On December 6, 2015 Curis, Inc. (NASDAQ:CRIS), a biotechnology company focused on the development and commercialization of innovative drug candidates for the treatment of human cancers, reported data from the completed dose escalation and ongoing expansion stages of the Phase 1 trial of CUDC-907, an oral dual inhibitor of histone deacetylase (HDAC) and phosphoinositide 3-kinase (PI3K) enzymes (Press release, Curis, DEC 6, 2015, View Source [SID:1234508438]). These data were presented at the American Society of Hematology (ASH) (Free ASH Whitepaper)’s (ASH) (Free ASH Whitepaper) Annual Meeting in Orlando, FL. The data demonstrated that treatment with CUDC-907 resulted in complete (CRs) and partial responses (PRs) in heavily pretreated patients with relapsed/ refractory diffuse large B cell lymphoma (RR-DLBCL), including those harboring alterations of the MYC oncogene, a poor performing sub-group for which there are no approved targeted therapies.
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In the ongoing Phase 1 trial of CUDC-907, 8 objective responses (3 CRs and 5 PRs) were reported in 18 response-evaluable patients out of a total of 25 patients with RR-DLBCL enrolled in the trial. These results include 1 CR among 2 response-evaluable patients out of a total of 3 patients treated with CUDC-907 in combination with the standard dose of rituximab. The remaining 16 evaluable patients were treated with CUDC-907 monotherapy. In a retrospective post hoc analysis, among the 8 patients who achieved objective responses, 5 had tumors with MYC oncogene alterations (defined as chromosome translocation involving MYC gene locus, gain in MYC gene copy number, or MYC protein over-expression in =40% tumor cells). Among the remaining 3 patients who achieved objective responses, 2 had MYC protein expression in less than 40% of tumor cells, and the third patient’s MYC status is unknown.
In preclinical studies, CUDC-907 treatment of DLBCL cell lines was shown to result in complete suppression of MYC protein levels in a rapid and dose dependent manner. Additionally, anti-tumor activity was observed in multiple in vivo MYC-altered DLBCL models.
"Preliminary data for CUDC-907 in patients with multiply relapsed DLBCL appear encouraging, even in those with MYC-altered lymphoma, providing the rationale for further investigation in a Phase 2 trial," said Dr. Anas Younes, MD, Chief of the Lymphoma Service of the Memorial Sloan Kettering Cancer Center in New York City and the Principal Investigator of the Phase 1 trial. "There is a high unmet need for novel therapies for patients with RR-DLBCL, and particularly for the subset of patients with MYC-altered DLBCL due to their poor prognosis."
Based on promising clinical activity observed in patients with RR-DLBCL, particularly those with cancers harboring MYC alterations, Curis expects to initiate a Phase 2 trial to examine CUDC-907 in patients with MYC-altered DLBCL. In this trial, approximately 120 patients with relapsed/refractory disease will be randomly assigned to receive CUDC-907 as monotherapy or CUDC-907 with the standard dose of rituximab. Patients will remain on treatment until progression of disease, discontinuation for safety reasons, or other reasons for treatment discontinuation. The primary endpoint of the trial is objective response rate with secondary endpoints that include progression free survival, overall survival and duration of response. Positive results with CUDC-907 monotherapy will lead to an expansion of patient enrollment and discussion with the FDA regarding potential registration strategy in this patient population. The rituximab combination treatment arm of the Phase 2 trial is intended to inform the design of a confirmatory, randomized trial of CUDC-907 in combination with rituximab as compared to rituximab in combination with standard of care chemotherapy.
"We are pleased to report promising clinical activity of CUDC-907 in patients with DLBCL, particularly those with tumors that harbor MYC alterations," said Ali Fattaey, Ph.D., Curis’ President and Chief Executive Officer. "These clinical results are consistent with our preclinical observations where CUDC-907 has a rapid and dramatic effect on MYC protein levels and provides significant anti-tumor activity in in vivo models. We are thankful to our patients for their participation in the Phase 1 clinical trial and, based on these data, we expect the start of a Phase 2 trial that will exclusively enroll patients with relapsed/ refractory DLBCL known to have MYC alterations based on pre-specified selection criteria."
The Phase 1 dose escalation and expansion trial was designed to determine the maximum tolerated dose (MTD), recommended Phase 2 dose and preliminary anti-cancer activity of oral CUDC-907 in patients with relapsed/refractory lymphoma or multiple myeloma (MM). At the time of data cut-off for the ASH (Free ASH Whitepaper) presentation, a total of 72 patients had been enrolled in the trial, including 25 with RR-DLBCL. In the completed dose escalation phase, patients received CUDC-907 daily (QD, doses: 30 or 60 mg), or intermittently on twice weekly (BIW) or thrice weekly (TIW) schedules (doses: 60, 90, 120 or 150 mg) or on a 5 days on, 2 days off (5/2) schedule (dose: 60 mg). CUDC-907 dosed at 60 mg on the 5/2 schedule was determined to be the recommended Phase 2 dose (RP2D). The expansion phase of the trial is ongoing to assess the safety and tolerability of CUDC-907 at the RP2D of 60 mg 5/2 with or without the standard dose of rituximab.
The most common drug related adverse events (AEs) reported in the study have been low grade (Grade 1 and 2) diarrhea, fatigue and nausea. Dose limiting toxicities (DLTs) have consisted of diarrhea and hyperglycemia, and occurred on the QD, BIW and TIW schedules. No DLT occurred at the RP2D of 60 mg 5/2. Other drug-related Grade 3 or 4 AEs reported in 3 or more patients included thrombocytopenia and neutrophil decrease (hematologic AEs) as well as diarrhea, hyperglycemia and fatigue (non-hematologic AEs).
Out of the 25 patients with RR-DLBCL included in the ASH (Free ASH Whitepaper) presentation, 18 were evaluable for response assessment per protocol at the time of data cut-off. The best responses observed in patients with RR-DLBCL were CR (3 patients), PR (5 patients) stable disease or SD (4 patients) and progressive disease or PD (6 patients). A post hoc analysis of pathology reports and/or tumor samples collected showed that 5 of the 8 patients with objective responses had tumors with alterations in MYC oncogene. MYC alterations in the tumor tissue were determined by established criteria used to identify either MYC gene aberrations (copy number gains or translocations) by fluorescent in situ hybridization (FISH) or MYC protein expression by immunohistochemistry (IHC).
About CUDC-907:
CUDC-907 is an oral, dual inhibitor of Class I and II HDAC, as well as Class I PI3K enzymes. Specifically, CUDC-907 is designed to inhibit HDACs 1, 2, 3, 6 and 10 and PI3K-alpha, delta and beta isoforms. CUDC-907 is currently undergoing investigation in a Phase 1 trial to assess its safety, pharmacokinetics and preliminary anti-cancer activity in patients with relapsed/refractory lymphomas and multiple myeloma. CUDC-907 is also being investigated in a separate Phase 1 trial in patients with advanced solid tumors including those with hormone receptor positive breast cancer or with NUT midline carcinoma. The development of CUDC-907 has been supported in part by The Leukemia & Lymphoma Society (LLS) under a funding agreement established in 2011 between Curis and LLS’s Therapy Acceleration Program. For additional details of CUDC-907’s Phase 1 studies, please refer to www.clinicaltrials.gov (study identifiers: NCT01742988 and NCT02307240).