Phase I Trial of a Novel Combination of An HDAC Inhibitor (LBH589) and An mTOR Inhibitor (RAD001) in Lymphoid and Plasma Cell Malignancies

The PI3K-Akt pathway is critical to tumor growth in lymphoid malignancies and mTOR inhibitors have shown promising activity in lymphoid malignancies. However, alternate signaling pathways allow cells to escape the effect of mTOR inhibition. Pre-clinical studies have shown that the combination of LBH589, an HDAC inhibitor, with the mTOR inhibitor RAD001 results in potent synergy. We then explored this combination in a phase I/II clinical trial.

Patients with relapsed multiple myeloma (MM), non-Hodgkin lymphoma (NHL) or Hodgkin Lymphoma (HL) were enrolled into a phase I trial of escalating doses of LBH589 and RAD001. The doses are shown in the table. The study utilized a 3+ 3 design with MTD defined as the maximum dose resulting in less than 2 dose limiting toxicities (DLT) during the first cycle among 6 patients treated at that dose. DLT was defined as a grade 4 neutropenia or thrombocytopenia lasting >= 7 days, febrile neutropenia or any other grade >=3 non-hematologic toxicity considered possibly related to the drugs. Once MTD was determined, patients were enrolled into two separate phase 2 studies, one for relapsed MM and another for relapsed NHL or HL.

Twenty-six patients were enrolled to the phase 1 study; 23 were eligible for MTD analysis. There were 16 patients with NHL, 4 with HL and 3 with MM. Median age was 61 (range, 24–73) and 17 were male. The median number of prior therapies was 4 (range 2–11), including a prior stem cell transplant in 11 (48%). No DLT was observed at any of the doses tested in the trial (See below). Hematological toxicities were the most common AEs observed, with a grade 3 or 4 hematologic AE in 15 patients and grade 3 or 4 non-hematologic AEs in 6 patients across all cycles administered. Grade 3 and 4 hematologic AEs included 10 patients with neutropenia and 8 patients with thrombocytopenia. Grade 3 and 4 non-hematologic AEs included hyperglycemia, hypertriglyceridemia, hypophosphatemia, diarrhea, pneumonia and mucositis in one patient each. Overall, 10 responses (43%) were seen (Table).

The combination of LBH589 and RAD0001 is tolerated at the doses tested, with hematological toxicities being the most common adverse events. The recommended phase II dose is LBH 40 mg MWF every other week along with 5 mg RAD001 every day in 4-week cycles. Clinical efficacy was seen in all diseases tested with partial responses seen in NHL and HL as well as a minor response in a patient with refractory myeloma, who had previously failed single agent RAD001. Phase 2 trials are ongoing in both disease groups.

Kumar:Merck: Consultancy, Honoraria; Celgene: Consultancy, Research Funding; Millennium Pharmaceuticals, Inc.: Research Funding; Genzyme: Research Funding; Novartis: Research Funding. Off Label Use: Use of the investigational agent MLN9708 for the treatment of previously untreated multiple myeloma. Lacy:Celgene: Research Funding. Reeder:Celgene: Research Funding; Millennium Pharmaceuticals Inc.: Research Funding; Novartis: Research Funding.