Phase 1 Trial Testing Single Agent CUDC-907, a Novel, Oral Dual Inhibitor of Histone Deacetylase (HDAC) and PI3K: Initial Assessment of Patients with Relapsed or Refractory (RR) Diffuse Large B-Cell Lymphoma (DLBCL), Including Double Expressor (DE) Lymphoma

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.

Overview of Targeted Drugs for Mature B-Cell Non-hodgkin Lymphomas

“…CUDC-907 is a class I-II oral double-inhibitor of HDAC and PI3K (α, β, γ) enzymes (111,220,(220)(221)(222).…”

Targeting Cancer at the Intersection of Signaling and Epigenetics

“…Indeed, this agent, CUDC-907, was shown to kill tumors cells in vitro and suppress tumor growth in vivo in DLBCL and thyroid cancer models (Kotian et al 2017, Mondello et al 2017. A first-in-man phase I study was performed in patients with relapsed or refractory lymphoma or multiple myeloma (Oki et al 2017, Younes et al 2015; https://www.clinicaltrials.gov/ identifier NCT01742988). CUDC-907 was well tolerated, a phase II trial was initiated based on the success of this trial (9 of 21 objective responses in DCBCL), and the FDA granted an orphan drug designation to CUDC-907 for the treatment of patients with DLBCL (Landsberg et al 2016).…”

“…CUDC-907 was well tolerated, a phase II trial was initiated based on the success of this trial (9 of 21 objective responses in DCBCL), and the FDA granted an orphan drug designation to CUDC-907 for the treatment of patients with DLBCL (Landsberg et al 2016). Retrospective analysis of responding patients indicated that responding tumors were enriched for Myc amplification (Younes et al 2015). Preclinical studies have now shown that CUDC-907 suppresses Myc expression in DCBCL cells and tumors and that Myc suppression partially contributes to the death induced by CUDC-907 (Sun et al 2017).…”