Matthew H. Taylor¹, Alan Sandler^1,2, Walter J. Urba³, Antonio M. P. Omuro⁴, Greg S. Gorman⁵, Rashida A. Karmali^6*

Show more
¹ Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA.
² Genentech, San Francisco, CA, USA.
³ Earle A Chiles Research Institute, Providence Cancer Center, Portland, OR, USA.
⁴ Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
⁵ Samford University, Birmingham, AL, USA.
⁶ Tactical Therapeutics Inc., New York, NY, USA.
Show less

Abstract: Pre-clinical studies suggest carboxyamidotriazole orotate (CTO) demonstrates anti-tumor activity through modulation of multiple tyrosine kinase signaling pathways and interactions with the tumor microenvironment. We determined the safety and tolerability, pharmacokinetic profile, maximum tolerated dose, and recommended Phase II dose of CTO monotherapy in patients with advanced solid tumors. In this first-in-human Phase I clinical trial, eligible patients with advanced solid tumors were enrolled to receive a once-daily dose of CTO following a standard 3 + 3 Phase I design (starting at 50 mg/m2/day) with dose escalations of 30% - 100%. Dose limiting toxicity (DLT) was defined in the first cycle of treatment. Measurable disease and response were defined by RECIST version 1.1. Forty-four patients were evaluable for safety. CTO-related grade 3 toxicities included diarrhea (2.5%), fatigue (5.0%), lymphopenia (2.5%) and transient creatine phosphokinase (CPK) elevation (2.5%). There were no grade 4 or 5 toxicities. Steady state plasma levels of CAI (CTO metabolite) were achieved by day 12 with a half life estimate of 55 hr. Although no objective response rates were observed, nine patients with rapidly progressive and treatment-refractory tumors achieved stable disease (SD) durable for up to 14 months. The maximum tolerated dose for CTO alone was 427 mg/m2/day. The dose-limiting toxicity was grade 3 fatigue. CTO is orally bioavailable, safe, well tolerated and produces disease stabilization in a broad range of heavily treated refractory tumors. Combination trials of CTO with other antineoplastic agents are ongoing.

Keywords: CTO, Safety, Ca-Dependent Signaling Pathways

Cite this paper: Taylor, M. , Sandler, A. , Urba, W. , Omuro, A. , Gorman, G. , Karmali, R. (2015) Effect of Carboxyamidotriazole Orotate, a Modulator of Calcium-Dependent Signaling Pathways, on Advanced Solid Tumors. Journal of Cancer Therapy, 6, 322-333. doi: 10.4236/jct.2015.64035.

References

[1]   Cole, K. and Kohn, E. (1994) Calcium-Mediated Signal Transduction: Biology, Biochemistry, and Therapy. Cancer and Metastasis Reviews, 13, 31-44.
http://dx.doi.org/10.1007/BF00690417

[2]   Corrado, C., Flugy, A.M., Taverna, S., Raimondo, S., Guggino, G., Karmali, R., et al. (2012) Carboxyamidotriazole-Orotate Inhibits the Growth of Imatinib-Resistant Chronic Myeloid Leukemia Cells and Modulates Exosomes-Stimulated Angiogenesis. PLoS ONE, 7, e42310.
http://dx.doi.org/10.1371/journal.pone.0042310

[3]   Karmali, R.A. and Miele, G. (2013) Pharmacodynamic Transcriptional Markers of Carboxyamidotriazole Orotate (CTO) Exposure in Anagen Hair. Molecular Cancer Therapeutics, 12, A233.
http://dx.doi.org/10.1158/1535-7163.TARG-13-A233

[4]   Bauer, K.S., Cude, K.J., Dixon, S.C., Kruger, E.A. and Figg, W.D. (2000) Carboxyamido-Triazole Inhibits Angiogenesis by Blocking the Calcium-Mediated Nitric Oxide Synthase-Vascular Endothelial Growth Factor Pathway. The Journal of Pharmacology and Experimental Therapeutics, 292, 31-37.

[5]   Berlin, J., Tutsch, K.D., Hutson, P., Cleary, J., Rago, R.P., Arzoomanian, R.Z., et al. (1997) Phase I Clinical and Pharmacokinetic Study of Oral Carboxyamidotrazole, a Signal Transduction Inhibitor. Journal of Clinical Oncology, 15, 781-789.

[6]   Kohn, E.C., Figg, W.D., Sarosy, G.A., Bauer, K.S., Davis, P.A., Soltis, M.J., et al. (1997) Phase I Trial of Micronized Formulation Carboxyamidotriazole in Patients with Refractory Solid Tumors: Pharmacokinetics, Clinical Outcome, and Comparison of Formulations. Journal of Clinical Oncology, 15, 1985-1993.

[7]   Bauer, K.S., Figg, W.D., Hamilton, J.M., Jones, E.C., Premkumar, A., Steinberg, S.M., et al. (1999) A Pharmacokinetically Guided Phase II Study of Carboxyamido-Triazole in Androgen-Independent Prostate Cancer. Clinical Cancer Research, 5, 2324-2329.

[8]   Berlin, J., Tutsch, K.D., Arzoomanian, R.Z., Alberti, D., Binger, K., Feierabend, C., et al. (2002) Phase I and Pharmacokinetic Study of a Micronized Formulation of Carboxyamidotriazole, a Calcium Signal Transduction Inhibitor: Toxicity, Bioavailability and the Effect of Food. Clinical Cancer Research, 8, 86-94.

[9]   Desai, A., Innocenti, F., Janisch, L., DeMario, M., Shepard, D., Ramirez, J., et al. (2004) A Phase I Trial of Pharmacokinetic Modulation of Carboxyamidotriazole (CAI) with Ketoconazole in Patients with Advanced Cancer. Cancer Chemotherapy and Pharmacology, 54, 377-384.
http://dx.doi.org/10.1007/s00280-004-0841-y

[10]   Bochis, R.J., Chabala, J.C. and Fisher H. (1986) 5 Amino or Substituted Amino 1, 2, 3-Triazoles. US Patent 4,590,201.

[11]   Karmali, R.A. (2013) Compositions and Processes for Preparing 5-Amino or Substituted Amino 1, 2, 3-Triazoles and Tri-Azole Orotate Formulations.US Patent 8,377,973.

[12]   Grover, G.J., Kelly, J., Moore, G., Jacoby, H., Karmali, R.A. and Gorman, G.S. (2007) Comparative Pharmacokinetics profile of Carboxyamidotriazole and Carboxyamidotriazole-Orotate. Cancer Therapy, 5, 437-442.

[13]   Kohn, E.C. and Liotta, L.A. (1990) L651582: A Novel Antiproliferative and Antimetastasis Agent. Journal of the National Cancer Institute, 82, 54-60.
http://dx.doi.org/10.1093/jnci/82.1.54

[14]   Felder, C.C., Ma, A.L., Liotta, L.A. and Kohn, E.C. (1991) The Antiproliferative and Antimetastatic Compound L651582 Inhibits Muscarinic Acetylcholine Receptor-Stimulated Calcium Influx and Arachidonic Acid Release. The Journal of Pharmacology and Experimental Therapeutics, 257, 967-971.

[15]   Kohn, E.C., Sandeen, M.A. and Liotta, L.A. (1992) In Vivo Efficacy of a Novel Inhibitor of Selected Signal Transduction Pathways Including Calcium, Arachidonate, and Inositol Phosphates. Cancer Research, 52, 3208-3212.

[16]   Kohn, E.C., Felder, C.C., Jacobs, W., Holmes, K.A., Day, A., Freer, R., et al. (1994) Structure-Function Analysis of Signal and Growth Inhibition by Carboxyamido-Triazole, CAI. Cancer Research, 54, 935-942.

[17]   Kohn, E.C., Alessandro, R., Spoonster, J., Wersto, R.P. and Liotta, L.A. (1995) Angiogenesis: Role of Calcium-Mediated Signal Transduction. Proceedings of the National Academy of Sciences of the United States of America, 92, 1307-1311.
http://dx.doi.org/10.1073/pnas.92.5.1307

[18]   Lambert, P.A., Somers, K.D., Kohn, E.C. and Perry, R.R. (1997) Antiproliferative and Antiinvasive Effects of Carboxyamidotriazole on Breast Cancer Cell Lines. Surgery, 122, 372-379.
http://dx.doi.org/10.1016/S0039-6060(97)90029-5

[19]   Karmali, R.A., Maxuitenko, Y., Gorman, G. and Page, J.G. (2011) Carboxyamidotriazole Orotate and Cytotoxic Chemotherapy Have a Synergistic Effect on Tumor Inhibition in Glioblastoma and Colon Xenograft Mouse Models. Cancer Therapy, 8, 71-80.

[20]   Karmali, R.A., Maxuitenko, Y.Y., Gorman, G.S. and Qu, Z.C. (2012) Combinatorial Treatment with Carboxyamidotriazole-Orotate and Temozolomide in SC-Implanted Human LOX IMVI Melanoma Xenografts. Journal of Solid Tumors, 2, 13-28.
http://dx.doi.org/10.5430/jst.v2n5p13

[21]   Karmali, R.A., Maxuitenko, Y. and Gorman, G. (2013) Treatment with Paclitaxel Orotate and Carboxyamidotriazole Orotate in SC-Implanted OVCAR-5 Human Ovarian Tumor Xenografts. Journal of Cancer Therapy, 4, 857-871.
http://dx.doi.org/10.4236/jct.2013.44098