Phase I clinical study of oral olaparib in pediatric patients with refractory solid tumors: study protocol

Masatoshi Takagi,Ryuji Koike,Hajime Hosoi,Kenichi Yoshimura,Shuki Mizutani,Kazuhisa Hasebe,Chitose Ogawa,Masashi Nagata,Toshimi Kimura,Masato Yasuhara,Minoru Imai,Kiyoshi Nobori,Eri Ishibashi,Yuki Aoki-Nogami,Tomoko Iehara,Pariko Yorozu,Tetsuro Kihara

doi:10.1186/s12887-019-1409-7

Abstract

BackgroundThere is no established standard chemotherapy for recurrent pediatric solid tumors such as neuroblastoma and sarcoma. Since some of these tumor cells show dysfunctions in homologous recombination repair, the goal is to conduct a phase I study of olaparib, a poly(ADP-ribose) polymerase inhibitor. In this clinical trial, the aims are to evaluate the safety, tolerability, and efficacy of olaparib in pediatric patients with refractory solid tumors and to recommend a dose for phase II trials.MethodsIn this open-label, multicenter study, olaparib tablets (62.5, 125, and 187.5 mg/m2 b.i.d.) will be administered orally in a standard 3 + 3 dose escalation design. Patients aged 3 to 18 years with recurrent pediatric solid tumors are eligible. Pharmacokinetic and pharmacodynamic analyses will also be performed.DiscussionThis study aims to extend the indications for olaparib by assessing its safety and efficacy in pediatric refractory solid tumor patients.Trial registrationUMIN-CTR (UMIN000025521); Registered on January 4, 2017.

Highlights

There is no established standard chemotherapy for recurrent pediatric solid tumors such as neuroblastoma and sarcoma
It has been shown that osteosarcoma cells with genetic signatures of BRCAness are susceptible to the poly(ADP-ribose) polymerase (PARP) inhibitor [8]. These results suggest that a PARP inhibitor may be an effective drug for Ewing’s sarcoma and osteosarcoma
One of the hallmarks of cancer is genomic instability, which is associated with clonal evolution

Summary

Discussion

One of the hallmarks of cancer is genomic instability, which is associated with clonal evolution. Molecular-targeted therapy focusing on cancer-specific molecular signatures has been developing, and most are inhibitors of signaling pathways. Molecular-targeted therapy based on inhibiting DDR in cancer cells offers the potential for a greater therapeutic window by tailoring treatment to patients with tumors lacking specific DDR functions. Several cancers have mutations in or epigenetically silenced homologous recombination-associated genes, which explains the genetic instability that drives cancer development. We have designed a phase I clinical study using olaparib, a PARP inhibitor, for these refractory solid tumors in pediatric patients. Phase I trials of new drugs in children are generally carried out only after several trials in adults [19]. These clinical trials are mostly initiated by academic investigators.

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