PMID- 27977433
OWN - NLM
STAT- MEDLINE
DCOM- 20171106
LR  - 20221207
IS  - 1473-5741 (Electronic)
IS  - 0959-4973 (Linking)
VI  - 28
IP  - 3
DP  - 2017 Mar
TI  - Phase I dose-escalation study of plitidepsin in combination with sorafenib or 
      gemcitabine in patients with refractory solid tumors or lymphomas.
PG  - 341-349
LID - 10.1097/CAD.0000000000000457 [doi]
AB  - This phase I trial evaluated the combination of the marine-derived 
      cyclodepsipeptide plitidepsin (trade name Aplidin) with sorafenib or gemcitabine 
      in advanced cancer and lymphoma patients. The study included two treatment arms: 
      a sorafenib/plitidepsin (S/P) and a gemcitabine/plitidepsin (G/P) arm. In the S/P 
      arm, patients were treated orally with sorafenib continuous dosing at two dose 
      levels (DL1: 200 mg twice daily and DL2: 400 mg twice daily) combined with 
      plitidepsin (1.8 mg/m, day 1, day 8, day 15, and, q4wk, intravenously). In the 
      G/P arm, patients with solid tumors or lymphoma were treated at four different 
      DLs with a combination of gemcitabine (DL1: 750 mg/m, DL2-DL4: 1000 mg/m) and 
      plitidepsin (DL1-DL2: 1.8 mg/m; DL3: 2.4 mg/m; DL4: 3 mg/m). Both agents were 
      administered intravenously on day 1, day 8, day 15, and, q4wk. Forty-four 
      patients were evaluable for safety and toxicity. The safety of the combination of 
      plitidepsin with sorafenib or gemcitabine was manageable. Most adverse events 
      (AEs) were mild; no grade 4 treatment-related AEs were reported in any of the 
      groups (except for one grade 4 thrombocytopenia in the gemcitabine arm). The most 
      frequently reported study drug-related (or of unknown relationship) AEs were 
      palmar-plantar erythrodysesthesia, erythema, nausea, vomiting, and fatigue in the 
      S/P arm and nausea, fatigue, and vomiting in the G/P arm. In the S/P arm, one 
      dose-limiting toxicity occurred in two out of six patients treated at the maximum 
      dose tested (DL2): palmar-plantar erythrodysesthesia and grade 2 aspartate 
      aminotransferase/alanine aminotransferase increase that resulted in omission of 
      days 8 and 15 plitidepsin infusions. In the G/P arm, one dose-limiting toxicity 
      occurred in two out of six patients at DL4: grade 2 alanine aminotransferase 
      increase resulted in omission of days 8 and 15 plitidepsin infusions and grade 4 
      thrombocytopenia. The recommended dose for the combination of plitidepsin with 
      sorafenib was not defined because of a sponsor decision (no expansion cohort to 
      confirm) and for plitidepsin with gemcitabine, it was 2.4 mg/m plitidepsin with 
      1000 mg/m gemcitabine. In the S/P group, objective disease responses were not 
      observed; however, disease stabilization (>/=3months) was observed in four 
      patients. In the gemcitabine group, two lymphoma patients showed an objective 
      response (partial response and complete response) and nine patients showed 
      disease stabilization (>/=3months). Combining plitidepsin with gemcitabine and 
      sorafenib is feasible for advanced cancer patients; some objective responses were 
      observed in heavily pretreated lymphoma patients.
FAU - Aspeslagh, Sandrine
AU  - Aspeslagh S
AD  - aGustave Roussy Cancer Centre, Paris-Saclay University, Drug Development 
      Department (DITEP), Villejuif bHospices Civils de Lyon, Centre Hospitalier Lyon 
      Sud, Pierre Benite Cedex cHematology and Cellular Therapy Department, CIC INSERM 
      1415, University Hospital Centre, Tours, France dCancer Institute of New Jersey, 
      New Brunswick, New Jersey, USA ePharmaMar, S.A., Colmenar Viejo, Madrid, Spain.
FAU - Stein, Mark
AU  - Stein M
FAU - Bahleda, Rastilav
AU  - Bahleda R
FAU - Hollebecque, Antoine
AU  - Hollebecque A
FAU - Salles, Gilles
AU  - Salles G
FAU - Gyan, Emmanuel
AU  - Gyan E
FAU - Fudio, Salvador
AU  - Fudio S
FAU - Extremera, Sonia
AU  - Extremera S
FAU - Alfaro, Vicente
AU  - Alfaro V
FAU - Soto-Matos, Arturo
AU  - Soto-Matos A
FAU - Soria, Jean-Charles
AU  - Soria JC
LA  - eng
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Multicenter Study
PL  - England
TA  - Anticancer Drugs
JT  - Anti-cancer drugs
JID - 9100823
RN  - 0 (Depsipeptides)
RN  - 0 (Peptides, Cyclic)
RN  - 0 (Phenylurea Compounds)
RN  - 0W860991D6 (Deoxycytidine)
RN  - 25X51I8RD4 (Niacinamide)
RN  - 9ZOQ3TZI87 (Sorafenib)
RN  - Y76ID234HW (plitidepsin)
RN  - 0 (Gemcitabine)
SB  - IM
MH  - Administration, Oral
MH  - Adult
MH  - Aged
MH  - Aged, 80 and over
MH  - Antineoplastic Combined Chemotherapy Protocols/*administration & dosage/*adverse 
      effects
MH  - Deoxycytidine/administration & dosage/adverse effects/analogs & derivatives
MH  - Depsipeptides/administration & dosage/adverse effects/pharmacokinetics
MH  - Dose-Response Relationship, Drug
MH  - Female
MH  - Humans
MH  - Lymphoma/*drug therapy/metabolism
MH  - Male
MH  - Middle Aged
MH  - Neoplasms/*drug therapy/metabolism
MH  - Niacinamide/administration & dosage/adverse effects/analogs & derivatives
MH  - Peptides, Cyclic
MH  - Phenylurea Compounds/administration & dosage/adverse effects
MH  - Prospective Studies
MH  - Sorafenib
MH  - Young Adult
MH  - Gemcitabine
EDAT- 2016/12/16 06:00
MHDA- 2017/11/07 06:00
CRDT- 2016/12/16 06:00
PHST- 2016/12/16 06:00 [pubmed]
PHST- 2017/11/07 06:00 [medline]
PHST- 2016/12/16 06:00 [entrez]
AID - 10.1097/CAD.0000000000000457 [doi]
PST - ppublish
SO  - Anticancer Drugs. 2017 Mar;28(3):341-349. doi: 10.1097/CAD.0000000000000457.