Immunotoxin therapy of small-cell lung cancer: a phase I study of N901-blocked ricin.
OBJECTIVE
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.


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.


CONCLUSIONS
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.
Lynch
T J
TJ
Hematology-Oncology Unit, Massachusetts General Hospital, Boston 02114, USA. Lynch.Thomas@mgh.harvard.edu
Lambert
J M
JM
Coral
F
F
Shefner
J
J
Wen
P
P
Blattler
W A
WA
Collinson
A R
AR
Ariniello
P D
PD
Braman
G
G
Cook
S
S
Esseltine
D
D
Elias
A
A
Skarin
A
A
Ritz
J
J
D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use*; D018288:Carcinoma, Small Cell / Q000276:immunology / Q000628:therapy*; D005260:Female; D006321:Heart / Q000187:drug effects; D006801:Humans; D018796:Immunoconjugates; D000922:Immunotoxins / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use*; D008175:Lung Neoplasms / Q000276:immunology / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D009420:Nervous System / Q000187:drug effects; D012276:Ricin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000097:blood / Q000627:therapeutic use; D016896:Treatment Outcome
D000911:Antibodies, Monoclonal; D018796:Immunoconjugates; D000922:Immunotoxins; C080540:N901 MoAb-blocked ricin conjugate; D012276:Ricin