A Randomized, Phase II Trial of Cetuximab With or Without PX-866, an Irreversible Oral Phosphatidylinositol 3-Kinase Inhibitor, in Patients With Metastatic Colorectal Carcinoma

Daniel W. Bowles, Mark Kochenderfer, Allen Cohn, Lucas Sideris, Nghia Nguyen, Vivian Cline-Burkhardt, Ian Schnadig, Minsig Choi, Lisle Nabell, Arvind Chaudhry, Robert Ruxer, Antonio Ucar, Diana Hausman, Luke Walker, Alexander Spira, Antonio Jimeno

Research output: Contribution to journalArticle

Abstract

The phosphotidyinositol-3 kinase (PI3K) pathway in frequently activated on metastatic colorectal carcinoma (CRC). We combined a novel PI3K inhibitor, PX-866, with cetuximab for patients with KRAS codon 12 wide type metastatic CRC. Patients receiving PX-866 plus cetuximab did not improvement in response rate, progression-free survival, or overall survival compared to cetuximab alone. Toxicity, especially gastrointestinal, was higher in the combination arm. Background The phosphotidylinositol-3 kinase (PI3K)/serine-threonine kinase/mammalian target of rapamycin signaling pathway is frequently altered in colorectal cancer (CRC). PX-866 is an oral, irreversible, pan-isoform inhibitor of PI3K. This randomized phase II study evaluated cetuximab with or without PX-866 in patients with metastatic, anti-epidermal growth factor receptor-naive, KRAS codon 12 and 13 wild-type CRC. Patients and Methods Patients with metastatic CRC who had received both oxaliplatin and irinotecan were randomized (1:1) to cetuximab (400 mg/m2 loading then 250 mg/m2 weekly) with or without PX-866 (8 mg orally daily; arms A and B, respectively). The primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate, overall survival (OS), toxicity, and correlation of relevant biomarkers with efficacy outcomes. Results A total of 85 patients were enrolled. The median PFS was 59 days versus 104 days for arms A (cetuximab + PX-866) and B (cetuximab alone), respectively (P = .77). OS between the 2 arms (266 vs. 333 days for arm A vs. B) were similar (P = .83). Overall toxicity, including treatment-related toxicity, was higher in arm A compared with arm B, especially in terms of all-grade nausea (66% vs. 37%), vomiting (50% vs. 29%), diarrhea (64% vs. 18%), and rash (66% vs. 37%). Grade 3 diarrhea occurred in 19% of patients in Arm A and 0% in Arm B. PIK3CA mutations and PTEN loss by immunohistochemistry were infrequently seen. Conclusion The addition of PX-866 to cetuximab did not improve PFS, objective response rate, or OS in patients with metastatic CRC. The combination arm had greater toxicity and may have been harmful in this study.

Original languageEnglish (US)
Pages (from-to)337-344.e2
JournalClinical Colorectal Cancer
Volume15
Issue number4
DOIs
StatePublished - Dec 1 2016
Externally publishedYes

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Phosphatidylinositol 3-Kinase
Colorectal Neoplasms
Disease-Free Survival
Phosphotransferases
oxaliplatin
irinotecan
Codon
Survival
Diarrhea
PX-866
Cetuximab
Protein-Serine-Threonine Kinases
Sirolimus
Exanthema
Epidermal Growth Factor Receptor
Nausea
Vomiting
Protein Isoforms
Survival Rate
Biomarkers

Keywords

  • Combination therapy
  • EGFR
  • KRAS
  • PI3K
  • PIK3CA

ASJC Scopus subject areas

  • Oncology
  • Gastroenterology

Cite this

A Randomized, Phase II Trial of Cetuximab With or Without PX-866, an Irreversible Oral Phosphatidylinositol 3-Kinase Inhibitor, in Patients With Metastatic Colorectal Carcinoma. / Bowles, Daniel W.; Kochenderfer, Mark; Cohn, Allen; Sideris, Lucas; Nguyen, Nghia; Cline-Burkhardt, Vivian; Schnadig, Ian; Choi, Minsig; Nabell, Lisle; Chaudhry, Arvind; Ruxer, Robert; Ucar, Antonio; Hausman, Diana; Walker, Luke; Spira, Alexander; Jimeno, Antonio.

In: Clinical Colorectal Cancer, Vol. 15, No. 4, 01.12.2016, p. 337-344.e2.

Research output: Contribution to journalArticle

Bowles, DW, Kochenderfer, M, Cohn, A, Sideris, L, Nguyen, N, Cline-Burkhardt, V, Schnadig, I, Choi, M, Nabell, L, Chaudhry, A, Ruxer, R, Ucar, A, Hausman, D, Walker, L, Spira, A & Jimeno, A 2016, 'A Randomized, Phase II Trial of Cetuximab With or Without PX-866, an Irreversible Oral Phosphatidylinositol 3-Kinase Inhibitor, in Patients With Metastatic Colorectal Carcinoma', Clinical Colorectal Cancer, vol. 15, no. 4, pp. 337-344.e2. https://doi.org/10.1016/j.clcc.2016.03.004
Bowles, Daniel W. ; Kochenderfer, Mark ; Cohn, Allen ; Sideris, Lucas ; Nguyen, Nghia ; Cline-Burkhardt, Vivian ; Schnadig, Ian ; Choi, Minsig ; Nabell, Lisle ; Chaudhry, Arvind ; Ruxer, Robert ; Ucar, Antonio ; Hausman, Diana ; Walker, Luke ; Spira, Alexander ; Jimeno, Antonio. / A Randomized, Phase II Trial of Cetuximab With or Without PX-866, an Irreversible Oral Phosphatidylinositol 3-Kinase Inhibitor, in Patients With Metastatic Colorectal Carcinoma. In: Clinical Colorectal Cancer. 2016 ; Vol. 15, No. 4. pp. 337-344.e2.
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abstract = "The phosphotidyinositol-3 kinase (PI3K) pathway in frequently activated on metastatic colorectal carcinoma (CRC). We combined a novel PI3K inhibitor, PX-866, with cetuximab for patients with KRAS codon 12 wide type metastatic CRC. Patients receiving PX-866 plus cetuximab did not improvement in response rate, progression-free survival, or overall survival compared to cetuximab alone. Toxicity, especially gastrointestinal, was higher in the combination arm. Background The phosphotidylinositol-3 kinase (PI3K)/serine-threonine kinase/mammalian target of rapamycin signaling pathway is frequently altered in colorectal cancer (CRC). PX-866 is an oral, irreversible, pan-isoform inhibitor of PI3K. This randomized phase II study evaluated cetuximab with or without PX-866 in patients with metastatic, anti-epidermal growth factor receptor-naive, KRAS codon 12 and 13 wild-type CRC. Patients and Methods Patients with metastatic CRC who had received both oxaliplatin and irinotecan were randomized (1:1) to cetuximab (400 mg/m2 loading then 250 mg/m2 weekly) with or without PX-866 (8 mg orally daily; arms A and B, respectively). The primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate, overall survival (OS), toxicity, and correlation of relevant biomarkers with efficacy outcomes. Results A total of 85 patients were enrolled. The median PFS was 59 days versus 104 days for arms A (cetuximab + PX-866) and B (cetuximab alone), respectively (P = .77). OS between the 2 arms (266 vs. 333 days for arm A vs. B) were similar (P = .83). Overall toxicity, including treatment-related toxicity, was higher in arm A compared with arm B, especially in terms of all-grade nausea (66{\%} vs. 37{\%}), vomiting (50{\%} vs. 29{\%}), diarrhea (64{\%} vs. 18{\%}), and rash (66{\%} vs. 37{\%}). Grade 3 diarrhea occurred in 19{\%} of patients in Arm A and 0{\%} in Arm B. PIK3CA mutations and PTEN loss by immunohistochemistry were infrequently seen. Conclusion The addition of PX-866 to cetuximab did not improve PFS, objective response rate, or OS in patients with metastatic CRC. The combination arm had greater toxicity and may have been harmful in this study.",
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T1 - A Randomized, Phase II Trial of Cetuximab With or Without PX-866, an Irreversible Oral Phosphatidylinositol 3-Kinase Inhibitor, in Patients With Metastatic Colorectal Carcinoma

AU - Bowles, Daniel W.

AU - Kochenderfer, Mark

AU - Cohn, Allen

AU - Sideris, Lucas

AU - Nguyen, Nghia

AU - Cline-Burkhardt, Vivian

AU - Schnadig, Ian

AU - Choi, Minsig

AU - Nabell, Lisle

AU - Chaudhry, Arvind

AU - Ruxer, Robert

AU - Ucar, Antonio

AU - Hausman, Diana

AU - Walker, Luke

AU - Spira, Alexander

AU - Jimeno, Antonio

PY - 2016/12/1

Y1 - 2016/12/1

N2 - The phosphotidyinositol-3 kinase (PI3K) pathway in frequently activated on metastatic colorectal carcinoma (CRC). We combined a novel PI3K inhibitor, PX-866, with cetuximab for patients with KRAS codon 12 wide type metastatic CRC. Patients receiving PX-866 plus cetuximab did not improvement in response rate, progression-free survival, or overall survival compared to cetuximab alone. Toxicity, especially gastrointestinal, was higher in the combination arm. Background The phosphotidylinositol-3 kinase (PI3K)/serine-threonine kinase/mammalian target of rapamycin signaling pathway is frequently altered in colorectal cancer (CRC). PX-866 is an oral, irreversible, pan-isoform inhibitor of PI3K. This randomized phase II study evaluated cetuximab with or without PX-866 in patients with metastatic, anti-epidermal growth factor receptor-naive, KRAS codon 12 and 13 wild-type CRC. Patients and Methods Patients with metastatic CRC who had received both oxaliplatin and irinotecan were randomized (1:1) to cetuximab (400 mg/m2 loading then 250 mg/m2 weekly) with or without PX-866 (8 mg orally daily; arms A and B, respectively). The primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate, overall survival (OS), toxicity, and correlation of relevant biomarkers with efficacy outcomes. Results A total of 85 patients were enrolled. The median PFS was 59 days versus 104 days for arms A (cetuximab + PX-866) and B (cetuximab alone), respectively (P = .77). OS between the 2 arms (266 vs. 333 days for arm A vs. B) were similar (P = .83). Overall toxicity, including treatment-related toxicity, was higher in arm A compared with arm B, especially in terms of all-grade nausea (66% vs. 37%), vomiting (50% vs. 29%), diarrhea (64% vs. 18%), and rash (66% vs. 37%). Grade 3 diarrhea occurred in 19% of patients in Arm A and 0% in Arm B. PIK3CA mutations and PTEN loss by immunohistochemistry were infrequently seen. Conclusion The addition of PX-866 to cetuximab did not improve PFS, objective response rate, or OS in patients with metastatic CRC. The combination arm had greater toxicity and may have been harmful in this study.

AB - The phosphotidyinositol-3 kinase (PI3K) pathway in frequently activated on metastatic colorectal carcinoma (CRC). We combined a novel PI3K inhibitor, PX-866, with cetuximab for patients with KRAS codon 12 wide type metastatic CRC. Patients receiving PX-866 plus cetuximab did not improvement in response rate, progression-free survival, or overall survival compared to cetuximab alone. Toxicity, especially gastrointestinal, was higher in the combination arm. Background The phosphotidylinositol-3 kinase (PI3K)/serine-threonine kinase/mammalian target of rapamycin signaling pathway is frequently altered in colorectal cancer (CRC). PX-866 is an oral, irreversible, pan-isoform inhibitor of PI3K. This randomized phase II study evaluated cetuximab with or without PX-866 in patients with metastatic, anti-epidermal growth factor receptor-naive, KRAS codon 12 and 13 wild-type CRC. Patients and Methods Patients with metastatic CRC who had received both oxaliplatin and irinotecan were randomized (1:1) to cetuximab (400 mg/m2 loading then 250 mg/m2 weekly) with or without PX-866 (8 mg orally daily; arms A and B, respectively). The primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate, overall survival (OS), toxicity, and correlation of relevant biomarkers with efficacy outcomes. Results A total of 85 patients were enrolled. The median PFS was 59 days versus 104 days for arms A (cetuximab + PX-866) and B (cetuximab alone), respectively (P = .77). OS between the 2 arms (266 vs. 333 days for arm A vs. B) were similar (P = .83). Overall toxicity, including treatment-related toxicity, was higher in arm A compared with arm B, especially in terms of all-grade nausea (66% vs. 37%), vomiting (50% vs. 29%), diarrhea (64% vs. 18%), and rash (66% vs. 37%). Grade 3 diarrhea occurred in 19% of patients in Arm A and 0% in Arm B. PIK3CA mutations and PTEN loss by immunohistochemistry were infrequently seen. Conclusion The addition of PX-866 to cetuximab did not improve PFS, objective response rate, or OS in patients with metastatic CRC. The combination arm had greater toxicity and may have been harmful in this study.

KW - Combination therapy

KW - EGFR

KW - KRAS

KW - PI3K

KW - PIK3CA

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