Delivery of a liposomal c-raf-1 antisense oligonucleotide by weekly bolus dosing in patients with advanced solid tumors: a phase I study.
OBJECTIVE
Rapid cleavage in vivo and inefficient cellular uptake limit the clinical utility of antisense oligonucleotides (AON). Liposomal formulation may promote better intratumoral AON delivery and inhibit degradation in vivo. We conducted the first clinical evaluation of this concept using a liposomal AON complementary to the c-raf-1 proto-oncogene (LErafAON).


METHODS
A dose escalation study was done to determine the maximum tolerated dose and to characterize the toxicities of LErafAON given as weekly intravenous infusion for 8 weeks to adults with advanced solid tumors. Pharmacokinetic analysis and evaluation of c-raf-1 target suppression in peripheral blood mononuclear cells were included.


RESULTS
Twenty-two patients received LErafAON (median 7 infusions; range 1-27) at doses of 1, 2, 4, and 6 mg/kg/week. Across all dose cohorts patients experienced infusion-related hypersensitivity reactions including flushing, dyspnea, hypoxia, rigors, back pain, and hypotension. Prolonged infusion duration and pretreatment with acetaminophen, H1- and H2-antagonists, and corticosteroids reduced the frequency and severity of these reactions. Progressive thrombocytopenia was dose-limiting at 6 mg/kg/week. No objective responses were observed. Two patients treated at the maximum tolerated dose of 4 mg/kg/week had evidence of stable disease, with dosing extended beyond 8 weeks. Pharmacokinetic analysis revealed persistence of detectable circulating rafAON at 24 hours in 7 of 10 patients in the highest 2 dose cohorts. Suppression of c-raf-1 mRNA was noted in two of five patients analyzed.


CONCLUSIONS
Dose-independent hypersensitivity reactions and dose-dependent thrombocytopenia limited tolerance of LErafAON. Future clinical evaluation of this approach will depend on modification of the liposome composition.
Rudin
Charles M
CM
The University of Chicago, Chicago, Illinois, USA. rudin@jhmi.edu
Marshall
John L
JL
Huang
Chao Hui
CH
Kindler
Hedy L
HL
Zhang
Chuanbo
C
Kumar
Deepak
D
Gokhale
Prafulla C
PC
Steinberg
Joyce
J
Wanaski
Steve
S
Kasid
Usha N
UN
Ratain
Mark J
MJ
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D005260:Female; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000009:adverse effects* / Q000379:methods*; D006801:Humans; D000860:Hypoxia / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008081:Liposomes / Q000378:metabolism*; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000628:therapy*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D000090063:Proto-Oncogene Mas; D019908:Proto-Oncogene Proteins c-raf / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism; D013921:Thrombocytopenia / Q000209:etiology; D013997:Time Factors; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D008081:Liposomes; C000715470:MAS1 protein, human; D016376:Oligonucleotides, Antisense; D000090063:Proto-Oncogene Mas; D012333:RNA, Messenger; D019908:Proto-Oncogene Proteins c-raf