PMID- 32146550
OWN - NLM
STAT- MEDLINE
DCOM- 20210902
LR  - 20231112
IS  - 1573-0646 (Electronic)
IS  - 0167-6997 (Print)
IS  - 0167-6997 (Linking)
VI  - 38
IP  - 5
DP  - 2020 Oct
TI  - Phase I study of metformin in combination with carboplatin/paclitaxel 
      chemotherapy in patients with advanced epithelial ovarian cancer.
PG  - 1454-1462
LID - 10.1007/s10637-020-00920-7 [doi]
AB  - Background Metformin use is associated with reduced cancer risk in 
      epidemiological studies and has preclinical anti-cancer activity in ovarian 
      cancer models. The primary objective of this phase I study was to determine the 
      recommended phase II dose (RP2D) of metformin in combination with 
      carboplatin/paclitaxel in patients with ovarian cancer. Secondary objectives were 
      to describe safety and pharmacokinetics. Methods In this single-center trial the 
      RP2D of metformin in combination with carboplatin area under the 
      concentration-time curve (AUC) 6 and paclitaxel 175 mg/m(2) every 3 weeks (q3w) 
      in patients with advanced epithelial ovarian cancer was determined using a 3 + 3 
      escalation rule at three fixed dose levels: 500 mg three times daily (tds), 
      850 mg tds and 1000 mg tds. Metformin was commenced on day 3 of cycle 1 and 
      continued until 3 weeks after the last chemotherapy administration. The RP2D was 
      defined as the dose level at which 0 of 3 or </= 1 of 6 evaluable subjects 
      experienced a metformin-related dose-limiting toxicity (DLT). Safety was assessed 
      according to CTCAE v4.0. Plasma and serum samples for pharmacokinetic (PK) 
      analyses were collected during treatment cycles 1 and 2. Results Fifteen patients 
      with epithelial ovarian cancer and an indication for neo-adjuvant (n = 5) or 
      palliative (n = 10) treatment were included. No DLTs were observed. Three 
      patients discontinued study treatment during cycle 1 for other reasons than DLT. 
      Six patients were treated at the RP2D of metformin 1000 mg tds. The most frequent 
      low-grade toxicities were anemia, hypomagnesemia and diarrhea. Grade 3 adverse 
      events (AEs) occurred in ten patients, most common were leucopenia (n = 4), 
      thrombocytopenia (n = 3) and increased GGT (n = 3). There were no grade 4 AEs. 
      Metformin increased the platinum (Pt) AUC (Delta22%, p = 0.013) and decreased the Pt 
      clearance (Delta-28%, p = 0.013). Metformin plasma levels were all within the 
      therapeutic range for diabetic patients (0.1-4 mg/L). Conclusion The RP2D of 
      metformin in combination with carboplatin and paclitaxel in advanced ovarian 
      cancer is 1000 mg tds. This is higher than the RP2D reported for combination with 
      targeted agents. A potential PK interaction of metformin with carboplatin was 
      identified.
FAU - Broekman, K Esther
AU  - Broekman KE
AD  - Department of Medical Oncology, University Medical Center Groningen, University 
      of Groningen, PO Box 30.001, 9700 RB, Groningen, the Netherlands.
FAU - Hof, Marieke A J
AU  - Hof MAJ
AD  - Department of Clinical Pharmacy and Pharmacology, University Medical Center 
      Groningen, University of Groningen, Groningen, the Netherlands.
FAU - Touw, Daan J
AU  - Touw DJ
AD  - Department of Clinical Pharmacy and Pharmacology, University Medical Center 
      Groningen, University of Groningen, Groningen, the Netherlands.
FAU - Gietema, Jourik A
AU  - Gietema JA
AD  - Department of Medical Oncology, University Medical Center Groningen, University 
      of Groningen, PO Box 30.001, 9700 RB, Groningen, the Netherlands.
FAU - Nijman, Hans W
AU  - Nijman HW
AD  - Department of Obstetrics and Gynecology, University Medical Center Groningen, 
      University of Groningen, Groningen, the Netherlands.
FAU - Lefrandt, Joop D
AU  - Lefrandt JD
AD  - Department of Internal Medicine, University Medical Center Groningen, University 
      of Groningen, Groningen, the Netherlands.
FAU - Reyners, An K L
AU  - Reyners AKL
AD  - Department of Medical Oncology, University Medical Center Groningen, University 
      of Groningen, PO Box 30.001, 9700 RB, Groningen, the Netherlands.
FAU - Jalving, Mathilde
AU  - Jalving M
AD  - Department of Medical Oncology, University Medical Center Groningen, University 
      of Groningen, PO Box 30.001, 9700 RB, Groningen, the Netherlands. 
      m.jalving@umcg.nl.
LA  - eng
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20200307
PL  - United States
TA  - Invest New Drugs
JT  - Investigational new drugs
JID - 8309330
RN  - 0 (Antineoplastic Agents)
RN  - 9100L32L2N (Metformin)
RN  - BG3F62OND5 (Carboplatin)
RN  - P88XT4IS4D (Paclitaxel)
SB  - IM
MH  - Aged
MH  - Antineoplastic Agents/*administration & dosage/pharmacokinetics
MH  - Antineoplastic Combined Chemotherapy Protocols/*administration & 
      dosage/pharmacokinetics
MH  - Carboplatin/*administration & dosage/pharmacokinetics
MH  - Carcinoma, Ovarian Epithelial/*drug therapy
MH  - Female
MH  - Humans
MH  - Metformin/*administration & dosage/pharmacokinetics
MH  - Middle Aged
MH  - Ovarian Neoplasms/*drug therapy/metabolism
MH  - Paclitaxel/*administration & dosage/pharmacokinetics
PMC - PMC7497683
OTO - NOTNLM
OT  - Chemotherapy
OT  - Metformin
OT  - Ovarian cancer
OT  - Safety
COIS- K.E. Broekman, M.A.J. Hof, D.J. Touw, J.D. Lefrandt and A.K.L. Reyners have no 
      conflicts of interest to declare. J.A. Gietema: research grants to the 
      institution of Roche, AbbVie, Siemens. H.W. Nijman: Clinical studies: Aduro, 
      Vicinivax, Merck, DCPrime, AIMM. Founder and stock owner of Vicinivax. M. 
      Jalving: Advisory Boards: Merck, BMS, Novartis, Pierre Fabre, Tesaro, 
      AstraZeneca. Speakers' fees: Sanofi. Clinical studies: BMS, AbbVie, Merck, 
      Cristal Therapeutics. All fees paid to institution.
EDAT- 2020/03/09 06:00
MHDA- 2021/09/03 06:00
PMCR- 2020/03/07
CRDT- 2020/03/09 06:00
PHST- 2020/01/13 00:00 [received]
PHST- 2020/02/28 00:00 [accepted]
PHST- 2020/03/09 06:00 [pubmed]
PHST- 2021/09/03 06:00 [medline]
PHST- 2020/03/09 06:00 [entrez]
PHST- 2020/03/07 00:00 [pmc-release]
AID - 10.1007/s10637-020-00920-7 [pii]
AID - 920 [pii]
AID - 10.1007/s10637-020-00920-7 [doi]
PST - ppublish
SO  - Invest New Drugs. 2020 Oct;38(5):1454-1462. doi: 10.1007/s10637-020-00920-7. Epub 
      2020 Mar 7.