Phase I Trial of Suberoylanilide Hydroxamic Acid (SAHA) + Bortezomib (Bort) in Relapsed Multiple Myeloma (MM) Patients (pts).
Authors: Badros Ashraf , Philip S. , Niesvizky R. , Goloubeva O. , Harris C. , Zweibel J. , Wright J. , Burger A. , Grant S. , Baer M.R. , Egorin M.J. 
Published: October 2019

SAHA, vorinostat, an oral, histone deacetylase inhibitor, affects cell growth by modifying the transcription of cellular proteins such as histones, transcription factors, ubiqutin E3 ligases and stress response proteins (e.g. HSP90). In vitro, SAHA showed synergistic cytotoxicity with the proteasome inhibitor Bort in MM cells by disrupting aggregates of the ubiquitin conjugated aggresomes. The aims of the study were to determine the MTD, pharmacokinetics (PK) and pharmacodynamic (PD) effects and activity of SAHA plus Bort in pts with relapsed/refractory MM. Twenty-one Pts have been treated. Median age was 55 yrs (range 38–79). Median time from MM diagnosis to study entry was 5.3 yrs (range: 1.5–15 yrs). Isotypes included IgG (n=10), IgA (n=5), light chain (n=4), and nonsecretory (n=2). Twelve Pts had complex karyotype. Median number of prior regimens was 6 (range 3–10); including tandem SCT (n=11), one SCT (n=8), thalidomide (n=21) and lenalidomide (n=14). Nineteen pts had received a median of 2 (range: 1–5) Bort-based prior regimens, 14 Pts had PD to last Bort therapy. 19 pts had PD to last therapy, with a median of 20 days (15–39) between last therapy and study entry. Only 2 patients were in first relapse on thalidomide maintenance. Five 3-Pt cohorts were evaluated at various dose levels as outlined in the table below.The MTD of SAHA in cycle 1 was 400 mg daily, as 2 DLTs, grade 4 prolonged QT interval and grade 4-fatigue occurred in the 500 mg daily cohort. Several grade 3–4 toxicities were observed after cycle 2, including myelo-suppression requiring transfusional support and growth factors. Non-hematological toxicities grade 2 and higher included fatigue (n=5), diarrhea (n=3), atrial fibrillation (n=1), shingles (n=1), pneumonia (n=2, bacterial and RSV). In 16 pts evaluable for response, there was 1 nCR and 7 PR (overall response rate of 50%), 6 pts had stable disease and 3 had PD. At last follow up, three pts remain in remission off therapy for 3–5 months, 9 had PD and 5 have died. Dexamethasone was added 4 pts in cycle 2; with no upgrade in response. The PK of SAHA after a single oral dose were linear from 100–500 mg with mean AUC (0.7 + 0.45 to 4.4+ 0.07), Cmax (0.3 + 0.14 to 1.2 + 0.06) and Tmax (1.3 + 0.4 to 2.3 + 2.5). Ten pts had CD-138+ cells isolated from bone marrow on day 1 [median, 1.8 × 106, range: 0.2–42.6] and on day 11 of the first cycle [median, 0.9 × 106: range: 0.4–5.4] for PD studies. The MTD for SAHA plus Bort was 400 mg daily × 8 days plus1.3 mg/ m2 days 1, 4, 8 and 11. SAHA administration after Bort does not affect PK. The regimen showed promising responses in Bort-refractory pts and should be evaluated in a phase II trial.

Study schedule/response Cohort Bort (mg/m2) SAHA (mg) No. Pts No Cycles Response Bort days 1, 4, 8, 11 of 21-day cycle + SAHA days 4–11. Pts received 8 cycles. Dexamethasone was added for nonresponders, cycle 2. * Of 10 pts to be treated at MTD. PR, partial response; NE, not evaluable; SD/PD, stable/progressive disease. 1 1.0 100 bid 3 5, 7, 5 SD, SD, SD 2 1.3 100 bid 3 5, 6, 3 SD, PR, PD 3 1.3 200 bid 3 8, 3, 8 VGPR, SD, PR 4 1.3 400 daily 3 5, 3, 3 SD, PD, PR 5 1.3 500 daily 3 7, 1, 1 PR, NE, NE MTD 1.3 400 daily 6* 4, 3, 2, “1, 1, 1” PR, PR, PR, “too early for evaluation”