Trial Title:
Pilot Study of Vinblastine and Tovorafenib in Pediatric Patients With Recurrent/Progressive RAF Altered Low Grade Gliomas
NCT ID:
NCT06381570
Condition:
Low-grade Glioma
Conditions: Official terms:
Glioma
Vinblastine
Conditions: Keywords:
RAF altered
non-NF1
Study type:
Interventional
Study phase:
Early Phase 1
Overall status:
Recruiting
Study design:
Allocation:
N/A
Intervention model:
Single Group Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
Tovorafenib
Description:
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)
Other name:
Vinblastine
Summary:
This is a Pilot, multicenter, open-label study of patients less than or equal to 25
years, with recurrent or progressive LGG harboring a CRAF or BRAF alteration, including
BRAF V600 mutations and KIAA1549: BRAF fusions. Patients with BRAF or CRAF alterations
will be identified through molecular assays as routinely performed at Clinical Laboratory
Improvement Amendments (CLIA) of 1988 or other similarly certified laboratories.
The study will be conducted in two sequential phases:
Phase A: A Feasibility (combination dose finding) phase, followed by Phase B: An Efficacy
phase. The maximum tolerated dose (MTD)/Recommended Phase 2 Dose (RP2D) of the
combination as determined in Phase A would be the dose used in Phase B. The patients on
Phase A who were below the MTD/RP2D would be eligible for intra-patient dose escalation
to MTD/RP2D subject to criteria outlined later
Detailed description:
Phase A (Feasibility Phase) A feasibility phase will be conducted to establish the
maximum tolerated dose (MTD/RP2D) of the combination of vinblastine + tovorafenib using
the Rolling 6 design.
Patients will receive vinblastine and tovorafenib on Days 1, 8, 15, 22 of each cycle for
a total duration of 17 cycles followed by 7 additional cycles of tovorafenib alone. One
cycle of protocol therapy is 28 days.
Treatment cycles will repeat every 28 days for a total of 24 cycles in the absence of
disease progression or unacceptable toxicity. Patients will undergo radiographic
evaluation of their disease at the end of every third cycle, starting with the end of
Cycle 3.
The RP2D of tovorafenib of 420 mg/m2 once weekly (not exceeding 600 mg) in combination
with vinblastine (4mg/m2) will be used as the starting dose and will be
de-escalated/escalated as per Table 4. Dose of tovorafenib will not be escalated further.
Patients will be treated on protocol therapy for a total of 24 cycles, the vinblastine
and tovorafenib for a total duration of 17 cycles followed by 7 additional cycles of
alone tovorafenib, unless disease progression, unacceptable toxicity occurs, or
withdrawal from the study occurs. Missed doses of either vinblastine or tovorafenib will
not be made up.
Phase B (Expansion/Efficacy Phase) Once the MTD/RP2D of the combination, vinblastine +
tovorafenib has been established, the expansion/efficacy phase will be initiated at the
dose determined in Phase A.
Patient will receive vinblastine and tovorafenib weekly on Days 1, 8, 15, 22 of each
cycle at dose determined in Phase A for a total duration of 17 cycles followed by 7
additional cycles of tovorafenib alone. One cycle of protocol therapy is 28 days.
Treatment cycles will repeat every 28 days in the absence of disease progression or
unacceptable toxicity. Patients will undergo radiographic evaluation of their disease at
the end of every third cycle, starting with the end of Cycle 3.
Patients will be treated on protocol therapy for a total of 24 cycles, the vinblastine
and tovorafenib for a total duration of 17 cycles followed by 7 additional cycles of
alone tovorafenib, unless disease progression or unacceptable toxicity occurs, unless
disease progression, unacceptable toxicity or withdrawal from study occurs. Missed doses
of either vinblastine or tovorafenib will not be made up.
Criteria for eligibility:
Criteria:
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.
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.
Gender:
All
Minimum age:
0 Weeks
Maximum age:
25 Years
Healthy volunteers:
No
Locations:
Facility:
Name:
The Hospital for Sick Children
Address:
City:
Toronto
Zip:
M5G 1X8
Country:
Canada
Status:
Recruiting
Contact:
Last name:
Nirav Thacker
Phone:
6137377600
Phone ext:
6525
Email:
nthacker@cheo.on.ca
Start date:
March 21, 2024
Completion date:
March 21, 2029
Lead sponsor:
Agency:
Daniel Morgenstern
Agency class:
Other
Collaborator:
Agency:
The Hospital for Sick Children
Agency class:
Other
Source:
The Hospital for Sick Children
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT06381570
