Final results from a phase I study of oral TRC102 (methoxyamine HCl), an inhibitor of base-excision repair, to potentiate the activity of pemetrexed in patients with refractory cancer.
2010; Lippincott Williams & Wilkins; Volume: 28; Issue: 15_suppl Linguagem: Inglês
10.1200/jco.2010.28.15_suppl.2576
ISSN1527-7755
AutoresGlen J. Weiss, Michael Gordon, Lee S. Rosen, P. Savvides, B. J. Adams, Delia Alvarez, L. Liu, Yan‐Ming Xu, S L Gerson, B. R. Leigh,
Tópico(s)Acute Lymphoblastic Leukemia research
Resumo2576 Background: TRC102 is a small-molecule inhibitor of base-excision repair (BER) that is nearly completely bioavailable after oral administration. TRC102 covalently binds to apurinic/apyrimidinic (AP) sites induced by alkylator or antimetabolite chemotherapy. TRC102-bound DNA is not a substrate for BER enzymes and is instead cleaved by topoisomerase II resulting in double-strand breaks that trigger apoptosis. Methods: The safety, pharmacokinetics (PK), and pharmacodynamics (PD) of oral TRC102 combined with i.v. pemetrexed was evaluated in patients with advanced refractory cancer. Patients were required to have ECOG PS ≤ 1 and adequate organ function. TRC102 alone was administered on days 1- 4 of a 2-week cycle followed by TRC102 (D1-4) and 500 mg/m2 pemetrexed (D1) every 3 weeks thereafter. Results: 28 patients were enrolled and treated with a total of 93 cycles of TRC102 at 15 mg/m2 (n=4), 30 mg/m2 (n=7), 60 mg/m2 (n=11) and 100 mg/m2 (n=6). The maximum tolerated dose (MTD) was exceeded at 100 mg/m2 due to grade 3 anemia in 50% of patients. No other DLTs were reported. Other adverse events possibly related to TRC102 included grade 3/4 neutropenia without fever, grade 3 thrombocytopenia, grade 1/2 fatigue, and grade 1/2 asthenia. TRC102 plasma concentrations required for in vivo activity were achieved at all dose levels studied (Cmax > 50 ng/mL, t3/4 > 24 hr). PD studies confirmed that TRC102 binds pemetrexed-induced AP sites. One patient at 30 mg/m2 TRC102 with tonsillar squamous cell cancer metastatic to the lung had RECIST-defined PR that is ongoing in cycle 14. Stable disease for ≥ 3 cycles was seen in 3 patients at 30 mg/m2, 2 patients at 60 mg/m2, and 4 patients at 100 mg/m2, including one patient with squamous cell lung cancer who had SD for 9 cycles. Conclusions: Daily oral TRC102 is well-tolerated at doses expected to inhibit BER and potentiate the activity of chemotherapy. The recommended phase II dose is 60 mg/m2 p.o. for 4 days in combination with standard dose pemetrexed. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration TRACON Pharma TRACON Pharma TRACON Pharma TRACON Pharma
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