A Phase 1 Trial of Fluphenazine HCl (Fz), a Serotonin Antagonist, in Relapsed and Refractory Multiple Myeloma
Authors: Stadtmauer Edward A. , Siegel David , Vogl Dan T , Stinnett James , Narayanan Geetha , Bapsy P.P. , Ganesan Trivadi , Jain Minish , Prasad Sripada V.S.S , McNair Douglas S , DeYoung Linda , Lane Alice , Silver Bruce 
Published: April 2020

Abstract
Background: Serotonin (5-HT) is a lymphocyte growth factor, and lymphocytes bear 5-HT receptors. Fz has anti-serotonergic properties and a favorable safety profile. Fz inhibits growth of Jurkat leukemia cells at concentrations of 1–10 μM (Schleuning M et al, Anticancer Research 1993;13:599–602). Other serotonin receptor antagonists have been shown to have in vitro and pre-clinical in vivo anti-myeloma effects mainly mediated by apoptosis (Ocio EM, et al, Blood 2006 108:Abs 2597). In vitro studies show 10μM Fz exposure for 18hr kills many myeloma and leukemic cell lines, while sparing non-activated, normal, human lymphocytes. In rat studies, Fz partitions into bone marrow (BM) 100× more avidly than into blood. Fz was thus selected for a proof of concept phase 1 trial in patients (pts) with previously treated myeloma.
Methods: Pts with myeloma had failed at least 2 prior regimens; had measurable serum or urine M-proteins, or skewed free light chain ratio per central lab assay; had adequate organ function and performance status (ECOG &lt;3); and were not on selective serotoin reuptake inhibitors (SSRIs), tricyclic, or norepinephrine reuptake inhibitor drugs or other anti-serotonergic agents. Fz was given i.v. in a dose escalating “3+3 design” in three divided 5-minute injections at 0, 6, and 12 hrs once every 28 days. Total Fz doses per 3-bolus exposure were 0.11, 0.23, 0.34, 0.57, 0.80, and 1.14 mg/kg. Serum samples for Fz PK analysis were collected from all patients during cycle 1. A single (time-paired with a serum PK sample) BM biopsy for BM Fz level was obtained from a subset of pts.
Results: 21 pts (13M; 8F) from 7 sites in the U.S. and India, median age 55 yrs (range 30–75) were enrolled, 3 pts were enrolled per dose cohort, except for 6 pts at 0.34 mg/kg. Median number prior regimens was 4; 15/21 had prior thalidomide or lenalidomide or both; 10/21 had prior bortezomib; 8/21 had prior stem cell transplant (including 2 with tandem transplant, 1 had a third salvage transplant). A MTD was not reached. One DLT, grade 3 extra-pyramidal reaction (EPR) of acute dystonia with stiff jaw, occurred at 0.34 mg/kg. Six pts experienced EPR (4M; 2F) typically occurring 30–36 hrs post first dose; intensity and frequency were not dose related. All EPR except the 1 DLT were grade 1 or 2. Fifteen serious adverse events (SAEs) occurred in 10 pts, all assessed as unrelated to Fz. The most common ≥ gr 3 non-serious AEs were anemia, thrombocytopenia, and back pain, none of which was assessed as related to Fz. All cases of orthostatic hypotension, agitation, EPR, sedation, somnolence, and 3 of 4 cases of fatigue were deemed related to Fz. Comparison of time-paired BM and serum Fz concentrations in 6 pts showed 4–77-fold higher Fz levels in the marrow over serum in the first 49 hrs post-dosing. The best response through 2 cycles of treatment per Blade criteria in 19 evaluable pts was stable disease in 3 pts (0.23, 0.34, and 0.80 mg/kg; duration 2, 5, and 6 cycles).
Conclusion: Fluphenazine may be safely given to pts with relapsed and refractory myeloma at the doses and schedule described, with EPR and sedation that are generally mild and manageable. Fz partitions 1–2 log greater into human BM compared with serum. A MTD was not reached, and additional studies are planned with more dose-intensive schedules.