Phase I Study of Panobinostat plus Everolimus in Patients with Relapsed or Refractory Lymphoma

Abstract

Purpose To evaluate the safety and efficacy of panobinostat plus everolimus in patients with relapsed Hodgkin and non-Hodgkin lymphoma. The concept was supported by the single agent clinical activity of histone deacetylase inhibitors and mTOR inhibitors, and on the in vitro mechanism-based synergistic antiproliferative activity. Experimental Design This was a phase I study in patients with relapsed or refractory Hodgkin and non-Hodgkin lymphoma using panobinostat orally on Monday/Wednesday/Friday and everolimus orally daily. Toxicity and responses were assessed in dose escalation cohort followed by expansion cohort at maximum tolerated dose. Exploratory analysis of serum cytokine levels were performed. Results Thirty patients were enrolled onto four dose levels The dose limiting toxicity was thrombocytopenia. The maximal tolerated dose was panobinostat 20 mg and everolimus 10 mg. Grade 3/4 toxicity included thrombocytopenia (64%), neutropenia (47%), anemia (20%), infection (10%), fatigue (7%) and dyspnea (7%). A total of 10 patients (33%) (indolent lymphoma, T-cell lymphoma, mantle cell lymphoma, and Hodgkin lymphoma) achieved objective responses. In patients with Hodgkin lymphoma (n=14), overall response rate was 43% with complete response rate of 15%. In patients with Hodgkin lymhpoma, multiple serum cytokine levels decreased significantly after treatment with this combination therapy. Of note, clinical responses were associated with a decrease in serum interleukin-5 levels (day 8, p=0.013 and day 15, p=0.021). Conclusions Our data suggest that the combination therapy is active but with significant thrombocytopenia. Future studies should explore alternate scheduling and different compounds that target the same pathways to improve the tolerability of this novel combination.

Targeting histone deacetylases in T-cell lymphoma

“…[101] The major DLT and AE was thrombocytopenia, and the ORR was 33%. Investigators concluded that future studies should explore alternate scheduling and different HDACi and mTOR inhibitors to improve tolerability.…”

Activity of everolimus (RAD001) in relapsed and/or refractory multiple myeloma: a phase I study

“…46 However, in a phase I trial combining everolimus with panobinostat in lymphoma patients, severe thrombocytopenia occurred. 47 Recently, based on in vitro synergism, 48 the combination of everolimus and lenalidomide was explored in a phase I trial and was found to have promising activity and acceptable tolerability in patients with relapsed MM. 49 Interestingly, weekly bortezomib combined with temsirolimus showed promising activity in relapsed MM, with responses in patients who had been refractory to prior bortezomib-containing regimens.…”

Brentuximab vedotin for the treatment of Hodgkin’s and non-Hodgkin’s lymphoma

“…The mammalian target of rapamycin inhibitor everolimus has been studied as a single agent and in combination with panobinostat. As a single agent, everolimus has been one of the more promising therapies with an ORR of 47%, however, here did not seem to be a synergistic effect of the combination of panobinostat and everolimus [17]. Lenalidomide has shown similar results with relapsed disease with one-third of patients having an objective response [18].…”