A phase I, pharmacokinetic and biologic correlative study of oblimersen sodium (Genasense, G3139) and irinotecan in patients with metastatic colorectal cancer.
OBJECTIVE
To assess the feasibility and antitumor activity of oblimersen sodium, an antisense oligonucleotide directed to the Bcl-2 mRNA, combined with irinotecan in patients with advanced colorectal carcinoma, characterize the pharmacokinetic behavior of both oblimersen sodium and irinotecan, and examine Bcl-2 protein inhibition in peripheral blood mononuclear cells (PBMC).


METHODS
Patients were treated with escalating doses of oblimersen sodium administered by continuous intravenous infusion (CIVI) days 1-8, and irinotecan administered intravenously on day 6 once every 3 weeks.


RESULTS
Twenty patients received a total of 84 courses at doses ranging from 3 to 7 mg/kg/day for oblimersen sodium and from 280 to 350 mg/m2 for irinotecan. Febrile neutropenia and diarrhea limited escalation of oblimersen sodium and irinotecan to 5 mg/kg/day and 350 mg/m2, respectively. Other toxicities included nausea, vomiting, fever and fatigue. Steady-state plasma concentrations were achieved within 48 h of beginning oblimersen sodium treatment and the agent was undetectable 24 h after the discontinuation of the infusion. Reduction in levels of Bcl-2 protein in PBMC was documented following treatment with oblimersen sodium. One patient experienced a partial response and 10 additional patients had stable disease lasting 2.5-10 months.


CONCLUSIONS
The combination is well tolerated at the recommended phase II oblimersen sodium dose of 7 mg/kg/day CIVI days 1-8 with irinotecan 280 mg/m2 intravenously on day 6 every 3 weeks.
Mita
M M
MM
Institute for Drug Development, Cancer Therapy and Research Center, San Antonio, TX 78229, USA.
Ochoa
L
L
Rowinsky
E K
EK
Kuhn
J
J
Schwartz
G
G
Hammond
L A
LA
Patnaik
A
A
Yeh
I-T
IT
Izbicka
E
E
Berg
K
K
Tolcher
A W
AW
D000328:Adult; D000368:Aged; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D005260:Female; D006801:Humans; D000077146:Irinotecan; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008231:Lymphopenia / Q000139:chemically induced; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009503:Neutropenia / Q000139:chemically induced; D016376:Oligonucleotides, Antisense / Q000235:genetics / Q000493:pharmacokinetics*; D013873:Thionucleotides / Q000235:genetics / Q000493:pharmacokinetics*
D000972:Antineoplastic Agents, Phytogenic; D004338:Drug Combinations; D016376:Oligonucleotides, Antisense; D013873:Thionucleotides; D000077146:Irinotecan; C408162:oblimersen; D002166:Camptothecin