A Phase I pharmacokinetic and biological correlative study of oblimersen sodium (genasense, g3139), an antisense oligonucleotide to the bcl-2 mRNA, and of docetaxel in patients with hormone-refractory prostate cancer.
OBJECTIVE
To assess the feasibility of administering oblimersen sodium, a phosphorothioate antisense oligonucleotide directed to the Bcl-2 mRNA, with docetaxel to patients with hormone-refractory prostate cancer; to characterize the pertinent pharmacokinetic parameters, Bcl-2 protein inhibition in peripheral blood mononuclear cell(s) (PBMC) and tumor; and to seek preliminary evidence of antitumor activity.


METHODS
Patients were treated with increasing doses of oblimersen sodium administered by continuous i.v. infusion on days 1 to 6 and docetaxel administered i.v. over 1 h on day 6 every 3 weeks. Plasma was sampled to characterize the pharmacokinetic parameters of both oblimersen and docetaxel, and Bcl-2 protein expression was measured from paired collections of PBMCs pretreatment and post-treatment.


RESULTS
Twenty patients received 124 courses of the oblimersen and docetaxel combination at doses ranging from 5 to 7 mg/kg/day oblimersen and 60 to 100 mg/m(2) docetaxel. The rate of severe fatigue accompanied by severe neutropenia was unacceptably high at doses exceeding 7 mg/kg/day oblimersen and 75 mg/m(2) docetaxel. Nausea, vomiting, and fever were common, but rarely severe. Oblimersen mean steady-state concentrations were 3.44 +/- 1.31 and 5.32 +/- 2.34 at the 5- and 7-mg/kg dose levels, respectively. Prostate-specific antigen responses were observed in 7 of 12 taxane-naïve patients, but in taxane-refractory patients no responses were observed. Preliminary evaluation of Bcl-2 expression in diagnostic tumor specimens was not predictive of response to this therapy.


CONCLUSIONS
The recommended Phase II doses for oblimersen and docetaxel on this schedule are 7 mg/kg/day continuous i.v. infusion days 1 to 6, and 75 mg/m(2) i.v. day 6, respectively, once every 3 weeks. The absence of severe toxicities at this recommended dose, evidence of Bcl-2 protein inhibition in PBMC and tumor tissue, and encouraging antitumor activity in HPRC patients warrant further clinical evaluation of this combination.
Tolcher
Anthony W
AW
Institute for Drug Development, Cancer Therapy, and Research Center, San Antonio, Texas 78229, USA. atolcher@idd.org
Kuhn
John
J
Schwartz
Garry
G
Patnaik
Amita
A
Hammond
Lisa A
LA
Thompson
Ian
I
Fingert
Howard
H
Bushnell
David
D
Malik
Shazli
S
Kreisberg
Jeffrey
J
Izbicka
Elzbieta
E
Smetzer
Leslie
L
Rowinsky
Eric K
EK
D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001706:Biopsy; D000077143:Docetaxel; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D006801:Humans; D007150:Immunohistochemistry; D007262:Infusions, Intravenous; D007963:Leukocytes, Mononuclear / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D016376:Oligonucleotides, Antisense / Q000493:pharmacokinetics*; D010766:Phosphorylation; D017430:Prostate-Specific Antigen / Q000096:biosynthesis; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism; D043823:Taxoids / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D013873:Thionucleotides / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D013997:Time Factors
D000970:Antineoplastic Agents; D016376:Oligonucleotides, Antisense; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D043823:Taxoids; D013873:Thionucleotides; D000077143:Docetaxel; C408162:oblimersen; D017430:Prostate-Specific Antigen