VIENNA – The investigational dual HDAC and Pi3K inhibitor CUDC-907 was reasonably tolerated and clinically active in a phase I study of relapsed or refractory lymphomas and multiple myeloma.
Among 44 patients evaluable for response, 7 had objective responses (16%).
Two complete and four partial responses occurred in 10 evaluable patients with diffuse large B-cell lymphoma (DLBCL).
One partial response was reported in 12 evaluable patients with Hodgkin lymphoma.
Stable disease was the best response in 4 of 6 evaluable patients with multiple myeloma and 11 of 16 patients with other lymphomas, Dr. Yasuhiro Oki reported at the annual congress of the European Hematology Association.
The first-in-human trial enrolled 57 patients with lymphoma (DLBCL, Hodgkin, Burkitt, follicular, gray zone, lymphoplasmacytic, mantle cell, marginal zone, and small lymphocytic) or multiple myeloma that was refractory to or relapsed after at least two prior regimens.
The median number of prior regimens was 5 (range 2-10), including prior histone deacetylase (HDAC) inhibitors in 11% and prior phosphatidylinositol 3-kinase (Pi3K) inhibitors in 9%.
The 3+3 design tested three different once-daily dosing schedules for the oral small molecule: 30 mg and 60 mg, 5 days on and 2 days off (5/2) 60 mg, and intermittent twice- or thrice-weekly at 60 mg, 90 mg, 120 mg, and 150 mg. The safety and efficacy data are from the completed dose escalation and ongoing expansion stages of the phase I trial with CUDC-907 administered as monotherapy.
Median treatment duration in the DLBCL group was 3 months, with treatment ongoing in some patients beyond 2 years. Long-term responders have included three patients with transformed follicular lymphoma (t-FL)/DLBCL, one with so-called triple-hit status involving translocations/rearrangements of MYC, BCL-2, and BCL-6 genes, according to Dr. Oki of University of Texas MD Anderson Cancer Center in Houston.
The patient with Hodgkin lymphoma who responded had failed four prior therapies, but experienced a 42% reduction in tumor size on imaging by cycle two and a partial response to 60 mg 5/2 CUDC-907 by cycle six.
At least one adverse event (AE) occurred in 50 of the 57 patients, but AEs have been reversible with standard interventions, dose holds, or dose reductions, he added.
The most common grade 3/4 AEs reported in two or more patients were diarrhea, hyperglycemia, fatigue, thrombocytopenia, and decreased neutrophils.
Four dose-limiting toxicities occurred in three patients: grade 3 diarrhea in the 60-mg once-daily and 150-mg thrice-weekly dose groups and grade 4 hyperglycemia in the 60-mg once-daily and 150-mg twice-weekly dose groups.
“The 5/2 60-mg and thrice-weekly 120-mg dosing was found to be reasonably tolerated while still achieving objective responses,” Dr. Oki noted in the poster.
The ongoing expansion phase is evaluating CUDC-907 at the recommended phase II doses of 60 mg 5/2 and 120 mg thrice-weekly in patients with relapsed refractory DLBCL, Hodgkin lymphoma, and multiple myeloma.
The trial is currently enrolling patients with DLBCL for treatment with CUDC-907 monotherapy and in combination with standard-dose rituximab.
Phase II testing of CUDC-907 in combination with rituximab in relapsed/refractory DLBCL is projected to start at the earliest in fourth-quarter 2015, according to the authors.
CUDC-907 (60 mg 5/2 and 120 mg three times weekly) is also being evaluated in advanced or relapsed solid tumors in an ongoing phase I trial.
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