PMID- 28004284 OWN - NLM STAT- MEDLINE DCOM- 20180321 LR - 20240313 IS - 1573-0646 (Electronic) IS - 0167-6997 (Print) IS - 0167-6997 (Linking) VI - 35 IP - 3 DP - 2017 Jun TI - A phase I study of tivantinib in combination with temsirolimus in patients with advanced solid tumors. PG - 290-297 LID - 10.1007/s10637-016-0418-8 [doi] AB - Background A wide variety of human cancers exhibit dysregulated c-Met activity that has implications in oncogenesis. Phosphorylation of c-Met results in activation of the PI3K/AKT/mTOR pathway. Combined blockade of c-Met and mTOR pathways has shown efficacy in preclinical studies. Tivantinib is a c-Met inhibitor and temsirolimus is a selective mTOR inhibitor. We aimed to determine the maximum tolerated dose (MTD) and the recommended phase II dose (RP2D), dose-limiting toxicities (DLT), adverse events (AEs), clinical activity and pharmacokinetic (PK) parameters of the combination. Methods This open-label phase I study used a 3 + 3 dose escalation design. Patients (pts) were treated with escalating doses of tivantinib (120-360 mg tablets orally twice daily) and temsirolimus (20 mg IV weekly) followed by dose expansion at the MTD. Separate cohorts were planned for extensive (normal) and poor tivantinib metabolizers based on CYP2C19 genotypes. Cycles were 28 days besides cycle 1 that was 35 days to allow for PK analysis. Results Twenty-nine pts. [median age 58 (range 28-77)] were enrolled (21 in dose escalation and 8 in dose expansion). All were extensive CYP2C19 metabolizers. The most common types of cancer were colorectal, ovarian and non-small cell lung. Sixteen out of 21 and 6 out of 8 pts. were evaluable for DLT evaluation per protocol in the dose escalation and dose expansion phases, respectively. Pts remained on study for a median of 71 days (range 18-296). The MTD and RP2D was tivantinib 240 mg twice daily and temsirolimus 20 mg weekly. DLTs included grade (gr) 4 neutropenia (2 pts.; 1 with gr 3 febrile neutropenia), gr 3 abdominal pain (1 pt) and gr 2 mucositis resulting in inadequate drug delivery. The most common treatment related AEs grade >/= 2 included: anemia (gr 2 in 9 pts., gr 3 in 3 pts), fatigue (gr 2 in 10 pts), anorexia (gr 2 in 9 pts), hypoalbuminemia (gr 2 in 6 pts., gr 3 in 2 pts), hypophosphatemia (gr 2 in 2 pts., gr 3 in 5 pts) and nausea (gr 2 in 6 pts., gr 3 in 1 pt). One pt. with ovarian cancer had a confirmed partial response and remained on study for 10 months, a second patient with ovarian cancer had stable disease and remained on study for 6 months and a third pt. with squamous cell carcinoma of the tongue had stable disease and remained on study for 7 months. Pharmacokinetic analysis showed that there is no interaction in the plasma concentrations between tivantinib and temsirolimus. Conclusions The combination of tivantinib with temsirolimus appears to be well tolerated with evidence of clinical activity. FAU - Kyriakopoulos, Christos E AU - Kyriakopoulos CE AD - University of Wisconsin Carbone Cancer Center, University of Wisconsin-Madison, 600 Highland Avenue, Madison, WI, 53792, USA. ckyriako@medicine.wisc.edu. FAU - Braden, Amy M AU - Braden AM AD - University of Wisconsin Carbone Cancer Center, University of Wisconsin-Madison, 600 Highland Avenue, Madison, WI, 53792, USA. FAU - Kolesar, Jill M AU - Kolesar JM AD - University of Wisconsin Carbone Cancer Center, University of Wisconsin-Madison, 600 Highland Avenue, Madison, WI, 53792, USA. FAU - Eickhoff, Jens C AU - Eickhoff JC AD - University of Wisconsin Carbone Cancer Center, University of Wisconsin-Madison, 600 Highland Avenue, Madison, WI, 53792, USA. FAU - Bailey, Howard H AU - Bailey HH AD - University of Wisconsin Carbone Cancer Center, University of Wisconsin-Madison, 600 Highland Avenue, Madison, WI, 53792, USA. FAU - Heideman, Jennifer AU - Heideman J AD - University of Wisconsin Carbone Cancer Center, University of Wisconsin-Madison, 600 Highland Avenue, Madison, WI, 53792, USA. FAU - Liu, Glenn AU - Liu G AD - University of Wisconsin Carbone Cancer Center, University of Wisconsin-Madison, 600 Highland Avenue, Madison, WI, 53792, USA. FAU - Wisinski, Kari B AU - Wisinski KB AD - University of Wisconsin Carbone Cancer Center, University of Wisconsin-Madison, 600 Highland Avenue, Madison, WI, 53792, USA. LA - eng GR - P30 CA014520/CA/NCI NIH HHS/United States GR - U01 CA062491/CA/NCI NIH HHS/United States GR - UM1 CA186716/CA/NCI NIH HHS/United States PT - Clinical Trial, Phase I PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20161221 PL - United States TA - Invest New Drugs JT - Investigational new drugs JID - 8309330 RN - 0 (ARQ 197) RN - 0 (Antineoplastic Agents) RN - 0 (Protein Kinase Inhibitors) RN - 0 (Pyrrolidinones) RN - 0 (Quinolines) RN - 624KN6GM2T (temsirolimus) RN - EC 1.14.14.1 (CYP2C19 protein, human) RN - EC 1.14.14.1 (Cytochrome P-450 CYP2C19) RN - EC 2.7.10.1 (MET protein, human) RN - EC 2.7.10.1 (Proto-Oncogene Proteins c-met) RN - W36ZG6FT64 (Sirolimus) SB - IM MH - Adult MH - Aged MH - Antineoplastic Agents/adverse effects/blood/pharmacokinetics/*therapeutic use MH - Antineoplastic Combined Chemotherapy Protocols/adverse effects/pharmacokinetics/*therapeutic use MH - Cytochrome P-450 CYP2C19/metabolism MH - Female MH - Humans MH - Male MH - Maximum Tolerated Dose MH - Middle Aged MH - Neoplasms/*drug therapy/metabolism MH - Protein Kinase Inhibitors/adverse effects/blood/pharmacokinetics/*therapeutic use MH - Proto-Oncogene Proteins c-met/*antagonists & inhibitors MH - Pyrrolidinones/adverse effects/blood/pharmacokinetics/*therapeutic use MH - Quinolines/adverse effects/blood/pharmacokinetics/*therapeutic use MH - Sirolimus/adverse effects/*analogs & derivatives/blood/pharmacokinetics/therapeutic use PMC - PMC5809175 MID - NIHMS938683 OTO - NOTNLM OT - C-met OT - PI3K/AKT/mTOR OT - Phase I OT - Temsirolimus OT - Tivantinib COIS- Conflict of interest: The authors declare that they have no conflict of interest. EDAT- 2016/12/23 06:00 MHDA- 2018/03/22 06:00 PMCR- 2018/02/12 CRDT- 2016/12/23 06:00 PHST- 2016/11/09 00:00 [received] PHST- 2016/12/13 00:00 [accepted] PHST- 2016/12/23 06:00 [pubmed] PHST- 2018/03/22 06:00 [medline] PHST- 2016/12/23 06:00 [entrez] PHST- 2018/02/12 00:00 [pmc-release] AID - 10.1007/s10637-016-0418-8 [pii] AID - 10.1007/s10637-016-0418-8 [doi] PST - ppublish SO - Invest New Drugs. 2017 Jun;35(3):290-297. doi: 10.1007/s10637-016-0418-8. Epub 2016 Dec 21.