Panobinostat PK/PD profile in combination with bortezomib and dexamethasone in patients with relapsed and relapsed/refractory multiple myeloma.
OBJECTIVE
Panobinostat, a potent pan-deacetylase inhibitor, improved progression-free survival (PFS) in patients with relapsed and refractory multiple myeloma when combined with bortezomib and dexamethasone in a phase 3 trial, PANORAMA-1. This study aims to explore exposure-response relationship for panobinostat in this combination in a phase 1 trial, B2207 and contrast with data from historical single-agent studies.


METHODS
Panobinostat plasma concentration-time profiles were obtained in patients from PANORAMA-1 (n = 12) and B2207 (n = 12) trials. Overall response rates (ORR) and major adverse events (AE) by panobinostat exposure were investigated in the B2207 trial. Panobinostat PK data from combination trials were contrasted with data from single-agent studies.


RESULTS
At maximum tolerated dose (MTD), the geometric mean of panobinostat area under curve from 0 to 24 h (AUC0-24) was 47.5 ng h/mL (77 % CV), and maximum plasma concentration (Cmax) was 8.1 ng/mL (90 % CV). These values were comparable with exposure data obtained in PANORAMA-1, but were 20 % lower than those without dexamethasone, and ∼ 50 % lower from single-agent trials, likely due to enzyme induction by dexamethasone. Higher levels of panobinostat exposure were associated with higher response rates and higher incidences of diarrhea and thrombocytopenia.


CONCLUSIONS
Apparent panobinostat exposure-AE and exposure-ORR relationships were observed when combined with bortezomib and dexamethasone in the treatment of patients with relapsed and refractory multiple myeloma. The addition of dexamethasone facilitated best response even though plasma exposure of panobinostat was reduced. Combination with a strong enzyme inducer should be avoided in future trials to prevent further reduction of panobinostat exposure.
Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA. song.mu@novartis.com.
Song
S
Mu
Hiroshima University Hospital, Hiroshima, Japan.
Yoshiaki
Y
Kuroda
Osaka University Graduate School of Medicine, Osaka, Japan.
Hirohiko
H
Shibayama
Osaka City University Hospital, Osaka, Japan.
Masayuki
M
Hino
Novartis Pharma KK, Tokyo, Japan.
Takeshi
T
Tajima
Novartis Pharma AG, Basel, Switzerland.
Claudia
C
Corrado
Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
Rong
R
Lin
Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
Edward
E
Waldron
Novartis Pharma S.A.S, Rueil-Malmaison, France.
Florence
F
Binlich
Japanese Red Cross Medical Center, Tokyo, Japan.
Kenshi
K
Suzuki
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use; D000069286:Bortezomib / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D003907:Dexamethasone / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D004311:Double-Blind Method; D019008:Drug Resistance, Neoplasm; D006801:Humans; D006877:Hydroxamic Acids / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D007211:Indoles / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009101:Multiple Myeloma / Q000188:drug therapy / Q000378:metabolism; D009364:Neoplasm Recurrence, Local; D000077767:Panobinostat
D000970:Antineoplastic Agents; D006877:Hydroxamic Acids; D007211:Indoles; D000069286:Bortezomib; D003907:Dexamethasone; D000077767:Panobinostat
Clinical trials; Histone deacetylase inhibitor; Panobinostat; Pharmacodynamics; Pharmacokinetics