Abstract
Panobinostat (LBH589) is a highly potent pan-deacetylase inhibitor (DACi), which induces cytotoxicity at <10nM in multiple myeloma (MM) cell lines resistant to conventional therapies. It modulates 2 targets implicated in MM by controlling cell proliferation and survival through HSP90 and inducing apoptosis through the aggresome pathway. Here we report the preliminary results of a Phase II, single arm, multicenter study of panobinostat in patients with measurable MM disease who had received at least 2 prior lines of therapy (including bortezomib and lenalidomide or thalidomide) and who were also refractory to their most recent line of therapy. The study was designed to assess: response rate (CR/PR) by the IBMTR/EBMTR criteria, safety, and tolerability of 20 mg/day of oral panobinostat given on a Monday/Wednesday/Friday (MWF) dosing schedule. 3 or more responders in 25 patients in stage 1 of the study were required for the initiation of Stage 2. A total of 38 pts (24 males, 14 females; median age 61 years [43–72]) have been enrolled between February and October 2007. Median time since last prior therapy was 33 days, median number of prior therapies was 5 (2–12). Median treatment duration was 45 days (5–377 days). Overall, panobinostat was well tolerated, and no new safety signals were reported. Mild or moderate level of nausea, as well as fatigue/asthenia, occurred in half of the patients. The most common Grade 3/4 AEs were cytopenias, with neutropenia, thrombocytopenia, and anemia in 32%, 26%, and 16% of patients, respectively. Other Grade 3/4 AEs included infections: 8 occurrences (3 of pneumonia; 2 of septic shock; and back pain, hypercalcemia, and hypokalemia in 3 pts each). No cardiac (including significant QTc prolongation, pericarditis, or pericardial effusion) or thromboembolic events were reported. SAEs potentially related to study drug were observed in 3 pts and included nausea (2), diarrhea and vomiting (1), and reduced general condition (1). 5 patients discontinued therapy for AE: 2 due to acute renal failure which was progression coincident, 2 due to elevated creatinine suspected to be study drug related, and 1 for worsening on study of peripheral neuropathy (non-related). 1 patient died on study due to a cerebral vascular accident (assessed by the investigator as not study drug related). QT intervals (QTcF) were monitored per study protocol and out of >1500 post dose ECGs, 1 pt showed a Grade 2 prolongation of QTcF value above 480 ms, 2 pts had a QTcF increase of ≥60 ms compared to baseline, and 10 pts had a minimal 30–<60 ms increase of QTcF compared to baseline. A clinical durable response was observed in a 43-yr-old female patient, whose urine kappa light chain MM with bone lesions was progressing on lenalidomide/dexamethasone prior to enrollment. The patient had 5 prior lines of therapy, including auto-SCT twice (5 years apart), bortezomib, and thalidomide. Response was rapid, with a 60% reduction of urine M protein at Cycle 2 and 90% at Cycle 4. PR was confirmed in Cycle 7, including stabilized bone lesions, and is sustained at 11 months on therapy with urine light chain stable below the “measurable disease” level of 100mg/24hrs and urine IF still positive, thus a VGPR. A quick and dramatic reduction in angiogenesis markers (VEGF, sVEGFR1, and bFGF) was seen starting on Cycle 1, Day 8 of treatment, as well as a reduction (50%) of seric free light chain, which continued further throughout the later cycles. A second patient on study for >12 months is continuing to show clinical benefit after failing 10 prior lines of therapy (including Auto-SCT, bortezomib, lenalidomide, and thalidomide) and is maintaining MR. Stable disease observations of >3 months occurred in 3 pts. Single-agent, oral panobinostat at 20 mg/day thrice weekly was well tolerated and safe in this study. Evidence has since been obtained from clinical responses in patients with various hematological malignancies that higher doses of single-agent panobinostat can provide more optimal dosing schedules than the 20 mg dose. Thus, although the current study at the 20 mg schedule did not meet its objective, the observation of 1 durable VGPR and 1 durable and ongoing MR, in addition to transient disease stabilization in 3/38 patients, are encouraging results, especially at this low dose, warranting further clinical investigation of panobinostat. The analysis of final study results will be presented.
Anti-DKK1 mAb (BHQ880) as a potential therapeutic agent for multiple myeloma