Inhibition of histone deacetylase (HDAC) provides a novel approach for cancer treatment. Bortezomib and panobinostat are active agents in multiple myeloma (MM) and have a synergistic antimyeloma effect when used in combination. Both compounds have also shown anabolic bone effect.
We conducted a phase I exploratory study IV formulation of panobinostat in combination with bortezomib in relapsed/refractory MM patients who had failed at least one line of prior therapy. Patients were assigned to their dose levels in a classical 3+3 cohort design. Primary objective was to assess the toxicity of a fixed dose of bortezomib in combination with escalating doses of panobinostat to define the maximum tolerated dose (MTD). The secondary objective was to determine the osteoblastic response. Bortezomib was administered iv at the dose of 1 mg/m2 during cycles on days 1, 4, 8, and 11 of each 21 days cycle. Panobinostat was administered iv starting at cycle 2 on days 1 and 8 of the 21 day cycle, 5 mg/m2 n=1–3, 10 mg/m2 n=4–9, 15 mg/m2 n=10–12 (one screening failure). Patients with at least stable disease after the first 2 cycles (Phase I Portion of the Study) were allowed to continue to a maximum of 12 cycles.
PTH was measured during the first two cycles, every 20 minutes starting one hour before infusion for a total of seven time points on days 1 and 4, and single pre dose on days 8 and 11 during cycles 1 and 2.
Bone marrow (BM) aspiration and biopsies were collected at baseline, after the completion of second cycle and at the end of the study. H&E stained core biopsy slides were scanned using Scan Scope XT system. We developed classifier algorithms using Genie pattern recognition image analysis software to calculate Trabecular Volume (TV), Bone Volume (BV). RNA obtained from separate core biopsies at baseline and after second cycle was used to complete Gene Expression Profiling (GEP) studies. The paired t test was used to identify significantly gene changes.
Eleven patients with a median age of 58 years (range 44 to 70) were enrolled. 45% of patients received ≥ 3 previous lines of therapy. 45% was previously exposed to Bortezomib and 63% of patients failed prior autologous stem cell transplant. All eleven patients completed two cycles of therapy, 10 patients continued treatment, and three completed a total of 12 cycles. No MTD was reached with a 15 mg/m2IV Panobinostat dose. Using IMWG criteria after the second cycle of treatment we observed 1CR, 3 PR, 5 SD, 2 patients experienced PD. Best response during the entire treatment included 2 CR, 2 VGPR, 4 SD (≥ SD 72%). Common grade 3/4 AEs included: thrombocytopenia (36%), neutropenia (45%), leukopenia (54%), lymphopenia (18%), with no treatment-related mortality.
The median baseline of Trabecular Volume/Hematopietic Area (TV/HA) was 27.6% (range 8.1–46%). Comparing the baseline to the end of study samples, an increment of TV/HA was noted in 6 of 9 available patients. The average TV/HA increment was 19.4% (range 9.9–38.3%).
72% of patients (n=8) showed changes in PTH level during treatment. Serial PTH samples significantly increased during treatment, from a mean of 39.4 pg/L (±22.3) at baseline, to a mean of 50.2 pg/L (±36.8) at day 4 cycle 2 (p=0.003). GEP from bone marrow baseline core biopsies were compared to post-treatment samples. A total of 3783 probe sets were found to be differentially expressed. 30% of genes were over-expressed and 70% were down regulated. Interestingly decorin, which function has been associated to antimyeloma effect of osteoblasts, and its down-stream target p21-activated kinase 4 (PAK4) were significantly increased in the post-treatment samples (p=0.04, p=0.03 respectively with 2.0 ratio) suggesting a bone anabolic and antimyeloma effect of these drugs in combination.
The combination of IV Panobinostat and Bortezomib has predictable and manageable safety profile with significant antimyeloma activity as reflected by ≥ SD 72%, ≥ PR 36% including 18% CR. Changes in bone indices were observed by a computer assisted image analysis. Hormonal changes and genes studies also support an osteoblastic/anabolic effect of panobinostat in combination with bortezomib in relapsed/refractory MM patients.
Zangari:Millennium, Onyx, Cephalon, Incyte: Research Funding, Speakers Bureau.
Asterisk with author names denotes non-ASH members.