Phase I study of PM00104 (Zalypsis®) administered as a 1-hour weekly infusion resting every fourth week in patients with advanced solid tumors.
PM00104 (Zalypsis®) is a new synthetic alkaloid with potent cytotoxic activity against tumor cell lines. This phase I clinical trial determined the maximal tolerated dose (MTD) and recommended dose (RD) for phase II trials of PM00104 administered as a 1-hour intravenous (i.v.) infusion weekly for three consecutive weeks resting every fourth week (d1,8,15 q4wk). Forty-nine patients with advanced solid malignancies received PM00104 following a toxicity-guided, accelerated, dose-escalation design. Doses evaluated ranged from 0.07 to 3.0 mg/m(2). Dose-limiting toxicities (DLTs) appeared at the highest doses tested and comprised grade 3 diarrhea and grade 4 lipase increase at 2.0 mg/m(2); grade 1 thrombocytopenia and grade 2 neutropenia with two infusion omissions, grade 3 fatigue and grade 4 febrile neutropenia at 2.5 mg/m(2); and grade 3/4 fatigue, grade 4 neutropenia lasting >5 days and grade 4 thrombocytopenia at 3.0 mg/m(2). RD was established at 2.0 mg/m(2). PM00104-related adverse events at the RD were mostly grade 1/2, with fatigue, nausea and vomiting as the most common. Transient and manageable myelosuppression and transaminase increases were also reported. Main pharmacokinetic parameters increased linearly with dose. Disease stabilization lasting ≥ 3 months was found in 4 patients with cervical carcinoma, colorectal adenocarcinoma, lachrymal adenoid carcinoma, and bladder carcinoma (n=1 each). In conclusion, PM00104 2.0 mg/m(2) 1-hour, d1,8,15 q4wk showed a positive risk-benefit ratio, which has supported its further evaluation in three ongoing phase II clinical trials.
SITEP (Service des Innovations Thérapeutiques Précoces), Institute Gustave Roussy, 114, rue Edouard Vaillant, 94800, Villejuif, France. christophe.massard@igr.fr
Christophe
C
Massard
Jane
J
Margetts
Nadia
N
Amellal
Yvette
Y
Drew
Ratislav
R
Bahleda
Peter
P
Stephens
Peter
P
Stevens
Jean Pierre
JP
Armand
Hilary
H
Calvert
Jean Charles
JC
Soria
Cinthya
C
Coronado
Carmen
C
Kahatt
Vicente
V
Alfaro
Mariano
M
Siguero
Carlos
C
Fernández-Teruel
Ruth
R
Plummer
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy*; D044005:Tetrahydroisoquinolines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D055815:Young Adult
D000970:Antineoplastic Agents; C500383:PM 00104; D044005:Tetrahydroisoquinolines