PMID- 33638305
OWN - NLM
STAT- MEDLINE
DCOM- 20210719
LR  - 20211204
IS  - 2045-7634 (Electronic)
IS  - 2045-7634 (Linking)
VI  - 10
IP  - 6
DP  - 2021 Mar
TI  - A phase I trial of the mTOR inhibitor temsirolimus in combination with 
      capecitabine in patients with advanced malignancies.
PG  - 1944-1954
LID - 10.1002/cam4.3672 [doi]
AB  - BACKGROUND: Temsirolimus is an mTOR antagonist with proven anticancer efficacy. 
      Preclinical data suggest greater anticancer effect when mTOR inhibitors are 
      combined with cytotoxic chemotherapy. We performed a Phase I assessment of the 
      combination of temsirolimus and capecitabine in patients with advanced solid 
      tumors. METHODS: Patients were enrolled in an alternating dose escalation of 
      temsirolimus (at 15 or 25 mg IV weekly) and capecitabine (at 750, 1000, and 
      1250 mg/m(2) twice daily) in separate Q2-week and Q3-week cohorts. At the 
      recommended Phase II doses (RP2Ds) of temsirolimus and capecitabine (Q2), seven 
      patients were also treated with oxaliplatin (85 mg/m(2) , day 1) to determine 
      triplet combination safety and efficacy. RESULTS: Forty-five patients were 
      enrolled and 41 were evaluable for dose-limiting toxicities (DLTs). The most 
      common adverse events (AEs) were mucositis, fatigue, and thrombocytopenia. The 
      most common grade 3/4 AEs were hypophosphatemia and anemia. Five patients had 
      DLTs, including hypophosphatemia, mucositis, and thrombocytopenia. The RP2Ds were 
      temsirolimus 25 mg +capecitabine 1000 mg/m(2) (Q2); and temsirolimus 25 mg 
      +capecitabine 750 mg/m(2)  (Q3). Of the 38 patients evaluable for response, one 
      had a partial response (PR) and 19 had stable disease (SD). The overall disease 
      control rate was 52%. Five of the 20 patients with SD/PR maintained disease 
      control for >6 months. CONCLUSIONS: The combination of temsirolimus and 
      capecitabine is safe on both a Q2-week and a Q3-week schedule. The combination 
      demonstrated promising evidence of disease control in this highly refractory 
      population and could be considered for testing in disease-specific phase II 
      trials.
CI  - (c) 2021 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.
FAU - Trivedi, Neel D
AU  - Trivedi ND
AD  - Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, 
      Washington, DC, USA.
FAU - Armstrong, Samantha
AU  - Armstrong S
AD  - Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, 
      Washington, DC, USA.
FAU - Wang, Hongkun
AU  - Wang H
AD  - Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, 
      Washington, DC, USA.
FAU - Hartley, Marion
AU  - Hartley M
AUID- ORCID: 0000-0001-5516-297X
AD  - The Ruesch Center for the Cure of Gastrointestinal Cancers, Lombardi 
      Comprehensive Cancer Center, Georgetown University Medical Center, Washington, 
      DC, USA.
FAU - Deeken, John
AU  - Deeken J
AD  - Inova Schar Cancer Institute, Inova Health System, Falls Church, VA, USA.
FAU - Ruth He, A
AU  - Ruth He A
AD  - Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, 
      Washington, DC, USA.
FAU - Subramaniam, Deepa
AU  - Subramaniam D
AD  - Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, 
      Washington, DC, USA.
FAU - Melville, Heather
AU  - Melville H
AD  - Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, 
      Washington, DC, USA.
FAU - Albanese, Chris
AU  - Albanese C
AD  - Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, 
      Washington, DC, USA.
FAU - Marshall, John L
AU  - Marshall JL
AUID- ORCID: 0000-0002-3449-2344
AD  - Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, 
      Washington, DC, USA.
FAU - Hwang, Jimmy
AU  - Hwang J
AD  - Levine Cancer Institute, Carolinas HealthCare System, Charlotte, NC, USA.
FAU - Pishvaian, Michael J
AU  - Pishvaian MJ
AUID- ORCID: 0000-0002-1165-9041
AD  - Department of Oncology, Johns Hopkins University School of Medicine, SKCC, 
      Washington, DC, USA.
LA  - eng
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20210227
PL  - United States
TA  - Cancer Med
JT  - Cancer medicine
JID - 101595310
RN  - 0 (Antineoplastic Agents)
RN  - 04ZR38536J (Oxaliplatin)
RN  - 624KN6GM2T (temsirolimus)
RN  - 6804DJ8Z9U (Capecitabine)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Anemia/chemically induced
MH  - Antineoplastic Agents/*administration & dosage/adverse effects
MH  - Antineoplastic Combined Chemotherapy Protocols/*administration & dosage/adverse 
      effects
MH  - Capecitabine/*administration & dosage
MH  - Drug Administration Schedule
MH  - Fatigue/chemically induced
MH  - Female
MH  - Fever/chemically induced
MH  - Humans
MH  - Hypophosphatemia/chemically induced
MH  - Male
MH  - Middle Aged
MH  - Mucositis/chemically induced
MH  - Neoplasms/*drug therapy/pathology
MH  - Oxaliplatin/administration & dosage/adverse effects
MH  - Sirolimus/administration & dosage/adverse effects/*analogs & derivatives
MH  - TOR Serine-Threonine Kinases/*antagonists & inhibitors
MH  - Thrombocytopenia/chemically induced
MH  - Treatment Outcome
PMC - PMC7957175
OTO - NOTNLM
OT  - 5-fluorouracil
OT  - capecitabine
OT  - colorectal cancer
OT  - mTOR
OT  - temsirolimus
COIS- Michael J. Pishvaian: Speaker/Consultant: AstraZeneca/MedImmune, Halozyme, Merck, 
      and Sirtex Medical. Travel, Accommodations, and Expenses Support: 
      AstraZeneca/MedImmune, Merck, and Sirtex Medical. Stock: Perthera. Research 
      Funding to the Institution: Bavarian Nordic, MedImmune; Neel D. Trivedi: No 
      disclosures to report related to this work; Samantha Armstrong: No disclosures to 
      report related to this work; Hongkun Wang: No disclosures to report related to 
      this work; Marion Hartley: No disclosures to report related to this work; John 
      Deeken: No disclosures to report related to this work; A. Ruth He: No disclosures 
      to report related to this work; Deepa Subramaniam: No disclosures to report 
      related to this work; Heather Melville: No disclosures to report related to this 
      work; Chris Albanese: No disclosures to report related to this work; John L 
      Marshall: No disclosures to report related to this work; Jimmy Hwang: No 
      disclosures to report related to this work.
EDAT- 2021/02/28 06:00
MHDA- 2021/07/20 06:00
PMCR- 2021/02/27
CRDT- 2021/02/27 05:45
PHST- 2020/09/18 00:00 [revised]
PHST- 2020/07/07 00:00 [received]
PHST- 2020/11/10 00:00 [accepted]
PHST- 2021/02/28 06:00 [pubmed]
PHST- 2021/07/20 06:00 [medline]
PHST- 2021/02/27 05:45 [entrez]
PHST- 2021/02/27 00:00 [pmc-release]
AID - CAM43672 [pii]
AID - 10.1002/cam4.3672 [doi]
PST - ppublish
SO  - Cancer Med. 2021 Mar;10(6):1944-1954. doi: 10.1002/cam4.3672. Epub 2021 Feb 27.