A safety study of a mixed-backbone oligonucleotide (GEM231) targeting the type I regulatory subunit α of protein kinase A using a continuous infusion schedule in patients with refractory solid tumors

Sanjay Goel, Kavita Desai, Anca Bulgaru, Abbie Fields, Gary Goldberg, Sudhir Agrawal, Russell Martin, Michael Grindel, Sridhar Mani

Research output: Contribution to journalArticle

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Abstract

Purpose: The purpose of this study was to define the safety and pharmacodynamics of GEM231, a mixed backbone antisense oligonucleotide targeting the type I regulatory subunit α of protein kinase A, administered as a continuous i.v. infusion. Experimental Design: Fourteen cancer patients received escalating doses of GEM231 as a 3-day (1 patient) or a 5-day continuous i.v. infusion (13 patients) at doses ranging from 80 to 180 mg/m2/day. Results: The maximum tolerated dose of GEM231 was 180 mg/m2/day, based on dose-limiting elevation of serum transaminases (STs). At the recommended Phase II dose, 120 mg/m2/day (n = 8), the median number of cycles delivered was 2 (range, 1-4 cycles). Toxicities were tolerable, with one patient experiencing grade 3 ST elevation after 8 weeks. Plasma activated partial thromboplastin time changes were transient, reached a peak at the end of each weekly infusion, and were not associated with spontaneous bleeding. There was a significant difference between the mean preinfusion and postinfusion activated partial thromboplastin time measurements (2.05 s; P = 0.029). The most significant nonhematological toxicity was elevation in ST, usually observed after ≥4 weeks of therapy. There was a positive correlation between weekly dose and change in aspartate and alanine aminotransferase from baseline [r2 = 0.56 (P = 0.031) and r 2 = 0.64 (P = 0.019), respectively]. ST elevations were reversible to near baseline in all patients within 3-4 weeks of interruption of GEM231 dosing. Low-grade fatigue was common (57%), cumulative by weeks 4-6, and reversible after GEM231 discontinuation. Conclusions: GEM231 administered as a continuous infusion is safe; however, continuous protracted dosing is limited by ST elevations. Alternative dosing schedules should include intermittent administration to minimize cumulative toxicity. Additional studies using intermittent continuous infusion schedules of GEM231 are warranted.

Original languageEnglish (US)
Pages (from-to)4069-4076
Number of pages8
JournalClinical Cancer Research
Volume9
Issue number11
StatePublished - Nov 1 2003

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Cyclic AMP-Dependent Protein Kinases
Oligonucleotides
Appointments and Schedules
Transaminases
Safety
Neoplasms
Serum
Partial Thromboplastin Time
Maximum Tolerated Dose
Antisense Oligonucleotides
Aspartate Aminotransferases
GEM231
Alanine Transaminase
Fatigue
Research Design
Hemorrhage

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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A safety study of a mixed-backbone oligonucleotide (GEM231) targeting the type I regulatory subunit α of protein kinase A using a continuous infusion schedule in patients with refractory solid tumors. / Goel, Sanjay; Desai, Kavita; Bulgaru, Anca; Fields, Abbie; Goldberg, Gary; Agrawal, Sudhir; Martin, Russell; Grindel, Michael; Mani, Sridhar.

In: Clinical Cancer Research, Vol. 9, No. 11, 01.11.2003, p. 4069-4076.

Research output: Contribution to journalArticle

Goel, Sanjay ; Desai, Kavita ; Bulgaru, Anca ; Fields, Abbie ; Goldberg, Gary ; Agrawal, Sudhir ; Martin, Russell ; Grindel, Michael ; Mani, Sridhar. / A safety study of a mixed-backbone oligonucleotide (GEM231) targeting the type I regulatory subunit α of protein kinase A using a continuous infusion schedule in patients with refractory solid tumors. In: Clinical Cancer Research. 2003 ; Vol. 9, No. 11. pp. 4069-4076.
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abstract = "Purpose: The purpose of this study was to define the safety and pharmacodynamics of GEM231, a mixed backbone antisense oligonucleotide targeting the type I regulatory subunit α of protein kinase A, administered as a continuous i.v. infusion. Experimental Design: Fourteen cancer patients received escalating doses of GEM231 as a 3-day (1 patient) or a 5-day continuous i.v. infusion (13 patients) at doses ranging from 80 to 180 mg/m2/day. Results: The maximum tolerated dose of GEM231 was 180 mg/m2/day, based on dose-limiting elevation of serum transaminases (STs). At the recommended Phase II dose, 120 mg/m2/day (n = 8), the median number of cycles delivered was 2 (range, 1-4 cycles). Toxicities were tolerable, with one patient experiencing grade 3 ST elevation after 8 weeks. Plasma activated partial thromboplastin time changes were transient, reached a peak at the end of each weekly infusion, and were not associated with spontaneous bleeding. There was a significant difference between the mean preinfusion and postinfusion activated partial thromboplastin time measurements (2.05 s; P = 0.029). The most significant nonhematological toxicity was elevation in ST, usually observed after ≥4 weeks of therapy. There was a positive correlation between weekly dose and change in aspartate and alanine aminotransferase from baseline [r2 = 0.56 (P = 0.031) and r 2 = 0.64 (P = 0.019), respectively]. ST elevations were reversible to near baseline in all patients within 3-4 weeks of interruption of GEM231 dosing. Low-grade fatigue was common (57{\%}), cumulative by weeks 4-6, and reversible after GEM231 discontinuation. Conclusions: GEM231 administered as a continuous infusion is safe; however, continuous protracted dosing is limited by ST elevations. Alternative dosing schedules should include intermittent administration to minimize cumulative toxicity. Additional studies using intermittent continuous infusion schedules of GEM231 are warranted.",
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T1 - A safety study of a mixed-backbone oligonucleotide (GEM231) targeting the type I regulatory subunit α of protein kinase A using a continuous infusion schedule in patients with refractory solid tumors

AU - Goel, Sanjay

AU - Desai, Kavita

AU - Bulgaru, Anca

AU - Fields, Abbie

AU - Goldberg, Gary

AU - Agrawal, Sudhir

AU - Martin, Russell

AU - Grindel, Michael

AU - Mani, Sridhar

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