Phase I trial of ISIS 5132, an antisense oligonucleotide inhibitor of c-raf-1, administered by 24-hour weekly infusion to patients with advanced cancer

C. M. Rudin, J. Holmlund, Sridhar Mani, S. Mani, W. M. Stadler, P. Schumm, B. P. Monia, J. F. Johnston, R. Geary, R. Z. Yu, T. J. Kwoh, F. A. Dorr, M. J. Ratain

Research output: Contribution to journalArticle

126 Citations (Scopus)

Abstract

Raf-1 is a serine/threonine kinase that functions as a critical effector of Ras-mediated signal transduction via the mitogen-activated protein kinase pathway. Constitutive activation of this pathway directly contributes to malignant transformation in many human tumors. A 20-base phosphorothioate oligonucleotide complementary to c-raf-1 mRNA (ISIS 5132; CGP 69846A) has been shown to specifically suppress Raf-1 expression both in vitro and in vivo. This Phase I trial, involving 22 patients with advanced cancer, was designed to evaluate the safety, feasibility, and maximum tolerated dose of ISIS 5132 administration as a weekly 24-h i.v. infusion. Pharmacokinetic analysis was performed, and c-raf-1 mRNA levels in peripheral blood mononuclear cells were assessed using quantitative reverse transcription-PCR. This trial defined a maximum tolerated dose of 24 mg/kg/week on this schedule. Two of four patients treated at 30 mg/kg/week had serious adverse events after the first dose of ISIS 5132, including acute hemolytic anemia and acute renal failure and anasarca. There were no major responses documented. Dose-dependent complement activation was demonstrated on this schedule, but not on previously evaluated schedules, of ISIS 5132 administration. In contrast to other trials of ISIS 5132, there appeared to be no consistent suppression of peripheral blood mononuclear cell c-raf-1 mRNA level on this schedule at any of the dose levels analyzed. These data suggest that the efficacy and toxicity profiles of antisense oligonucleotides may be highly dependent on the schedule of administration and support the analysis of the putative molecular target in the evaluation of novel therapeutics.

Original languageEnglish (US)
Pages (from-to)1214-1220
Number of pages7
JournalClinical Cancer Research
Volume7
Issue number5
StatePublished - 2001
Externally publishedYes

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Antisense Oligonucleotides
Appointments and Schedules
Neoplasms
Maximum Tolerated Dose
Messenger RNA
Blood Cells
Phosphorothioate Oligonucleotides
Complement Activation
Protein-Serine-Threonine Kinases
Hemolytic Anemia
Mitogen-Activated Protein Kinases
Acute Kidney Injury
Reverse Transcription
ISIS 5132
Signal Transduction
Edema
Pharmacokinetics
Safety
Polymerase Chain Reaction

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Phase I trial of ISIS 5132, an antisense oligonucleotide inhibitor of c-raf-1, administered by 24-hour weekly infusion to patients with advanced cancer. / Rudin, C. M.; Holmlund, J.; Mani, Sridhar; Mani, S.; Stadler, W. M.; Schumm, P.; Monia, B. P.; Johnston, J. F.; Geary, R.; Yu, R. Z.; Kwoh, T. J.; Dorr, F. A.; Ratain, M. J.

In: Clinical Cancer Research, Vol. 7, No. 5, 2001, p. 1214-1220.

Research output: Contribution to journalArticle

Rudin, CM, Holmlund, J, Mani, S, Mani, S, Stadler, WM, Schumm, P, Monia, BP, Johnston, JF, Geary, R, Yu, RZ, Kwoh, TJ, Dorr, FA & Ratain, MJ 2001, 'Phase I trial of ISIS 5132, an antisense oligonucleotide inhibitor of c-raf-1, administered by 24-hour weekly infusion to patients with advanced cancer', Clinical Cancer Research, vol. 7, no. 5, pp. 1214-1220.
Rudin, C. M. ; Holmlund, J. ; Mani, Sridhar ; Mani, S. ; Stadler, W. M. ; Schumm, P. ; Monia, B. P. ; Johnston, J. F. ; Geary, R. ; Yu, R. Z. ; Kwoh, T. J. ; Dorr, F. A. ; Ratain, M. J. / Phase I trial of ISIS 5132, an antisense oligonucleotide inhibitor of c-raf-1, administered by 24-hour weekly infusion to patients with advanced cancer. In: Clinical Cancer Research. 2001 ; Vol. 7, No. 5. pp. 1214-1220.
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AU - Mani, Sridhar

AU - Mani, S.

AU - Stadler, W. M.

AU - Schumm, P.

AU - Monia, B. P.

AU - Johnston, J. F.

AU - Geary, R.

AU - Yu, R. Z.

AU - Kwoh, T. J.

AU - Dorr, F. A.

AU - Ratain, M. J.

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