Study design
This study is the first phase I, multicenter (Tokyo Medical and Dental University, National Cancer Center Hospital, and Kyoto Prefectural University of Medicine), single-arm, open-label trial of olaparib in pediatric patients with refractory solid tumors. The protocol has been reviewed and approved by the Institutional Review Boards of each participating institution (Tokyo Medical and Dental University: Approved No. 2016–1001, National Cancer Center: Approved No. T4406 and Kyoto Prefectural University of Medicine: Approved No. 2017–036).
Study drug
The investigational drug is olaparib, the identification code is AZD2281, and the chemical name is 4-[(3-{[4-(cyclopropylcarbonyl)piperazin-1-yl]carbonyl}-4-fluorophenyl)methyl]phthalazin-1(2H)-one. The agent type is a tablet, inclusion volume is 25 mg per tablet, and drugs are stored at 30 °C or less. Olaparib is manufactured by AbbVie Inc. (North Chicago, IL) and provided by Astrazeneca (Cambridge, United Kingdom), and trade name is Lynparza®. It is an inhibitor of PARP, an enzyme involved in DNA repair. It acts against cancers in patients with hereditary BRCA1 or BRCA2 mutations, which include some ovarian, breast, and prostate cancers [
9‐
12].
Protocol treatment
This is the first phase I clinical study of olaparib in pediatric patients. In adults, the olaparib tablet was shown to be well tolerated up to the 300 mg b.i.d. dose in non-Japanese, as well as in Japanese, patients with solid tumors [
14,
15]. The present study is, therefore, designed to evaluate the safety and tolerability of olaparib at 100, 200, and 300 mg, which are one-third, two-thirds, and the same doses as the adult dose, respectively, in the previous study (300 mg), and to determine the DLT of olaparib in order to obtain the basis for RD for the next phase.
It has been reported that children can receive the same weight-based or BSA-based doses as adults in many cases [
16]. The standard Japanese adult BSA is 1.6 m
2, with the calculation formula of BSA as follows:
$$ \mathrm{BSA}\ \left({\mathrm{m}}^2\right)=\surd \left(\left(\mathrm{height}\left(\mathrm{cm}\right)\times \mathrm{weight}\left(\mathrm{kg}\right)\right)\div 3600\right) $$
(The height is rounded off to the nearest whole number, the weight is rounded off to the first decimal place, and the BSA is rounded off to the second decimal place).
Thus, the well-tolerated dose of 300 mg in adults converted using BSA is 187.5 mg/m
2 per dose. Similarly, 200 mg is 125 mg/m
2, and 100 mg is 62.5 mg/m
2. The clinical hypothesis is that single agent administration of olaparib 187.5 mg/m
2 b.i.d. to pediatric refractory solid tumor patients can be performed safely. Since patients take 25 mg tablets, the one-time dose is determined according to BSA as shown in Table
2.
Table 2
Olaparib administration doses (mg) per BSA
0.40 ≤ BSA < 0.50 | 25 | 50 | 75 |
0.50 ≤ BSA < 0.60 | 25 | 50 | 75 |
0.60 ≤ BSA < 0.70 | 25 | 75 | 100 |
0.70 ≤ BSA < 0.80 | 25 | 75 | 125 |
0.80 ≤ BSA < 0. 90 | 50 | 100 | 150 |
0.90 ≤ BSA < 1.00 | 50 | 100 | 150 |
1.00 ≤ BSA < 1.10 | 50 | 125 | 175 |
1.10 ≤ BSA < 1.20 | 50 | 125 | 200 |
1.20 ≤ BSA < 1.30 | 75 | 150 | 225 |
1.30 ≤ BSA < 1.40 | 75 | 150 | 225 |
1.40 ≤ BSA < 1.50 | 75 | 175 | 250 |
1.50 ≤ BSA < 1.60 | 75 | 175 | 275 |
1.60 ≤ BSA | 100 | 200 | 300 |
Only on the first day (cycle 0 day 1: C0d1), the patient takes olaparib once in the morning 1 h after a meal and fasts for 2 h after administration to avoid the effect of meals. The patient is observed for 48 h for the pharmacokinetic and pharmacodynamic analyses. From C0d1 evening to C0d3 evening, the patient is not administered the investigational drug. Cycle 1 starts from the fourth day of cycle 0, and the patient is administered the drug in the morning and evening, every 12 h, for 28 days as one cycle.
Patients who continue to benefit from treatment, that is, show complete response (CR), partial response (PR), or stable disease (SD), may have the option to continue treatment upon agreement between the investigator and sponsor, and upon study drug availability. If treatment continues beyond the predesigned schedule, study procedures should continue to be performed at the same frequency described in the dose escalation phase.
Definition of DLT
DLT is evaluated by the standard 3 + 3 dose escalation design. The DLT evaluation period is from the first day of cycle 0 to the 28th day of cycle 1 (C0d1 - C1d28), including the drug holiday. In case of discontinuation of the investigational drug beyond C1d28 due to toxicity related to the drug, the DLT evaluation period is extended up to 14 days.
DLT is defined as the following events occurred during the DLT evaluation period and is judged by the investigator or sub-investigator as having a high probability of investigational drug relevance, with or without disappearance of toxicity.
1)
Neutropenia (< 500/μL) that persists for more than 5 days without fever.
2)
Neutropenia (< 500/μL) with fever or sepsis
3)
Thrombocytopenia (< 25,000/μL)
4)
CTCAE grade 3 or higher anemia
5)
When blood transfusion is performed.
6)
CTCAE grade 3 or 4 non-hematologic toxicity, except for fatigue, nausea, vomiting, diarrhea, muscle pain, and arthralgia recovering to CTCAE grade 2 or less within 7 days after treatment.
7)
CTCAE grade 2 or higher cardiotoxicity or neurotoxicity
8)
Toxicity resulting in discontinuation of protocol treatment during the first cycle.
9)
Other toxicity not recovering to grade 1 or less within 14 days of events that resulted in drug withdrawal during the first cycle. When the drug is taken only once a day, it is defined as 1 day off.
Determination of the existence of DLT or undecidable is primarily performed by the investigator at each institution, but the final judgment is made by the coordinating doctor. In case of doubt in the judgment of DLT, opinions can be requested from the efficacy and safety evaluation committee.
Standard 3 + 3 dose escalation for DLT evaluation and RD definition
The daily first, second, and third doses of olaparib are 125, 250 and 375 mg/m2, respectively. Dose escalation is performed in a standard phase I 3 + 3 design. The target sample size is 18. A minimum of 6 cases are required for DLT evaluation, and the dose level showing DLT in 1 or less of 6 patients is judged as the RD. The RD is determined by the clinical trial coordinating doctor after deliberation with the efficacy and safety evaluation committee.
Pharmacokinetics of olaparib in pediatric patients
In a pharmacokinetic analysis, the plasma concentration of olaparib is measured before the first dose, and 1, 2, 3, 6, 8, and 12 h (24 and 48 h only in C0d1) after administration on C0d1 and C1d15. Pharmacokinetic parameters, such as AUC, Cmax, Tmax, and T1/2, will be estimated.
Pharmacodynamics of olaparib in pediatric patients
Blood samples are collected 6 h before and 6 h after the administration of olaparib on C0d1, and 6 h before and 6 h after the first dose of C1d15. PARP inhibitory activity by olaparib is measured in peripheral blood mononuclear cells. When the protocol treatment is interrupted or original diseases are confirmed to have exacerbated, the PARP inhibitory activity in blood mononuclear cells should be measured.
Efficacy assessment method
Tumor reduction effect is assessed according to new response evaluation criteria in solid tumors: Revised RECIST guideline, version 1.1 [
17]. Radiologic assessments using CT and/or MRI are performed within 28 days before registration, which is used as baseline, and at odd cycles. At each time point, the treatment response is assessed as CR, PR, progressive disease (PD), SD, or not all evaluated (NE). Overall response at each time point is also assessed according to revised RECIST.
Statistical methods
Descriptive statistics are used to define the study population, safety, tolerability, pharmacokinetic and pharmacodynamic data, and tumor response.