Phase I Analysis of the Safety and Pharmacodynamics of the Novel Broad Spectrum Histone Deacetylase Inhibitor (HDACi) PCI-24781 in Relapsed and Refractory Lymphoma.

PCI-24781 is a novel oral pan-HDACi with potent preclinical anti-tumor activity in lymphoma cell lines and models and has previously demonstrated safety and clinical benefit in solid cancers (Undevia et al, ASCO 2008). In lymphoma cell lines, PCI-24781 was causes increased oxidative stress and NF-κB inhibition that results in caspase-dependent apoptosis (Evens et al, Clin Ca Res 2009). Based in part on this encouraging pre-clinical data, a phase I/II clinical trial was designed for patients with relapsed/refractory lymphoma.

The primary objective of the phase I component of this protocol was to determine the maximum tolerated dose (MTD) for testing in the phase II portion of the trial. PCI-24781 was given orally twice daily at escalating doses of 30–60mg/m² on a 4-week cycle on two treatment schedules: 5 days/week x 3 weeks (schedule 1) or 7 days/week every other week (schedule 2). A standard 3+3 phase I dose escalation scheme was used. Tubulin and histone acetylation were measured in peripheral blood mononuclear cells (PBMCs). Data presented here consists of the completed phase I dose escalation component of the clinical trial.

25 pts enrolled with 7 pts continuing on treatment. The median age was 63 years, while the median number of prior treatments was 3. The histologies included: diffuse large B-cell lymphoma (DLBCL) (9), follicular lymphoma (FL) (4), Hodgkin lymphoma (3), CLL/SLL (2), mantle-cell lymphoma (2), nodal peripheral T-cell lymphoma (2), and cutaneous T-cell lymphoma (1). The best tolerated doses were 30 mg/m² on schedule 1 and 45 mg/m² on schedule 2, both with no adverse events (AEs) > grade 2. AEs ≥ grade 3 were thrombocytopenia (n=4) and diarrhea (n=1) and thus were dose limiting. One DLBCL pt with a history of renal insufficiency and renal involvement by lymphoma experienced a serious AE of renal failure, which was deemed possibly related to PCI-24781. Of note, no pericarditis, pericardial effusion, or QT prolongation were seen at any dose level of PCI-24781. Twelve pts were evaluable for response. Two confirmed responses have been seen (1 complete remission (CR), 1 partial remission (PR)), while six patients had stable disease (SD) with the median length of SD being 15 weeks (range, 6–17+). The longest duration of response (CR) was 8 cycles (32+ weeks). Both responses were seen in FL (2/4); one patient (PR) had received prior CHOP, R-ESHAP, and autologous transplant, while the other patient (CR) was rituximab-refractory and had failed 5 prior therapies. Pharmacodynamic monitoring revealed a dose-dependent increase in tubulin acetylation at 4 hours following the first dose, however this did not correlate with response or toxicity.

PCI-24781 is a well tolerated pan-HDACi, including complete absence of prolonged QT abnormalities. Preliminary clinical benefit in heavily pre-treated relapsed/refractory lymphoma patients was documented in the phase I portion of this study. Accrual will continue to the phase II component of the clinical trial.

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