Phase 1 study of TLK286 (Telcyta) administered weekly in advanced malignancies.
OBJECTIVE
To determine the dose-limiting toxicities, maximum tolerated dose, and pharmacokinetics of TLK286, a novel cancer prodrug, administered weekly.


METHODS
Patients with advanced malignancies were treated with TLK286 administered weekly by i.v. infusion over 30 min in escalating doses 60-960 mg/m(2). A treatment cycle was defined as 3 weekly treatments. Patients underwent tumor assessments on day 43, and those patients receiving clinical benefit continued on treatment until disease progression or unacceptable toxicity. Safety was assessed by the WHO criteria.


RESULTS
Thirty-seven patients received 111 cycles of TLK286 at eight dose levels (median, 3 cycles; range, 1-16 cycles). In this study, TLK286 given weekly at 960 mg/m(2) was well tolerated without dose-limiting toxicities. TLK286-related toxicities included grade 1-2 nausea and vomiting, fatigue and anemia. Nine of 31 evaluable patients continued therapy beyond day 43 and received a median of 5 cycles (range of 3-16 cycles) and experienced durable stable disease or minor tumor regression. Pharmacokinetic characteristics of TLK286 are described by an optimized two-compartment model. Mild to moderate renal or hepatic organ dysfunction did not impact the elimination of TLK286.


CONCLUSIONS
TLK286 administered weekly at doses up to 960 mg/m(2) were well tolerated. The safety and antitumor activity observed in a broad range of cancer types supports Phase 2 disease-specific investigations of TLK286 given weekly at 960 mg/m(2).
Rosen
Lee S
LS
Jonsson Comprehensive Cancer Center, University of California, Los Angeles, California, USA.
Laxa
Bernadette
B
Boulos
Leny
L
Wiggins
Laura
L
Keck
James G
JG
Jameson
Anneliese J
AJ
Parra
Richard
R
Patel
Kiran
K
Brown
Gail L
GL
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D019540:Area Under Curve; D003603:Cytotoxins / Q000627:therapeutic use*; D005260:Female; D005500:Follow-Up Studies; D005978:Glutathione / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D008956:Models, Chemical; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000188:drug therapy*; D013997:Time Factors
D000970:Antineoplastic Agents; D003603:Cytotoxins; C107479:TER 286; D005978:Glutathione