A phase I trial of SJG-136 (NSC#694501) in advanced solid tumors.
OBJECTIVE
SJG-136 is a pyrrolobenzodiazepine dimer that forms DNA crosslinks and has demonstrated broad antitumor activity. We undertook this trial to determine the maximum-tolerated dose (MTD), toxicities and pharmacokinetic (PK) profile of SJG-136 in patients with an advanced solid tumor.


METHODS
In this phase I study, patients were treated with SJG-136 on days 1, 8 and 15 of a 28-day cycle. Dose levels studied were 10, 20, 40 and 60 microg/m2. PK parameters of SJG-136 were assessed following the intravenous administration of SJG-136 on days 1 and 15 of cycle 1.


RESULTS
Twenty-one patients with advanced solid tumors were treated. Patients had a median of two prior chemotherapy regimens. Fatigue was dose-limiting with SJG-136 60 microg/m2/day administered on days 1, 8 and 15 of a 28-day cycle. Grade 3 thrombocytopenia and delayed onset liver toxicity were seen in one patient each. PK parameters of SJG-136 indicated dose-proportional increases in systemic exposure with increasing doses. No objective responses were seen.


CONCLUSIONS
For patients with advanced solid tumors, the MTD of SJG-136 is 40 microg/m2/day administered on days 1, 8 and 15 of a 28-day cycle. The major dose limiting toxicity was fatigue. Alternative dosing strategies are now being evaluated.
Janjigian
Yelena Y
YY
Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer Center, Weill Medical College of Cornell University, 1275 York Avenue, New York, NY 10065, USA.
Lee
Wooin
W
Kris
Mark G
MG
Miller
Vincent A
VA
Krug
Lee M
LM
Azzoli
Christopher G
CG
Senturk
Emir
E
Calcutt
M Wade
MW
Rizvi
Naiyer A
NA
D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D001570:Benzodiazepinones / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D003110:Colonic Neoplasms / Q000188:drug therapy; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004361:Drug Tolerance; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy; D008297:Male; D020714:Maximum Tolerated Dose; D008545:Melanoma / Q000188:drug therapy; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000188:drug therapy; D011758:Pyrroles / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy
C423343:1,1'-((propane-1,3-diyl)dioxy)bis(7-methoxy-2-methylidene-1,2,3,10,11,11a-hexahydro-5H-pyrrolo(2,1-c)(1,4)benzodiazepin-5,11-dione); D000970:Antineoplastic Agents; D001570:Benzodiazepinones; D011758:Pyrroles