First phase 1 clinical study of olaparib in pediatric patients with refractory solid tumors

Masatoshi Takagi; Chitose Ogawa; Tomoko Iehara; Yuki Aoki-Nogami; Eri Ishibashi; Minoru Imai; Toshimi Kimura; Masashi Nagata; Masato Yasuhara; Mitsuko Masutani; Kenichi Yoshimura; Daisuke Tomizawa; Atsushi Ogawa; Kan Yonemori; Aoi Morishita; Satoshi Miyamoto; Junko Takita; Tetsuro Kihara; Kiyoshi Nobori; Kazuhisa Hasebe; Fuyuki Miya; Sadakatsu Ikeda; Yoko Shioda; Kimikazu Matsumoto; Junya Fujimura; Shuki Mizutani; Tomohiro Morio; Hajime Hosoi; Ryuji Koike

doi:10.1002/cncr.34270

First phase 1 clinical study of olaparib in pediatric patients with refractory solid tumors

Cancer. 2022 Aug 1;128(15):2949-2957. doi: 10.1002/cncr.34270. Epub 2022 May 20.

Authors

Masatoshi Takagi¹, Chitose Ogawa², Tomoko Iehara³, Yuki Aoki-Nogami², Eri Ishibashi⁴, Minoru Imai⁴, Toshimi Kimura⁵, Masashi Nagata⁶, Masato Yasuhara⁶, Mitsuko Masutani⁷, Kenichi Yoshimura^{8

9}, Daisuke Tomizawa¹⁰, Atsushi Ogawa¹¹, Kan Yonemori¹², Aoi Morishita¹, Satoshi Miyamoto¹, Junko Takita¹³, Tetsuro Kihara⁴, Kiyoshi Nobori¹⁴, Kazuhisa Hasebe⁴, Fuyuki Miya¹⁵, Sadakatsu Ikeda¹⁶, Yoko Shioda¹⁰, Kimikazu Matsumoto¹⁰, Junya Fujimura¹⁷, Shuki Mizutani¹, Tomohiro Morio¹, Hajime Hosoi³, Ryuji Koike¹⁴

Affiliations

¹ Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan.
² Department of Pediatric Oncology, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan.
³ Department of Pediatrics, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto, Japan.
⁴ University Research Administration Division, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan.
⁵ Department of Pharmacy, Tokyo Women's Medical University, Shinjuku-ku, Tokyo, Japan.
⁶ Department of Pharmacokinetics and Pharmacodynamics, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo.
⁷ Department of Molecular and Genomic Biomedicine, Center for Bioinformatics and Molecular Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
⁸ Innovative Clinical Research Center, Kanazawa University, Kanazawa, Ishikawa, Japan.
⁹ Future Medical Center, Hiroshima University Hospital, Minami-ku, Hiroshima, Japan.
¹⁰ National Center for Child Health and Development, Children's Cancer Center, Setagaya-ku, Tokyo, Japan.
¹¹ Pediatrics, Niigata Cancer Center Hospital, Chuo-ku, Niigata, Japan.
¹² Medical Oncology, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan.
¹³ Department of Pediatrics, Kyoto University, Sakyo-ku, Kyoto, Japan.
¹⁴ Medical Innovation Promotion Center, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan.
¹⁵ Department of Medical Science Mathematics, Medical Research Institute, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan.
¹⁶ Department of Precision Cancer Medicine, Center for Innovative Cancer Treatment, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan.
¹⁷ Department of Pediatrics and Adolescent Medicine, Juntendo University, School of Medicine, Bunkyo-ku, Tokyo, Japan.

PMID: 35593736
DOI: 10.1002/cncr.34270

Abstract

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.

Keywords: Phase 1 study; child; olaparib; poly(ADP-ribose) polymerase; solid tumor.

Publication types

Clinical Trial, Phase I
Multicenter Study
Research Support, Non-U.S. Gov't

MeSH terms

Adult
Antineoplastic Agents* / adverse effects
Child
Humans
Neoplasm Recurrence, Local / drug therapy
Neuroblastoma* / drug therapy
Neuroblastoma* / genetics
Phthalazines / adverse effects
Piperazines
Poly(ADP-ribose) Polymerase Inhibitors / adverse effects
Poly(ADP-ribose) Polymerases

Substances

Antineoplastic Agents
Phthalazines
Piperazines
Poly(ADP-ribose) Polymerase Inhibitors
Poly(ADP-ribose) Polymerases
olaparib