A Phase I Trial of the Intravenous (IV) Hsp90 Inhibitor 17-DMAG (alvespimycin) in Patients (pts) with Relapsed Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL)

Abstract 1800

17-DMAG is a geldanamycin derivative that binds the N-terminal domain of the heat shock protein Hsp90, a molecular chaperone protein important in maintaining enzymatic activity of several client proteins involved in cellular signaling pathways. This binding disrupts the interaction between Hsp90 and its client proteins, several important to signaling and survival pathways in CLL including kinases AKT, IKK-α and IKK-β. IKK-α and IKK-β activate the NF-kB pathway, which plays a critical role in promoting proliferation and survival of CLL cells. In vitro data has demonstrated that 17-DMAG is cytotoxic to primary CLL cells, exhibiting minimal toxicity towards normal B-, T- and NK-cells, which may be less immunosuppressive than other available therapies. A prior phase I study of 17-DMAG showed it was safe with clinical activity in pts with relapsed leukemia. This phase I study was designed to determine the maximum tolerated dose (MTD) and dose limiting toxicities (DLTs) in pts with relapsed CLL/SLL as well as to assess preliminary efficacy and determine feasibility of measuring different pharmacodynamic (PD) markers including Hsp90 client proteins AKT, IKK-α and IKK-β.

Eligibility included pts with relapsed CLL/SLL requiring therapy by the 2008 International Workshop on CLL guidelines who had received at least one prior therapy including fludarabine (F), equivalent nucleoside analogue (NA) or alternative regimen if contraindication to F existed. Inclusion criteria included normal creatinine (cr) or cr clearance ≥50, AST/ALT ≤ 2.5 × upper limits of normal and QTc 500 msec. Treatment consisted of 17-DMAG IV at escalating dose levels (dl) (16 mg/m², 20 mg/m², 24 mg/m²) given on days 1, 4, 8 and 11 of 21 day cycles in a standard cohort-of-3 dose-escalation. All pts were treated for a minimum of 2 cycles in the absence of progressive disease. An expansion cohort of 12 patients was planned at the MTD in order to gain more data on safety and tolerability of 17-DMAG as well as to assess feasibility of measuring PD endpoints in these pts.

Fifteen pts (10 males) with a median age of 59 (range 49–76) previously treated with a median of 5 prior therapies (range 1–14) were enrolled. Thirteen pts had prior NA therapy and 1 pt had prior allogeneic stem cell transplant. Five pts were enrolled on dl 1 (16 mg/m²), 3 pts on dl 2 (20 mg/m²) and 6 pts on dl 3 (24 mg/m²). No DLT's were observed and 24 mg/m² was determined to be the MTD. One pt was enrolled in the expansion cohort at the MTD. Fourteen of the 15 pts were evaluable for response. Seven pts progressed prior to finishing 1 month of therapy; 4 pts prior to finishing 2 months of therapy and 3 pts prior to finishing 3 months of therapy. Of these 3 pts considered to have stable disease, 2 were treated at dl 2 and 1 was treated at dl 3. Two pts died while on study, both with complications of progressive disease considered unrelated to therapy. Grade 3–4 events included anemia (67%), neutropenia (53%), thrombocytopenia (20%), pain (20%), electrolyte abnormalities (20%), infection (14%), hypertension (14%), dyspnea (14%), hypoxia (7%), hemolysis (7%) and upper gastrointestinal hemorrhage (7%). All were considered unrelated to treatment. Correlative studies included immunoblot analysis of Hsp90 client proteins and real time PCR for NF-kB target genes. We found IKKα and IKKβ levels decreased at cycle 1, day 1 (C1D1) at 24 hours in 4 of 7 pt samples which were evaluable, while AKT levels were not altered to a large extent. Additionally real time PCR was performed to determine any effect on NF-kB target genes Mcl-1, Bcl-2, as these have been previously demonstrated by our group to be decreased by 17-DMAG treatment in vitro. There was a variable effect on these target genes at C1D1 at 24 hours that correlated with the decrease in IKKα and IKKβ. Additionally, SOCS3, a gene that is silenced in CLL and has been demonstrated to increase in vitro with 17-DMAG treatment, was also increased in vivo.

IV 17-DMAG given to pts with relapsed CLL/SLL was well tolerated with no DLTs observed. Correlatives suggest that inhibition of Hsp90 may not be complete at the highest dose on this schedule, and higher doses or alternative schedules may be beneficial. Oral administration may provide a more consistent dosing schedule leading to continuous inhibition of Hsp90 and more pronounced effect on downstream signaling pathways. Further mechanistic studies with 17-DMAG as well as alternative Hsp90 inhibitors are being pursued pre-clinically at OSU.