Volume 17, Issue 5, Pages 622-631 (May 2016) Safety, tolerability, and preliminary activity of CUDC-907, a first-in-class, oral, dual inhibitor of HDAC and PI3K, in patients with relapsed or refractory lymphoma or multiple myeloma: an open-label, dose-escalation, phase 1 trial  Dr Anas Younes, MD, Jesus G Berdeja, MD, Manish R Patel, MD, Ian Flinn, MD, John F Gerecitano, MD, Sattva S Neelapu, MD, Kevin R Kelly, MD, Amanda R Copeland, MSN, Amy Akins, BSN, Myles S Clancy, MBA, Lucy Gong, PharmD, Jing Wang, PhD, Anna Ma, MS, Jaye L Viner, MD, Yasuhiro Oki, MD  The Lancet Oncology  Volume 17, Issue 5, Pages 622-631 (May 2016) DOI: 10.1016/S1470-2045(15)00584-7 Copyright © 2016 Elsevier Ltd Terms and Conditions

Figure 1 Trial profile Number of patients assigned to each dose and schedule. *Although no DLT occurred within this cohort, the cohort was expanded for safety reasons. The Lancet Oncology 2016 17, 622-631DOI: (10.1016/S1470-2045(15)00584-7) Copyright © 2016 Elsevier Ltd Terms and Conditions

Figure 2 Best response (maximum target lesion decrease) from baseline in patients with lymphoma (n=33) Maximum decrease from baseline is shown, measured by PET or CT according to the Revised Response Criteria for Malignant Lymphoma; if the lesion only increased, then the lowest measured increase is presented. Data are for the 33 patients with lymphoma in the response-evaluable dose-escalation population. Each bar represents an individual patient. *This patient had a reduction in the target lesion, but developed a concurrent new lesion and therefore was classified as having progressive disease. †This patient was shown to have a maximum target lesion reduction of about 60% on CT, but was classified as having a complete response as measured by 18F-fluorodeoxyglucose PET. ‡Other lymphomas were lymphoplasmacytic (n=3), small lymphocytic (n=3), mantle-cell (n=3), follicular (n=2), gray-zone (n=1), marginal-zone (n=1), and T-cell (n=1) lymphoma. The Lancet Oncology 2016 17, 622-631DOI: (10.1016/S1470-2045(15)00584-7) Copyright © 2016 Elsevier Ltd Terms and Conditions

Figure 3 Best response (maximum decrease in serum or urine M-protein or serum free light chain) from baseline in patients with myeloma (n=4) Maximum decrease from baseline of serum or urine M-protein or serum free light chain (as applicable), which were used to assess each patient with multiple myeloma for disease response, according to the International Uniform Response Criteria for Multiple Myeloma; if only an increase was measured, then the lowest measured increase is presented. Each bar represents an individual patient. Patients 1 and 3 were assessed using serum M-protein, patient 2 was assessed using urine M-protein, and patient 4 was assessed using serum free light chain measurements. Patient 1 had achieved stable disease for 33 months, ongoing at the time of data cutoff. Patient 3 achieved stable disease for 3 months. The Lancet Oncology 2016 17, 622-631DOI: (10.1016/S1470-2045(15)00584-7) Copyright © 2016 Elsevier Ltd Terms and Conditions

Figure 4 CUDC-907 and metabolite concentrations in plasma, 60 mg 5/2 dose (n=6) Cycle 1, day 15 data from six patients who received CUDC-907 at 60 mg at the 5/2 dosing schedule during the expansion phase of the trial. Datapoints show mean and error bars show SD. The Lancet Oncology 2016 17, 622-631DOI: (10.1016/S1470-2045(15)00584-7) Copyright © 2016 Elsevier Ltd Terms and Conditions

Figure 5 Biomarkers of CUDC-907 activity in peripheral blood, 60 mg 5/2 dose (n=3) Data from peripheral blood mononuclear cell samples obtained from three patients during cycle 1 who received CUDC-907 at 60 mg at the 5/2 dosing schedule in the expansion phase of the trial. The ratio of phosphorylated AKT relative to unphosphorylated AKT and acetylated histone H3 relative to non-acetylated histone H3 is shown. Baseline (before dose) is before treatment on day 1 of cycle 1. Datapoints show mean and error bars show SD. Ac-H3=acetylated histone H3. pAKT=phosphorylated AKT. *Day 8 and day 15 were expected to have similar pharmacodynamic read-outs, so to reduce the volume of blood collected on the trial we only took a pre-dose sample on day 8, with the expectation that 1 h and 4 h measurements would be very similar to data from day 15. The Lancet Oncology 2016 17, 622-631DOI: (10.1016/S1470-2045(15)00584-7) Copyright © 2016 Elsevier Ltd Terms and Conditions