A phase i study of the safety and pharmacokinetics of the hypoxia-activated prodrug TH-302 in combination with doxorubicin in patients with advanced soft tissue sarcoma

Kristen N. Ganjoo, Lee D Cranmer, James E. Butrynski, Daniel Rushing, Douglas Adkins, Scott H. Okuno, Gustavo Lorente, Stew Kroll, Virginia K. Langmuir, Sant P. Chawla

Research output: Contribution to journalArticle

51 Citations (Scopus)

Abstract

Purpose: The purpose of this study was to determine the dose-limiting toxicities (DLT), maximum tolerated dose (MTD), safety, pharmacokinetics and preliminary activity of TH-302, a hypoxia-activated prodrug, in combination with doxorubicin in patients with advanced soft tissue sarcoma. Patients and Methods: TH-302 was administered intravenously on days 1 and 8 and doxorubicin 75 mg/m2 on day 1 (2 h after TH-302) of every 3-week cycle. TH-302 starting dose was 240 mg/m2 with a classic 3 + 3 dose escalation. Pharmacokinetics were assessed on days 1 and 8 of cycle 1. Tumor assessments were performed after every second cycle. Results: Sixteen patients enrolled. Prophylactic growth factor support was added due to grade 4 neutropenia. The MTD was 300 mg/m2. DLTs at 340 mg/m2 were neutropenia-associated infection and grade 4 thrombocytopenia. Common adverse events included fatigue, nausea and skin rash. There was no evidence of pharmacokinetic interaction between TH-302 and doxorubicin. Five of 15 (33%) evaluable patients had a partial response by RECIST (Response Evaluation Criteria in Solid Tumors) criteria. Conclusions: The hematologic toxicity of doxorubicin is increased when combined with TH-302. This can be mitigated by prophylactic growth factor support. Toxicities were manageable and there was evidence of antitumor activity.

Original languageEnglish (US)
Pages (from-to)50-56
Number of pages7
JournalOncology
Volume80
Issue number1-2
DOIs
StatePublished - Jun 2011

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Prodrugs
Sarcoma
Doxorubicin
Pharmacokinetics
Safety
Maximum Tolerated Dose
Neutropenia
Intercellular Signaling Peptides and Proteins
Exanthema
Nausea
Fatigue
Hypoxia
TH 302
Infection
Neoplasms

Keywords

  • Hypoxia-activated prodrug
  • Phase I clinical trial
  • Soft tissue sarcoma
  • TH-302

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

A phase i study of the safety and pharmacokinetics of the hypoxia-activated prodrug TH-302 in combination with doxorubicin in patients with advanced soft tissue sarcoma. / Ganjoo, Kristen N.; Cranmer, Lee D; Butrynski, James E.; Rushing, Daniel; Adkins, Douglas; Okuno, Scott H.; Lorente, Gustavo; Kroll, Stew; Langmuir, Virginia K.; Chawla, Sant P.

In: Oncology, Vol. 80, No. 1-2, 06.2011, p. 50-56.

Research output: Contribution to journalArticle

Ganjoo, KN, Cranmer, LD, Butrynski, JE, Rushing, D, Adkins, D, Okuno, SH, Lorente, G, Kroll, S, Langmuir, VK & Chawla, SP 2011, 'A phase i study of the safety and pharmacokinetics of the hypoxia-activated prodrug TH-302 in combination with doxorubicin in patients with advanced soft tissue sarcoma', Oncology, vol. 80, no. 1-2, pp. 50-56. https://doi.org/10.1159/000327739
Ganjoo, Kristen N. ; Cranmer, Lee D ; Butrynski, James E. ; Rushing, Daniel ; Adkins, Douglas ; Okuno, Scott H. ; Lorente, Gustavo ; Kroll, Stew ; Langmuir, Virginia K. ; Chawla, Sant P. / A phase i study of the safety and pharmacokinetics of the hypoxia-activated prodrug TH-302 in combination with doxorubicin in patients with advanced soft tissue sarcoma. In: Oncology. 2011 ; Vol. 80, No. 1-2. pp. 50-56.
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