This study aims to demonstrate the effectiveness of dabrafenib with trametinib in pediatric patients with BRAF V600 mutant relapsed refractory HGG.This study aims to demonstrate the effectiveness of dabrafenib with trametinib compared to…
ID
Source
Brief title
Condition
- Nervous system neoplasms malignant and unspecified NEC
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary objective for HGG cohort is: to evaluate the anti-tumor activity
of dabrafenib in combination with trametinib as measured by overall response
rate (ORR) to the combination therapy by investigator assessment using the RANO
criteria.
The primary objective for LGG cohort is: Compare the anti-tumor activity of
dabrafenib in combination with trametinib versus carboplatin with vincristine,
as measured by overall response rate (ORR) by central independent assessment
using the RANO criteria.
Secondary outcome
For HGG: 1. Evaluate ORR by central independent review
2. Evaluate duration of response (DOR) by investigator and central independent
review
3. Evaluate time to response (TTR) by investigator and central independent
review
4. Evaluate progression free survival (PFS) by investigator and central
independent review
5. Evaluate overall survival (OS)
6. Evaluate the safety profile of dabrafenib in combination with trametinib in
the study population
7. To characterize the pharmacokinetics of dabrafenib, its metabolites and
trametinib in the study population
For LGG: 1. ORR by central independent review assessment per RANO criteria
2. DOR, calculated as the time from the date of the first documented confirmed
response (CR or PR) to the first documented progression or death due to any
cause, as assessed separately by investigator and central independent reviewer
per RANO criteria.
3. PFS, defined as time from first dose of study treatment to progression or
death due to any cause, as assessed separately by central independent reviewer
and investigator per RANO criteria
4. TTR, calculated as the time from the start date of study treatment to first
documented confirmed response CR or PR (which must be confirmed subsequently)
as assessed separately by investigator and independent central reviewer per
RANO criteria
5. OS, defined as the time from first dose of study treatment to death due to
any cause
6. Incidence of adverse events and serious adverse events, changes in
laboratory results, vital signs, ECG and ECHO.
7. To characterize the pharmacokinetics of dabrafenib, its metabolites and
trametinib in the study population
For both cohorts LGG and HGG: Plasma concentration-time profiles of dabrafenib,
its metabolites and trametinib and PK parameters
Background summary
HGG typically arise from cells within the glial lineage and are classified by
the World Health Organization (WHO) as either grade III or IV meaning that they
are highly aggressive tumors with characteristic pathological findings. HGGs
are rare tumors in the pediatric population, and comprise approximately 8-12%
of all primary, pediatric central nervous system (CNS) tumors. Approximately
350-400 new cases of pediatric HGG are diagnosed in Europe yearly.
Current therapies for children with HGGs are limited and the long-term outcomes
are poor despite aggressive multimodality therapy and improvements in
neurosurgery, radiotherapy, and chemotherapy. The majority of patients do
develop recurrent disease. The EMA suggested after a pediatric research expert
meeting that pediatric patients with relapsed, refractory, and or resistant
HGGs should consider experimental treatments available in clinical trials.
The prognostic role of BRAF V600 mutation in pediatric HGG is unclear, but
available data suggest that BRAF V600 mutation may be prognostically favourable
in pediatric HGG. For this reason, the historical RR in BRAF V600 mutant
pediatric relapsed refractory HGG may be higher than that observed in
unselected populations, where the RR is less than 12%. The combination of
dabrafenib with trametinib in adults with BRAF V600 mutant melanoma, NSCLC and
other tumors have resulted in improved efficacy over dabrafenib monotherapy and
suggests that greater efficacy may also be seen in the pediatric setting such
as patients with relapsed refractory BRAF V600 mutant HGG. Given the high unmet
medical need in pediatric HGG, the encouraging efficacy of dabrafenib
monotherapy in pediatric patients with BRAF V600 mutant HGG, and the improved
efficacy seen in adult cancer studies upon the addition of trametinib to
dabrafenib, this study aims to demonstrate the effectiveness of dabrafenib with
trametinib in pediatric patients with BRAF V600 mutant relapsed refractory HGG.
Low grade glioma (LGG) also represents a diverse group of histologically
distinct tumor types, including pilocytic astrocytoma, ganglioglioma, and
astrocytoma and others. They are distinguished from HGG generally by their
lower apparent mitotic rates. Although LGGs are also rare pediatric tumor
types, they are approximately 2 times as common(incidence 1.68 cases per
100,000) as HGG.
Treatment goals generally are to prolong overall and progression free survival
while minimizing morbidity of treatment. Surgical removal, when practical. The
extent of resection is predictive of progression free interval. Most patients
will eventually experience progression of their disease and require
post-surgical therapy like chemotherapy with carboplatin and vincristine.
The BRAF V600 mutation is identified in about 17% of pediatric LGG tumors.
Research revealed that those patients whose tumor harbored the BRAF V600
mutation had worse PFS and OS than those with tumors with wild type sequence
at BRAF V600. This research also revealed a lower ORR for these patients when
treated with chemotherapy with apparent 11% PR+CR rate.
Pediatric patients with LGG harboring a BRAF V600 mutation have a poorer
prognosis than those without this mutation, and require improved treatment
options
Study objective
This study aims to demonstrate the effectiveness of dabrafenib with trametinib
in pediatric patients with BRAF V600 mutant relapsed refractory HGG.
This study aims to demonstrate the effectiveness of dabrafenib with trametinib
compared to chemotherapy (vincristin and carboplatine) in pediatric patients
with BRAF V600 mutant LGG.
Study design
This is a multi-center, global, single arm, open-label, phase II study
evaluating the effect of dabrafenib in combination with trametinib in children
and adolescent patients with LGG BRAF V600 positive mutation and BRAF V600
mutation positive relapsed, refractory, high grade gliomas (HGG). Approximately
142 patients will be enrolled into the study, of which 40 patients with HGG and
102 patients with LGG. All patients with HGG and two third of the patient with
LGG will receive oral dabrafenib twice daily and trametinib once daily based
on weight, age and appropriate dose level. One third of the patients with LGG
will receive chemotherapy.
Patients may continue study treatment until disease progression or loss of
clinical benefit as determined by the investigator, occurrence of unacceptable
toxicity, withdrawal of consent or lost to follow-up, or sponsor termination of
the study. Patients with LGG who have progressed after receiving chemotherapy
do have the possiblity to start with treatment of dabrafenib and trametinib.
All patients will be followed for survival for at least 2 years after the last
study treatment (except if consent is withdrawn, patient death, lost to
follow-up or study is discontinued). An interim analysis for futility will be
implemented to allow possible termination of recruitment and the study in the
event that there is insufficient efficacy.
Intervention
Childeren with HGG will be treated with dabrafenib (capsules or oral solution),
twice daily and trametinib (tablets or oral solution), once daily based onbased
on weight, age and appropirate dose level.
Two third of the childeren with LGG will be treated with dabrafenib (capsules
or oral solution), twice daily and trametinib (tablets or oral solution), once
daily based onbased on weight, age and appropirate dose level.
One third of the childeren with LGG wil be treated with chemotherapy
(vincristin and carboplatine). If they progress they can cross-over to
treatment with dabrafenib and trametinib.
Study burden and risks
The risks of dabrafenib and trametinib.
The risks and discomforts of the research assessments (scans, x ray, blood
drawn, biopsy, opthalmic examinations, ECG and ECHO, physical exam, use of
anticonception)
Keep a diary and the amount of visits to the hospital.
Haaksbergweg 16
Amsterdam 1101 BX
NL
Haaksbergweg 16
Amsterdam 1101 BX
NL
Listed location countries
Age
Inclusion criteria
- Male or female >= 1 and <18 years of age.
- HGG cohort only: Relapsed, progressed, or failed to respond to frontline
therapy.
- LGG cohort: progressive disease following surgical excision, or
non-surgical candidates with necessity to begin first systemic treatment
- Histologically confirmed diagnosis of High Grade Glioma (Grade III or IV
glioma as defined by WHO histological classification system, revised 2016),
including anaplastic pleomorphic xanthoastrocytoma (aPXA) and anaplastic
ganglioglioma.
- LGG defined by WHO histological classification system
- BRAF V600 mutation-positive tumor
- confirmed measurable disease.
- Tumor tissue (archival or newly obtained) must be provided for testing HGG
histopathology and HGG and LGG BRAF mutational status.
- Karnofsky/Lansky performance score of >=50%.
- Adequate bone marrow function in the absence of growth factor support.
- Adequate renal function, liver function, and cardiac function.
- If receiving glucocorticoids, patient must be on a stable or weaning dose for
at least 7 days prior to first dose of study treatment.
Exclusion criteria
- Malignancy OTHER than BRAF V600 mutant HGG and LGG.
- Previous treatment with dabrafenib or another RAF inhibitor, trametinib or
another MEK inhibitor, or an ERK inhibitor.
- HGG: Cancer therapy or investigational drugs within 3 weeks preceding the
first dose of study treatment.
- LGG: Any systemic anticancer therapy or investigational drugs prior to
enrollment.
- HGG: Radiotherapy to CNS glioma lesions within 3 months prior to first dose
of study treatment, unless there is clear evidence of radiologic progression
outside of the field of radiation.
- LGG: Radiotherapy to CNS glioma lesions at any point prior to enrollment.
- History of malignancy with confirmed activating RAS mutation or with BRAF
fusion such as BRF-KIAA1549.
- Current use of a prohibited medication or herbal preparation or requires any
of these medications during the study. See Section 6.4 for details of the
protocol.
- Unresolved toxicity greater than NCI CTCAE v 4.03 grade 2 from previous
anti-cancer therapy,
- History of allergic reactions attributed to compounds of similar chemical or
biologic composition to dabrafenib, trametinib and their excipients. LGG also
history
of allergic reactions or contraindications to the use of carboplatin or
vincristine.
- Autologous or allogeneic stem cell transplant within 3 months prior to the
first dose of study treatment
- History or current diagnosis of cardiac disease indicating significant risk
of safety for patients participating in the study
- Uncontrolled medical conditions, psychological, familial, sociological, or
geographical conditions that do not permit compliance with the protocol; or
unwillingness or inability to follow the procedures required in the protocol.
- Presence of active GI disease or other condition that will interfere
significantly with the absorption of drugs.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR201500401520-NL |
| CCMO | NL62996.078.17 |