Phase I clinical trial of drug-monoclonal antibody conjugates in patients with advanced colorectal carcinoma: a preliminary report.
Melphalan (MEL), an alkylating agent, has been modified to a derivative, N-acetylmelphalan (N-AcMEL), which can be conjugated to anticolon cancer monoclonal antibodies (MoAbs 30.6, I-1, and JGT) and used for immunochemotherapy. The final immunoconjugates possess potent cytotoxicity and specificity in preclinical studies. In a phase I clinical study, N-AcMEL-MoAb conjugates were administered via the hepatic artery to 10 patients, nine of whom had disseminated colorectal cancer (including the liver) and one of whom had Dukes' C colon cancer that had been resected. The selection of MoAb was based on the immunoperoxidase staining of the primary colon cancer tissue. Thus far doses of 1000 mg/m2 MoAb conjugated to 20 mg/m2 of N-AcMEL have been administered with no significant side effects, whereas MEL unconjugated to monoclonal antibodies would have caused myelosuppression in a proportion of patients at the same dosage. Serum antimouse antibody responses were noted in all of the patients; febrile reactions were noted with higher doses but were easily controlled with antipyretics, antihistamines and, if necessary, steroids. Serum sickness developed in one patient who was given a second course of treatment in the presence of human antimouse antibody, but the episode was self-limiting. Eight of the 10 patients had evaluable disease. Subjective improvement was noted in almost all of the patients examined, and 33%, or 3 of 9, of the treatments (nine courses of treatment in eight patients with evaluable disease; one of the patients had two courses of treatment) led to antitumor responses (minor response) by objective assessment with computed tomography of the liver. It is important to note that treatment with N-AcMEL-MoAb conjugates was safe at a dose of 20 mg/m2 of N-AcMEL, whereas the efficacy of such a form of treatment remains to be determined.
Tjandra
J J
JJ
Department of Pathology, University of Melbourne, Parkville, Victoria, Australia.
Pietersz
G A
GA
Teh
J G
JG
Cuthbertson
A M
AM
Sullivan
J R
JR
Penfold
C
C
McKenzie
I F
IF
Smyth
M
M
D000328:Adult; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D002272:Carcinoembryonic Antigen / Q000032:analysis; D002277:Carcinoma / Q000628:therapy*; D015179:Colorectal Neoplasms / Q000628:therapy*; D004341:Drug Evaluation; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D000922:Immunotoxins / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D008558:Melphalan / Q000008:administration & dosage / Q000031:analogs & derivatives*; D008875:Middle Aged; D009362:Neoplasm Metastasis; D014057:Tomography, X-Ray Computed
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D002272:Carcinoembryonic Antigen; D000922:Immunotoxins; C051105:N-acetylmelphalan; D008558:Melphalan