A phase II study of the antisense oligonucleotide GTI-2040 plus docetaxel and prednisone as first-line treatment in castration-resistant prostate cancer

Srikala S. Sridhar, Christina M. Canil, Kim N. Chi, Sebastien J. Hotte, Scott Ernst, Lisa Wang, Eric X. Chen, Agnes Juhasz, Yun Yen, Peter Murray, James A. Zwiebel, Malcolm J. Moore

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

Purpose: GTI-2040 is a novel antisense oligonucleotide to the R2 subunit of ribonucleotide reductase. This phase II trial was conducted to determine the efficacy and tolerability of GTI-2040 when combined with docetaxel and prednisone for the treatment of patients with castration-resistant prostate cancer (CRPC). Methods: Chemo-naïve CRPC patients with adequate performance status and organ function were treated with docetaxel 75 mg/m2 IV on day 1 plus GTI-2040 5 mg/kg/day by continuous intravenous infusion day 1-14 on a 21 day cycle, with prednisone 5 mg orally twice daily. The primary endpoint was PSA response rate. Pharmacokinetic studies of GTI-2040 and pharmacodynamic studies on peripheral blood mononuclear cells (PBMC) were also performed. Results: Twenty-two patients in total (19 from this study and 3 from a prior phase I/II study at this institution) were treated at the recommended phase II dose. A confirmed PSA response was seen in 9/22 patients (41%). Of 16 patients with measurable disease, there was 1 partial response (PR) and 12 stable disease (SD) lasting 3.6 months (median), as best response. The most common toxicities were anemia, fatigue, lymphopenia, leucopenia and neutropenia. Grade 3+ toxicities included neutropenia, lymphopenia, leucopenia, fatigue, febrile neutropenia and hypophosphatemia. Conclusions: The PSA response rate of GTI-2040 in combination with docetaxel and prednisone just met the minimum phase II criteria for further enrollment. However, after evaluation of all the clinical data, further study of this dose and schedule of GTI-2040 in CRPC was not recommended.

Original languageEnglish
Pages (from-to)927-933
Number of pages7
JournalCancer Chemotherapy and Pharmacology
Volume67
Issue number4
DOIs
Publication statusPublished - Apr 1 2011
Externally publishedYes

Fingerprint

docetaxel
Antisense Oligonucleotides
Castration
Prednisone
Prostatic Neoplasms
Lymphopenia
Leukopenia
Neutropenia
Fatigue
Toxicity
Therapeutics
Fatigue of materials
Pharmacodynamics
Hypophosphatemia
Febrile Neutropenia
Pharmacokinetics
Intravenous Infusions
GTI2040
Anemia
Blood Cells

Keywords

  • Castrate-resistant prostate cancer
  • Docetaxel
  • GTI-2040
  • Phase II

ASJC Scopus subject areas

  • Oncology
  • Toxicology
  • Pharmacology
  • Cancer Research
  • Pharmacology (medical)

Cite this

A phase II study of the antisense oligonucleotide GTI-2040 plus docetaxel and prednisone as first-line treatment in castration-resistant prostate cancer. / Sridhar, Srikala S.; Canil, Christina M.; Chi, Kim N.; Hotte, Sebastien J.; Ernst, Scott; Wang, Lisa; Chen, Eric X.; Juhasz, Agnes; Yen, Yun; Murray, Peter; Zwiebel, James A.; Moore, Malcolm J.

In: Cancer Chemotherapy and Pharmacology, Vol. 67, No. 4, 01.04.2011, p. 927-933.

Research output: Contribution to journalArticle

Sridhar, SS, Canil, CM, Chi, KN, Hotte, SJ, Ernst, S, Wang, L, Chen, EX, Juhasz, A, Yen, Y, Murray, P, Zwiebel, JA & Moore, MJ 2011, 'A phase II study of the antisense oligonucleotide GTI-2040 plus docetaxel and prednisone as first-line treatment in castration-resistant prostate cancer', Cancer Chemotherapy and Pharmacology, vol. 67, no. 4, pp. 927-933. https://doi.org/10.1007/s00280-010-1389-7
Sridhar, Srikala S. ; Canil, Christina M. ; Chi, Kim N. ; Hotte, Sebastien J. ; Ernst, Scott ; Wang, Lisa ; Chen, Eric X. ; Juhasz, Agnes ; Yen, Yun ; Murray, Peter ; Zwiebel, James A. ; Moore, Malcolm J. / A phase II study of the antisense oligonucleotide GTI-2040 plus docetaxel and prednisone as first-line treatment in castration-resistant prostate cancer. In: Cancer Chemotherapy and Pharmacology. 2011 ; Vol. 67, No. 4. pp. 927-933.
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abstract = "Purpose: GTI-2040 is a novel antisense oligonucleotide to the R2 subunit of ribonucleotide reductase. This phase II trial was conducted to determine the efficacy and tolerability of GTI-2040 when combined with docetaxel and prednisone for the treatment of patients with castration-resistant prostate cancer (CRPC). Methods: Chemo-na{\"i}ve CRPC patients with adequate performance status and organ function were treated with docetaxel 75 mg/m2 IV on day 1 plus GTI-2040 5 mg/kg/day by continuous intravenous infusion day 1-14 on a 21 day cycle, with prednisone 5 mg orally twice daily. The primary endpoint was PSA response rate. Pharmacokinetic studies of GTI-2040 and pharmacodynamic studies on peripheral blood mononuclear cells (PBMC) were also performed. Results: Twenty-two patients in total (19 from this study and 3 from a prior phase I/II study at this institution) were treated at the recommended phase II dose. A confirmed PSA response was seen in 9/22 patients (41{\%}). Of 16 patients with measurable disease, there was 1 partial response (PR) and 12 stable disease (SD) lasting 3.6 months (median), as best response. The most common toxicities were anemia, fatigue, lymphopenia, leucopenia and neutropenia. Grade 3+ toxicities included neutropenia, lymphopenia, leucopenia, fatigue, febrile neutropenia and hypophosphatemia. Conclusions: The PSA response rate of GTI-2040 in combination with docetaxel and prednisone just met the minimum phase II criteria for further enrollment. However, after evaluation of all the clinical data, further study of this dose and schedule of GTI-2040 in CRPC was not recommended.",
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AU - Hotte, Sebastien J.

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AU - Wang, Lisa

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