TY - JOUR
T1 - Study Protocol
T2 - Phase-Ib Trial of Nivolumab Combined With Metformin for Refractory/Recurrent Solid Tumors
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
N1 - Funding Information:
TK has received a research grant outside the current work from Chugai Pharmaceuticals Japan. KH has received honoraria outside the current work from Ono Pharmaceutical, AstraZeneca, Astellas, Novartis, BMS, MSD, Eli Lilly Japan, Daiichi-Sankyo Pharmaceutical, Boehringer-Ingelheim, Nihon Kayaku, Taiho Pharmaceutical, and Chugai Pharmaceutical. KH also has received research funding outside the current work from Ono Pharmaceutical, AstraZeneca, Boehringer-Ingelheim, Astellas, Novartis, BMS, Eli Lilly Japan, MSD, and Chugai Pharmaceutical. KK has received honoraria from Eli Lilly Japan, Nihon Kayaku, AstraZeneca, Daiichi-Sankyo Pharmaceutical, Chugai Pharmaceutical, Taiho Pharmaceutical, and Sanofi-Aventis. The remaining authors have stated that they have no conflicts of interest.
Funding Information:
The authors wish to acknowledge and thank the investigators, coordinators, and all of the other investigators who have contributed to this study. We especially appreciate Dr. Shigeki Umemura (National Cancer Center Hospital East), Dr. Hisashi Endo (Fukuyama City Hospital), Dr. Takayasu Kurata (Kansai Medical University Hospital), Dr. Hitomi Kataoka (Okayama University Hospital) for the effort as a member of the independent data monitoring committee, Dr. Toshihiko Doi (National Cancer Center Hospital East) for the effort as a medical adviser, Dr. Wataru Okamoto (National Cancer Center Hospital East) for the effort as a translational research coordinator, and Akiko Nishioka (NHO Shikoku Cancer Center), Kaoru Miyake, Satoshi Kuroda, and Satoko Hiroe (Okayama University Hospital) for expert technical support. This study has been conducted with dedicated support from the Center for Innovative Clinical Medicine, Okayama University Hospital (Kunihisa Kamikawa, Masayoshi Nakabayashi, Yuko Ohe, Chikayo Harada, Michihiro Yoshida, and Jun Sakurai).
PY - 2018/11
Y1 - 2018/11
N2 - 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.
AB - 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.
KW - Anti-PD-1 antibody
KW - Metformin
KW - Nivolumab
KW - Non–small-cell lung cancer
KW - Phase-Ib
UR - http://www.scopus.com/inward/record.url?scp=85054060912&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85054060912&partnerID=8YFLogxK
U2 - 10.1016/j.cllc.2018.07.010
DO - 10.1016/j.cllc.2018.07.010
M3 - Article
C2 - 30172698
AN - SCOPUS:85054060912
VL - 19
SP - e861-e864
JO - Clinical Lung Cancer
JF - Clinical Lung Cancer
SN - 1525-7304
IS - 6
ER -