A randomized, phase 2 trial of docetaxel with or without PX-866, an irreversible oral phosphatidylinositol 3-kinase inhibitor, in patients with relapsed or metastatic head and neck squamous cell cancer

Antonio Jimeno, Julie E. Bauman, Charles Weissman, Douglas Adkins, Ian Schnadig, Patrice Beauregard, Daniel W. Bowles, Alexander Spira, Benjamin Levy, Nagashree Seetharamu, Diana Hausman, Luke Walker, Charles M. Rudin, Keisuke Shirai

Research output: Contribution to journalArticle

Abstract

Introduction: The phosphotidylinositol-3 kinase (PI3K)/serine-threonine kinase (AKT)/mammalian target of rapamycin (mTOR) signaling pathway is frequently altered in head and neck squamous cell cancer (HNSCC). PX-866 is an oral, irreversible, pan-isoform inhibitor of PI3K. Preclinical models revealed synergy with docetaxel and a phase 1 trial demonstrated tolerability of this combination. This randomized phase 2 study evaluated PX-866 combined with docetaxel in patients with advanced, refractory HNSCC. Methods: Patients with locally advanced, recurrent or metastatic HNSCC who had received at least one and no more than two prior systemic treatment regimens were randomized (1:1) to a combination of docetaxel (75 mg/m2IV every 21 days) with or without PX-866 (8 mg PO daily; Arms A and B, respectively). The primary endpoint was progression free survival (PFS). Secondary endpoints included objective response rate (RR), overall survival (OS), toxicity, and correlation of biomarker analyses with efficacy outcomes. Results: 85 patients were enrolled. There was a non-significant improvement in response rate in the combination arm (14% vs. 5%; P = 0.13). Median PFS was 92 days in Arm A and 82 days in Arm B (P= 0.42). There was no difference in OS between the two arms (263 vs. 195 days; P = 0.62). Grade 3 or higher adverse events were infrequent, but more common in the combination arm with respect to diarrhea (17% vs. 2%), nausea (7% vs. 0%), and febrile neutropenia (21% vs. 5%); grade 3 or higher anemia was more frequent in arm B (7% vs. 27%). PIK3CA mutations or PTEN loss were infrequently observed. Conclusion: The addition of PX-866 to docetaxel did not improve PFS, RR, or OS in patients with advanced, refractory HNSCC without molecular pre-selection.

Original languageEnglish (US)
Pages (from-to)383-388
Number of pages6
JournalOral Oncology
Volume51
Issue number4
DOIs
StatePublished - 2015

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docetaxel
Phosphatidylinositol 3-Kinase
Squamous Cell Neoplasms
Head and Neck Neoplasms
Arm
Head
Disease-Free Survival
Phosphotransferases
Survival Rate
Febrile Neutropenia
Survival
Protein-Serine-Threonine Kinases
Sirolimus
PX-866
Nausea
Anemia
Diarrhea
Protein Isoforms
Biomarkers

Keywords

  • Docetaxel
  • Head and neck squamous cell cancer
  • PI3K
  • PIK3CA

ASJC Scopus subject areas

  • Oncology
  • Oral Surgery
  • Cancer Research

Cite this

A randomized, phase 2 trial of docetaxel with or without PX-866, an irreversible oral phosphatidylinositol 3-kinase inhibitor, in patients with relapsed or metastatic head and neck squamous cell cancer. / Jimeno, Antonio; Bauman, Julie E.; Weissman, Charles; Adkins, Douglas; Schnadig, Ian; Beauregard, Patrice; Bowles, Daniel W.; Spira, Alexander; Levy, Benjamin; Seetharamu, Nagashree; Hausman, Diana; Walker, Luke; Rudin, Charles M.; Shirai, Keisuke.

In: Oral Oncology, Vol. 51, No. 4, 2015, p. 383-388.

Research output: Contribution to journalArticle

Jimeno, Antonio ; Bauman, Julie E. ; Weissman, Charles ; Adkins, Douglas ; Schnadig, Ian ; Beauregard, Patrice ; Bowles, Daniel W. ; Spira, Alexander ; Levy, Benjamin ; Seetharamu, Nagashree ; Hausman, Diana ; Walker, Luke ; Rudin, Charles M. ; Shirai, Keisuke. / A randomized, phase 2 trial of docetaxel with or without PX-866, an irreversible oral phosphatidylinositol 3-kinase inhibitor, in patients with relapsed or metastatic head and neck squamous cell cancer. In: Oral Oncology. 2015 ; Vol. 51, No. 4. pp. 383-388.
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abstract = "Introduction: The phosphotidylinositol-3 kinase (PI3K)/serine-threonine kinase (AKT)/mammalian target of rapamycin (mTOR) signaling pathway is frequently altered in head and neck squamous cell cancer (HNSCC). PX-866 is an oral, irreversible, pan-isoform inhibitor of PI3K. Preclinical models revealed synergy with docetaxel and a phase 1 trial demonstrated tolerability of this combination. This randomized phase 2 study evaluated PX-866 combined with docetaxel in patients with advanced, refractory HNSCC. Methods: Patients with locally advanced, recurrent or metastatic HNSCC who had received at least one and no more than two prior systemic treatment regimens were randomized (1:1) to a combination of docetaxel (75 mg/m2IV every 21 days) with or without PX-866 (8 mg PO daily; Arms A and B, respectively). The primary endpoint was progression free survival (PFS). Secondary endpoints included objective response rate (RR), overall survival (OS), toxicity, and correlation of biomarker analyses with efficacy outcomes. Results: 85 patients were enrolled. There was a non-significant improvement in response rate in the combination arm (14{\%} vs. 5{\%}; P = 0.13). Median PFS was 92 days in Arm A and 82 days in Arm B (P= 0.42). There was no difference in OS between the two arms (263 vs. 195 days; P = 0.62). Grade 3 or higher adverse events were infrequent, but more common in the combination arm with respect to diarrhea (17{\%} vs. 2{\%}), nausea (7{\%} vs. 0{\%}), and febrile neutropenia (21{\%} vs. 5{\%}); grade 3 or higher anemia was more frequent in arm B (7{\%} vs. 27{\%}). PIK3CA mutations or PTEN loss were infrequently observed. Conclusion: The addition of PX-866 to docetaxel did not improve PFS, RR, or OS in patients with advanced, refractory HNSCC without molecular pre-selection.",
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T1 - A randomized, phase 2 trial of docetaxel with or without PX-866, an irreversible oral phosphatidylinositol 3-kinase inhibitor, in patients with relapsed or metastatic head and neck squamous cell cancer

AU - Jimeno, Antonio

AU - Bauman, Julie E.

AU - Weissman, Charles

AU - Adkins, Douglas

AU - Schnadig, Ian

AU - Beauregard, Patrice

AU - Bowles, Daniel W.

AU - Spira, Alexander

AU - Levy, Benjamin

AU - Seetharamu, Nagashree

AU - Hausman, Diana

AU - Walker, Luke

AU - Rudin, Charles M.

AU - Shirai, Keisuke

PY - 2015

Y1 - 2015

N2 - Introduction: The phosphotidylinositol-3 kinase (PI3K)/serine-threonine kinase (AKT)/mammalian target of rapamycin (mTOR) signaling pathway is frequently altered in head and neck squamous cell cancer (HNSCC). PX-866 is an oral, irreversible, pan-isoform inhibitor of PI3K. Preclinical models revealed synergy with docetaxel and a phase 1 trial demonstrated tolerability of this combination. This randomized phase 2 study evaluated PX-866 combined with docetaxel in patients with advanced, refractory HNSCC. Methods: Patients with locally advanced, recurrent or metastatic HNSCC who had received at least one and no more than two prior systemic treatment regimens were randomized (1:1) to a combination of docetaxel (75 mg/m2IV every 21 days) with or without PX-866 (8 mg PO daily; Arms A and B, respectively). The primary endpoint was progression free survival (PFS). Secondary endpoints included objective response rate (RR), overall survival (OS), toxicity, and correlation of biomarker analyses with efficacy outcomes. Results: 85 patients were enrolled. There was a non-significant improvement in response rate in the combination arm (14% vs. 5%; P = 0.13). Median PFS was 92 days in Arm A and 82 days in Arm B (P= 0.42). There was no difference in OS between the two arms (263 vs. 195 days; P = 0.62). Grade 3 or higher adverse events were infrequent, but more common in the combination arm with respect to diarrhea (17% vs. 2%), nausea (7% vs. 0%), and febrile neutropenia (21% vs. 5%); grade 3 or higher anemia was more frequent in arm B (7% vs. 27%). PIK3CA mutations or PTEN loss were infrequently observed. Conclusion: The addition of PX-866 to docetaxel did not improve PFS, RR, or OS in patients with advanced, refractory HNSCC without molecular pre-selection.

AB - Introduction: The phosphotidylinositol-3 kinase (PI3K)/serine-threonine kinase (AKT)/mammalian target of rapamycin (mTOR) signaling pathway is frequently altered in head and neck squamous cell cancer (HNSCC). PX-866 is an oral, irreversible, pan-isoform inhibitor of PI3K. Preclinical models revealed synergy with docetaxel and a phase 1 trial demonstrated tolerability of this combination. This randomized phase 2 study evaluated PX-866 combined with docetaxel in patients with advanced, refractory HNSCC. Methods: Patients with locally advanced, recurrent or metastatic HNSCC who had received at least one and no more than two prior systemic treatment regimens were randomized (1:1) to a combination of docetaxel (75 mg/m2IV every 21 days) with or without PX-866 (8 mg PO daily; Arms A and B, respectively). The primary endpoint was progression free survival (PFS). Secondary endpoints included objective response rate (RR), overall survival (OS), toxicity, and correlation of biomarker analyses with efficacy outcomes. Results: 85 patients were enrolled. There was a non-significant improvement in response rate in the combination arm (14% vs. 5%; P = 0.13). Median PFS was 92 days in Arm A and 82 days in Arm B (P= 0.42). There was no difference in OS between the two arms (263 vs. 195 days; P = 0.62). Grade 3 or higher adverse events were infrequent, but more common in the combination arm with respect to diarrhea (17% vs. 2%), nausea (7% vs. 0%), and febrile neutropenia (21% vs. 5%); grade 3 or higher anemia was more frequent in arm B (7% vs. 27%). PIK3CA mutations or PTEN loss were infrequently observed. Conclusion: The addition of PX-866 to docetaxel did not improve PFS, RR, or OS in patients with advanced, refractory HNSCC without molecular pre-selection.

KW - Docetaxel

KW - Head and neck squamous cell cancer

KW - PI3K

KW - PIK3CA

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