Purpose Histone deacetylase (HDAC) inhibition improves the efficacy of proteasome inhibition for multiple myeloma but adds substantial toxicity. Preclinical models suggest that the observed synergy is due to the role of HDAC6 in mediating resistance to proteasome inhibition via the aggresome/autophagy pathway of protein degradation. Experimental Design We conducted a phase 1/2 trial of the HDAC6-selective inhibitor ricolinostat to define the safety, preliminary efficacy, and recommended phase 2 dose in combination with standard proteasome inhibitor therapy. Patients with relapsed or refractory multiple myeloma received oral ricolinostat on days 1–5 and 8–12 of each 21-day cycle. Results Single agent ricolinostat therapy resulted in neither significant toxicity nor clinical responses. Combination therapy with bortezomib and dexamethasone was well tolerated during dose escalation but led to dose-limiting diarrhea in an expansion cohort at a ricolinostat dose of 160 mg twice daily. Combination therapy at a ricolinostat dose of 160 mg daily in a second expansion cohort was well tolerated, with less severe hematologic, gastrointestinal, and constitutional toxicities compared with published data on non-selective HDAC inhibitors. The overall response rate in combination with daily ricolinostat at ≥160 mg was 37%. The response rate to combination therapy among bortezomib-refractory patients was 14%. Samples taken during therapy showed dose-dependent increases of acetylated tubulin in peripheral blood lymphocytes. Conclusions At the recommended phase 2 dose of ricolinostat of 160 mg daily, the combination with bortezomib and dexamethasone is safe, well tolerated, and active, suggesting that selective inhibition of HDAC6 is a promising approach to multiple myeloma therapy.

Once-daily oral dosing of ZD6474 at 300 mg/day is generally well tolerated in patients with advanced solid tumors, and this dose is being investigated in phase II trials.

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CTCb is an intensification regimen with a low mortality that delivers a significantly increased dose of agents with known activity at conventional doses in breast cancer. Although the duration of PR is short as expected, CRs appear to be durable.

Purpose: ZD6126 is a novel vascular targeting agent currently undergoing clinical evaluation. It acts by destabilizing the microtubulin of fragile and proliferating neoendothelial cells in tumors. The drug leads to blood vessel congestion, the selective destruction of the vasculature, and extensive necrosis in experimental tumors. The aim of the study reported here was to assess the ability of dynamic contrast enhanced magnetic resonance imaging (MRI) to measure the antivascular effects of ZD6126 in tumors.Experimental Design: The work was carried out in mice bearing C38 colon adenocarcinoma and in patients with advanced cancers. MRI was performed before and 6 h (human tumors) or 24 h (C38 tumors) after i.v. drug administration. Contrast agent (gadolinium diethylenetriaminepentaacetate) enhancement was characterized by the initial area under the gadolinium diethylenetriaminepentaacetate uptake versus time curve (IAUC). IAUC reflects blood flow, vascular permeability, and the fraction of interstitial space.Results: The median IAUC was reduced in all C38 tumors after ZD6126 administration [by 6 -48% at 50 mg/kg (n ‫؍‬ 3)], 58 -91% at 100 mg/kg (n ‫؍‬ 4), and 11-93% at 200 mg/kg (n ‫؍‬ 6). In contrast, the administration of vehicle only led to no consistent change in median IAUC (n ‫؍‬ 4). The ZD6126-induced changes in median IAUC appeared to be dose dependent (P ‫؍‬ 0.045). No ZD6126-induced changes were apparent in murine muscle. Similar effects were seen in preliminary data from human tumors (11 tumors studied, 9 patients). At doses of 80 mg/m 2 and higher, the median IAUC post-ZD6126 treatment was reduced in all of the tumors studied (8 tumors, 6 patients) to 36 -72% from the baseline value. There was a significant trend of increasing reductions with increasing exposure (P < 0.01). No drug-induced changes in human muscle or spleen IAUC were apparent. The reproducibility of the median IAUC parameter was investigated in patients. In 19 human tumors (measured in 19 patients) inter-and intratumor coefficients of variation were 64 and 18%.Conclusions: The contrast enhanced-MRI measured median IAUC is a useful end point for quantifying ZD6126 antivascular effects in human tumors.