Summary Background Current treatment options for patients with relapsed or refractory (RR) lymphoma and multiple myeloma (MM) are limited, highlighting the unmet need for effective therapies in these disease settings. CUDC-907 is an oral, first-in-class, small molecule that is designed to inhibit both histone deacetylase (HDAC) and phosphoinositide 3-kinase (PI3K) enzymes, which are members of common oncogenic pathways in hematologic malignancies. This study examines CUDC-907 monotherapy in patients with RR lymphoma and MM. Methods This open-label, non-randomized, first-in-man, phase 1 multi-center trial enrolled adult patients with lymphoma or MM who were refractory to or relapsed after ≥2 prior regimens. CUDC-907 was orally administered in a standard 3+3 dose escalation design using three different dosing schedules which enrolled sequentially as follows: once daily (QD), then intermittent twice (BIW) or thrice weekly (TIW) that enrolled simultaneously, and finally five days on/two days off (5/2) in 21-day cycles. Dosing started at 30 mg for QD and 60 mg for other schedules, escalating in 30 mg increments. Patients continued to receive CUDC-907 until disease progression or other treatment discontinuation criteria were met. The primary objective was to determine the maximum-tolerated dose and recommended phase 2 dose (RP2D); secondary objectives were to assess the safety and tolerability, and preliminary anti-cancer activity. Results from the completed dose escalation phase are presented. Safety analyses were conducted in all patients who received at least one dose of study medication; efficacy analyses were conducted in all patients who received at least one dose of study drug and underwent at least one post-baseline response assessment. This ongoing trial is registered at ClinicalTrials.gov, number NCT01742988. Findings Forty-four heavily pretreated patients received CUDC-907 up to a maximum of 60 mg for the QD and 5/2 schedules, and 150 mg for the intermittent schedules in the dose escalation phase. The most common Grade ≥3 adverse events were thrombocytopenia (n=9, 20%), neutropenia (n=3, 7%), and hyperglycemia (n=3, 7%). Dose limiting toxicities (DLTs) were diarrhea and hyperglycemia; no DLTs were observed on the 5/2 schedule. Eleven of 44 patients reported serious AEs, 3 of which were considered treatment-related: epistaxis and the DLTs of diarrhea and hyperglycemia. AEs led to dose reductions in 6 patients and treatment discontinuation in 7 patients. Thirty-seven patients were evaluable for response. Five out of 9 patients with diffuse large B-cell lymphoma (DLBCL) achieved objective responses (2 complete responses [CR], 3 partial responses [PR]). Three of these objective responses (1 CR, 2PR) occurred in patients with transformed follicular (t-FL) DLBCL. Stable disease (SD) has been observed in 21 (57%) of 37 response-evaluable patients including DLBCL, Hodgkin lymphoma (HL), and MM. On the basis of the response and tolerability profile, the RP2D of CUDC-907 was determined to be 60 mg on the 5/2 sch...

No abstract

DLBCL, the most common lymphoid malignancy in adults, is an aggressive form of non-Hodgkin lymphoma (NHL) with significant heterogeneity in terms of gene expression, prognosis and response to treatment. Certain histone modifications and HDAC expression patterns have been implicated in the pathobiology of DLBCL and other cancers. Aberrant PTEN/PI3K/AKT signaling is also frequently observed in a variety of human cancers including DLBCL, where loss of PTEN activity and/or activating mutations in PI3K and AKT have been shown to reduce apoptosis and promote cell proliferation. Synergistic anti-tumor effects achieved with HDAC and PI3K inhibitor combinations in various DLBCL xenograft models have provided a strong rationale for testing a highly potent dual HDAC and PI3K inhibitor, CUDC-907. Significant anti-tumor effects have been observed across a wide range of DLBCL models exposed to CUDC-907, including the U2932 ABC DLBCL model that harbors BCL2 translocation and over-expresses cMYC and BCL6, and the WSU-DLCL-2 GCB DLBCL model that harbors EZH2 mutation. These disease mechanisms and preclinical data have led to testing of CUDC-907 in an ongoing Phase 1 trial in patients (pts) with various hematologic cancers. Sixty-three heavily pre-treated pts with lymphoma or multiple myeloma have received CUDC-907 in 21-day cycles according to once daily (QD), intermittent (BIW or TIW), or five days on/two days off (5/2) dosing schedules. CUDC-907 was escalated in 30 mg increments such that pts received 30-60 mg QD, 60-150 mg intermittently, or 60 mg 5/2. A dose expansion using the 60 mg 5/2 dose and schedule is ongoing. Thus far, CUDC-907 has demonstrated a manageable side effect profile and sustained clinical efficacy, particularly in the subset of pts with RR DLBCL. The most common treatment-related adverse events (AEs) were diarrhea (54%; 5% Grade ≥3), fatigue (37%; 3% Grade ≥3), nausea (22%) and thrombocytopenia (18%; 14% Grade ≥3), with dose limiting toxicities of hyperglycemia (QD and BIW schedules) and diarrhea (QD and TIW schedules). Side effects were reversible and manageable. Among 11/18 subjects with RR DLBCL who were evaluable for disease response, 6/11 (55%) achieved objective responses (2 CRs and 4 PRs); lasting a median of 119 days (range: 48 - 354+). Of 7 pts with sufficient tissue, 3 response-evaluable pts were found to over-express MYC and BCL2 by IHC, meeting criteria applied to "double-expressor" (DE) DLBCL. On CUDC-907 monotherapy, 2/3 confirmed pts with DE DLBCL have attained objective responses: 1 ongoing CR (followed by autologous stem cell transplant) and 1PR (lasting 132 days). The third response-evaluable pt with DE DLBCL has experienced lengthy stabilization of disease (171+ days). Signals emerging from preclinical and clinical studies suggest that pts with DLBCL, including those with particularly aggressive disease, may derive benefit from treatment with CUDC-907. Enrollment of pts with RR DLBCL is ongoing into the expansion phase of the Phase 1 trial that is testing CUDC-907 on the 60 mg 5/2 RP2D as monotherapy and in combination with rituximab. Tissue obtained from pts with RR DLBCL treated with CUDC-907 will be assessed for MYC, BCL2, and other genetic aberrations that will be correlated with clinical outcomes observed in the trial. A Phase 2 trial of CUDC-907 in RR NHL is currently being planned, with emphasis on MYC aberrations. Disclosures Younes: Celgene: Honoraria; Incyte: Honoraria; Janssen: Honoraria; Seattle Genetics: Honoraria, Research Funding; Bayer: Honoraria; Bristol Meyer Squibb: Honoraria; Novartis: Research Funding; Sanofi-Aventis: Honoraria; Johnson and Johnson: Research Funding; Curis: Research Funding; Takeda Millenium: Honoraria. Berdeja:Acetylon: Research Funding; Onyx: Research Funding; Abbvie: Research Funding; Curis: Research Funding; Celgene: Research Funding; Takeda: Research Funding; MEI: Research Funding; Novartis: Research Funding; Janssen: Research Funding; BMS: Research Funding; Array: Research Funding. Flinn:Celgene Corporation: Research Funding. Clancy:Curis: Employment, Equity Ownership. Ma:Curis: Employment, Equity Ownership. Sun:Curis: Employment, Equity Ownership. Tian:Curis: Employment, Equity Ownership. Wang:Curis: Employment, Equity Ownership. Viner:Curis: Employment, Equity Ownership.

Detrimental changes of blood and erythrocyte rheology, and fluid exchange between the vascular and interstitial spaces, which influence the rate that oxygen is supplied to the patient, occur during cardiac bypass surgery. Venous flow is subject to a pulsatile and uncertain variation, because the vena cava is more than 30 mmHg below atmospheric pressure. This occurs because the patient is about 1 m above the air-blood surface of the bypass reservoir. Before any reliable study of fluid exchange can be undertaken this effect must be controlled. It was then established that optimum oxygen exchange occurs when equilibration of the plasma oncotic pressure and the capillary hydrostatic pressure is achieved without alteration of the interstitial fluid volume. At the lower arterial blood pressures used during bypass, it is necessary to reduce the plasma oncotic pressure by using an appropriate volume of crystalloid prime.