RESUMEN
This phase II trial was undertaken to determine the toxicities, response rate, pharmacokinetics and frequency of human anti-mouse antibody (HAMA) and anti-ricin antibody (HARA) when the B-cell restricted immunotoxin anti-B4-bR was administered to patients with previously treated multiple myeloma (MM). Five patients with MM were scheduled to receive a 7 d continuous infusion of anti-B4-bR. The initial four patients received therapy at 40 microg/kg lean body weight (LBW)/d. Two patients received a 7 d infusion, one patient received 6 d, and another patient 5 d of therapy. The fifth patient was treated for 7 d at a lower dose of 30 microg/kg LBW/d because of the side-effects observed in the initial patients. Pharmacokinetic studies demonstrated a peak serum level >2.6 nM in three of the patients. Side-effects of therapy included hepatic transaminase elevations, myalgias, thrombocytopenia, nausea, vomiting, decrease in performance status, and capillary leak syndrome. One patient developed HAMA and two patients HARA. One patient developed neurologic toxicity with akinetic mutism, and died following therapy. No patient demonstrated a significant decline in M-component during therapy. We concluded that anti-B4-bR can be administered by continuous infusion to patients with multiple myeloma, although immunotoxin levels >3 nM were associated with increased incidence of toxicity and required dose adjustment. Future trials using anti-B4-bR in MM will be needed to determine the optimal dose and administration schedule in this patient population, and to determine whether there is evidence of biologic activity.
Asunto(s)
Anticuerpos Monoclonales/administración & dosificación , Antígenos CD19/inmunología , Inmunotoxinas/administración & dosificación , Mieloma Múltiple/terapia , Ricina/administración & dosificación , Adulto , Anciano , Anticuerpos Monoclonales/sangre , Femenino , Humanos , Inmunotoxinas/sangre , Inmunotoxinas/farmacocinética , Infusiones Intravenosas , Masculino , Mieloma Múltiple/sangre , Ricina/sangreRESUMEN
PURPOSE: Immunotoxins could improve outcome in small-cell lung cancer (SCLC) by targeting tumor cells that are resistant to chemotherapy and radiation. N901 is a murine monoclonal antibody that binds to the CD56 (neural cell adhesion molecule [NCAM]) antigen found on cells of neuroendocrine origin, including SCLC. N901-bR is an immunoconjugate of N901 antibody with blocked ricin (bR) as the cytotoxic effector moiety. N901-bR has more than 700-fold greater selectivity in vitro for killing the CD56+ SCLC cell line SW-2 than for an antigen-negative lymphoma cell line. Preclinical studies suggested the potential for clinically significant cardiac and neurologic toxicity. We present a phase I study of N901-bR in relapsed SCLC. PATIENTS AND METHODS: Twenty-one patients (18 relapsed, three primary refractory) with SCLC were entered onto this study. Successive cohorts of at least three patients were treated at doses from 5 to 40 microg/kg/d for 7 days. The initial three cohorts received the first day's dose (one seventh of planned dose) as a bolus infusion before they began the continuous infusion on the second day to observe acute toxicity and determine bolus pharmacokinetics. Toxicity assessment included nerve-conduction studies (NCS) and radionuclide assessment of left ventricular ejection fraction (LVEF) before and after N901-bR administration to fully assess potential neurologic and cardiac toxicity. RESULTS: The dose-limiting toxicity (DLT) of N901-bR given by 7-day continuous infusion is capillary leak syndrome, which occurred in two of three patients at the dose of 40 microg/kg (lean body weight [LBW])/d. Detectable serum drug levels equivalent to effective in vitro drug levels were achieved at the 20-, 30-, and 40-microg/kg(LBW)/d dose levels. Specific binding of the immunotoxin to tumor cells in bone marrow, liver, and lung was observed. Cardiac function remained normal in 15 of 16 patients. No patient developed clinically significant neuropathy. However, a trend was noted for amplitude decline in serial NCS of both sensory and motor neurons. One patient with refractory SCLC achieved a partial response. CONCLUSION: N901-bR is an immunotoxin with potential clinical activity in SCLC. N901-bR is well tolerated when given by 7-day continuous infusion at the dose of 30 microg/kg(LBW)/d. Neurologic and cardiac toxicity were acceptable when given to patients with refractory SCLC. A second study to evaluate this agent after induction chemoradiotherapy in both limited- and extensive-stage disease was started following completion of this study.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Carcinoma de Células Pequeñas/terapia , Inmunotoxinas/uso terapéutico , Neoplasias Pulmonares/terapia , Ricina/análogos & derivados , Adulto , Anciano , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/sangre , Carcinoma de Células Pequeñas/inmunología , Femenino , Corazón/efectos de los fármacos , Humanos , Inmunoconjugados , Inmunotoxinas/efectos adversos , Inmunotoxinas/sangre , Neoplasias Pulmonares/inmunología , Masculino , Persona de Mediana Edad , Sistema Nervioso/efectos de los fármacos , Ricina/efectos adversos , Ricina/sangre , Ricina/uso terapéutico , Resultado del TratamientoRESUMEN
The systemic toxicity of an immunoconjugate of blocked ricin and the anti-CD19 monoclonal antibody, anti-B4, was studied in cynomolgus monkeys to evaluate its safety for use in humans. Anti-B4-blocked Ricin (Anti-B4-bR) is a highly cytotoxic immunoconjugate which can kill up to 5 logs of antigen positive target cells at concentrations easily achievable in blood. Subacute toxicity studies with Anti-B4-bR were performed in 20 cynomolgus monkeys and 4 rhesus monkeys, which, unlike humans, do not express the CD19 epitope recognized by the anti-B4 antibody on their B-lymphocytes. Anti-B4-bR was administered to cynomolgus monkeys by 5 daily intravenous bolus injections of 10 or 100 micrograms/kg/day, and non-conjugated blocked ricin was administered by 5 daily intravenous bolus injections of 30 micrograms/kg/day. Total doses of the conjugate of 200, 500, 1000 or 1500 micrograms/kg were also delivered to rhesus monkeys by continuous intravenous infusion over seven days. The clinical signs of toxicity, clinical pathology parameters, and gross and microscopic tissue changes associated with Anti-B4-bR were minimal to moderate where present, and primarily hepatic. In monkeys treated with 5 x 10 micrograms/kg of Anti-B4-bR, lesions were noticeable on day 7 after the start of the treatment but were less severe or absent on day 14, suggesting that the toxic effects were reversible. Clearance of the conjugate from the serum after bolus injections of Anti-B4-bR was evaluated by ELISA and demonstrated an initial t 1/2(alpha) of 1.4-2.0 h and a secondary t 1/2(beta) of about 14 h. Serum concentrations of Anti-B4-bR were about 10-20-fold lower at 24 h as compared to 1 h after each of the 5 bolus injections in monkeys. Continuous infusion of Anti-B4-bR in primates achieved plateau levels of the immunotoxin in blood for almost the entire duration of the infusion. The therapeutic utility of the Anti-B4-bR is currently being evaluated in patients with B-cell malignancies.