Date: 2016-04-04
Type of information: Publication of results in a medical journal
phase: 1
Announcement: publication of results in The Lancet Oncology
Company: Curis (USA - MA)
Product: CUDC-907 - mesylate synthetic small molecule inhibitor of HDAC and PI3K
Action
mechanism: histone deacetylase inhibitor/phosphoinositide 3-kinase (PI3K) inhibitor. CUDC-907 is an oral, dual inhibitor of histone deacetylase (HDAC) and phosphoinositide 3-kinase (PI3K) enzymes that is currently under investigation in Phase 1 clinical studies in patients with relapsed or refractory lymphomas or multiple myeloma as well as in patients with advanced/ relapsed solid tumors, including hormone receptor positive (HR+)/ HER2-negative breast cancer or midline carcinoma with certain NUT gene rearrangements.
Disease: relapsed/refractory lymphoma or multiple myeloma
Therapeutic area: Cancer - Oncology
Country:
Trial
details: 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).
Latest
news: * On April 4, 2016, Curis announced the publication of results from the dose escalation part of the Phase 1 clinical trial in The Lancet Oncology. The publication, titled "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" was authored by the clinical investigators of the first-in-man Phase 1 study as well as members of Curis' clinical and scientific teams. The publication is also accompanied by an independent commentary in the journal titled "Dual inhibition of oncogenic targets for B-cell malignancies" by Paul G. Richardson, M.D., R.J. Corman Professor of Medicine at the Jerome Lipper Multiple Myeloma Center at Dana Farber Cancer Institute. * On December 6, 2015, Curis presented 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. These data were presented at the American Society of Hematology's (ASH) 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.
"The data from the Phase 1 monotherapy trial for CUDC-907, especially in heavily pretreated patients with relapsed/ refractory DLBCL are very encouraging and we look forward to data emerging from the current Phase 2 trial in patients with MYC-altered DLBCL," said Dr. Anas Younes, M.D., Chief of the Lymphoma Service of the Memorial Sloan Kettering Cancer Center in New York City, the Principal Investigator of the Phase 1 trial and the publication's senior author.
Based on the clinical activity observed in patients with relapsed/ refractory-DLBCL, particularly those with cancers harboring MYC alterations, Curis has initiated a Phase 2 trial to evaluate CUDC-907 in patients with MYC-altered RR-DLBCL.
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.
At the time of data cut-off for the ASH 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 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.
