RESUMEN
Our aim was to establish, in patients with solid tumors, the dose-limiting toxicity, maximum tolerated dose (MTD), and pharmacology of PNU-145156E, a new sulfonated distamycin A derivative that blocked circulating angiogenesis-promoting growth factors in animal studies and exhibited an antitumor effect in murine solid tumors. In a Phase I study, PNU-145156E was administered i.v. every 6 weeks. Included were patients with solid tumors; an Eastern Cooperative Oncology Group performance score
Asunto(s)
Inhibidores de la Angiogénesis/efectos adversos , Inhibidores de la Angiogénesis/farmacocinética , Distamicinas/efectos adversos , Distamicinas/farmacocinética , Neoplasias/tratamiento farmacológico , Adulto , Anciano , Inhibidores de la Angiogénesis/sangre , Área Bajo la Curva , Coagulación Sanguínea/efectos de los fármacos , Distamicinas/sangre , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Infusiones Intravenosas , Masculino , Tasa de Depuración Metabólica , Persona de Mediana Edad , Neoplasias/sangre , Selección de PacienteRESUMEN
Tallimustine [PNU 152241 (FCE 24517)] is a synthetic derivative of the DNA minor groove binder distamycin A, in which the NH2-terminal formyl group is substituted by benzoyl mustard. In this Phase I clinical trial, patients with advanced solid tumors received i.v. bolus injections of tallimustine daily for 3 consecutive days. Patients were treated at six dosage levels of 33.3 micrograms/m2/day to 250 micrograms/m2/day for 3 consecutive days, with courses of therapy repeated every 28 days. Detailed pharmacokinetic blood sampling was performed during the first 3 days of the first course of tallimustine. The plasma samples were analyzed by high-performance liquid chromatography with UV detection. Forty-eight eligible patients were treated at all six dosage levels. The dominant dose-related toxicity of tallimustine was neutropenia, becoming dose limiting at 250 micrograms/m2/day. At this dosage level, one patient experienced febrile neutropenia, and a second patient died on study of indeterminate cause. Thrombocytopenia was not observed, and only 10 patients developed anemia < 8.0 gm/dl. Sporadic elevation of liver enzymes or bilirubin was observed but was not dose related. Pharmacokinetic analysis gave reliable results for 33 patients. For most patients, analysis of the data best fit a three-exponential model. Dose-related increases in areas under the concentration-time curve and end-of-infusion concentrations were observed. There was no significant plasma accumulation of tallimustine over the 3 days of administration. The terminal half-life of tallimustine in individual patients ranged from 6.83 to 39.02 h following the last dose. In summary, the recommended Phase II dosage for tallimustine is 200 micrograms/m2/day for 3 consecutive days every 28 days. Neutropenia is the principal toxicity of this agent at this dosage and schedule.
Asunto(s)
Antineoplásicos/efectos adversos , Distamicinas/efectos adversos , Neoplasias/tratamiento farmacológico , Compuestos de Mostaza Nitrogenada/efectos adversos , Adulto , Anciano , Distamicinas/administración & dosificación , Distamicinas/farmacocinética , Femenino , Humanos , Masculino , Persona de Mediana Edad , Compuestos de Mostaza Nitrogenada/administración & dosificación , Compuestos de Mostaza Nitrogenada/farmacocinéticaRESUMEN
Despite progress in leukemia therapy, only 20-30% of patients with acute myelogenous leukemia (AML) are cured. 1-beta-D-arabinofuranosylcytosine- and topoisomerase II-reactive drugs are the primary therapeutic agents used. The aim of this study was to evaluate the potential activity of tallimustine in leukemia. In this study, we first investigated the efficacy and toxic effects of tallimustine, a distamycin-A derivative, in a human leukemia model in severe combined immunodeficient (SCID) mice. On the basis of its dramatic activity in this preclinical study, a Phase I study of tallimustine at a starting dose of 300 microgram/m2/day for 3 days every 3-4 weeks was conducted in patients with refractory or relapsed leukemia. In SCID mice grafted with a human myelomonocytic leukemia cell line, tallimustine resulted in complete remission of disease in most mice at tolerable dosages ranging from 0.86 to 3.0 mg/kg/day for 3 days and was combined effectively and safely with a 2-day schedule of high-dose ara-C. In the Phase I study, 26 patients with refractory or relapsed leukemia were treated. The maximum tolerated dose was 900 microgram/m2/day for 3 days every 3-4 weeks. This dose was 3 times higher than the maximum tolerated dose in solid tumors and was limited by severe mucositis. Magnesium and potassium wasting were also observed, but other side effects (fatigue and gastrointestinal) were minor. Two (8%) patients with AML achieved complete remission and two achieved hematological improvement with persistent thrombocytopenia. The results of this study indicate that tallimustine has promising activity in AML. Future studies may combine tallimustine with other agents known to be active against AML, and investigate its activity in other hematological malignancies. The recommended Phase II single-agent dose of tallimustine is 750-900 microgram/m2/day for 3 days, and combination studies may start at 50-66% of this dose schedule. The SCID mouse model of human leukemia may be promising in the preclinical evaluation and selection of potential antileukemic agents.
Asunto(s)
Antineoplásicos/efectos adversos , Distamicinas/efectos adversos , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia/tratamiento farmacológico , Compuestos de Mostaza Nitrogenada/efectos adversos , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Animales , Antineoplásicos/administración & dosificación , Citarabina/uso terapéutico , Diarrea/inducido químicamente , Distamicinas/administración & dosificación , Esquema de Medicación , Femenino , Humanos , Inyecciones Intravenosas , Leucemia Mielomonocítica Aguda/tratamiento farmacológico , Ratones , Ratones SCID , Persona de Mediana Edad , Náusea/inducido químicamente , Compuestos de Mostaza Nitrogenada/administración & dosificación , Trasplante Heterólogo , Células Tumorales Cultivadas , Vómitos/inducido químicamenteRESUMEN
Tallimustine binds to the minor groove of DNA where it alkylates the N3 position of adenine and may interfere with gene transcription. We conducted a phase II trial of Tallimustine given at a dose of 750 micrograms/m2 intravenously every 4 weeks in patients with small cell lung cancer progressing or relapsing following cisplatin or carboplatin-based chemotherapy. We treated 14 eligible patients with a performance status 0, 1 or 2, bi-dimensionally measurable disease and adequate end-organ function. The main toxicity was neutropenia with a median granulocyte count of 0.1 x 10(9) per liter (range 0-3.9) and four patients (27%) developing febrile neutropenia. In addition, most patients (93%) experienced lethargy. No objective responses were seen. A mixed response was seen in one patient and three others had stable disease for a median of 3.7 months. We conclude that Tallimustine is an ineffective agent in previously treated small cell lung cancer.
Asunto(s)
Antineoplásicos/uso terapéutico , Carcinoma de Células Pequeñas/tratamiento farmacológico , Distamicinas/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Compuestos de Mostaza Nitrogenada/uso terapéutico , Anciano , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Canadá , Carcinoma de Células Pequeñas/mortalidad , Carcinoma de Células Pequeñas/patología , Progresión de la Enfermedad , Distamicinas/administración & dosificación , Distamicinas/efectos adversos , Relación Dosis-Respuesta a Droga , Femenino , Estudios de Seguimiento , Humanos , Infusiones Intravenosas , Recuento de Leucocitos , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia , Neutropenia/sangre , Neutropenia/inducido químicamente , Compuestos de Mostaza Nitrogenada/administración & dosificación , Compuestos de Mostaza Nitrogenada/efectos adversosRESUMEN
BACKGROUND: Tallimustine, a benzoyl nitrogen mustard derivative of the antiviral agent distamycin A, is a new alkylating agent which binds to A-T rich regions of DNA in the minor groove producing highly sequence-specific alkylations. Its main preclinical features are a significant antitumor activity in animal models and a lack of cross-resistance in vitro and in vivo with L-PAM. Myelotoxicity was dose-limiting in animals, with a more than 100-fold difference in bone marrow sensitivity between mice and dogs. PATIENTS AND METHODS: Forty adult patients (pts) with solid malignancies were entered in the study. The drug was administered as an IV bolus every 4 weeks. CBC was repeated twice a week and serial assessments of renal function were performed in the week following the first cycle. From the starting dose of 50 micrograms/m2, corresponding to 1/3 of the highest non-toxic dose (HNTD) in dogs, there were increases through 10 dose levels, with reliance only on the features of the myelotoxicity observed. RESULTS: The main toxic effect was neutropenia which was dose-limiting, selective and short-lasting. Only previously-untreated pts received doses of 750 micrograms/m2 or more, with grade 4 neutropenia occurring in > or = 75% of the cycles. The maximally tolerable dose (MTD) was defined as 1250 micrograms/m2, with 3 of 3 pts developing febrile neutropenia requiring IV antibiotics. A platelet count of < 100 x 10(3)/microliters was observed in only one pt. Bone marrow aspiration performed in selected pts on days 8 and 15 confirmed a highly selective impairment by tallimustine of the myeloid lineage, with rapid recovery of the proliferative compartment. Pharmacokinetic studies performed at 1000 micrograms/m2 and 1250 micrograms/m2 showed a rapid fall of the plasma levels within the first 2 hours with drug concentrations between 100 ng/ml and 400 ng/ml within the first hour. A partial response of 4 months' duration was reported in one previously-untreated pt with cutaneous recurrences of malignant mesothelioma. CONCLUSIONS: The report of some antitumour efficacy, the high selectivity of neutropenia, the lack of significant non-hematological toxic effects and the occurrence of detectable but still low plasma drug concentrations suggest that further clinical evaluation of higher doses of tallimustine in combination with colony-stimulating factors would be justified.