PMID- 31583436
OWN - NLM
STAT- MEDLINE
DCOM- 20200527
LR  - 20200527
IS  - 1432-0843 (Electronic)
IS  - 0344-5704 (Linking)
VI  - 84
IP  - 6
DP  - 2019 Dec
TI  - A phase I delayed-start, randomized and pharmacodynamic study of metformin and 
      chemotherapy in patients with solid tumors.
PG  - 1323-1331
LID - 10.1007/s00280-019-03967-3 [doi]
AB  - PURPOSE: Metformin activates AMP-related pathways leading to inactivation of 
      mammalian target of rapamycin (mTOR) and suppression of its downstream effectors, 
      crucial for cancer growth. Epidemiologic studies showed a reduced incidence and 
      improved survival in cancer patients. We conducted a prospective phase I study to 
      assess the safety of metformin in combination with chemotherapy in patients with 
      solid tumors. METHODS: We conducted a delayed-start randomized trial of 
      non-diabetic patients in two stages. In Stage 1, we randomized patients to two 
      arms: concurrent arm (metformin with chemo) vs. delayed arm (chemo alone). In 
      Stage 2, patients in delayed arm were crossed over to receive metformin. Patients 
      received metformin 500 mg twice daily with chemotherapy to define dose-limiting 
      toxicities (DLTs) in both stages. Secondary endpoints assessed adverse events 
      (AEs) and response rates. Translational correlates included effects of metformin 
      on expression and phosphorylation of 5' adenosine monophosphate-activated protein 
      kinase (AMPK) by western blot in PBMCs. RESULTS: A total of 100 patients were 
      enrolled (51 in delayed arm vs. 49 concurrent arm). Rate of DLTs in patients 
      receiving metformin with chemotherapy was 6.1% vs. 7.8% in patients receiving 
      chemotherapy alone. DLTs seen with addition of metformin included those 
      associated with established chemo adverse events. No lactic acidosis or 
      hypoglycemia occurred. Restaging showed stable disease in 46% at cessation of 
      metformin. 28% of patients with measurable tumor markers showed improvement. AMPK 
      phosphorylation showed a four- to sixfold increase in AMPK phosphorylation after 
      metformin. CONCLUSIONS: This is the largest phase I study of metformin combined 
      with chemotherapy, which suggests that metformin can be given safely with 
      chemotherapy, and offers a platform for future studies. Post-metformin increase 
      in AMPK phosphorylation may potentially explain lack of disease progression in 
      nearly half of our patients. FUNDING: UL1 TR001064. CLINICAL TRIAL INFORMATION: 
      NCT01442870.
FAU - Saif, Mohammad Wasif
AU  - Saif MW
AD  - Northwell Health Cancer Institute, 1111 Marcus Avenue, 2nd Floor, Lake Success, 
      NY, 11042, USA. wsaif@northwell.edu.
AD  - Tufts Cancer Center, Tufts Medical Center, Boston, MA, USA. wsaif@northwell.edu.
FAU - Rajagopal, Shrikar
AU  - Rajagopal S
AD  - Tufts Cancer Center, Tufts Medical Center, Boston, MA, USA.
FAU - Caplain, Jennifer
AU  - Caplain J
AD  - Tufts Cancer Center, Tufts Medical Center, Boston, MA, USA.
FAU - Grimm, Elizabeth
AU  - Grimm E
AD  - Tufts Cancer Center, Tufts Medical Center, Boston, MA, USA.
FAU - Serebrennikova, Oksana
AU  - Serebrennikova O
AD  - Tufts Cancer Center, Tufts Medical Center, Boston, MA, USA.
FAU - Das, Madhumita
AU  - Das M
AD  - Tufts Cancer Center, Tufts Medical Center, Boston, MA, USA.
FAU - Tsichlis, Philip N
AU  - Tsichlis PN
AD  - Tufts Cancer Center, Tufts Medical Center, Boston, MA, USA.
FAU - Martell, Robert
AU  - Martell R
AD  - Tufts Cancer Center, Tufts Medical Center, Boston, MA, USA.
LA  - eng
SI  - ClinicalTrials.gov/NCT01442870
GR  - UL1TR001064/CA/NCI NIH HHS/United States
GR  - UL1TR001064/CA/NCI NIH HHS/United States
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Randomized Controlled Trial
PT  - Research Support, N.I.H., Extramural
DEP - 20191003
PL  - Germany
TA  - Cancer Chemother Pharmacol
JT  - Cancer chemotherapy and pharmacology
JID - 7806519
RN  - 9100L32L2N (Metformin)
RN  - EC 2.7.11.31 (AMP-Activated Protein Kinases)
SB  - IM
MH  - AMP-Activated Protein Kinases/metabolism
MH  - Adolescent
MH  - Adult
MH  - Aged
MH  - Antineoplastic Combined Chemotherapy Protocols/administration & dosage/*adverse 
      effects/pharmacokinetics
MH  - Drug Administration Schedule
MH  - Drug-Related Side Effects and Adverse Reactions/*epidemiology/etiology
MH  - Female
MH  - Humans
MH  - Male
MH  - Metformin/administration & dosage/*adverse effects/pharmacokinetics
MH  - Middle Aged
MH  - Neoplasms/*drug therapy/mortality/pathology
MH  - Phosphorylation/drug effects
MH  - Progression-Free Survival
MH  - Prospective Studies
MH  - Time Factors
MH  - Young Adult
OTO - NOTNLM
OT  - AMP-activated protein kinase (AMPK)
OT  - Anti-diabetic
OT  - Biguanide
OT  - Cancer
OT  - Chemotherapy
OT  - Diabetes
OT  - Metformin
OT  - mTOR
EDAT- 2019/10/05 06:00
MHDA- 2020/05/28 06:00
CRDT- 2019/10/05 06:00
PHST- 2019/08/13 00:00 [received]
PHST- 2019/09/25 00:00 [accepted]
PHST- 2019/10/05 06:00 [pubmed]
PHST- 2020/05/28 06:00 [medline]
PHST- 2019/10/05 06:00 [entrez]
AID - 10.1007/s00280-019-03967-3 [pii]
AID - 10.1007/s00280-019-03967-3 [doi]
PST - ppublish
SO  - Cancer Chemother Pharmacol. 2019 Dec;84(6):1323-1331. doi: 
      10.1007/s00280-019-03967-3. Epub 2019 Oct 3.