Phase II study of the safety and antitumor activity of the hypoxia-activated prodrug TH-302 in combination with doxorubicin in patients with advanced soft tissue sarcoma

Sant P. Chawla, Lee D. Cranmer, Brian A. Van Tine, Damon R. Reed, Scott Heitaka Okuno, James E. Butrynski, Douglas R. Adkins, Andrew E. Hendifar, Stew Kroll, Kristen N. Ganjoo

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Abstract

Patients and Methods: In this open-label phase II study, TH-302 300 mg/m2 was administered intravenously on days 1 and 8 with doxorubicin 75 mg/m2 on day 1 of each 21-day cycle. After six cycles, patients with stable and/or responding disease could receive maintenance monotherapy with TH-302.

Purpose: TH-302, a prodrug of the cytotoxic alkylating agent bromo-isophosphoramide mustard, is preferentially activated in hypoxic conditions. This phase II study investigated TH-302 in combination with doxorubicin, followed by single-agent TH-302 maintenance therapy in patients with first-line advanced soft tissue sarcoma (STS) to assess progression-free survival (PFS), response rate, overall survival, safety, and tolerability.

Results: Ninety-one patients initiated TH-302 plus doxorubicin induction treatment. The PFS rate at 6 months (primary efficacy measure) was 58% (95% CI, 46% to 68%). Median PFS was 6.5 months (95% CI, 5.8 to 7.7 months); median overall survival was 21.5 months (95% CI, 16.0 to 26.2 months). Best tumor responses were complete response (n = 2 [2%]) and partial response (n = 30 [34%]). During TH-302 maintenance (n = 48), five patients improved from stable disease to partial response, and one patient improved from partial to complete response. The most common adverse events during induction were fatigue, nausea, and skin and/or mucosal toxicities as well as anemia, thrombocytopenia, and neutropenia. These were less severe and less frequent during maintenance. There was no evidence of TH-302-related hepatic, renal, or cardiac toxicity.

Conclusion: PFS, overall survival, and tumor response compared favorably with historical outcomes achieved with other first-line chemotherapies for advanced STS. A phase III study of TH-302 is ongoing (NCT01440088).

Original languageEnglish (US)
Pages (from-to)3299-3306
Number of pages8
JournalJournal of Clinical Oncology
Volume32
Issue number29
DOIs
StatePublished - Oct 10 2014

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Prodrugs
Sarcoma
Doxorubicin
Safety
Disease-Free Survival
Maintenance
Survival
Survival Rate
TH 302
Hypoxia
Alkylating Agents
Cytotoxins
Neutropenia
Thrombocytopenia
Nausea
Fatigue
Anemia
Neoplasms
Kidney
Drug Therapy

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Medicine(all)

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Phase II study of the safety and antitumor activity of the hypoxia-activated prodrug TH-302 in combination with doxorubicin in patients with advanced soft tissue sarcoma. / Chawla, Sant P.; Cranmer, Lee D.; Van Tine, Brian A.; Reed, Damon R.; Okuno, Scott Heitaka; Butrynski, James E.; Adkins, Douglas R.; Hendifar, Andrew E.; Kroll, Stew; Ganjoo, Kristen N.

In: Journal of Clinical Oncology, Vol. 32, No. 29, 10.10.2014, p. 3299-3306.

Research output: Contribution to journalArticle

Chawla, Sant P. ; Cranmer, Lee D. ; Van Tine, Brian A. ; Reed, Damon R. ; Okuno, Scott Heitaka ; Butrynski, James E. ; Adkins, Douglas R. ; Hendifar, Andrew E. ; Kroll, Stew ; Ganjoo, Kristen N. / Phase II study of the safety and antitumor activity of the hypoxia-activated prodrug TH-302 in combination with doxorubicin in patients with advanced soft tissue sarcoma. In: Journal of Clinical Oncology. 2014 ; Vol. 32, No. 29. pp. 3299-3306.
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abstract = "Patients and Methods: In this open-label phase II study, TH-302 300 mg/m2 was administered intravenously on days 1 and 8 with doxorubicin 75 mg/m2 on day 1 of each 21-day cycle. After six cycles, patients with stable and/or responding disease could receive maintenance monotherapy with TH-302.Purpose: TH-302, a prodrug of the cytotoxic alkylating agent bromo-isophosphoramide mustard, is preferentially activated in hypoxic conditions. This phase II study investigated TH-302 in combination with doxorubicin, followed by single-agent TH-302 maintenance therapy in patients with first-line advanced soft tissue sarcoma (STS) to assess progression-free survival (PFS), response rate, overall survival, safety, and tolerability.Results: Ninety-one patients initiated TH-302 plus doxorubicin induction treatment. The PFS rate at 6 months (primary efficacy measure) was 58{\%} (95{\%} CI, 46{\%} to 68{\%}). Median PFS was 6.5 months (95{\%} CI, 5.8 to 7.7 months); median overall survival was 21.5 months (95{\%} CI, 16.0 to 26.2 months). Best tumor responses were complete response (n = 2 [2{\%}]) and partial response (n = 30 [34{\%}]). During TH-302 maintenance (n = 48), five patients improved from stable disease to partial response, and one patient improved from partial to complete response. The most common adverse events during induction were fatigue, nausea, and skin and/or mucosal toxicities as well as anemia, thrombocytopenia, and neutropenia. These were less severe and less frequent during maintenance. There was no evidence of TH-302-related hepatic, renal, or cardiac toxicity.Conclusion: PFS, overall survival, and tumor response compared favorably with historical outcomes achieved with other first-line chemotherapies for advanced STS. A phase III study of TH-302 is ongoing (NCT01440088).",
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T1 - Phase II study of the safety and antitumor activity of the hypoxia-activated prodrug TH-302 in combination with doxorubicin in patients with advanced soft tissue sarcoma

AU - Chawla, Sant P.

AU - Cranmer, Lee D.

AU - Van Tine, Brian A.

AU - Reed, Damon R.

AU - Okuno, Scott Heitaka

AU - Butrynski, James E.

AU - Adkins, Douglas R.

AU - Hendifar, Andrew E.

AU - Kroll, Stew

AU - Ganjoo, Kristen N.

PY - 2014/10/10

Y1 - 2014/10/10

N2 - Patients and Methods: In this open-label phase II study, TH-302 300 mg/m2 was administered intravenously on days 1 and 8 with doxorubicin 75 mg/m2 on day 1 of each 21-day cycle. After six cycles, patients with stable and/or responding disease could receive maintenance monotherapy with TH-302.Purpose: TH-302, a prodrug of the cytotoxic alkylating agent bromo-isophosphoramide mustard, is preferentially activated in hypoxic conditions. This phase II study investigated TH-302 in combination with doxorubicin, followed by single-agent TH-302 maintenance therapy in patients with first-line advanced soft tissue sarcoma (STS) to assess progression-free survival (PFS), response rate, overall survival, safety, and tolerability.Results: Ninety-one patients initiated TH-302 plus doxorubicin induction treatment. The PFS rate at 6 months (primary efficacy measure) was 58% (95% CI, 46% to 68%). Median PFS was 6.5 months (95% CI, 5.8 to 7.7 months); median overall survival was 21.5 months (95% CI, 16.0 to 26.2 months). Best tumor responses were complete response (n = 2 [2%]) and partial response (n = 30 [34%]). During TH-302 maintenance (n = 48), five patients improved from stable disease to partial response, and one patient improved from partial to complete response. The most common adverse events during induction were fatigue, nausea, and skin and/or mucosal toxicities as well as anemia, thrombocytopenia, and neutropenia. These were less severe and less frequent during maintenance. There was no evidence of TH-302-related hepatic, renal, or cardiac toxicity.Conclusion: PFS, overall survival, and tumor response compared favorably with historical outcomes achieved with other first-line chemotherapies for advanced STS. A phase III study of TH-302 is ongoing (NCT01440088).

AB - Patients and Methods: In this open-label phase II study, TH-302 300 mg/m2 was administered intravenously on days 1 and 8 with doxorubicin 75 mg/m2 on day 1 of each 21-day cycle. After six cycles, patients with stable and/or responding disease could receive maintenance monotherapy with TH-302.Purpose: TH-302, a prodrug of the cytotoxic alkylating agent bromo-isophosphoramide mustard, is preferentially activated in hypoxic conditions. This phase II study investigated TH-302 in combination with doxorubicin, followed by single-agent TH-302 maintenance therapy in patients with first-line advanced soft tissue sarcoma (STS) to assess progression-free survival (PFS), response rate, overall survival, safety, and tolerability.Results: Ninety-one patients initiated TH-302 plus doxorubicin induction treatment. The PFS rate at 6 months (primary efficacy measure) was 58% (95% CI, 46% to 68%). Median PFS was 6.5 months (95% CI, 5.8 to 7.7 months); median overall survival was 21.5 months (95% CI, 16.0 to 26.2 months). Best tumor responses were complete response (n = 2 [2%]) and partial response (n = 30 [34%]). During TH-302 maintenance (n = 48), five patients improved from stable disease to partial response, and one patient improved from partial to complete response. The most common adverse events during induction were fatigue, nausea, and skin and/or mucosal toxicities as well as anemia, thrombocytopenia, and neutropenia. These were less severe and less frequent during maintenance. There was no evidence of TH-302-related hepatic, renal, or cardiac toxicity.Conclusion: PFS, overall survival, and tumor response compared favorably with historical outcomes achieved with other first-line chemotherapies for advanced STS. A phase III study of TH-302 is ongoing (NCT01440088).

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