Study Protocol: Phase-Ib Trial of Nivolumab Combined With Metformin for Refractory/Recurrent Solid Tumors

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Abstract

Although immune checkpoint inhibitors have shown significant survival benefits in the treatment of several cancers, optimal outcomes have been limited to certain subsets of patients. In a previous study, we found that the addition of metformin to nivolumab, an anti-programmed cell death protein 1 (PD-1) antibody, yielded substantial tumor regression in mouse models. Further analysis revealed that the number of tumor-infiltrating CD8 T cells had increased markedly. Based on this result, we have launched an investigator-initiated open-label phase-Ib clinical trial. The objectives of this trial are to investigate the safety, efficacy, and pharmacokinetics of a metformin-nivolumab combination treatment. This study consists of 2 parts. The recommended dose of metformin combined with nivolumab is determined in part 1. The safety and efficacy of the optimal dose of metformin to be delivered in conjunction with nivolumab are examined in part 2. Patient eligibility is based on the following criteria: pathologic diagnosis of refractory/recurrent solid tumor (part 1), and non–small-cell lung cancer or pancreatic cancer refractory to standard primary treatment (part 2); no prior use of immune checkpoint inhibitor; performance status 0 or 1; age ≥ 20 years; and adequate organ function. The primary endpoints are safety in part 1 and safety and pharmacokinetics in part 2. The maximum tolerated dose and recommended dose are determined in part 1 by the 3 + 3 cohort method, and the dose-limiting toxicity evaluation period for each patient is 4 weeks from the start of administration. In part 2, metformin is administered at the optimal dose determined in part 1. Total enrollment is 9 to 18 patients for part 1 and 30 patients for part 2. Enrollment began in 2017, and will be completed by 2019. The University Hospital Medical Information Network registration number for this study is 000028405.

Original languageEnglish
JournalClinical Lung Cancer
DOIs
Publication statusAccepted/In press - Jan 1 2018

Fingerprint

Metformin
Safety
Neoplasms
Programmed Cell Death 1 Receptor
Pharmacokinetics
Information Services
Maximum Tolerated Dose
Pancreatic Neoplasms
Non-Small Cell Lung Carcinoma
Therapeutics
Research Personnel
nivolumab
Clinical Trials
T-Lymphocytes
Survival
Antibodies

Keywords

  • Anti-PD-1 antibody
  • Metformin
  • Nivolumab
  • Non–small-cell lung cancer
  • Phase-Ib

ASJC Scopus subject areas

  • Oncology
  • Pulmonary and Respiratory Medicine
  • Cancer Research

Cite this

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title = "Study Protocol: Phase-Ib Trial of Nivolumab Combined With Metformin for Refractory/Recurrent Solid Tumors",
abstract = "Although immune checkpoint inhibitors have shown significant survival benefits in the treatment of several cancers, optimal outcomes have been limited to certain subsets of patients. In a previous study, we found that the addition of metformin to nivolumab, an anti-programmed cell death protein 1 (PD-1) antibody, yielded substantial tumor regression in mouse models. Further analysis revealed that the number of tumor-infiltrating CD8 T cells had increased markedly. Based on this result, we have launched an investigator-initiated open-label phase-Ib clinical trial. The objectives of this trial are to investigate the safety, efficacy, and pharmacokinetics of a metformin-nivolumab combination treatment. This study consists of 2 parts. The recommended dose of metformin combined with nivolumab is determined in part 1. The safety and efficacy of the optimal dose of metformin to be delivered in conjunction with nivolumab are examined in part 2. Patient eligibility is based on the following criteria: pathologic diagnosis of refractory/recurrent solid tumor (part 1), and non–small-cell lung cancer or pancreatic cancer refractory to standard primary treatment (part 2); no prior use of immune checkpoint inhibitor; performance status 0 or 1; age ≥ 20 years; and adequate organ function. The primary endpoints are safety in part 1 and safety and pharmacokinetics in part 2. The maximum tolerated dose and recommended dose are determined in part 1 by the 3 + 3 cohort method, and the dose-limiting toxicity evaluation period for each patient is 4 weeks from the start of administration. In part 2, metformin is administered at the optimal dose determined in part 1. Total enrollment is 9 to 18 patients for part 1 and 30 patients for part 2. Enrollment began in 2017, and will be completed by 2019. The University Hospital Medical Information Network registration number for this study is 000028405.",
keywords = "Anti-PD-1 antibody, Metformin, Nivolumab, Non–small-cell lung cancer, Phase-Ib",
author = "Toshio Kubo and Takashi Ninomiya and Katsuyuki Hotta and Toshiyuki Kozuki and Shinichi Toyooka and Hiroyuki Okada and Toshiyoshi Fujiwara and Heiichiro Udono and Katsuyuki Kiura",
year = "2018",
month = "1",
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doi = "10.1016/j.cllc.2018.07.010",
language = "English",
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AU - Kubo, Toshio

AU - Ninomiya, Takashi

AU - Hotta, Katsuyuki

AU - Kozuki, Toshiyuki

AU - Toyooka, Shinichi

AU - Okada, Hiroyuki

AU - Fujiwara, Toshiyoshi

AU - Udono, Heiichiro

AU - Kiura, Katsuyuki

PY - 2018/1/1

Y1 - 2018/1/1

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KW - Non–small-cell lung cancer

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