Phase IB study of induction chemotherapy with XELOX, followed by radiation therapy, carboplatin, and everolimus in patients with locally advanced esophageal cancer

Nabil F. Saba, Seth Force, Charley Staley, Felix Fernandez, Field Willingham, Allan Pickens, Kenneth Cardona, Zhengjia Chen, Laura Goff, Dana Cardin, Eric Lambright, Jon Nesbitt, Alyssa Krasinskas, Kristin Higgins, R. Donald Harvey, Taofeek Owonikoko, Suresh S. Ramalingam, Dong M. Shin, Jonathan J. Beitler, Bassel F. El-RayesSafia Salaria, Wael El-Rifai, Jerome Landry, A. B. Chakravarthy

Research output: Contribution to journalArticle

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Abstract

Purpose: Preclinical studies have shown synergy between everolimus, an mTOR inhibitor, radiation, and platinum agents. We conducted a phase IB trial to determine the recommended phase II dose of everolimus with carboplatin and radiation. Materials and Methods: Patients with stage II/III esophageal cancer were enrolled. Following 2 cycles of Capecitabine/Oxaliplatin (XELOX), patients with no disease progression, received 50.4 Gy in 28 fractions and concurrent weekly carboplatin (area under the curve=2), with escalating doses of everolimus. A standard 3+3 dose escalation design was used. Results: Nineteen patients were enrolled. Two patients were screen failures and 4 were removed due to poor tolerance to XELOX (n=2) or disease progression (n=2). All treated patients had adenocarcinoma. Median age was 58 (44 to 71 y) and 85% were male patients. One patient at dose level 1 was replaced due to ongoing anxiety. One of 6 patients had a dose-limiting toxicity of bowel ischemia that was fatal. At dose level 2, two of 6 patients had a dose-limiting toxicity (fever with neutropenia and nausea). The recommended phase II dose of everolimus was 2.5 mg QOD. Grade ≥3 toxicities included lymphopenia (11%), nausea (10%), low white blood cell (8.0%) vomiting (5.5%), decreased neutrophils (4.0%). All patients achieved an R0 resection with a pathologic response rate of 40% and a pathologic complete response (ypCR) rate of 23%. The 2-year progression-free survival and overall survival were 50% and 49.6%, respectively. Conclusions: The recommended phase II dose of everolimus with concurrent weekly carboplatin and radiation is 2.5 mg QOD.

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Induction Chemotherapy
Carboplatin
Esophageal Neoplasms
Radiotherapy
oxaliplatin
Radiation
Nausea
Disease Progression
XELOX
Everolimus
Lymphopenia
Neutropenia
Platinum
Disease-Free Survival
Area Under Curve
Vomiting
Adenocarcinoma
Neutrophils
Leukocytes
Fever

Keywords

  • everolimus in esophageal cancer
  • mTOR and radiation
  • mTOR in esophageal cancer
  • radiation and everolimus
  • XELOX and esophageal cancer

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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Phase IB study of induction chemotherapy with XELOX, followed by radiation therapy, carboplatin, and everolimus in patients with locally advanced esophageal cancer. / Saba, Nabil F.; Force, Seth; Staley, Charley; Fernandez, Felix; Willingham, Field; Pickens, Allan; Cardona, Kenneth; Chen, Zhengjia; Goff, Laura; Cardin, Dana; Lambright, Eric; Nesbitt, Jon; Krasinskas, Alyssa; Higgins, Kristin; Harvey, R. Donald; Owonikoko, Taofeek; Ramalingam, Suresh S.; Shin, Dong M.; Beitler, Jonathan J.; El-Rayes, Bassel F.; Salaria, Safia; El-Rifai, Wael; Landry, Jerome; Chakravarthy, A. B.

In: American Journal of Clinical Oncology: Cancer Clinical Trials, 01.01.2019.

Research output: Contribution to journalArticle

Saba, NF, Force, S, Staley, C, Fernandez, F, Willingham, F, Pickens, A, Cardona, K, Chen, Z, Goff, L, Cardin, D, Lambright, E, Nesbitt, J, Krasinskas, A, Higgins, K, Harvey, RD, Owonikoko, T, Ramalingam, SS, Shin, DM, Beitler, JJ, El-Rayes, BF, Salaria, S, El-Rifai, W, Landry, J & Chakravarthy, AB 2019, 'Phase IB study of induction chemotherapy with XELOX, followed by radiation therapy, carboplatin, and everolimus in patients with locally advanced esophageal cancer', American Journal of Clinical Oncology: Cancer Clinical Trials. https://doi.org/10.1097/COC.0000000000000524
Saba, Nabil F. ; Force, Seth ; Staley, Charley ; Fernandez, Felix ; Willingham, Field ; Pickens, Allan ; Cardona, Kenneth ; Chen, Zhengjia ; Goff, Laura ; Cardin, Dana ; Lambright, Eric ; Nesbitt, Jon ; Krasinskas, Alyssa ; Higgins, Kristin ; Harvey, R. Donald ; Owonikoko, Taofeek ; Ramalingam, Suresh S. ; Shin, Dong M. ; Beitler, Jonathan J. ; El-Rayes, Bassel F. ; Salaria, Safia ; El-Rifai, Wael ; Landry, Jerome ; Chakravarthy, A. B. / Phase IB study of induction chemotherapy with XELOX, followed by radiation therapy, carboplatin, and everolimus in patients with locally advanced esophageal cancer. In: American Journal of Clinical Oncology: Cancer Clinical Trials. 2019.
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abstract = "Purpose: Preclinical studies have shown synergy between everolimus, an mTOR inhibitor, radiation, and platinum agents. We conducted a phase IB trial to determine the recommended phase II dose of everolimus with carboplatin and radiation. Materials and Methods: Patients with stage II/III esophageal cancer were enrolled. Following 2 cycles of Capecitabine/Oxaliplatin (XELOX), patients with no disease progression, received 50.4 Gy in 28 fractions and concurrent weekly carboplatin (area under the curve=2), with escalating doses of everolimus. A standard 3+3 dose escalation design was used. Results: Nineteen patients were enrolled. Two patients were screen failures and 4 were removed due to poor tolerance to XELOX (n=2) or disease progression (n=2). All treated patients had adenocarcinoma. Median age was 58 (44 to 71 y) and 85{\%} were male patients. One patient at dose level 1 was replaced due to ongoing anxiety. One of 6 patients had a dose-limiting toxicity of bowel ischemia that was fatal. At dose level 2, two of 6 patients had a dose-limiting toxicity (fever with neutropenia and nausea). The recommended phase II dose of everolimus was 2.5 mg QOD. Grade ≥3 toxicities included lymphopenia (11{\%}), nausea (10{\%}), low white blood cell (8.0{\%}) vomiting (5.5{\%}), decreased neutrophils (4.0{\%}). All patients achieved an R0 resection with a pathologic response rate of 40{\%} and a pathologic complete response (ypCR) rate of 23{\%}. The 2-year progression-free survival and overall survival were 50{\%} and 49.6{\%}, respectively. Conclusions: The recommended phase II dose of everolimus with concurrent weekly carboplatin and radiation is 2.5 mg QOD.",
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T1 - Phase IB study of induction chemotherapy with XELOX, followed by radiation therapy, carboplatin, and everolimus in patients with locally advanced esophageal cancer

AU - Saba, Nabil F.

AU - Force, Seth

AU - Staley, Charley

AU - Fernandez, Felix

AU - Willingham, Field

AU - Pickens, Allan

AU - Cardona, Kenneth

AU - Chen, Zhengjia

AU - Goff, Laura

AU - Cardin, Dana

AU - Lambright, Eric

AU - Nesbitt, Jon

AU - Krasinskas, Alyssa

AU - Higgins, Kristin

AU - Harvey, R. Donald

AU - Owonikoko, Taofeek

AU - Ramalingam, Suresh S.

AU - Shin, Dong M.

AU - Beitler, Jonathan J.

AU - El-Rayes, Bassel F.

AU - Salaria, Safia

AU - El-Rifai, Wael

AU - Landry, Jerome

AU - Chakravarthy, A. B.

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Purpose: Preclinical studies have shown synergy between everolimus, an mTOR inhibitor, radiation, and platinum agents. We conducted a phase IB trial to determine the recommended phase II dose of everolimus with carboplatin and radiation. Materials and Methods: Patients with stage II/III esophageal cancer were enrolled. Following 2 cycles of Capecitabine/Oxaliplatin (XELOX), patients with no disease progression, received 50.4 Gy in 28 fractions and concurrent weekly carboplatin (area under the curve=2), with escalating doses of everolimus. A standard 3+3 dose escalation design was used. Results: Nineteen patients were enrolled. Two patients were screen failures and 4 were removed due to poor tolerance to XELOX (n=2) or disease progression (n=2). All treated patients had adenocarcinoma. Median age was 58 (44 to 71 y) and 85% were male patients. One patient at dose level 1 was replaced due to ongoing anxiety. One of 6 patients had a dose-limiting toxicity of bowel ischemia that was fatal. At dose level 2, two of 6 patients had a dose-limiting toxicity (fever with neutropenia and nausea). The recommended phase II dose of everolimus was 2.5 mg QOD. Grade ≥3 toxicities included lymphopenia (11%), nausea (10%), low white blood cell (8.0%) vomiting (5.5%), decreased neutrophils (4.0%). All patients achieved an R0 resection with a pathologic response rate of 40% and a pathologic complete response (ypCR) rate of 23%. The 2-year progression-free survival and overall survival were 50% and 49.6%, respectively. Conclusions: The recommended phase II dose of everolimus with concurrent weekly carboplatin and radiation is 2.5 mg QOD.

AB - Purpose: Preclinical studies have shown synergy between everolimus, an mTOR inhibitor, radiation, and platinum agents. We conducted a phase IB trial to determine the recommended phase II dose of everolimus with carboplatin and radiation. Materials and Methods: Patients with stage II/III esophageal cancer were enrolled. Following 2 cycles of Capecitabine/Oxaliplatin (XELOX), patients with no disease progression, received 50.4 Gy in 28 fractions and concurrent weekly carboplatin (area under the curve=2), with escalating doses of everolimus. A standard 3+3 dose escalation design was used. Results: Nineteen patients were enrolled. Two patients were screen failures and 4 were removed due to poor tolerance to XELOX (n=2) or disease progression (n=2). All treated patients had adenocarcinoma. Median age was 58 (44 to 71 y) and 85% were male patients. One patient at dose level 1 was replaced due to ongoing anxiety. One of 6 patients had a dose-limiting toxicity of bowel ischemia that was fatal. At dose level 2, two of 6 patients had a dose-limiting toxicity (fever with neutropenia and nausea). The recommended phase II dose of everolimus was 2.5 mg QOD. Grade ≥3 toxicities included lymphopenia (11%), nausea (10%), low white blood cell (8.0%) vomiting (5.5%), decreased neutrophils (4.0%). All patients achieved an R0 resection with a pathologic response rate of 40% and a pathologic complete response (ypCR) rate of 23%. The 2-year progression-free survival and overall survival were 50% and 49.6%, respectively. Conclusions: The recommended phase II dose of everolimus with concurrent weekly carboplatin and radiation is 2.5 mg QOD.

KW - everolimus in esophageal cancer

KW - mTOR and radiation

KW - mTOR in esophageal cancer

KW - radiation and everolimus

KW - XELOX and esophageal cancer

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DO - 10.1097/COC.0000000000000524

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JO - American Journal of Clinical Oncology

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