Summary
Carbetimer (carboxyimamidate) is a low molecular weight derivative of ethylene/maleic anhydride polymer. This compound has demonstrated antitumor activity against several animal models with a daily x 5 schedule appearing most effective. A phase I clinical study of the daily x 5 schedule repeated every 28 days was therefore performed. Forty-one evaluable patients received 66 evaluable cycles of Carbetimer at daily doses ranging from 100–11000 mg/m2. Hypercalcemia was the dose limiting toxicity with both patients at the 11000 mg/m2 daily dose level and one patient who received 6 cycles of drug at the 4200 mg/m2 dose level developing severe hypercalcemia not explained by the underlying malignancy. Mild nausea, concentration and rate dependent arm pain at the site of infusion, proteinuria, and coagulopathy were also seen. Calcium balance studies revealed hypercalciuria, suggesting increased mobilization of calcium rather than renal retention. In vitro coagulation studies revealed concentration dependent prolongation of the partial thromboplastin time and thrombin time. No complete or partial responses were seen. However mixed response or biochemical response (reduction in serum lactic dehydrogenase) were seen in 5 patients with melanoma or renal cancer. Due to unacceptable toxicity at the 11000 mg/m2 daily dose level, Carbetimer 8500 mg/m2 is the recommended dose for a 5-day treatment schedule every 28 days. Special attention should be directed toward possible activity against melanoma and renal cancer.
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References
Regelson W: Future direction of synthetic polyanions (pyran copolymer). Cancer Treat Rep 62: 1853–1856, 1978
Regelson W: The biological activity of the synthetic polyanion, pyran copolymer (Diveema, MVE, 46015) and the heterocyclic Bis DEAE fluorenone derivative, Tolorone and congeners: Clinical and laboratory effects of these agents as modulators of host resistance. PharmacTher 15: 1–44, 1981
Fields JE, Asculai SS, Johnson JH, Johnson RK: Carboxyimamidate, a low-molecular-weight polyelectrolyte with antitumor properties and low toxicity. J Med Chem 25: 1060–1064, 1982
Falk RE, Makowka L, Nossal NA, Rotstein LE, Falk JA: Comparison of the antitumor effects of a synthetic biopolymer and standard adjuvants. Surgery 88: 126–136, 1980
Carbetimer Investigational Brochure, GD Searle & Co, February 24, 1988
Rozencweig M, Von Hoff DD, Staquet MJ, Penta JS, Guarino AM, Muggia FM: Animal toxicology for early clinical trials (Abstr) Proc Amer Assoc Cancer Res Amer Soc Clin Oncol 20: 26, 1979
Miller AB, Hoogstraten B, Staquet M, Winkler A: Reporting results of cancer treatment. Cancer 47: 207–214, 1981
Kisner D, Paget GE, Melink T, Weiss G, Kuhn J, Von Hoff D: Phase I clinical trial of carbetimer (Abstr) Proc Amer Soc Clin Oncol 3: 23, 1984
Toueini E, Dodion P, De Valeriola D, Crespeigne N, Piccart M, Ries F, Hochster H, Kenis Y: Phase I trial with carbetimer given on a 5-day schedule (Abstr) Fifth NCI-EORTC Symposium on New Drugs in Cancer Therapy. October 22–24, 1986, Amsterdam, The Netherlands, Abstract 8.15
Berdel WE, Schick HD, Danhauser-Riedl S, Fink U, Remy W, Reichert A, Ankele A, Prauer HW, Siewert JR, Rastetter J: Phase I trial of the polyelectrolyte carbetimer administered i.v. once every four weeks. Invest New Drugs 6: 189, 1988
Hanauske A-R, Melink TJ, Harman GS, Clark GM, Craig JB, Koeller JM, Boldt DH, Kantor B, Kisner DL, Orczyk G, Anderson DW, Paget E, Sarosy GA, Von Hoff DD: Phase I clinical trial of carbetimer. Cancer Res 48: 5353–5357, 1988
Luna MC, Ardalan B, Orczyk G: Studies on the mechanism of Carbetimer induced hypercalcemia (Abstr) Proc Amer Assoc Cancer Res 28: 443, 1987
Regelson W: The growth-regulating activity of polyanions: A theoretical discussion of their place in the intercellular environment and their role in cell physiology. Adv Cancer Res 11: 223–304, 1968
Powell ML, Hersh EM, Gutterman JU, Zander AR, Granati L, Alexanian R, Hortobagyi G, Murphy SG: Phase I study of MVE-2 therapy in human cancer. Proc Amer Assoc Cancer Res 22: 189, 1981
Machovich R, Nagy M, Gyorgyi-Edelenyi J, Csomor K, Horvath I: Anticoagulant effect of sulphated poly/vinyl alcohol-acrylic acid/copolymers. Thromb Haemost 56: 397–400, 1986
Fromm M, Schick HD, Fink U, Reichert A, Rastetter J, Berdel WE: Phase I trial of the low-molecular weight polyelectrolyte Carbetimer administered i.v. (Abstr) Proc Amer Assoc Cancer Res 27: 206, 1986
Kisner DL, Mehta P, Paget GE, Von Hoff DD: Activity of Carbetimer in a human tumor cloning system. Invest New Drugs 2: 55–58, 1984
Harris GJ, Turner JN, Von Hoff DD: Growth of carcinoma of the esophagus and gastroesophageal junction in a human tumor cloning assay. Cancer Drug Deliv 3: 273–278, 1986
Fromm M, Schick HD, Scheiber H, Fink U, Reichert A, Rastetter J, Berdel WE: Assay-dependent toxicity of the low-molecular weight polyelectrolyte Carbetimer in cells from human tumors and leukemias in vitro and report on a clinical Phase I trial (Abstr) Proc Amer Soc Clin Oncol 4: 29, 1985
Ardalan B, Paget GE: Mechanism of action of a new antitumor agent, Carbetimer. Cancer Res 46: 5473–5476, 1986
Hrishikeshavan HJ, Ardalan B, Paget E: Inhibition of cyclic nucleotide phosphodiesterase by Carbetimer in a human melanoma (Abstr) Proc Amer Assoc Cancer Res 27: 280, 1986
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Grunberg, S.M., Ehler, E., Francis, R.B. et al. Phase I trial of a 5-day course of carbetimer. Invest New Drugs 8 (Suppl 1), S41–S49 (1990). https://doi.org/10.1007/BF00171983
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DOI: https://doi.org/10.1007/BF00171983