea, was 20 days (range 0–224). Median duration of panobinostat treatment was 26 days (1–334). No MCyR was observed, and therefore, Stage 2 of the study was not opened. However, one CHR, accompanied by the eradication of the BCR-ABL T315i mutated clone, occurred in Cycle 2 (Week 6). This pt remained on panobinostat without progression until Cycle 12 (Week 48). Overall, non-hematological AEs were similar to the safety profile of 20 mg/day panobinostat reported before.1 Gastrointestinal AEs were reported by 10 pts (nausea; all Gr 1–2, but 1 Gr 3), diarrhea in 7 pts, and vomiting in 5 pts. Fatigue was reported in 8 pts and asthenia in 3 pts. An atrial fibrillation (Gr 2) in 1 pt and a QTcF prolongation >500 ms (Gr 3) in another pt required study drug discontinuation. 5 serious AEs were reported as possibly related to study drug: pulmonary embolism and the QTcF prolongation (see above) in 1 pt, and sepsis, followed by multiple organ failure with fatal outcome in a second pt. SAEs considered as non-related to study drug included: 1 case each of DVT, lung infection, pericardial effusion, pleural effusion, and cardiac failure. To date, 452 post baseline ECGs were assessed: minimal QTcF prolongations (30–60 ms) were seen in 4 and >60 ms in 1 pt. Gr 3/4 hematologic lab abnormalities were: anemia and neutropenia in 4 pts each and thrombocytopenia in 3 pts. Nonhematologic lab abnormalities were: Gr 4 hypokalemia (1), Gr 3 hyponatremia (1), hyperkalemia (1), and hypermagnesemia (2).Conclusions: No MCyR but 1 CHR with eradication of the T315i mutation were observed in 29 TKI-resistant CP CML pts, treated orally with 20 mg/day panobinostat, thrice weekly. Since the number of MCyRs required by the protocol was not seen, Stage 2 of the study was not opened. Safety/tolerability were comparable to what was reported for the same dose/schedule in other panobinostat studies, and no new safety findings were identified. The explanation that no more CRs were seen might be 2-fold:a dosing issue considering encouraging responses reported with oral, thrice weekly ≥40 mg/day single-agent panobinostat in pts with refractory Hodgkin's disease and AML1 andquite early hematologic progression in many pts, not allowing for longer exposure to panobinostat in this more resistant population.
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