A Study to Assess a Medicine Called Tovorafenib in Japanese Children and Young Adults With Brain Tumours

Официальное название

A Phase I, Open-label, Single-arm, Multicentre Study to Evaluate the Safety and Pharmacokinetics of Tovorafenib in Japanese Paediatric Participants With BRAF-altered Recurrent or Progressive Low-grade Glioma

Обзор

The purpose of this study is to evaluate safety and the way the body absorbs, distributes and gets rid of the study drug tovorafenib in the body in Japanese children, adolescents and young adults with specific brain tumours. This includes how the drug is absorbed, distributed and eliminated from the body (called pharmacokinetics). The study will also test how well the drug works to shrink brain tumours. In this study, all participants will receive tovorafenib orally once weekly. There will be four periods in this study: 1. Screening period (up to 4 weeks): Participants will be evaluated to determine if they can take part in the study, requiring at least one visit to the study centre. 2. Treatment period (up to 24 months): All eligible participants will receive tovorafenib. This requires five visits for the first 2 months (Cycle 1 and Cycle 2) followed by one visit every month (at the start of each treatment cycle). Participants will receive the first oral dose of tovorafenib on Day 1 of Cycle 1 at the study clinic. After Day 1, participants will need to take tovorafenib once weekly on Day 8, Day 15 and Day 22. Participants will be required to come to the study clinic in person at least five times for Cycle 1 and Cycle 2. In addition, participants will have one remote visit (telephone call) during Cycle 1. After Cycle 2, only one in-person clinic visit is required at the start of each treatment cycle. A participant will stop treatment if their disease gets worse, if treatment has a harmful effect, or if they do not want to take part in the study anymore. 3. End-of-Treatment Safety Follow-Up (30 days): Participants will have a clinic visit 30 days after stopping treatment to check their health. 4. Long-Term Follow-Up (up to 2 years): Participants will be monitored every 3 months unless they start a new anti-cancer treatment or leave the study. During the study, participants will undergo various health measurements and observations, including blood sampling and urine collections. Each participant will be in this study for up to approximately 4 years. Tovorafenib will be provided to participants who tolerate it for as long as their disease does not progress. Once tovorafenib becomes approved and commercially available in Japan, participants may transition to the commercial drug for continued treatment. A participant may withdraw consent to participate at any time.

Вмешательства

• Препарат Tovorafenib
  Tablet or powder for reconstitution / powder for oral suspension

Первичные конечные точки

• Percentage of participants experiencing Adverse Events (AEs) and Adverse Events of Special Interest (AESIs) [Срок оценки: From first dose until 30 days post-treatment]
• Percentage of participants experiencing Serious Adverse Events (SAEs) and AESIs [Срок оценки: Up to 4 years from first dose, including post-treatment monitoring]
• Area under the plasma concentration-time curve from time zero to last measurable concentration (AUC₀-t) of tovorafenib following a single dose [Срок оценки: From Cycle 1 Day 1 to Cycle 2 Day 8 (each cycle is 28 days)]
• Area under the plasma concentration-time curve from time zero extrapolated to infinity (AUC₀-inf) of tovorafenib following a single dose [Срок оценки: From Cycle 1 Day 1 to Cycle 2 Day 8 (each cycle is 28 days)]
• Maximum observed plasma concentration (Cmax) of tovorafenib following a single dose [Срок оценки: From Cycle 1 Day 1 to Cycle 2 Day 8 (each cycle is 28 days)]
• Time to maximum plasma concentration following a single dose (Tmax) of tovorafenib [Срок оценки: From Cycle 1 Day 1 to Cycle 2 Day 8 (each cycle is 28 days)]
• Terminal half-life (t½) of tovorafenib following a single dose [Срок оценки: From Cycle 1 Day 1 to Cycle 2 Day 8 (each cycle is 28 days)]
• Area under the plasma concentration-time curve over the dosing interval at steady-state (AUC₀-tau) of tovorafenib [Срок оценки: From Cycle 1 Day 1 to Cycle 2 Day 8 (each cycle is 28 days)]
• Maximum plasma concentration at steady-state (CmaxSS) of tovorafenib [Срок оценки: From Cycle 1 Day 1 to Cycle 2 Day 8 (each cycle is 28 days)]
• Minimum plasma concentration at steady-state (CminSS) of tovorafenib [Срок оценки: From Cycle 1 Day 1 to Cycle 2 Day 8 (each cycle is 28 days)]

Вторичные конечные точки (1)

• Change in total tumor volume over time [Срок оценки: Every 12 weeks from Cycle 1 Day 1 up to end of treatment (approximately 24 months).]

Критерии участия

Критерии включения

• Participants must be 6 months to 25 years of age, inclusive, with at least two generations of Japanese ancestry at the time of signing the informed assent/consent.
• Participants must have relapsed or progressive low-grade glioma with a documented known activating BRAF alteration, including BRAF V600 mutations and KIAA1549:BRAF fusions, as identified through molecular assays as routinely performed at Clinical Laboratory Improvement Amendments-certified or other similarly certified laboratories.
• Participants must have histopathologic verification of malignancy at either original diagnosis or relapse.
• Participants must have received at least one line of prior systemic therapy and have documented evidence of radiographic progression.
• Participants must have at least one evaluable and/or measurable lesion (imaging must be performed within 28 days of initiation of treatment) as defined by Response Assessment in Neuro-Oncology-high grade glioma criteria (T1 weighted lesion that can be reproducibly measured in at least two dimensions of at least 10 mm, visible on ≥2 axial slices that are preferably, at most, 5 mm apart with 0 mm skip).
• Participants must have fully recovered from the acute toxic effects of all prior anticancer chemotherapy
• Chronic toxicities from prior anticancer therapy must be stable and at National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0 Grade ≤2; ongoing retinopathy must be ≤1.
• Participants must have adequate hematologic, hepatic and renal function
• Participants receiving steroids for tumour-associated symptoms must be on a stable dose (e.g. no initial/loading dose, no increase or decrease) for 14 days prior to C1D1.
• Participants must be able to swallow tablets or liquid or administer through gastric access via a feeding tube (12 Fr or greater).

Критерии исключения

• Participant's tumour has an additional previously known or expected to be activating molecular alteration(s) (e.g. histone mutation, isocitrate dehydrogenase 1 and 2 mutations, fibroblast growth factor receptor mutations or fusions, MYBL v-myb avian myeloblastosis viral oncogene homolog-like alterations, neurofibromatosis type-1 somatic or germline mutations).
• Participant has symptoms of clinical progression without radiographically recurrent or radiographically progressive disease.
• Participant has known or suspected diagnosis of neurofibromatosis type 1 via genetic testing or current diagnostic criteria.
• Participant has history of any major disease (e.g. confirmed or suspected diagnosis of interstitial lung disease), other than the primary malignancy under study, that in the opinion of the investigator might interfere with safe protocol participation.
• Participant has a history or current evidence of central serous retinopathy (CSR), retinal vein occlusion (RVO), or ophthalmopathy present at baseline that would be considered a risk factor for CSR or RVO. Ophthalmological findings secondary to long-standing optic pathway glioma (such as visual loss, optic nerve pallor or strabismus) will NOT be considered significant abnormalities for the purposes of this study.
• Participant has major surgery within 14 days (2 weeks) prior to Cycle 1 Day 1 (does not include central venous access, cyst fenestration or cyst drainage, or ventriculoperitoneal shunt placement or revision).
• Participant has clinically significant active cardiovascular disease, history of myocardial infarction, deep vein thrombosis/pulmonary embolism within 6 months prior to C1D1, ongoing cardiomyopathy or current prolonged QT interval corrected for heart rate by Fridericia's formula interval >470 milliseconds based on triplicate electrocardiogram (ECG) average.
• Participant has nausea and vomiting NCI-CTCAE v5.0 Grade ≥2, malabsorption requiring supplementation or significant bowel or stomach resection that would preclude adequate absorption of tovorafenib.
• Participant is neurologically unstable despite adequate treatment (e.g. uncontrolled seizures).
• Concomitant medications that are strong inhibitors or inducers of CYP2C8 within 14 days before initiation of therapy. Concomitant medications that are substrates of breast cancer resistance protein (BCRP) with a narrow therapeutic index within 14 days before initiation of therapy.
• Participant has any clinically significant skin toxicity at Screening that in the opinion of the investigator would increase risk of severe skin toxicity when using investigational product.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Не применимо

Модель

Одна группа

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

Япония · 6 центров

• Kanagawa Children's Medical Center — Kanagawa
• Hyogo Prefectural Kobe Children's Hospital — Kobe
• Kyoto University Hospital — Kyoto
• Osaka City General Hospital — Osaka
• National Cancer Center Hospital — Tokyo
• National Center for Child Health and Development — Tokyo

Идентификаторы

NCT: NCT07441707 · CLIN-60310-450

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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