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
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.
