TY - JOUR
T1 - First phase 1 clinical study of olaparib in pediatric patients with refractory solid tumors
AU - Takagi, Masatoshi
AU - Ogawa, Chitose
AU - Iehara, Tomoko
AU - Aoki-Nogami, Yuki
AU - Ishibashi, Eri
AU - Imai, Minoru
AU - Kimura, Toshimi
AU - Nagata, Masashi
AU - Yasuhara, Masato
AU - Masutani, Mitsuko
AU - Yoshimura, Kenichi
AU - Tomizawa, Daisuke
AU - Ogawa, Atsushi
AU - Yonemori, Kan
AU - Morishita, Aoi
AU - Miyamoto, Satoshi
AU - Takita, Junko
AU - Kihara, Tetsuro
AU - Nobori, Kiyoshi
AU - Hasebe, Kazuhisa
AU - Miya, Fuyuki
AU - Ikeda, Sadakatsu
AU - Shioda, Yoko
AU - Matsumoto, Kimikazu
AU - Fujimura, Junya
AU - Mizutani, Shuki
AU - Morio, Tomohiro
AU - Hosoi, Hajime
AU - Koike, Ryuji
N1 - Funding Information:
Olaparib was kindly provided as a gift by AstraZeneca. This work was supported by the Japan Agency for Medical Research and Development (AMED) under Grant Number JP18lk0201048. AMED provided scientific review and funding for this protocol. AMED was not involved in the design of the study, and will not be involved in the collection, analysis, interpretation, or dissemination of study data.
Funding Information:
This work was supported by the Japan Agency for Medical Research and Development (AMED) under Grant Number JP18lk0201048.
Funding Information:
Olaparib was kindly provided as a gift by AstraZeneca. This work was supported by the Japan Agency for Medical Research and Development (AMED) under Grant Number JP18lk0201048. AMED provided scientific review and funding for this protocol. AMED was not involved in the design of the study, and will not be involved in the collection, analysis, interpretation, or dissemination of study data.
Publisher Copyright:
© 2022 American Cancer Society.
PY - 2022/8/1
Y1 - 2022/8/1
N2 - Background: The survival of patients with high-risk, refractory, relapsed, or metastatic solid tumors remains dismal. A poly(ADP-ribose) polymerase (PARP) inhibitor could be effective for the treatment of pediatric solid tumors with defective homologous recombination. Methods: This open-label, multicenter phase 1 clinical trial evaluated the safety, tolerability, and efficacy of olaparib, a PARP inhibitor, in pediatric patients with refractory solid tumors to recommend a dose for Phase 2 trials. Olaparib (62.5, 125, and 187.5 mg/m2 twice daily) was administered orally every day (1 cycle = 28 days) using a standard 3 + 3 dose-escalation design. Patients aged 3–18 years with recurrent pediatric solid tumors were eligible. Pharmacokinetic and pharmacodynamic analyses were performed. Results: Fifteen patients were enrolled and received olaparib monotherapy, which was well tolerated. The recommended phase 2 dose for daily administration was 187.5 mg/m2 twice daily. Pharmacokinetics were dose proportional. The area under the concentration-time curve from 0 to 12 h and the peak plasma concentration for 187.5 mg/m2 twice daily in children were comparable to previous data obtained in a 200-mg, twice-daily cohort and lower than those in the 300-mg twice-daily cohort in adults. Pharmacodynamic studies demonstrated substantial inhibition of PARP activity. Two partial responses were observed in patients with Wilms tumor and neuroblastoma. Conclusions: This report is the first clinical trial to describe the use of a PARP inhibitor as monotherapy in children. Olaparib was well tolerated, with preliminary antitumor responses observed in DNA damage response-defective pediatric tumors. Lay summary: This Phase 1 trial evaluated the efficacy and safety of olaparib in patients with refractory childhood solid tumors. Olaparib was well tolerated, achieving objective response in 2/15 patients. The DNA damage response was attenuated in nearly one-half of advanced neuroblastoma patients, demonstrating the utility of the PARP inhibitor. The results support further investigation of olaparib as a new treatment for DNA damage-response or repair-defective pediatric cancers.
AB - Background: The survival of patients with high-risk, refractory, relapsed, or metastatic solid tumors remains dismal. A poly(ADP-ribose) polymerase (PARP) inhibitor could be effective for the treatment of pediatric solid tumors with defective homologous recombination. Methods: This open-label, multicenter phase 1 clinical trial evaluated the safety, tolerability, and efficacy of olaparib, a PARP inhibitor, in pediatric patients with refractory solid tumors to recommend a dose for Phase 2 trials. Olaparib (62.5, 125, and 187.5 mg/m2 twice daily) was administered orally every day (1 cycle = 28 days) using a standard 3 + 3 dose-escalation design. Patients aged 3–18 years with recurrent pediatric solid tumors were eligible. Pharmacokinetic and pharmacodynamic analyses were performed. Results: Fifteen patients were enrolled and received olaparib monotherapy, which was well tolerated. The recommended phase 2 dose for daily administration was 187.5 mg/m2 twice daily. Pharmacokinetics were dose proportional. The area under the concentration-time curve from 0 to 12 h and the peak plasma concentration for 187.5 mg/m2 twice daily in children were comparable to previous data obtained in a 200-mg, twice-daily cohort and lower than those in the 300-mg twice-daily cohort in adults. Pharmacodynamic studies demonstrated substantial inhibition of PARP activity. Two partial responses were observed in patients with Wilms tumor and neuroblastoma. Conclusions: This report is the first clinical trial to describe the use of a PARP inhibitor as monotherapy in children. Olaparib was well tolerated, with preliminary antitumor responses observed in DNA damage response-defective pediatric tumors. Lay summary: This Phase 1 trial evaluated the efficacy and safety of olaparib in patients with refractory childhood solid tumors. Olaparib was well tolerated, achieving objective response in 2/15 patients. The DNA damage response was attenuated in nearly one-half of advanced neuroblastoma patients, demonstrating the utility of the PARP inhibitor. The results support further investigation of olaparib as a new treatment for DNA damage-response or repair-defective pediatric cancers.
KW - Phase 1 study
KW - child
KW - olaparib
KW - poly(ADP-ribose) polymerase
KW - solid tumor
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UR - http://www.scopus.com/inward/citedby.url?scp=85130438772&partnerID=8YFLogxK
U2 - 10.1002/cncr.34270
DO - 10.1002/cncr.34270
M3 - Article
C2 - 35593736
AN - SCOPUS:85130438772
SN - 0008-543X
VL - 128
SP - 2949
EP - 2957
JO - Cancer
JF - Cancer
IS - 15
ER -
