A multicenter, randomized, open-label Phase 2 study evaluating the safety and efficacy of three different regimens of oral panobinostat in combination with subcutaneous bortezomib and oral dexamethasone in patients with relapsed or relapsed/refractory multiple myeloma who have been previously exposed to immunomodulatory agents

Multiple myeloma (MM) is a malignant proliferation of plasma cells which
accounts for 10% to 15% of all hematologic malignancies and 20% of deaths
related to cancers of the blood and bone marrow in adults. Despite a survival
improvement from 45 to 60 months after the introduction of new therapies in the
past decade (proteasome inhibitors and immunomodulatory drugs, often used in
combination with dexamethasone), all patients ultimately progress. The
hallmarks of MM are bone marrow failure, renal failure, and bone disease.
Panobinostat (PAN) (trade name Farydak) is a histone deacetylase (HDAC)
inhibitor that inhibits the enzymatic activity of HDACs. HDACs catalyse the
removal of acetyl groups from the lysine residues of histones and some
non-histone proteins. Inhibition of HDAC activity results in increased
acetylation of histone proteins, an epigenetic alteration that results in a
relaxing of chromatin, leading to transcriptional activation. In vitro, PAN
caused the accumulation of acetylated histones and other proteins, inducing
cell cycle arrest and/or apoptosis of some transformed cells. Increased levels
of acetylated histones were observed in xenografts from mice that were treated
with PAN. PAN shows more cytotoxicity towards tumour cells compared to normal
cells. PAN has received approval from the FDA and in the EU in 2015 for the
treatment of patients with MM who have received at least 2 prior regimens,
including bortezomib (BTZ, a proteasome inhibitor) and an immunomodulatory
agent.
Results of a pivotal study (study code D2308) demonstrated superiority of the
combination of PAN + i.v. BTZ + dexamethasone (DEX) compared to placebo + iv
BTZ + DEX in patients with MM who progressed on at least one line of prior
therapy. Despite observing efficacy benefit, safety concerns were noted as the
most frequent AEs included thrombocytopenia and neutropenia, GI toxicities
(primarily diarrhea, nausea and vomiting), and fatigue/asthenia, which were
more frequent in the PAN arm compared to the placebo arm. Therefore, further
evaluation to improve the safety and tolerability of this combination is needed.
At the time of conduct, the study used the intravenous formulation of BTZ but
today, the subcutaneous formulation of BTZ has become standard of care as this
formulation has been shown to be associated with less GI toxicity and
peripheral neuropathy compared to the i.v. formulation, albeit without
compromising efficacy.
The purpose of the present study is to investigate the safety and efficacy of
three different regimens of PAN (20 mg 3 times per week, 20 mg two times per
week, and 10 mg 3 times per week) in combination with s.c. BTZ and DEX and to
identify the optimal regimen of PAN.

Primary:
To assess best overall response rate (ORR) up to 8 cycles.
Secondary:
ORR, complete response (CR), very good partial response (VGPR), progression
free survival (PFS), overall survival (OS), safety, PK, exposure-response
(efficacy and safety) relationship, time to progression (TTP), time to response
(TTR), duration of response (DOR), quality of life (QoL).

Multicenter phase II open-label study. 3 regimens of oral panobinostat (PAN) in
combination with subcutaneous bortezomib and oral dexamethasone. Cycles of 3
weeks. No treatment in week 3.
Randomization 1:1:1 to:
• PAN 20 mg 3 times per week
• PAN 20 mg 2 times per week
• PAN 10 mg 3 times per week.
BTZ injections (1.3 mg/m2): First 4 cycles: twice per week, thereafter: once
per week (if age <=75 years) of once per week from the start onwards (if age >75
years).
DEX tablets (10 [>75 y] -20 [<=75 y] mg/day): on the day of and the day after
an BTZ injection.
Treatment until disease progression or unacceptable side effects.
Follow-up for survival.
240 subjects

Treatment with PAN, BTZ and DEX.

Risk: Adverse effects of the combination of PAN, BTZ and DEX.
Burden: Cycles of 3 weeks. Cycle 1-4: 4 visits per cycle, from cycle 5 onwards:
2 visits per cycle. Duration mostly 2 hours.
S.c. injections (1 ml): once or twice per week during cycles 1-4 (age
dependent), thereafter once per week for all subjects.
Physical examination: once per cycle.
Blood tests (up to 40 ml/occasion): every visit.
collection of urine during 24 h: every cycle.
ECG: once per cycle.
Questionnaires (QLQ-C30 and FACT/GOG): day 1 of cycle 1, 3, 5 and 7 and every
4th cycle thereafter.
CT-/MRI scan: at baseline, more frequently if needed.
Electronic diaries for diarrhea management and medication intake at home.
Bone marrow puncture: twice, more frequently if needed.