Journal of Clinical Oncology, Vol 15, 723-734, Copyright © 1997 by American Society of Clinical Oncology
Immunotoxin therapy of small-cell lung cancer: a phase I study of N901- blocked ricin
TJ Lynch Jr, JM Lambert, F Coral, J Shefner, P Wen, WA Blattler, AR Collinson, PD Ariniello, G Braman, S Cook, D Esseltine, A Elias, A Skarin and J Ritz
Hematology-Oncology Unit, Massachusetts General Hospital, Boston 02114, USA. Lynch.Thomas@mgh.harvard.edu
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.
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