A phase 1 study of TRC102, an inhibitor of base excision repair, and pemetrexed in patients with advanced solid tumors

Michael S. Gordon, Lee S. Rosen, David Mendelson, Ramesk K Ramanathan, Jonathan Goldman, Lili Liu, Yan Xu, Stanton L. Gerson, Stephen P. Anthony, William D. Figg, Shawn Spencer, Bonne J. Adams, Charles P. Theuer, Bryan R. Leigh, Glen J. Weiss

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

Introduction 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. Purpose 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/m2/d. The MTD was exceeded at 100 mg/m2/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/m2/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.

Original languageEnglish (US)
Pages (from-to)714-723
Number of pages10
JournalInvestigational New Drugs
Volume31
Issue number3
DOIs
StatePublished - Jun 2013
Externally publishedYes

Fingerprint

Pemetrexed
DNA Repair
Maximum Tolerated Dose
Neoplasms
Antimetabolites
Thymidylate Synthase
Type II DNA Topoisomerase
Alkylating Agents
Disease Progression
Anemia
Pharmacokinetics
Apoptosis
Carcinoma
Safety

Keywords

  • Base excision repair
  • First-in-human
  • Methoxyamine
  • Pemetrexed
  • Phase 1
  • TRC102

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Oncology

Cite this

A phase 1 study of TRC102, an inhibitor of base excision repair, and pemetrexed in patients with advanced solid tumors. / Gordon, Michael S.; Rosen, Lee S.; Mendelson, David; Ramanathan, Ramesk K; Goldman, Jonathan; Liu, Lili; Xu, Yan; Gerson, Stanton L.; Anthony, Stephen P.; Figg, William D.; Spencer, Shawn; Adams, Bonne J.; Theuer, Charles P.; Leigh, Bryan R.; Weiss, Glen J.

In: Investigational New Drugs, Vol. 31, No. 3, 06.2013, p. 714-723.

Research output: Contribution to journalArticle

Gordon, MS, Rosen, LS, Mendelson, D, Ramanathan, RK, Goldman, J, Liu, L, Xu, Y, Gerson, SL, Anthony, SP, Figg, WD, Spencer, S, Adams, BJ, Theuer, CP, Leigh, BR & Weiss, GJ 2013, 'A phase 1 study of TRC102, an inhibitor of base excision repair, and pemetrexed in patients with advanced solid tumors', Investigational New Drugs, vol. 31, no. 3, pp. 714-723. https://doi.org/10.1007/s10637-012-9876-9
Gordon, Michael S. ; Rosen, Lee S. ; Mendelson, David ; Ramanathan, Ramesk K ; Goldman, Jonathan ; Liu, Lili ; Xu, Yan ; Gerson, Stanton L. ; Anthony, Stephen P. ; Figg, William D. ; Spencer, Shawn ; Adams, Bonne J. ; Theuer, Charles P. ; Leigh, Bryan R. ; Weiss, Glen J. / A phase 1 study of TRC102, an inhibitor of base excision repair, and pemetrexed in patients with advanced solid tumors. In: Investigational New Drugs. 2013 ; Vol. 31, No. 3. pp. 714-723.
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abstract = "Introduction 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. Purpose 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/m2/d. The MTD was exceeded at 100 mg/m2/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/m2/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.",
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AU - Rosen, Lee S.

AU - Mendelson, David

AU - Ramanathan, Ramesk K

AU - Goldman, Jonathan

AU - Liu, Lili

AU - Xu, Yan

AU - Gerson, Stanton L.

AU - Anthony, Stephen P.

AU - Figg, William D.

AU - Spencer, Shawn

AU - Adams, Bonne J.

AU - Theuer, Charles P.

AU - Leigh, Bryan R.

AU - Weiss, Glen J.

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N2 - Introduction 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. Purpose 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/m2/d. The MTD was exceeded at 100 mg/m2/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/m2/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.

AB - Introduction 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. Purpose 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/m2/d. The MTD was exceeded at 100 mg/m2/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/m2/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.

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