Phase II Pediatric Study With Dabrafenib in Combination With Trametinib in Patients With HGG and LGG

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT02684058
• Collaborator: (none)
• Enrollment: 149
• Locations: 57
• Arms: 3
• Anticipated Duration (Months): 65
• Patients Per Site: 2.6
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

The purpose of this study is to investigate the activity of dabrafenib in combination with trametinib in children and adolescent patients with BRAF V600 mutation positive low grade glioma or relapsed or refractory high grade glioma.

Condition or Disease	Intervention/Treatment	Phase
Diffuse Astrocytoma; Anaplastic Astrocytoma; Astrocytoma; Oligodendroglioma, Childhood; Anaplastic Oligodendroglioma; Glioblastoma; Pilocytic Astrocytoma; Giant Cell Astrocytoma; Pleomorphic Xanthoastrocytoma; Anaplastic Pleomorphic Xanthoastrocytoma; Angiocentric Glioma; Chordoid Glioma of Third Ventricle; Gangliocytoma; Ganglioglioma; Anaplastic Ganglioglioma; Dysplastic Gangliocytoma of Cerebrellum; Desmoplastic Infantile Astrocytoma and Ganglioglioma; Papillary Glioneuronal Tumor; Rosette-forming Glioneurona Tumor; Central Neurocytoma; Extraventricular Neurocytoma; Cerebellar Iponeurocytoma	Drug: dabrafenib; Drug: trametinib; Drug: Carboplatin with vincristine	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 149 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase II Open-label Global Study to Evaluate the Effect of Dabrafenib in Combination With Trametinib in Children and Adolescent Patients With BRAF V600 Mutation Positive Low Grade Glioma (LGG) or Relapsed or Refractory High Grade Glioma (HGG)
• Actual Study Start Date: Dec 28, 2017
• Actual Primary Completion Date: Aug 23, 2021
• Anticipated Study Completion Date: May 30, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: HGG cohort: Dabrafenib and trametinib HGG cohort: All patients in the HGG cohort will receive DRB+TMT	Drug: dabrafenib; dabrafenib oral, twice daily.; Other Names: DRB436 ; Drug: trametinib; trametinib oral, once daily.; Other Names: TMT212
Active Comparator: LGG cohort: Carboplatin with vincristine LGG cohort: Patients randomized 2:1 to either DRB+TMT or active comparator chemotherapy.	Drug: Carboplatin with vincristine; Chemotherapy of carboplatin with vincristine - LGG only
Experimental: LGG cohort: Dabrafenib and trametinib LGG cohort: Patients randomized 2:1 to either DRB+TMT or active comparator chemotherapy.	Drug: dabrafenib; dabrafenib oral, twice daily.; Other Names: DRB436 ; Drug: trametinib; trametinib oral, once daily.; Other Names: TMT212

Outcome Measures

Primary Outcome Measures

1. HGG cohort: Overall response rate (ORR) [Within the first 32 weeks of treatment]

   HGG cohort: ORR as determined by central independent assessment based on Magnetic resonance imaging MRI) or CT (CAT) scans using Response Assessment in Neuro-Oncology Criteria (RANO) criteria.

2. LGG cohort: Overall response rate (ORR) [Within the first 32 weeks of treatment]

   LGG cohort: ORR as determined by blinded central independent assessment based on MRI or CT scans using RANO criteria.

Secondary Outcome Measures

1. HGG cohort: Overall response rate (ORR) [Within the first 32 weeks of treatment]

   HGG cohort ORR as determined by investigator assessment based on Magnetic resonance imaging (MRI) or CT (CAT)scans using Response Assessment in Neuro-Oncology (RANO criteria)

2. HGG and LGG cohorts: Duration of response (DOR) [Within the first year of treatment]

   HGG and LGG cohorts: DOR as assessed separately by investigator and central review based on MRI or CT scans using RANO criteria

3. HGG and LGG cohorts: Time to response (TTR) [Within the first year of treatment]

   HGG and LGG cohorts: TTR as assessed separately by investigator and central review based on MRI or CT scans using RANO criteria

4. HGG and LGG cohorts: Overall survival (OS) [2 years from last patient dosed]

   HGG and LGG cohorts: OS as defined as the time from first dose to death due to any cause

5. HGG and LGG cohorts: Progression free survival (PFS) [Within 4 months of treatment]

   HGG and LGG cohorts: PFS as assessed separately by investigator and central review based on MRI or CT scans using RANO criteria

6. Patients on DRB+TMT: Area under the curve (AUClast) [Within the first month of treatment]

   Patients on DRB+TMT: Assessed from time zero to the last measurable sampling time

7. Patients on DRB+TMT: Area under the curve (AUCtau) [Within the first month of treatment]

   Patients on DRB+TMT: Calculated to the end of a dosing interval at steady state (12 hours)

8. Patients on DRB+TMT: Maximum Plasma Concentration (Cmax) [Within the first month of treatment]

   Patients on DRB+TMT: The maximum (peak) observed plasma drug concentration after a single dose

9. Patients on DRB+TMT: Time to reach maximum concentration (Tmax) [Within the first month of treatment]

   Patients on DRB+TMT: The time to reach maximum (peak) concentration of study drug after a single dose

10. Patients on DRB+TMT: Elimination half-life (T1/2) [Within the first month of treatment]

    Patients on DRB+TMT: The elimination half-life associated with the terminal slope of a semi-log concentration-time curve

11. Patients on DRB+TMT: Predose plasma concentration (Ctrough) [Within the first month of treatment]

    Patients on DRB+TMT: Measured concentration at the end of a dosing interval at steady state, taken directly before next study drug administration).

12. HGG and LGG cohorts: Adverse events [From first dose to end of treatment (EOT)]

    HGG cohort: Incidence of AEs and SAEs reported during treatment with dabrafenib and trametinib in this population. LGG cohort: Incidence of AEs and SAEs reported during treatment with dabrafenib and trametinib as compared to chemotherapy

13. HGG and LGG cohorts: Vital signs [First dose to end of treatment]

    HGG: Assess the safety of dabrafenib and trametinib in this population through monitoring changes in vital signs. LGG: Assess the safety of dabrafenib and trametinib in this population as compared to chemotherapy through monitoring changes in vital signs.

14. HGG and LGG cohorts: Abnormal lab values [First dose to end of treatment]

    HGG: Assess the safety of dabrafenib and trametinib in this population through hematology, chemistry and urinalysis tests. LGG: Assess the safety of dabrafenib and trametinib in this population as compared to chemotherapy through hematology, chemistry and urinalysis tests

15. HGG and LGG cohorts: Changes in Electrocardiogram (ECG) [First dose to end of treatment]

    HGG: Assess the safety of dabrafenib and trametinib in this population through changes in ECG values. LGG: Assess the safety of dabrafenib and trametinib as compared to chemotherapy in this population through changes in ECG values

16. HGG and LGG cohorts: ECHO [First dose to end of treatment]

    HGG: Assess the safety of dabrafenib and trametinib in this patient population through changes in ECHO results. LGG: Assess the safety of dabrafenib and trametinib in this patient population as compared to chemotherapy through changes in ECHO results.

17. LGG cohort: Overall response rate (ORR) [Within the first 32 weeks of treatment]

    LGG cohort: ORR as determined by investigator assessment based on MRI or CT scans using RANO criteria

18. HGG and LGG cohort: Palatability of pediatric formulations [Within the first 5 weeks of treatment]

    HGG and LGG cohort: Palatability questionnaire data for DRB suspension and TMT solution

19. LGG cohort: PROMIS Parent Proxy scale [Within the first 32 weeks of treatment]

    LGG cohort only: PROMIS parent proxy scale to estimate differences between treatment groups

20. HGG and LGG Cohorts: Clinical benefit rate (CBR) [Within the first 24 weeks of treatment]

    HGG and LGG cohorts: CBR as assessed separately by investigator and central review of MRI and CT scans per RANO criteria

21. LGG cohort: 2 year Overall survival (OS) [2 years from first dose]

    LGG cohort: OS as defined as the time from the first dose to death due to any cause

Eligibility Criteria

Criteria

• Ages Eligible for Study: 12 Months to 17 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Diagnosis of BRAF V600 mutant High Grade glioma that has relapsed, progressed or failed to respond to frontline therapy

• Diagnosis of BRAF V600 mutant Low Grade glioma with progressive disease following surgical excision, or non-surgical candidates with necessity to begin first systemic treatment because of a risk of neurological impairment with progression.

• Confirmed measurable disease

Exclusion Criteria:

• Previous treatment with dabrafenib, trametinib, other RAF inhibitor, other MEK or ERK inhibitor

• HGG patient: Cancer treatment within the past 3 weeks. LGG patient: Any systemic therapy or radiotherapy prior to enrollment

• LGG patients: history of allergic reaction or contraindications to the use of carboplatin or vincristine

• Stem cell transplant within the past 3 months

• History of heart disease

• Pregnant or lactating females

Other protocol-defined Inclusion/exclusion may apply.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Children's Hospital of Orange County	Orange	California	United States	92868
2	Childrens National Hospital	Washington	District of Columbia	United States	20010
3	Nicklaus Childrens Hospital	Miami	Florida	United States	33155
4	Ann and Robert H Lurie Childrens Hospital of Chicago	Chicago	Illinois	United States	60611
5	Indiana University School of Medicine	Indianapolis	Indiana	United States	46202-2810
6	Johns Hopkins University IDS Pharmacy John Hopkins Hospital	Baltimore	Maryland	United States	21287
7	Washington University School of Medicine SC	Saint Louis	Missouri	United States	63110
8	Cincinnati Children's Hospital Medical Center Cancer & Blood Disease Inst.	Cincinnati	Ohio	United States	45229-3039
9	St Jude Children's Research Hospital	Memphis	Tennessee	United States	38105
10	Texas Children s Hospital Baylor College of Medicine	Houston	Texas	United States	77030
11	Novartis Investigative Site	Caba	Buenos Aires	Argentina	C1428AQK
12	Novartis Investigative Site	Randwick	New South Wales	Australia	2130
13	Novartis Investigative Site	Parkville	Victoria	Australia	3052
14	Novartis Investigative Site	Brussels		Belgium	BE-B-1200
15	Novartis Investigative Site	Barretos	SP	Brazil	14784 400
16	Novartis Investigative Site	Sao Paulo	SP	Brazil	08270-070
17	Novartis Investigative Site	Sao Paulo	SP	Brazil
18	Novartis Investigative Site	Vancouver	British Colombia	Canada	V6H 3V4
19	Novartis Investigative Site	Toronto	Ontario	Canada	M5G 1X8
20	Novartis Investigative Site	Montreal	Quebec	Canada	H3T 1C5
21	Novartis Investigative Site	Brno		Czechia	613 00
22	Novartis Investigative Site	Praha 5		Czechia	150 06
23	Novartis Investigative Site	Copenhagen		Denmark	2100 O
24	Novartis Investigative Site	Tampere		Finland	33521
25	Novartis Investigative Site	Villejuif Cedex	Villejuif	France	94800
26	Novartis Investigative Site	Lille Cedex		France	59020
27	Novartis Investigative Site	Lyon Cedex		France	69373
28	Novartis Investigative Site	Paris		France	75231
29	Novartis Investigative Site	Strasbourg Cedex		France	F 67098
30	Novartis Investigative Site	Toulouse Cedex 9		France	31059
31	Novartis Investigative Site	Augsburg		Germany	86179
32	Novartis Investigative Site	Berlin		Germany	13353
33	Novartis Investigative Site	Essen		Germany	45147
34	Novartis Investigative Site	Gottingen		Germany	37075
35	Novartis Investigative Site	Hamburg		Germany	20246
36	Novartis Investigative Site	Heidelberg		Germany	69120
37	Novartis Investigative Site	Koeln		Germany	50937
38	Novartis Investigative Site	Petach-Tikva		Israel	49202
39	Novartis Investigative Site	Tel-Hashomer		Israel	52621
40	Novartis Investigative Site	Firenze	FI	Italy	50139
41	Novartis Investigative Site	Genova	GE	Italy	16147
42	Novartis Investigative Site	Milano	MI	Italy	20133
43	Novartis Investigative Site	Roma	RM	Italy	00165
44	Novartis Investigative Site	Torino	TO	Italy	10126
45	Novartis Investigative Site	Fukuoka city	Fukuoka	Japan	812-8582
46	Novartis Investigative Site	Setagaya-ku	Tokyo	Japan	157-8535
47	Novartis Investigative Site	Osaka		Japan	534-0021
48	Novartis Investigative Site	Utrecht	CS	Netherlands	3584
49	Novartis Investigative Site	Moscow		Russian Federation	117198
50	Novartis Investigative Site	Barcelona	Catalunya	Spain	08035
51	Novartis Investigative Site	Madrid		Spain	28009
52	Novartis Investigative Site	Valencia		Spain	46026
53	Novartis Investigative Site	Stockholm		Sweden	17176
54	Novartis Investigative Site	Zuerich		Switzerland	8032
55	Novartis Investigative Site	Leeds		United Kingdom	LS1 3EX
56	Novartis Investigative Site	Liverpool		United Kingdom	L12 2AP
57	Novartis Investigative Site	London		United Kingdom	WC1N 3JH

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT02684058
• Other Study ID Numbers: CDRB436G2201; 2015-004015-20
• First Posted: Feb 17, 2016
• Last Update Posted: Aug 11, 2022
• Last Verified: Aug 1, 2022

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Novartis Pharmaceuticals: Malignant glioma; BRAF mutant positive; High grade glioma; Low grade glioma; Dabrafenib; Trametinib; Pediatrics; Brain neoplasma
• Additional relevant MeSH terms: Glioblastoma; Glioma; Astrocytoma; Oligodendroglioma; Ganglioglioma; Neurocytoma; Ganglioneuroma; Carboplatin; Vincristine; Trametinib; Dabrafenib

Study Results

No Results Posted as of Aug 11, 2022