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

  • PHASE I STUDIES
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Summary

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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Acknowledgments

The authors would like to express their appreciation to the patients who participated in this investigational study and study staff.

Conflict of Interest Statement

Ms. Adams, Dr. Leigh and Dr. Theuer are shareholders and employees of TRACON Pharmaceuticals. Dr. Gerson is a shareholder of TRACON Pharmaceuticals and he and Dr. Liu are inventors of patents relating to TRC102 that are assigned to Case Western Reserve University and licensed to TRACON Pharmaceuticals. The remaining authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Pinnacle Oncology Hematology, 9055 E. Del Camino, Suite 100, Scottsdale, AZ, 85258, USA

    Michael S. Gordon & David Mendelson

  2. Los Angeles Division of Hematology-Oncology, University of California, Santa Monica, CA, USA

    Lee S. Rosen & Jonathan Goldman

  3. Virginia G. Piper Cancer Center Clinical Trials at Scottsdale Healthcare (VGPCC)/TGen, Scottsdale, AZ, USA

    Ramesh K. Ramanathan & Glen J. Weiss

  4. Seidman Cancer Center, University Hospitals Case Medical Center, Cleveland, OH, USA

    Lili Liu, Yan Xu & Stanton L. Gerson

  5. Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, USA

    Lili Liu, Yan Xu & Stanton L. Gerson

  6. Evergreen Hematology & Oncology, Spokane, WA, USA

    Stephen P. Anthony

  7. SAIC-Frederick, Inc., Center for Cancer Research, Frederick National Laboratory for Cancer Research, and Medical Oncology Branch, National Cancer Institute, NIH, Frederick, MD, USA

    William D. Figg & Shawn Spencer

  8. TRACON Pharmaceuticals, San Diego, CA, USA

    Bonne J. Adams, Charles P. Theuer & Bryan R. Leigh

Authors
  1. Michael S. Gordon
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  2. Lee S. Rosen
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  3. David Mendelson
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  4. Ramesh K. Ramanathan
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  5. Jonathan Goldman
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  6. Lili Liu
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  7. Yan Xu
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  8. Stanton L. Gerson
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  9. Stephen P. Anthony
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  10. William D. Figg
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  11. Shawn Spencer
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  12. Bonne J. Adams
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  13. Charles P. Theuer
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  14. Bryan R. Leigh
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  15. Glen J. Weiss
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Corresponding author

Correspondence to Michael S. Gordon.

Additional information

Research Funding

This Research was supported by TRACON Pharmaceuticals Inc San Diego CA

Presented in part at the following conferences

2009 ASCO Annual Meeting, Orlando, FL; 2010 AACR-IASLC Joint Conference on the Molecular Origins of Lung Cancer, Coronado, CA; 2010 IASLC Targeted Therapies for Lung Cancer Meeting, Santa Monica, CA; 2010 ASCO Annual Meeting, Chicago, IL

Trial registry number

NCT00692159

Electronic supplementary material

Below is the link to the electronic supplementary material.

Figure S1

Raw pooled spaghetti-plot of 381 data points in taken of plasmaTRC102 on C1D1 and C1D4 in nineteen subjects used for population pharmacokinetic modeling. (PDF 30 kb)

Figure S2

Individual pharmacokinetic fits of plasma TRC102 on C1D1 and C1D4 in nineteen subjects, using the population parameters with the individual covariates (red) and the individual parameters with the individual covariates (green). (PDF 45 kb)

Figure S3

Observed and predicted values of plasma TRC102 following population PK modeling displays goodness of model fit - base model of population and individual parameters (left and middle) and covariate model (right). Circle displays improvement in correlation between observed and predicted values using covariate model. (PDF 65 kb)

Figure S4

Monte Carlo simulation of 90 % confidence interval for population predicted plasma TRC102 displays suitability of final model. (PDF 49 kb)

Figure S5

(a) Estimated population pharmacokinetic parameter distributions, F = Female, M = Male (*reference group) shows reduction in variability (spread) in volume of distribution for male and female patients using covariate model. (b): displays the PK parameter distributions for the base model without covariates. (PDF 22 kb)

Figure S6

Categorical covariate boxplots, F = Female (reference), M = Male shows differences between PK parameters by gender. (PDF 15 kb)

Figure S7

Clinical Correlate - Relationship between half-life for individual patients, and their baseline serum creatinine (Spearman’s correlation = 0.5453, P = 0.0157) (PDF 19 kb)

Figure S8

Fitting Diagnostics - Empirical Distribution of Population and Individual Weighted Residuals (PWRES and IWRES) and Normalized Prediction Distribution Error (NPDE) along with QQ plots. (PDF 42 kb)

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Gordon, M.S., Rosen, L.S., Mendelson, D. et al. A phase 1 study of TRC102, an inhibitor of base excision repair, and pemetrexed in patients with advanced solid tumors. Invest New Drugs 31, 714–723 (2013). https://doi.org/10.1007/s10637-012-9876-9

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  • DOI: https://doi.org/10.1007/s10637-012-9876-9

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