Phase i trial of arginine deprivation therapy with ADI-PEG 20 plus docetaxel in patients with advanced malignant solid tumors

Benjamin K. Tomlinson, James A. Thomson, John S. Bomalaski, Monica Diaz, Taiwo Akande, Nichole Mahaffey, Tianhong Li, Mrinal P. Dutia, Karen Kelly, I. Yeh Gong, Thomas Semrad, David R Gandara, Chong-Xian Pan, Primo N Lara

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Abstract

Purpose: This phase I study examined the toxicity and tolerability of pegylated arginine deiminase (ADI-PEG 20) in combination with docetaxel in patients with advanced solid malignancies. Experimental Design: Eligible patients had histologically proven advanced solid malignancies, with any number of prior therapies, Zubrod performance status 0-2, and adequate organ function. Patients received ADI-PEG 20 weekly intramuscular injection ranging from 4.5 to 36 mg/m2 and up to 10 doses of docetaxel (75 mg/m2) every 3 weeks. Primary endpoints were safety, toxicity, and a recommended phase II dose. Circulating arginine levels were measured before each cycle. Tumor response was measured as a secondary endpoint every 6 weeks on study. Results: Eighteen patients received a total of 116 cycles of therapy through four dose levels of ADI-PEG 20. A single doselimiting toxicity (grade 3 urticarial rash) was observed at the 1st dose level, with no additional dose-limiting toxicities observed. Hematologic toxicities were common with 14 patients experiencing at least one grade 3 to 4 leukopenia. Fatigue was the most prevalent toxicity reported by 16 patients. Arginine was variably suppressed with 10 patients achieving at least a 50% reduction in baseline values. In 14 patients with evaluable disease, four partial responses (including 2 patients with PSA response) were documented, and 7 patients had stable disease. Conclusions: ADI-PEG 20 demonstrated reasonable toxicity in combination with docetaxel. Promising clinical activity was noted, and expansion cohorts are now accruing for both castrate-resistant prostate cancer and non-small cell lung cancer at a recommended phase II dose of 36 mg/m<sup>2</sup>.

Original languageEnglish (US)
Pages (from-to)2480-2486
Number of pages7
JournalClinical Cancer Research
Volume21
Issue number11
DOIs
StatePublished - Jun 1 2015

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docetaxel
Arginine
Neoplasms
Therapeutics
Intramuscular Injections
Leukopenia

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Phase i trial of arginine deprivation therapy with ADI-PEG 20 plus docetaxel in patients with advanced malignant solid tumors. / Tomlinson, Benjamin K.; Thomson, James A.; Bomalaski, John S.; Diaz, Monica; Akande, Taiwo; Mahaffey, Nichole; Li, Tianhong; Dutia, Mrinal P.; Kelly, Karen; Gong, I. Yeh; Semrad, Thomas; Gandara, David R; Pan, Chong-Xian; Lara, Primo N.

In: Clinical Cancer Research, Vol. 21, No. 11, 01.06.2015, p. 2480-2486.

Research output: Contribution to journalArticle

Tomlinson, Benjamin K. ; Thomson, James A. ; Bomalaski, John S. ; Diaz, Monica ; Akande, Taiwo ; Mahaffey, Nichole ; Li, Tianhong ; Dutia, Mrinal P. ; Kelly, Karen ; Gong, I. Yeh ; Semrad, Thomas ; Gandara, David R ; Pan, Chong-Xian ; Lara, Primo N. / Phase i trial of arginine deprivation therapy with ADI-PEG 20 plus docetaxel in patients with advanced malignant solid tumors. In: Clinical Cancer Research. 2015 ; Vol. 21, No. 11. pp. 2480-2486.
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abstract = "Purpose: This phase I study examined the toxicity and tolerability of pegylated arginine deiminase (ADI-PEG 20) in combination with docetaxel in patients with advanced solid malignancies. Experimental Design: Eligible patients had histologically proven advanced solid malignancies, with any number of prior therapies, Zubrod performance status 0-2, and adequate organ function. Patients received ADI-PEG 20 weekly intramuscular injection ranging from 4.5 to 36 mg/m2 and up to 10 doses of docetaxel (75 mg/m2) every 3 weeks. Primary endpoints were safety, toxicity, and a recommended phase II dose. Circulating arginine levels were measured before each cycle. Tumor response was measured as a secondary endpoint every 6 weeks on study. Results: Eighteen patients received a total of 116 cycles of therapy through four dose levels of ADI-PEG 20. A single doselimiting toxicity (grade 3 urticarial rash) was observed at the 1st dose level, with no additional dose-limiting toxicities observed. Hematologic toxicities were common with 14 patients experiencing at least one grade 3 to 4 leukopenia. Fatigue was the most prevalent toxicity reported by 16 patients. Arginine was variably suppressed with 10 patients achieving at least a 50{\%} reduction in baseline values. In 14 patients with evaluable disease, four partial responses (including 2 patients with PSA response) were documented, and 7 patients had stable disease. Conclusions: ADI-PEG 20 demonstrated reasonable toxicity in combination with docetaxel. Promising clinical activity was noted, and expansion cohorts are now accruing for both castrate-resistant prostate cancer and non-small cell lung cancer at a recommended phase II dose of 36 mg/m2.",
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T1 - Phase i trial of arginine deprivation therapy with ADI-PEG 20 plus docetaxel in patients with advanced malignant solid tumors

AU - Tomlinson, Benjamin K.

AU - Thomson, James A.

AU - Bomalaski, John S.

AU - Diaz, Monica

AU - Akande, Taiwo

AU - Mahaffey, Nichole

AU - Li, Tianhong

AU - Dutia, Mrinal P.

AU - Kelly, Karen

AU - Gong, I. Yeh

AU - Semrad, Thomas

AU - Gandara, David R

AU - Pan, Chong-Xian

AU - Lara, Primo N

PY - 2015/6/1

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N2 - Purpose: This phase I study examined the toxicity and tolerability of pegylated arginine deiminase (ADI-PEG 20) in combination with docetaxel in patients with advanced solid malignancies. Experimental Design: Eligible patients had histologically proven advanced solid malignancies, with any number of prior therapies, Zubrod performance status 0-2, and adequate organ function. Patients received ADI-PEG 20 weekly intramuscular injection ranging from 4.5 to 36 mg/m2 and up to 10 doses of docetaxel (75 mg/m2) every 3 weeks. Primary endpoints were safety, toxicity, and a recommended phase II dose. Circulating arginine levels were measured before each cycle. Tumor response was measured as a secondary endpoint every 6 weeks on study. Results: Eighteen patients received a total of 116 cycles of therapy through four dose levels of ADI-PEG 20. A single doselimiting toxicity (grade 3 urticarial rash) was observed at the 1st dose level, with no additional dose-limiting toxicities observed. Hematologic toxicities were common with 14 patients experiencing at least one grade 3 to 4 leukopenia. Fatigue was the most prevalent toxicity reported by 16 patients. Arginine was variably suppressed with 10 patients achieving at least a 50% reduction in baseline values. In 14 patients with evaluable disease, four partial responses (including 2 patients with PSA response) were documented, and 7 patients had stable disease. Conclusions: ADI-PEG 20 demonstrated reasonable toxicity in combination with docetaxel. Promising clinical activity was noted, and expansion cohorts are now accruing for both castrate-resistant prostate cancer and non-small cell lung cancer at a recommended phase II dose of 36 mg/m2.

AB - Purpose: This phase I study examined the toxicity and tolerability of pegylated arginine deiminase (ADI-PEG 20) in combination with docetaxel in patients with advanced solid malignancies. Experimental Design: Eligible patients had histologically proven advanced solid malignancies, with any number of prior therapies, Zubrod performance status 0-2, and adequate organ function. Patients received ADI-PEG 20 weekly intramuscular injection ranging from 4.5 to 36 mg/m2 and up to 10 doses of docetaxel (75 mg/m2) every 3 weeks. Primary endpoints were safety, toxicity, and a recommended phase II dose. Circulating arginine levels were measured before each cycle. Tumor response was measured as a secondary endpoint every 6 weeks on study. Results: Eighteen patients received a total of 116 cycles of therapy through four dose levels of ADI-PEG 20. A single doselimiting toxicity (grade 3 urticarial rash) was observed at the 1st dose level, with no additional dose-limiting toxicities observed. Hematologic toxicities were common with 14 patients experiencing at least one grade 3 to 4 leukopenia. Fatigue was the most prevalent toxicity reported by 16 patients. Arginine was variably suppressed with 10 patients achieving at least a 50% reduction in baseline values. In 14 patients with evaluable disease, four partial responses (including 2 patients with PSA response) were documented, and 7 patients had stable disease. Conclusions: ADI-PEG 20 demonstrated reasonable toxicity in combination with docetaxel. Promising clinical activity was noted, and expansion cohorts are now accruing for both castrate-resistant prostate cancer and non-small cell lung cancer at a recommended phase II dose of 36 mg/m2.

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