A phase 1 study of TRC102, an inhibitor of base excision repair, and pemetrexed in patients with advanced solid tumors.
BACKGROUND
TRC102 potentiates the activity of cancer therapies that induce base excision repair (BER) including antimetabolite and alkylating agents. TRC102 rapidly and covalently binds to apurinic/apyrimidinic (AP) sites generated during BER, and TRC102-bound DNA causes topoisomerase II-dependent irreversible strand breaks and apoptosis. This study assessed the safety, maximum-tolerated dose (MTD), pharmacokinetics and pharmacodynamics of TRC102 alone and in combination with pemetrexed.


OBJECTIVE
Patients with advanced solid tumors received oral TRC102 daily for 4 days. Two weeks later, patients began standard-dose pemetrexed on day 1 in combination with oral TRC102 on days 1 to 4. The pemetrexed-TRC102 combination was repeated every 3 weeks until disease progression.


METHODS
Twenty-eight patients were treated with TRC102 at 15, 30, 60 or 100 mg/m(2)/d. The MTD was exceeded at 100 mg/m(2)/d due to grade 3 anemia in 50 % of patients. TRC102 exposure increased in proportion to dose with a mean t1/2 of 28 h. A pharmacodynamic assay confirmed that TRC102 binds to pemetrexed-induced AP sites at all doses studied. Stable disease or better was achieved in 15 of 25 patients evaluable for response (60 %), including one patient with recurrent metastatic oropharyngeal carcinoma that expressed high levels of thymidylate synthase, who achieved a partial response and was progression free for 14 months.


CONCLUSIONS
When administered with pemetrexed, the maximum tolerated dose of oral TRC102 is 60 mg/m(2)/d for 4 days. Randomized controlled studies are planned to evaluate the clinical benefit of adding TRC102 to pemetrexed and other agents that induce BER.
Pinnacle Oncology Hematology, 9055 E. Del Camino, Suite 100, Scottsdale, AZ, 85258, USA. mgordon@azpoh.com
Michael S
MS
Gordon
Lee S
LS
Rosen
David
D
Mendelson
Ramesh K
RK
Ramanathan
Jonathan
J
Goldman
Lili
L
Liu
Yan
Y
Xu
Stanton L
SL
Gerson
Stephen P
SP
Anthony
William D
WD
Figg
Shawn
S
Spencer
Bonne J
BJ
Adams
Charles P
CP
Theuer
Bryan R
BR
Leigh
Glen J
GJ
Weiss
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000740:Anemia / Q000139:chemically induced; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D004260:DNA Repair; D005260:Female; D005971:Glutamates / Q000008:administration & dosage / Q000009:adverse effects; D006147:Guanine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D006801:Humans; D006898:Hydroxylamines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D000068437:Pemetrexed; D055815:Young Adult
D000970:Antineoplastic Agents; D005971:Glutamates; D006898:Hydroxylamines; D000068437:Pemetrexed; D006147:Guanine; C005214:methoxyamine