PMID- 24019544
OWN - NLM
STAT- MEDLINE
DCOM- 20131125
LR  - 20181202
IS  - 1527-7755 (Electronic)
IS  - 0732-183X (Linking)
VI  - 31
IP  - 29
DP  - 2013 Oct 10
TI  - Phase Ib study of panobinostat and bortezomib in relapsed or relapsed and 
      refractory multiple myeloma.
PG  - 3696-703
LID - 10.1200/JCO.2012.46.7068 [doi]
AB  - PURPOSE: Despite advancements, prognosis for patients with relapsed/refractory 
      multiple myeloma (MM) is poor, and novel therapies are needed. Panobinostat is a 
      potent deacetylase inhibitor that elicits synergistic effects on MM cells in 
      combination with bortezomib. This phase Ib study sought to determine the 
      maximum-tolerated dose (MTD) of panobinostat plus bortezomib in patients with 
      relapsed or relapsed and refractory MM. PATIENTS AND METHODS: In the 
      dose-escalation phase (n = 47), panobinostat was administered orally thrice 
      weekly every week in combination with bortezomib (21-day cycles). After MTD 
      determination, patients were evaluated in an expansion phase (n = 15) that 
      incorporated a 1-week treatment holiday of panobinostat, with dexamethasone added 
      in cycle 2. Additional assessments included safety, pharmacokinetics, and 
      efficacy per International Myeloma Working Group criteria. RESULTS: The MTD was 
      established at panobinostat 20 mg plus bortezomib 1.3 mg/m(2). Grade 3 or 4 
      adverse events (AEs) included thrombocytopenia (85.1%), neutropenia (63.8%), and 
      asthenia (29.8%) in the escalation phase, and thrombocytopenia (66.7%), 
      neutropenia (46.7%), and fatigue (20.0%) in the expansion phase. At MTD in the 
      escalation phase, eight patients (47.1%) discontinued therapy as a result of AEs, 
      whereas five patients (33.3%) discontinued treatment in the expansion phase. 
      Expansion phase patients demonstrated greater median treatment duration. Overall 
      response rate (ORR) was 73.3% in the expansion phase and 52.9% at the escalation 
      phase MTD. Among bortezomib-refractory patients, the ORR was 26.3%, and 42.1% of 
      patients had >/= minimal response. CONCLUSION: The MTD of panobinostat plus 
      bortezomib was determined and demonstrated activity in patients with relapsed or 
      relapsed/refractory MM, including bortezomib-refractory patients. A phase II/III 
      clinical trial program (Panobinostat or Placebo With Bortezomib and Dexamethasone 
      in Patients With Relapsed Multiple Myeloma [PANORAMA]) has been initiated.
FAU - San-Miguel, Jesus F
AU  - San-Miguel JF
AD  - Jesus F. San-Miguel and Maria Victoria Mateos, Servicio e Hematologia, Hospital 
      Universitario de Salamanca, Instituto de Investigacion Biomedica de Salamanca, 
      Institut de Bilogia Molecular de Barcelona (Universidad de Salamanca-Spanish 
      National Research Council), Salamanca; Joan Blade, Hospital Clinic de Barcelona, 
      Institut d'Investigacions Biomediques August Pi i Sunyer, Barcelona, Spain; Paul 
      G. Richardson and Kenneth C. Anderson, Dana-Farber Cancer Institute, Boston, MA; 
      David Siegel, Hackensack University Medical Center, Hackensack; Kaushal K. Mishra 
      and Song Mu, Novartis Pharmaceuticals Corporation, East Hanover, NJ; Andreas 
      Gunther, University of Kiel, Kiel; Orhan Sezer, Charite Universitatsmedizin 
      Berlin, Berlin, Germany; Richard LeBlanc, Maisonneuve-Rosemont Hospital, 
      Montreal, Quebec; Heather Sutherland, Vancouver General Hospital, Vancouver, 
      British Columbia, Canada; and Monika Sopala and Priscille M. Bourquelot, Novartis 
      Pharma AG, Basel, Switzerland.
FAU - Richardson, Paul G
AU  - Richardson PG
FAU - Gunther, Andreas
AU  - Gunther A
FAU - Sezer, Orhan
AU  - Sezer O
FAU - Siegel, David
AU  - Siegel D
FAU - Blade, Joan
AU  - Blade J
FAU - LeBlanc, Richard
AU  - LeBlanc R
FAU - Sutherland, Heather
AU  - Sutherland H
FAU - Sopala, Monika
AU  - Sopala M
FAU - Mishra, Kaushal K
AU  - Mishra KK
FAU - Mu, Song
AU  - Mu S
FAU - Bourquelot, Priscille M
AU  - Bourquelot PM
FAU - Victoria Mateos, Maria
AU  - Victoria Mateos M
FAU - Anderson, Kenneth C
AU  - Anderson KC
LA  - eng
SI  - ClinicalTrials.gov/NCT00737529
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20130909
PL  - United States
TA  - J Clin Oncol
JT  - Journal of clinical oncology : official journal of the American Society of 
      Clinical Oncology
JID - 8309333
RN  - 0 (Boronic Acids)
RN  - 0 (Hydroxamic Acids)
RN  - 0 (Indoles)
RN  - 0 (Pyrazines)
RN  - 69G8BD63PP (Bortezomib)
RN  - 9647FM7Y3Z (Panobinostat)
SB  - IM
MH  - Aged
MH  - Aged, 80 and over
MH  - Antineoplastic Combined Chemotherapy Protocols/*therapeutic use
MH  - Boronic Acids/*administration & dosage/adverse effects
MH  - Bortezomib
MH  - Female
MH  - Humans
MH  - Hydroxamic Acids/*administration & dosage/adverse effects/pharmacokinetics
MH  - Indoles/*administration & dosage/adverse effects/pharmacokinetics
MH  - Male
MH  - Maximum Tolerated Dose
MH  - Middle Aged
MH  - Multiple Myeloma/*drug therapy
MH  - Panobinostat
MH  - Pyrazines/*administration & dosage/adverse effects
EDAT- 2013/09/11 06:00
MHDA- 2013/12/16 06:00
CRDT- 2013/09/11 06:00
PHST- 2013/09/11 06:00 [entrez]
PHST- 2013/09/11 06:00 [pubmed]
PHST- 2013/12/16 06:00 [medline]
AID - JCO.2012.46.7068 [pii]
AID - 10.1200/JCO.2012.46.7068 [doi]
PST - ppublish
SO  - J Clin Oncol. 2013 Oct 10;31(29):3696-703. doi: 10.1200/JCO.2012.46.7068. Epub 
      2013 Sep 9.