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Phase 1 Study of Carfilzomib in Allogeneic Hematopoietic Cell Transplantation for High-Risk Hematologic Malignancies

Year: 2016

Type: article

Abstract: Allogeneic hematopoietic cell transplant (HCT) remains the primary curative option for patients (pts) with poor-risk hematologic malignancies, but graft-versus-host disease (GVHD) and relapse remain major obstacles. Inhibition of proteasome function results in down-regulation of the NF-κB signaling pathway, which has a pivotal role in maintaining malignant cell survival and in promoting GVHD inflammatory and immune response. The reversible proteasome inhibitor bortezomib may abrogate GVHD and relapse based on pre-clinical and clinical studies when added to mismatched unrelated donor HCTs. (Koreth J Clin Oncol 2012) Carfilzomib (CFZ) is an irreversible immunoproteasome inhibitor, with possibly increased efficacy and specificity to the immune and hematologic malignancy cells and a less off-target toxicity profile, especially myelosuppression, neuropathy and diarrhea. We are exploring the addition of CFZ to fludarabine based conditionings and tacrolimus/methotrexate (MTX) GVHD prophylaxis regimen. To identify the maximal tolerated dose of CFZ when administered on day +1, +2, +6, +7. The phase 1 design is 3+3. Eligible conditionings are fludarabine based. Tacrolimus is started on day -3 and tapered off by day +180. MTX 5 mg/m2 is given IV on day +1, +3, +6, +11. CFZ is given IV on days +1, +2 at 20 mg/m2/day fixed dose and on day +6, +7 at 4 dose levels: 20, 27, 36, 45 mg/m2/day. CFZ is given after MTX on day +1 and +6. Filgrastim 5 μg/kg/day is started on day +1 until engraftment. Dose-limiting toxicities (DLTs) are defined as any ≥grade 3 non-hematologic NCI CTC AEs v4 toxicities attributed to CFZ and occurring within 28 days of CFZ treatment (day +35). Since October 2014, 11 pts (M: F, 6:5) have been enrolled. Nine received all 4 doses; the other 2 received 3 and 2 doses only before being removed due to unrelated adverse events. Among 9 evaluable pts for DLTs, the median age was 55 (range, 29-61) years; all donors were 8/8 matched (7 sibling, 2 unrelated). Stem cell sources were peripheral blood in 8 and bone marrow in 1 unrelated donor. Primary diseases included myeloid malignancies in 5 and lymphoid malignancies in 4. All pts received the myeloablative reduced-toxicity fludarabine and busulfan x 4 (FluBu4). All 9 pts engrafted neutrophil and platelet at a median time of 10 (range, 10-15) and 12 (9-14) days, respectively. Expected common toxicities related to the FluBu4 treatment was oral mucositis. Median CD33+ and CD3+donor chimerisms were 100% and 90% at day 30, and were 100% and 91% at day 100, respectively. As of 10/1/15, no DLTs occurred in 9 evaluable pts who passed day +35, with the median transplant day of day +210 (range, 70-348). Adding the irreversible immunoproteasome inhibitor carfilzomib to fludarabine-based conditioning HCT appears safe and feasible. Dose escalation to level 4 (20/45 mg/m2) is ongoing and the results will be updated at the meeting.

Source: Transplantation and Cellular Therapy

DOI: 10.1016/j.bbmt.2015.11.837