Phase I study of liposome-encapsulated c-raf antisense oligodeoxyribonucleotide infusion in combination with radiation therapy in patients with advanced malignancies.
OBJECTIVE
Raf proteins are key elements of growth-related cellular signaling pathways and are a component of cancer cell resistance to radiation therapy. Antisense oligonucleotides to c-raf-1 permit highly selective inhibition of the gene product and offer a strategy for sensitizing cancer cells to radiation therapy. In this dose escalation study, we evaluated the safety of combined liposomal formulation of raf antisense oligonucleotide (LErafAON) and radiation therapy in patients with advanced malignancies.


METHODS
Patients with advanced solid tumors were treated with LErafAON in a phase I dose escalation study while receiving palliative radiation therapy. Drug-related and radiation-related toxicities were monitored. Pharmacokinetics and expression of c-raf-1 mRNA and Raf-1 protein were determined in peripheral blood mononuclear cells.


RESULTS
Seventeen patients with palliative indications for radiation therapy were entered into this study. Thirteen patients received daily infusions of LErafAON and four received twice-weekly infusions. Radiation therapy was delivered in daily 300-cGy fractions over 2 weeks. Patients tolerated radiation, and no unexpected radiation-related side effects were observed. Drug-related reactions (grade > or =2), such as back pain, chills, dyspnea, fatigue, fever, flushing, and hypertension, were observed in most patients and were managed by premedication with corticosteroids and antihistamines. Serious adverse events occurred in five patients, including acute infusion-related symptoms, abnormal liver function tests, hypoxia, dehydration, diarrhea, esophagitis, fever, hypokalemia, pharyngitis, and tachypnea. Twelve of 17 patients were evaluable for tumor response at completion of treatment; four showed partial response, four showed stable disease, and four experienced progressive disease. The intact rafAON was detected in plasma for 30 minutes to several hours. Six patients with partial response or stable disease were evaluable for c-raf-1 mRNA and/or Raf-1 protein expression. Inhibition of c-raf-1 mRNA was observed in three of five patients. Raf-1 protein was inhibited in four of five patients.


CONCLUSIONS
This is the first report of the combined modality treatment using antisense oligonucleotides with radiation therapy in patients with advanced cancer. A dose of 2.0 mg/kg of LErafAON administered twice weekly is tolerated with premedication and does not enhance radiation toxicity in patients. The observation of dose-dependent, infusion-related reactions has led to further modification of the liposomal composition for use in future clinical trials.
Department of Radiation Medicine, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, District of Columbia 20007, USA.dritscha@georgetown.edu
Anatoly
A
Dritschilo
Chao H
CH
Huang
Charles M
CM
Rudin
John
J
Marshall
Brian
B
Collins
Jeanne L
JL
Dul
Chuanbo
C
Zhang
Deepak
D
Kumar
Prafulla C
PC
Gokhale
Ateeq
A
Ahmad
Imran
I
Ahmad
Jeffrey W
JW
Sherman
Usha N
UN
Kasid
D015746:Abdominal Pain / Q000209:etiology; D000328:Adult; D000368:Aged; D015153:Blotting, Western; D003131:Combined Modality Therapy / Q000009:adverse effects; D003967:Diarrhea / Q000209:etiology; D004305:Dose-Response Relationship, Drug; D005260:Female; D005334:Fever / Q000209:etiology; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007262:Infusions, Intravenous; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy*; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D010612:Pharyngitis / Q000209:etiology; D019908:Proto-Oncogene Proteins c-raf / Q000097:blood / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
C483019:LErafAON; D009838:Oligodeoxyribonucleotides; D012333:RNA, Messenger; D019908:Proto-Oncogene Proteins c-raf