Phase I clinical trial of carbetimer.
Carbetimer (carbethimer, N-137, NED-137, carboxyimamidate) is a low molecular weight polyelectrolyte with antitumor activity in a variety of tumor models. This phase I trial evaluated a single dose of carbetimer infused over 1-2 h every 28 days. Forty-three patients received 71 courses of the drug at doses ranging from 180 to 8500 mg/m2. The dose-limiting toxicity was hypercalcemia (serum calcium greater than 12.5 mg/dl) noted in two of three patients at a dose of 8500 mg/m2. Serum calcium levels between 10.5 and 12.5 mg/dl were noted in an additional three patients treated at doses greater than or equal to 1600 mg/m2. Calcium balance studies in three patients treated at 6500 mg/m2 revealed an increase in urinary cyclic AMP and phosphate excretion after treatment accompanied by a mild elevation of serum parathyroid hormone. Immunological studies in these patients revealed a statistically significant increase in the percentage of peripheral T-helper cells. An increase in the T-helper/suppressor cell ratio was observed in two of the three patients studied. Interleukin 2 production by phytohemagglutinin-stimulated peripheral mononuclear cells was increased in two of three patients. One patient with a renal cell carcinoma showed a mixed response. The recommended dose for phase II trials as assessed from this study is 6500 mg/m2 as a single dose every 28 days.
Hanauske
A R
AR
Department of Medicine/Oncology, University of Texas Health Science Center, San Antonio 78284.
Melink
T J
TJ
Harman
G S
GS
Clark
G M
GM
Craig
J B
JB
Koeller
J M
JM
Boldt
D H
DH
Kantor
B
B
Kisner
D L
DL
Orczyk
G
G
D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use; D002118:Calcium / Q000097:blood / Q000652:urine; D000242:Cyclic AMP / Q000652:urine; D004341:Drug Evaluation; D005260:Female; D006801:Humans; D007376:Interleukin-2 / Q000096:biosynthesis; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D010710:Phosphates / Q000652:urine; D011108:Polymers / Q000009:adverse effects / Q000627:therapeutic use*; D012709:Serum Albumin / Q000032:analysis
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D007376:Interleukin-2; D010710:Phosphates; D011108:Polymers; D012709:Serum Albumin; C022084:carboxyimamidate; D000242:Cyclic AMP; D002118:Calcium