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Kinase Inhibitor

Dabrafenib + Trametinib + Hydroxychloroquine for Brain Tumor

Phase 1 & 2

Recruiting

Research Sponsored by Pediatric Brain Tumor Consortium

Eligibility Criteria Checklist

Specific guidelines that determine who can or cannot participate in a clinical trial

Must have

Patients must have weight >= 9 kg to enroll in Phase I or Phase II

Sexually active males must use a condom and agree not to father a child

Must not have

Patients receiving any other anti-cancer or investigational drug therapy

Patients with specific retinal conditions or active gastrointestinal disease

Timeline

Screening 3 weeks

Treatment Varies

Follow Up approximately 2 years from start of therapy

Awards & highlights

No Placebo-Only Group

Summary

This trial is designed to study the side effects and efficacy of adding hydroxychloroquine to dabrafenib and/or trametinib in children with brain tumors that have progressed or returned while receiving a similar agent.

Who is the study for?

This trial is for children with low or high grade brain tumors that have specific genetic mutations (BRAF V600, BRAF fusion/duplication) and may include those with neurofibromatosis type 1. Participants must have tried similar treatments without success, be in good health otherwise, not pregnant or breastfeeding, able to use contraception if applicable, and understand the study.

What is being tested?

The trial tests combining hydroxychloroquine with dabrafenib and/or trametinib to see if it's more effective at stopping tumor growth than current treatments. It's a phase I/II trial which means they're looking for the safest dose that works best against these types of brain tumors.

What are the potential side effects?

Possible side effects include issues affecting blood cells leading to increased infection risk or bleeding problems; liver, kidney or heart problems; eye issues; digestive disturbances; skin reactions; muscle weakness; headaches and potential interactions with other medications.

Eligibility Criteria

Inclusion Criteria

You may be eligible if you check “Yes” for the criteria below

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I weigh at least 9 kg.

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I am a sexually active male and will use a condom to prevent fathering a child.

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My neurological condition is stable and any seizures are under control.

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My blood, liver, kidney, and heart functions meet the required levels.

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I can do most activities but may need help.

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My cancer has returned or worsened and has a specific genetic makeup.

Exclusion Criteria

You may be eligible for the trial if you check “No” for criteria below:

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I am not on any other cancer treatment or experimental drugs.

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I have certain eye conditions or active stomach/intestine issues.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ approximately 2 years from start of therapy

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~approximately 2 years from start of therapy

This trial's timeline: 3 weeks for screening, Varies for treatment, and approximately 2 years from start of therapy for reporting.

Treatment Details

Study Objectives

Study objectives can provide a clearer picture of what you can expect from a treatment.

Primary study objectives

Area under the curve (AUC)

Maximum Plasma Concentration

Maximum Tolerated Dose (MTD)/ Recommended Phase 2 Dose (RP2D)

+1 more

Secondary study objectives

Phase I and II: Autophagy inhibition as assessed by the accumulation of LC3II in peripheral blood mononuclear cells

Phase I and II: Autophagy inhibition as assessed by the accumulation of p62 in peripheral blood mononuclear cells

Phase I and II: Presence of MAPK pathway aberrations (other than BRAF) as assessed by whole exome sequencing

+5 more

Side effects data

From 2021 Phase 3 trial • 552 Patients • NCT03551626

68%

Pyrexia

32%

Headache

30%

Blood creatine phosphokinase increased

27%

Diarrhoea

26%

Fatigue

26%

Chills

24%

Asthenia

23%

Nausea

21%

Arthralgia

21%

Rash

15%

Vomiting

15%

Myalgia

14%

Alanine aminotransferase increased

14%

Cough

13%

Lipase increased

13%

Aspartate aminotransferase increased

12%

Influenza like illness

12%

Oedema peripheral

Pain in extremity

Neutropenia

Abdominal pain

Constipation

Muscle spasms

Back pain

Blood alkaline phosphatase increased

Decreased appetite

Hypophosphataemia

Dyspnoea

Erythema

Hypertension

Amylase increased

Hyperglycaemia

Dry skin

Dizziness

Abdominal pain upper

Pain

Pruritus

Oropharyngeal pain

Ejection fraction decreased

Atrial fibrillation

Erysipelas

Cellulitis

Basal cell carcinoma

Pulmonary embolism

100%

80%

60%

40%

20%

Study treatment Arm

Dabrafenib+Trametinib (On-treatment)

Dabrafenib+Trametinib (Post-treatment Follow-up)

Awards & Highlights

No Placebo-Only Group

All patients enrolled in this study will receive some form of active treatment.

Trial Design

6Treatment groups

Experimental Treatment

Group I: Phase 2 Stratum 6 LGG with NF Type 1Experimental Treatment2 Interventions

LGG with Neurofibromatosis Type 1 will receive Trametinib and Hydroxychloroquine. All medications are administered orally with Trametinib given once per day and HCQ give twice per day at the recommended Phase 2 dose for a 28 day course. Courses may repeat until the patient meets an off treatment criteria.

Group II: Phase 2 Stratum 5 LGG with BRAF aberrationExperimental Treatment2 Interventions

LGG with BRAF duplication or fusion with any partner will receive Trametinib and Hydroxychloroquine. All medications are administered orally with Trametinib given once per day and HCQ give twice per day at the recommended Phase 2 dose for a 28 day course. Courses may repeat until the patient meets an off treatment criteria.

Group III: Phase 2 Stratum 4 HGG with BRAF V600 mutationExperimental Treatment3 Interventions

HGG with BRAF V600E/D/K mutation will receive Dabrafenib, Trametinib and Hydroxychloroquine. All medications are administered orally with Dabrafenib and HCQ given twice a day and Trametinib given once per day at the recommended Phase 2 dose for a 28 day course. Courses may repeat until the patient meets an off treatment criteria

Group IV: Phase 2 Stratum 3 LGG with BRAF V600 mutationExperimental Treatment3 Interventions

LGG with BRAF V600E/D/K mutation will receive Dabrafenib, Trametinib and Hydroxychloroquine. All medications are administered orally with Dabrafenib and HCQ given twice a day and Trametinib given once per day at the recommended Phase 2 dose for a 28 day course. Courses may repeat until the patient meets an off treatment criteria.

Group V: Phase 1 Stratum 2 BRAF aberration or LGG with NF1Experimental Treatment2 Interventions

LGG with BRAF duplication or fusion with any partner or LGG with NF1 will received Trametinib and Hydroxychloroquine. All medications are administered orally with Trametinib given once per day and HCQ give twice per day at the assigned dose for a 28 day course. Courses may repeat until the patient meets an off treatment criteria.

Group VI: Phase 1 Stratum 1 BRAF V600E LGG or HGGExperimental Treatment3 Interventions

LGG or HGG with BRAF V600E/D/K mutation will receive Dabrafenib, Trametinib and Hydroxychloroquine. All medications are administered orally with Dabrafenib and HCQ given twice a day and Trametinib given once per day at the assigned dose for a 28 day course. Courses may repeat until the patient meets an off treatment criteria.

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

Hydroxychloroquine

2017

Completed Phase 4

~5350

Trametinib

2014

Completed Phase 2

~1630