A phase i study of prolonged infusion of triapine in combination with fixed dose rate gemcitabine in patients with advanced solid tumors

Amir Mortazavi, Yonghua Ling, Ludmila Katherine Martin, Lai Wei, Mitch A. Phelps, Zhongfa Liu, Erica J. Harper, S. Percy Ivy, Xin Wu, Bing Sen Zhou, Xiyong Liu, Deidre Deam, J. Paul Monk, William J. Hicks, Yun Yen, Gregory A. Otterson, Michael R. Grever, Tanios Bekaii-Saab

Research output: Contribution to journalArticle

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Abstract

Purpose Prolonged exposure of cancer cells to triapine, an inhibitor of ribonucleotide reductase, followed by gemcitabine enhances gemcitabine activity in vitro. Fixed-dose-rate gemcitabine (FDR-G) has improved efficacy compared to standard-dose. We conducted a phase I trial to determine the maximum tolerated dose (MTD), safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy of prolonged triapine infusion followed by FDR-G. Experimental Design Triapine was given as a 24-hour infusion, immediately followed by FDR-G (1000 mg/m2 over 100-minute). Initially, this combination was administered days 1 and 8 of a 21-day cycle (Arm A, triapine starting dose 120 mg); but because of myelosuppression, it was changed to days 1 and 15 of a 28-day cycle (Arm B, starting dose of triapine 75 mg). Triapine steady-state concentrations (Css) and circulating ribonucleotide reductase M2-subunit (RRM2) were measured. Results Thirty-six patients were enrolled. The MTD was determined to be triapine 90 mg (24-hour infusion) immediately followed by gemcitabine 1000 mg/m2 (100-minute infusion), every 2 weeks of a 4-week cycle. DLTs included grade 4 thrombocytopenia, leukopenia and neutropenia. The treatment was well tolerated with fatigue, nausea/vomiting, fever, transaminitis, and cytopenias being the most common toxicities. Among 30 evaluable patients, 1 had a partial response and 15 had stable disease. Triapine PK was similar, although more variable, compared to previous studies using doses normalized to body-surface-area. Steady decline in circulating levels of RRM2 may correlate with outcome. Conclusions This combination was well tolerated and showed evidence of preliminary activity in this heavily pretreated patient population, including prior gemcitabine failure.

Original languageEnglish (US)
Pages (from-to)685-695
Number of pages11
JournalInvestigational New Drugs
Volume31
Issue number3
DOIs
StatePublished - Jun 1 2013
Externally publishedYes

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gemcitabine
Neoplasms
Maximum Tolerated Dose
Pharmacokinetics
Ribonucleotide Reductases
3-aminopyridine-2-carboxaldehyde thiosemicarbazone
Body Surface Area
Leukopenia
Neutropenia
Nausea
Vomiting
Fatigue

Keywords

  • Clinical Trial
  • Gemcitabine
  • Phase I
  • Triapine

ASJC Scopus subject areas

  • Oncology
  • Pharmacology
  • Pharmacology (medical)

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A phase i study of prolonged infusion of triapine in combination with fixed dose rate gemcitabine in patients with advanced solid tumors. / Mortazavi, Amir; Ling, Yonghua; Martin, Ludmila Katherine; Wei, Lai; Phelps, Mitch A.; Liu, Zhongfa; Harper, Erica J.; Ivy, S. Percy; Wu, Xin; Zhou, Bing Sen; Liu, Xiyong; Deam, Deidre; Monk, J. Paul; Hicks, William J.; Yen, Yun; Otterson, Gregory A.; Grever, Michael R.; Bekaii-Saab, Tanios.

In: Investigational New Drugs, Vol. 31, No. 3, 01.06.2013, p. 685-695.

Research output: Contribution to journalArticle

Mortazavi, A, Ling, Y, Martin, LK, Wei, L, Phelps, MA, Liu, Z, Harper, EJ, Ivy, SP, Wu, X, Zhou, BS, Liu, X, Deam, D, Monk, JP, Hicks, WJ, Yen, Y, Otterson, GA, Grever, MR & Bekaii-Saab, T 2013, 'A phase i study of prolonged infusion of triapine in combination with fixed dose rate gemcitabine in patients with advanced solid tumors', Investigational New Drugs, vol. 31, no. 3, pp. 685-695. https://doi.org/10.1007/s10637-012-9863-1
Mortazavi, Amir ; Ling, Yonghua ; Martin, Ludmila Katherine ; Wei, Lai ; Phelps, Mitch A. ; Liu, Zhongfa ; Harper, Erica J. ; Ivy, S. Percy ; Wu, Xin ; Zhou, Bing Sen ; Liu, Xiyong ; Deam, Deidre ; Monk, J. Paul ; Hicks, William J. ; Yen, Yun ; Otterson, Gregory A. ; Grever, Michael R. ; Bekaii-Saab, Tanios. / A phase i study of prolonged infusion of triapine in combination with fixed dose rate gemcitabine in patients with advanced solid tumors. In: Investigational New Drugs. 2013 ; Vol. 31, No. 3. pp. 685-695.
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abstract = "Purpose Prolonged exposure of cancer cells to triapine, an inhibitor of ribonucleotide reductase, followed by gemcitabine enhances gemcitabine activity in vitro. Fixed-dose-rate gemcitabine (FDR-G) has improved efficacy compared to standard-dose. We conducted a phase I trial to determine the maximum tolerated dose (MTD), safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy of prolonged triapine infusion followed by FDR-G. Experimental Design Triapine was given as a 24-hour infusion, immediately followed by FDR-G (1000 mg/m2 over 100-minute). Initially, this combination was administered days 1 and 8 of a 21-day cycle (Arm A, triapine starting dose 120 mg); but because of myelosuppression, it was changed to days 1 and 15 of a 28-day cycle (Arm B, starting dose of triapine 75 mg). Triapine steady-state concentrations (Css) and circulating ribonucleotide reductase M2-subunit (RRM2) were measured. Results Thirty-six patients were enrolled. The MTD was determined to be triapine 90 mg (24-hour infusion) immediately followed by gemcitabine 1000 mg/m2 (100-minute infusion), every 2 weeks of a 4-week cycle. DLTs included grade 4 thrombocytopenia, leukopenia and neutropenia. The treatment was well tolerated with fatigue, nausea/vomiting, fever, transaminitis, and cytopenias being the most common toxicities. Among 30 evaluable patients, 1 had a partial response and 15 had stable disease. Triapine PK was similar, although more variable, compared to previous studies using doses normalized to body-surface-area. Steady decline in circulating levels of RRM2 may correlate with outcome. Conclusions This combination was well tolerated and showed evidence of preliminary activity in this heavily pretreated patient population, including prior gemcitabine failure.",
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T1 - A phase i study of prolonged infusion of triapine in combination with fixed dose rate gemcitabine in patients with advanced solid tumors

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AU - Ling, Yonghua

AU - Martin, Ludmila Katherine

AU - Wei, Lai

AU - Phelps, Mitch A.

AU - Liu, Zhongfa

AU - Harper, Erica J.

AU - Ivy, S. Percy

AU - Wu, Xin

AU - Zhou, Bing Sen

AU - Liu, Xiyong

AU - Deam, Deidre

AU - Monk, J. Paul

AU - Hicks, William J.

AU - Yen, Yun

AU - Otterson, Gregory A.

AU - Grever, Michael R.

AU - Bekaii-Saab, Tanios

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N2 - Purpose Prolonged exposure of cancer cells to triapine, an inhibitor of ribonucleotide reductase, followed by gemcitabine enhances gemcitabine activity in vitro. Fixed-dose-rate gemcitabine (FDR-G) has improved efficacy compared to standard-dose. We conducted a phase I trial to determine the maximum tolerated dose (MTD), safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy of prolonged triapine infusion followed by FDR-G. Experimental Design Triapine was given as a 24-hour infusion, immediately followed by FDR-G (1000 mg/m2 over 100-minute). Initially, this combination was administered days 1 and 8 of a 21-day cycle (Arm A, triapine starting dose 120 mg); but because of myelosuppression, it was changed to days 1 and 15 of a 28-day cycle (Arm B, starting dose of triapine 75 mg). Triapine steady-state concentrations (Css) and circulating ribonucleotide reductase M2-subunit (RRM2) were measured. Results Thirty-six patients were enrolled. The MTD was determined to be triapine 90 mg (24-hour infusion) immediately followed by gemcitabine 1000 mg/m2 (100-minute infusion), every 2 weeks of a 4-week cycle. DLTs included grade 4 thrombocytopenia, leukopenia and neutropenia. The treatment was well tolerated with fatigue, nausea/vomiting, fever, transaminitis, and cytopenias being the most common toxicities. Among 30 evaluable patients, 1 had a partial response and 15 had stable disease. Triapine PK was similar, although more variable, compared to previous studies using doses normalized to body-surface-area. Steady decline in circulating levels of RRM2 may correlate with outcome. Conclusions This combination was well tolerated and showed evidence of preliminary activity in this heavily pretreated patient population, including prior gemcitabine failure.

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