Dose limiting toxicities (DLTs) of Grade 3 diarrhea and Grade 4 hyperglycemia were reported in 1 patient at the 60 mg QD dose. Treatment-related serious adverse events (AEs) of Grade 3 epistaxis (30 mg QD, n=1), and Grade 3 diarrhea and Grade 4 hyperglycemia (60 mg QD, n=1) were also reported with the daily schedule. To date, the most frequent (reported in ≥ 2 patients) Grade 3 or 4 AEs include thrombocytopenia, diarrhea and neutropenia, thus far only with the QD administration schedule. Toxicities have limited the ability to further dose escalate using the QD schedule. By contrast, no DLTs or dose interruptions have been reported for patients enrolled onto the BIW regimen at the 60mg dose level.
Eleven of the 13 patients included in the ASH presentation were evaluable for response assessment per protocol. One of these patients had mixed follicular lymphoma/ diffuse large B cell lymphoma and achieved a PR (70% reduction in a single target lesion) at the 30 mg QD dose level. Seven other patients have met criteria for SD, including 4 with SD lasting at least 4 cycles of treatment. One of these patients (MM) is currently in Cycle 13.
Preliminary pharmacokinetic analysis shows low CUDC-907 plasma levels as compared to its M1 and M2 (PI3K-active) metabolite species. This is consistent with animal studies that demonstrated higher levels of CUDC-907 in tissues as compared to plasma. Additional pharmacokinetic and pharmacodynamic analyses are ongoing.
About CUDC-907CUDC-907 is a 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, the combined inhibition of which Curis believes has synergistic effects against cancer cells and their microenvironment. In preclinical studies, CUDC-907 has demonstrated the ability to suppress multiple nodes of cellular survival and proliferation signaling pathways. In addition, preclinical data have shown that CUDC-907 inhibits compensatory pathways that are often utilized in cancer cells during the emergence of resistance to standard-of-care agents.