Low-grade Glioma
Conditions
Keywords
BRAF-altered Recurrent Low-grade Glioma, Progressive Low-grade Glioma
Brief summary
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.
Interventions
DRUGTovorafenib
Tablet or powder for reconstitution / powder for oral suspension
Sponsors
Ipsen
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
6 Months to 25 Years
Healthy volunteers
No
Inclusion criteria
* 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).
Exclusion criteria
* 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of participants experiencing Adverse Events (AEs) and Adverse Events of Special Interest (AESIs) | From first dose until 30 days post-treatment | — |
| Percentage of participants experiencing Serious Adverse Events (SAEs) and AESIs | Up to 4 years from first dose, including post-treatment monitoring | An Adverse event (AE) is any untoward medical occurrence, temporally associated with the use of study intervention, whether or not related to the study intervention. |
| Area under the plasma concentration-time curve from time zero to last measurable concentration (AUC₀-t) of tovorafenib following a single dose | From Cycle 1 Day 1 to Cycle 2 Day 8 (each cycle is 28 days) | AUC₀-t represents the total drug exposure over time from administration until the last measurable concentration after a single dose of tovorafenib. |
| Area under the plasma concentration-time curve from time zero extrapolated to infinity (AUC₀-inf) of tovorafenib following a single dose | From Cycle 1 Day 1 to Cycle 2 Day 8 (each cycle is 28 days) | AUC₀-inf estimates the total drug exposure from administration to infinite time, extrapolating beyond the last measurable concentration. |
| Maximum observed plasma concentration (Cmax) of tovorafenib following a single dose | From Cycle 1 Day 1 to Cycle 2 Day 8 (each cycle is 28 days) | Cmax is the highest concentration of tovorafenib observed in plasma after a single dose |
| Time to maximum plasma concentration following a single dose (Tmax) of tovorafenib | From Cycle 1 Day 1 to Cycle 2 Day 8 (each cycle is 28 days) | Tmax refers to the time point at which the maximum observed plasma concentration of tovorafenib is reached following a single dose |
| Terminal half-life (t½) of tovorafenib following a single dose | From Cycle 1 Day 1 to Cycle 2 Day 8 (each cycle is 28 days) | Terminal half-life (t½) will be assessed following a single dose of tovorafenib. |
| Area under the plasma concentration-time curve over the dosing interval at steady-state (AUC₀-tau) of tovorafenib | From Cycle 1 Day 1 to Cycle 2 Day 8 (each cycle is 28 days) | AUC₀-tau refers to the area under the plasma concentration-time curve over the dosing interval (tau) during steady-state conditions, representing total drug exposure per dosing cycle |
| Maximum plasma concentration at steady-state (CmaxSS) of tovorafenib | From Cycle 1 Day 1 to Cycle 2 Day 8 (each cycle is 28 days) | CmaxSS refers to the maximum observed plasma concentration of tovorafenib measured during steady-state conditions, after repeated dosing when drug input and elimination have reached equilibrium. |
| Minimum plasma concentration at steady-state (CminSS) of tovorafenib | From Cycle 1 Day 1 to Cycle 2 Day 8 (each cycle is 28 days) | CminSS refers to the lowest observed plasma concentration of tovorafenib during steady-state conditions, reflecting trough levels between doses. |
| Average Plasma Concentration at Steady-State (CavSS) of tovorafenib | From Cycle 1 Day 1 to Cycle 2 Day 8 (each cycle is 28 days) | CavSS refers to the average plasma concentration of tovorafenib over the dosing interval during steady-state conditions, calculated from multiple time points |
| Time to maximum plasma concentration at steady-state (TmaxSS) of tovorafenib | From Cycle 1 Day 1 to Cycle 2 Day 8 (each cycle is 28 days) | TmaxSS refers to the time point at which the maximum plasma concentration of tovorafenib is observed during steady-state conditions |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in total tumor volume over time | Every 12 weeks from Cycle 1 Day 1 up to end of treatment (approximately 24 months). | Assessment based on MRI imaging data to evaluate tumor volume and its evolution during treatment. |
Contacts
CONTACTIpsen Clinical Study Enquiries
STUDY_DIRECTORIpsen Medical Director
Ipsen
Outcome results
None listed