PMID- 32556884
OWN - NLM
STAT- MEDLINE
DCOM- 20220131
LR  - 20220202
IS  - 1573-0646 (Electronic)
IS  - 0167-6997 (Print)
IS  - 0167-6997 (Linking)
VI  - 39
IP  - 1
DP  - 2021 Feb
TI  - Phase I clinical trial of temozolomide and methoxyamine (TRC-102), an inhibitor 
      of base excision repair, in patients with advanced solid tumors.
PG  - 142-151
LID - 10.1007/s10637-020-00962-x [doi]
AB  - Temozolomide (TMZ) generates DNA adducts that are repaired by direct DNA and base 
      excision repair mechanisms. Methoxyamine (MX, TRC-102) potentiates TMZ activity 
      by binding to apurinic and apyrimidinic (AP) sites after removal of 
      N(3)-methyladenine and N(7)-methylguanine, inhibiting site recognition of AP 
      endonuclease. We conducted a phase I trial to determine the maximum tolerated 
      dose and dose-limiting toxicities (DLTs) of intravenous MX when given with oral 
      TMZ. Patients with advanced solid tumors and progression on standard treatment 
      were enrolled to a standard 3 + 3 dose escalation trial assessing escalating 
      doses of TMZ and MX. Tumor response was assessed per RECIST and adverse events 
      (AEs) by CTCAEv3. Pharmacokinetics (PK) of MX and COMET assays on peripheral 
      blood mononuclear cells were performed. 38 patients were enrolled-median age 
      59.5 years (38-76), mean number of cycles 2.9 [1-13]. No DLTs were observed. 
      Cycle 1 grade 3 AEs included fatigue, lymphopenia, anemia, INR, leukopenia, 
      neutropenia, allergic reaction, constipation, psychosis and paranoia. Cycle 2-13 
      grade 4 AEs included thrombocytopenia and confusion. A partial response was seen 
      in 1 patient with a pancreatic neuroendocrine tumor (PNET) and six additional 
      patients, each with different tumor types, demonstrated prolonged stable disease. 
      MX PK was linear with dose and was not affected by concomitant TMZ. TMZ 
      200 mg/m(2) daily x 5 may be safely administered with MX 150 mg/m(2) 
      intravenously once on day 1 with minimal toxicity. Further studies assessing this 
      drug combination in select tumor types where temozolomide has activity may be 
      warranted.
FAU - Eads, Jennifer R
AU  - Eads JR
AD  - Case Comprehensive Cancer Center, Case Western Reserve University, University 
      Hospitals Seidman Cancer Center, 11100 Euclid Avenue, Lakeside 1200, Cleveland, 
      OH, 44106, USA.
FAU - Krishnamurthi, Smitha S
AU  - Krishnamurthi SS
AD  - Case Comprehensive Cancer Center, Case Western Reserve University, University 
      Hospitals Seidman Cancer Center, 11100 Euclid Avenue, Lakeside 1200, Cleveland, 
      OH, 44106, USA.
FAU - Saltzman, Joel
AU  - Saltzman J
AD  - Case Comprehensive Cancer Center, Case Western Reserve University, University 
      Hospitals Seidman Cancer Center, 11100 Euclid Avenue, Lakeside 1200, Cleveland, 
      OH, 44106, USA.
FAU - Bokar, Joseph A
AU  - Bokar JA
AD  - Case Comprehensive Cancer Center, Case Western Reserve University, University 
      Hospitals Seidman Cancer Center, 11100 Euclid Avenue, Lakeside 1200, Cleveland, 
      OH, 44106, USA.
FAU - Savvides, Panos
AU  - Savvides P
AD  - St. Joseph's Hospital and Medical Center, University of Arizona Comprehensive 
      Cancer Center, University of Arizona, Phoenix, AZ, USA.
FAU - Meropol, Neal J
AU  - Meropol NJ
AD  - Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, 
      USA.
AD  - Flatiron Health, New York, NY, USA.
FAU - Gibbons, Joseph
AU  - Gibbons J
AD  - Case Comprehensive Cancer Center, Case Western Reserve University, University 
      Hospitals Seidman Cancer Center, 11100 Euclid Avenue, Lakeside 1200, Cleveland, 
      OH, 44106, USA.
FAU - Koon, Henry
AU  - Koon H
AD  - Case Comprehensive Cancer Center, Case Western Reserve University, University 
      Hospitals Seidman Cancer Center, 11100 Euclid Avenue, Lakeside 1200, Cleveland, 
      OH, 44106, USA.
FAU - Sharma, Neelesh
AU  - Sharma N
AD  - Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
FAU - Rogers, Lisa
AU  - Rogers L
AD  - Case Comprehensive Cancer Center, Case Western Reserve University, University 
      Hospitals Seidman Cancer Center, 11100 Euclid Avenue, Lakeside 1200, Cleveland, 
      OH, 44106, USA.
FAU - Pink, John J
AU  - Pink JJ
AD  - Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, 
      USA.
FAU - Xu, Yan
AU  - Xu Y
AD  - Case Comprehensive Cancer Center, Cleveland State University, Cleveland, OH, USA.
FAU - Beumer, Jan H
AU  - Beumer JH
AD  - UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA.
FAU - Riendeau, John
AU  - Riendeau J
AD  - Case Comprehensive Cancer Center, Case Western Reserve University, University 
      Hospitals Seidman Cancer Center, 11100 Euclid Avenue, Lakeside 1200, Cleveland, 
      OH, 44106, USA.
FAU - Fu, Pingfu
AU  - Fu P
AD  - Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, 
      USA.
FAU - Gerson, Stanton L
AU  - Gerson SL
AD  - Case Comprehensive Cancer Center, Case Western Reserve University, University 
      Hospitals Seidman Cancer Center, 11100 Euclid Avenue, Lakeside 1200, Cleveland, 
      OH, 44106, USA.
FAU - Dowlati, Afshin
AU  - Dowlati A
AUID- ORCID: 0000-0003-4535-6839
AD  - Case Comprehensive Cancer Center, Case Western Reserve University, University 
      Hospitals Seidman Cancer Center, 11100 Euclid Avenue, Lakeside 1200, Cleveland, 
      OH, 44106, USA. Afshin.dowlati@case.edu.
LA  - eng
GR  - R01 CA086357/CA/NCI NIH HHS/United States
GR  - R21 CA126149/CA/NCI NIH HHS/United States
GR  - P30 CA047904/CA/NCI NIH HHS/United States
GR  - K12 CA076917/CA/NCI NIH HHS/United States
GR  - P30 CA043703/CA/NCI NIH HHS/United States
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20200617
PL  - United States
TA  - Invest New Drugs
JT  - Investigational new drugs
JID - 8309330
RN  - 0 (Antineoplastic Agents, Alkylating)
RN  - 0 (Hydroxylamines)
RN  - 9TZH4WY30J (methoxyamine)
RN  - YF1K15M17Y (Temozolomide)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Antineoplastic Agents, Alkylating/administration & dosage/adverse 
      effects/pharmacokinetics/*therapeutic use
MH  - Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics/therapeutic use
MH  - Area Under Curve
MH  - DNA Repair/drug effects
MH  - Dose-Response Relationship, Drug
MH  - Drug Synergism
MH  - Female
MH  - Half-Life
MH  - Humans
MH  - Hydroxylamines/administration & dosage/adverse 
      effects/pharmacokinetics/*therapeutic use
MH  - Male
MH  - Maximum Tolerated Dose
MH  - Metabolic Clearance Rate
MH  - Middle Aged
MH  - Neoplasms/*drug therapy
MH  - Temozolomide/adverse effects/pharmacokinetics/*therapeutic use
PMC - PMC7744386
MID - NIHMS1605069
OTO - NOTNLM
OT  - DNA repair
OT  - Methoxyamine
OT  - Phase I
OT  - TRC-102
OT  - Temozolomide
COIS- Conflict of Interest: Jennifer Eads reports no conflict of interest. Smitha S. 
      Krishnamurthi reports no conflict of interest Joel Saltzman reports no conflict 
      of interest Joseph A. Bokar reports no conflict of interest Panos Savvides 
      reports no conflict of interest Neal J. Meropol is an employee of Flatiron 
      Health, Inc., an independent subsidiary of the Roche Group. NJM holds equity 
      interest in Flatiron Health and Roche Joseph Gibbons reports no conflict of 
      interest Henry Koon is an employee of Bristol Myers Squibb Neelesh Sharma is an 
      employee of Novartis Lisa Rogers reports no conflict of interest John J. Pink 
      reports no conflict of interest Yan Xu reports no conflict of interest Jan H. 
      Beumer reports no conflict of interest John Riendeau reports no conflict of 
      interest Pingfu Fu reports no conflict of interest Stanton L. Gerson is inventor 
      of a patent on methoxyamine. The intellectual property on methoxyamine has been 
      licensed by Case Western Reserve University to Tracon Pharmaceuticals, Inc., and 
      Dr. Gerson owns stock in, and is a paid consultant for Tracon Pharmaceuticals, 
      Inc. Afshin Dowlati reports research support (to institution) by Ipsen, Tesaro, 
      Takeda, Astra Zeneca, Bayer, Eli-Lilly, Abbvie, Seattle Genetics, Bristol 
      Myers-Squibb, Regeneron, Amgen, Symphogen. Dr. Dowlati reports advisory role for 
      Seattle Genetics, Takeda, Abbvie, Bristol Myers-Squibb and Astra Zeneca
EDAT- 2020/06/20 06:00
MHDA- 2022/02/01 06:00
PMCR- 2022/02/01
CRDT- 2020/06/20 06:00
PHST- 2020/05/17 00:00 [received]
PHST- 2020/06/11 00:00 [accepted]
PHST- 2020/06/20 06:00 [pubmed]
PHST- 2022/02/01 06:00 [medline]
PHST- 2020/06/20 06:00 [entrez]
PHST- 2022/02/01 00:00 [pmc-release]
AID - 10.1007/s10637-020-00962-x [pii]
AID - 10.1007/s10637-020-00962-x [doi]
PST - ppublish
SO  - Invest New Drugs. 2021 Feb;39(1):142-151. doi: 10.1007/s10637-020-00962-x. Epub 
      2020 Jun 17.