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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT06381570




Registration number
NCT06381570
Ethics application status
Date submitted
10/04/2024
Date registered
24/04/2024
Date last updated
24/04/2024

Titles & IDs
Public title
Pilot Study of Vinblastine and Tovorafenib in Pediatric Patients With Recurrent/Progressive RAF Altered Low Grade Gliomas
Scientific title
VICTORY: A Pilot Study to Investigate Safety and Efficacy of Weekly Combination of Intravenous Vinblastine With Oral Type II RAF Inhibitor Tovorafenib in Pediatric Patients With Recurrent/Progressive RAF Altered Low Grade Gliomas
Secondary ID [1] 0 0
VICTORY/OZM-138
Universal Trial Number (UTN)
Trial acronym
VICTORY
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Low-grade Glioma 0 0
Condition category
Condition code
Cancer 0 0 0 0
Brain

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Tovorafenib

Treatment: Drugs: Tovorafenib
Tovorafenib for oral dosing is provided as an immediate-release tablet in 100 mg strength. The 100 mg tablets are red to yellowish red oval tablets. All products are labeled tovorafenib. In addition, tovorafenib is provided as a powder for reconstitution (PfR) in bottles (430mg per bottle to deliver 300 mg dose). Upon reconstitution with water, the concentration is 25 mg/mL.

Vinblastine is administered by intravenous route as IV push, sites to follow local administration guidelines, once weekly (central line, but peripheral line is also permitted)
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
MTD/RP2D
Timepoint [1] 0 0
2 years
Primary outcome [2] 0 0
Safety and Tolerability
Timepoint [2] 0 0
2 years
Primary outcome [3] 0 0
Overall response rate
Timepoint [3] 0 0
2 years
Secondary outcome [1] 0 0
Pharmacokinetics (Cmax vinblastine and tovorafenib)
Timepoint [1] 0 0
5 years (to complete analyses)
Secondary outcome [2] 0 0
Pharmacokinetics (AUC of vinblastine and tovorafenib)
Timepoint [2] 0 0
5 years (to complete analyses)
Secondary outcome [3] 0 0
Progression free survival
Timepoint [3] 0 0
3-year
Secondary outcome [4] 0 0
Duration of response
Timepoint [4] 0 0
3 years
Secondary outcome [5] 0 0
Clinical Benefit rate
Timepoint [5] 0 0
3 years

Eligibility
Key inclusion criteria
1. Age

a) Patients must be less than or equal to 25 years of age at the time of enrollment.
2. Study Group

a) Progressive/Recurrent LGG (non-NF1) with documented BRAF or CRAF alteration as identified through molecular assays as routinely performed at CLIA or other similar certified laboratories.
3. Diagnosis

1. All patients must have pathological confirmation of low-grade glioma with BRAF or CRAF alteration.
2. Patient must have progressive or recurrent LGG.
3. Must have at least 1 measurable lesion, as defined by RANO-LGG criteria.
4. Eligible histologies will include all tumors considered low-grade glioma or low-grade astrocytoma (WHO grade I and II) by WHO classification of Tumors of the Central Nervous system -5th edition revised with exception of subependymal giant cell astrocytoma.
4. Prior Therapy

1. Must have received at least 1 line of systemic therapy prior (at least a vinca alkaloid and/or single agent carboplatin and/or a MEK or BRAF inhibitor) and have documented evidence of radiographic progression.
2. Patients must have fully recovered from the acute toxic effects (= Grade I) of all prior anticancer chemotherapy and have undergone the following washout periods, as applicable.

i. Myelosuppressive chemotherapy: At least 21 days after the last dose of myelosuppressive chemotherapy (42 days if prior nitrosourea) ii. Radiation therapy (XRT): Radiation therapy to the measurable lesion(s) must be completed at least 6 months prior to administration of combination therapy. Patients who have documented radiographic progression less than 6 months from radiotherapy in 1 or more measurable lesions are eligible. At least 2 weeks after the last dose fraction of XRT to the non-target lesion.

iii. Investigational agent or any other anticancer therapy not defined above: At least four weeks prior to planned start of combination therapy, or five half-lives, whichever is shorter.

iv. Patients must have recovered from acute effects of any prior surgery. v. Chronic toxicities from prior anticancer therapy must be stable as per Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 Grade = 2, except ongoing retinopathy which must be = Grade 1.
5. Performance Level

a) Karnofsky (those 16 years and older) or Lansky (those younger than 16 years) performance score of at least 50. Patients who are unable to walk because of paralysis, but who are able to sit in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score.
6. Tumor Tissue Sample Confirmation that an archival tumor tissue sample is available. If an archival tumor tissue sample is not available, a fresh biopsy should be performed at baseline. Submission of tumor tissue and a blood sample are mandatory and must be submitted within 14 days from enrollment onto the study and prior to initiation of treatment. Biopsy may be either at initial diagnosis or recurrence.
7. Organ function

a) Adequate bone marrow function defined as: i. Absolute neutrophil count = 1000/mm3 ii. Platelet count (unsupported) = 100 x 109/L (transfusions allowed per institutional guidelines; last transfusion > 2 weeks prior to enrollment) iii. Hemoglobin (unsupported)= 10.0 g/dL (transfusions allowed per institutional guidelines; last transfusion > 4 weeks prior to enrollment) iv. Hematopoietic growth factors: At least 14 days after the last dose of a long-acting growth factor (e.g., Neulasta®) or 7 days for short-acting growth factor.

b) Adequate hepatic and renal function defined as: i. Total bilirubin = 1.5 x upper limit of normal (ULN) for age (patients with documented Gilbert's disease may be enrolled with sponsor approval and total bilirubin = 2 x ULN) ii. Serum glutamic-pyruvic transaminase (SGPT)/alanine aminotransferase (ALT) = 2.5 x ULN iii. Serum glutamic-oxaloacetic transaminase (SGOT)/aspartate transaminase (AST) = 2.5 x ULN iv. Serum creatinine within normal limits or estimated glomerular filtration rate

= 60 ml/min/1.73 m2 based on local institutional practice for determination. c) Thyroid functions tests within institutional normal range. Patients on a stable dose of thyroid replacement therapy for a minimum of 3 weeks before starting therapy are eligible.

d) Adequate cardiac function defined as: i. Left ventricular ejection fraction (LVEF) of = 50% as measured by echocardiogram (ECHO) or multiple-gated acquisition (MUGA) scan, or fractional shortening (FS) = 25% (Tissot et al., 2018) as measured by ECHO, within 14 days before enrollment (while not receiving medications for cardiac function). If normal practice at the institution is to provide the LVEF result as a range of values, then the upper value of the range will be used to determine the result.

ii. QTc (by Fridericia's formula) < 470ms as measured by electrocardiogram (ECG) within 14 days before enrollment (while not receiving medications for cardiac function).

e) Adequate central nervous system (CNS) function defined as: i. Patients with seizures should be stable and not have experienced a significant increase in seizure frequency within 14 days prior to enrollment.

ii. Patients with neurologic deficits should have deficits that are stable for a minimum of 14 days prior to enrollment.

iii. Patients receiving steroids for tumor-associated symptoms must be on a stable dose (e.g., no initial/loading dose, no increase or decrease) for 14 days prior to enrollment.
8. Study specific

1. Baseline ophthalmology assessment within 28 days of study enrollment.
2. MRI assessment within 28 days of study enrollment. MRI done for clinical indication but within the window for study would be permitted as baseline.
3. Ability to comply with treatment, laboratory monitoring, and required clinic visits for the duration of study participation.
4. Willingness of male and female patients with reproductive potential to use double effective birth control methods, defined as one used by the patient and another by his/her partner, for the duration of treatment and for 180 days following the last dose of study drug. Effective birth control methods are described in Appendix H.
5. Ability to swallow tablets or liquid, or gastric access via a nasal or gastric tube.
6. Patient is able to start treatment within 14 working days of screening.
7. Parent/guardian of child or adolescent patient has the ability to understand, agree to, and sign the study ICF and applicable pediatric assent form before initiation of any protocol related procedures; patient has the ability to give assent, as applicable, at the time of parental/guardian consent.
Minimum age
0 Weeks
Maximum age
25 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
* Patients meeting any of the following criteria are to be excluded from study participation:

1. Patient's tumor has additional previously known activating molecular alterations, other than BRAF or CRAF.
2. Known or suspected diagnosis of neurofibromatosis Type 1 (NF-1) via genetic testing or current diagnostic clinical criteria.
3. History of any major disease, other than the diagnosis of LGG, that might interfere with safe protocol participation.
4. Patient with a history or current evidence of central serous retinopathy (CSR), retinal vein occlusion (RVO), or ophthalmopathy present at baseline who 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 a significant abnormality for the purposes of this study.
5. Major surgery within 14 days (2 weeks) prior to enrollment (does not include central venous access, cyst fenestration or cyst drainage, or ventriculoperitoneal shunt placement or revision).
6. Clinically significant active cardiovascular disease, or history of myocardial infarction, or deep vein thrombosis/pulmonary embolism within 6 months prior to enrollment, ongoing cardiomyopathy, or current prolonged QT interval corrected for heart rate by Fridericia's formula (QTcF) interval > 470 ms based on triplicate ECG average.
7. Concomitant medications that are strong inhibitors or inducers of CYP2C8 or CYP3A4 within 14 days before initiation of therapy. Concomitant medications that are substrates of BCRP with a narrow therapeutic index within 14 days before initiation of therapy
8. Current enrollment in any other investigational treatment study. Participation on a concurrent observational or bio-sampling study is allowed.
9. Active systemic bacterial, viral, or fungal infection.
10. Nausea and vomiting = National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) 5.0 Grade 2 (for those not controlled by supportive care), malabsorption requiring supplementation, or significant bowel or stomach resection that would preclude adequate absorption of tovorafenib.
11. Patient has CTCAE v5.0 Grade 3, creatine phosphokinase (CPK) elevation (> 5 × ULN - 10 × ULN).
12. Patients who are neurologically unstable despite adequate treatment (e.g., uncontrolled seizures).
13. Pregnancy or lactation.
14. History of drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome or Stevens Johnsons syndrome (SJS). Patients with hypersensitivity to the investigational medicinal product or to any drug with similar chemical structure or to any other excipient present in the pharmaceutical form of the investigational medicinal product.
15. Other unspecified reasons that, in the opinion of the investigator, make the patient unsuitable for enrollment.

Study design
Purpose of the study
Treatment
Allocation to intervention
Not applicable
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 0
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
21/03/2024
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
21/03/2029
Actual
Sample size
Target
57
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
Recruitment outside Australia
Country [1] 0 0
Canada
State/province [1] 0 0
Ontario

Funding & Sponsors
Primary sponsor type
Other
Name
Daniel Morgenstern
Address
Country
Other collaborator category [1] 0 0
Other
Name [1] 0 0
The Hospital for Sick Children
Address [1] 0 0
Country [1] 0 0

Ethics approval
Ethics application status

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Daniel Morgenstern
Address 0 0
The Hospital for Sick Children
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Nirav Thacker
Address 0 0
Country 0 0
Phone 0 0
613-737-7600
Fax 0 0
Email 0 0
[email protected]
Contact person for scientific queries

No information has been provided regarding IPD availability


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

No documents have been uploaded by study researchers.

Results not provided in https://clinicaltrials.gov/study/NCT06381570