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A phase I safety and dose escalation trial of docetaxel combined with GEM®231, a second generation antisense oligonucleotide targeting protein kinase A R1α in patients with advanced solid cancers

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Summary

Purpose: GEM®231 is a second-generation antisense oligonucleotide targeting the mRNA of the R1α regulatory subunit of cAMP dependent protein kinase A. Preclinical studies have demonstrated synergistic antitumor activity when GEM®231 is combined with docetaxel. This trial assesses the safety of this combination. Experimental Design: Docetaxel was administered once every three weeks (one-cycle) at doses between 50–75 mg/m2. GEM®231 was administered twice weekly at 220 mg/m2 for 3 (schedule-A), or 2 (schedule-B) weeks. Results: Twenty patients with chemotherapy-refractory advanced cancer received a total of 39 cycles of therapy. Six patients in schedule-A received docetaxel 50 mg/m2, and 14 patients in schedule-B received docetaxel 50–75 mg/m2. In schedule-A, 2 of 6 patients developed cycle-1 dose limiting toxicity (DLT)-grade-3 fatigue or grade-3 serum transaminase elevation. In schedule-B, 1 of 4 patients developed cycle-1 DLT at the highest dose of docetaxel tested (75 mg/m2)—grade–3 febrile neutropenia. Subsequent dose escalations were not pursued since the overall incidence of grade-3 toxicities (including those that occurred after cycle 1) was 75%, and this dose was close to the single agent MTD of docetaxel. Grade-3 toxicities included fatigue (2 patients), transaminase elevation (4 patients), and altered mentation (1 patient). The mean post-infusion aPTT was significantly higher than the pre-infusion value [14.8 seconds; p<0.001]; however, there were no hemorrhagic episodes. Conclusions: The recommended dose for further development of the combination of docetaxel and GEM®231 is 75 mg/m2 and 220 mg/m2, respectively. It is important to administer GEM®231 twice weekly for 2 consecutive weeks followed by a one-week break.

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Abbreviations

aPTT:

activated partial thromboplastin time

ALT:

alanine aminotransferase

AST:

aspartate aminotransferase

ASO:

antisense oligonucleotide

cAMP:

cyclic adenosine monophosphate

DLT:

dose limiting toxicity

MTD:

maximum tolerated dose

PKA RIα:

regulatory subunit α of PKA-I

RPTD:

recommended phase two dose

ST:

serum transaminases

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Authors and Affiliations

  1. Albert Einstein Cancer Center, Bronx, NY

    Sanjay Goel (MD), Kavita Desai, Manuel Macapinlac, Scott Wadler, Gary Goldberg, Abbie Fields, Mark Einstein, Fabio Volterra, Benny Wong & Sridhar Mani

  2. Department of Oncology, Montefiore Medical Center, Bronx, NY

    Sanjay Goel (MD), Kavita Desai, Scott Wadler, Fabio Volterra, Benny Wong & Sridhar Mani

  3. Division of Gynecologic Oncology, Albert Einstein College of Medicine, Bronx, NY

    Gary Goldberg, Abbie Fields & Mark Einstein

  4. Jacobi Medical Center, Bronx, NY

    Manuel Macapinlac

  5. Hybridon, Inc., Cambridge, MA

    Russell Martin

  6. Department of Oncology, Weiler Hospital, 1825 Eastchester Road, Bronx, NY, 10461

    Sanjay Goel (MD)

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  1. Sanjay Goel
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  2. Kavita Desai
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  3. Manuel Macapinlac
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  10. Russell Martin
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  11. Sridhar Mani
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Correspondence to Sanjay Goel.

Additional information

This study was supported by grants from Hybridon, Inc. and Aventis Pharmaceuticals.

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Goel, S., Desai, K., Macapinlac, M. et al. A phase I safety and dose escalation trial of docetaxel combined with GEM®231, a second generation antisense oligonucleotide targeting protein kinase A R1α in patients with advanced solid cancers. Invest New Drugs 24, 125–134 (2006). https://doi.org/10.1007/s10637-006-2378-x

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