Dabrafenib/Trametinib/Hydroxychloroquine for Advanced Pretreated BRAF V600 Mutant Melanoma

Sponsor
Universitair Ziekenhuis Brussel
Study ID
NCT03754179
Phase
PHASE1/PHASE2
Status
Unknown

Conditions

Eligibility Criteria

Sex
ALL
Age
18 Years - N/A
Healthy Volunteers
Not accepted

Interventions

  • Dabrafenib — DRUG
    Upfront treatment with dabrafenib, trametinib and hydroxychloroquine in phase 1 and Arm A phase 2. Upfront treatment with dabrafenib and trametinib in Arm B phase 2 with add-on of hydroxychloroquine at progression of disease
  • Trametinib — DRUG
    Upfront treatment with dabrafenib, trametinib and hydroxychloroquine in phase 1 and Arm A phase 2. Upfront treatment with dabrafenib and trametinib in Arm B phase 2 with add-on of hydroxychloroquine at progression of disease
  • Hydroxychloroquine — DRUG
    Upfront treatment with dabrafenib, trametinib and hydroxychloroquine in phase 1 and Arm A phase 2. Add-on at progression of disease in Arm B phase 2

Study Details

This phase 1/2 trial addresses the efficacy and safety of the combination of dabrafenib, trametinib and the oral autophagy inhibitor hydroxychloroquine in patients with unresectable AJCC (American Joint Committee on Cancer) stage III or stage IV BRAF (v-Raf murine sarcoma viral oncogene homolog B) V600 mutant melanoma who are documented with progression of disease following treatment with a BRAF with or without MEK (MAPK/Erk kinase) inhibitor and treatment with an immune checkpoint inhibitor. The investigators hypothesize hydroxychloroquine will be able to overcome or prevent autophagy-driven resistance to dabrafenib and trametinib. The investigators will also investigate the value of plasma BRAF V600 mutant circulating tumor DNA (ctDNA) as a predictive or prognostic marker.

Key Dates

Start date
Jan 23, 2018
Status verified
Apr 2021
Primary completion
Dec 1, 2021
Completion
Jul 1, 2022

Study Design

Enrollment
63 participants (estimated)
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT

Arms

  • Experimental: Arm A phase 2
    Patients are eligible if they are diagnosed with BRAF V600 mutant unresectable AJCC (American Joint Committee on Cancer) stage III or IV melanoma and are documented with progression of disease following treatment with a BRAF with or without MEK inhibitor and treatment with an immune checkpoint inhibitor (at least an anti-PD1 \[programmed cell death 1\] antibody). Patients will be considered for study participation not earlier than 12 weeks after the last dosing of the prior BRAF with or without MEK inhibitor therapy and 4 weeks after the last dosing of immune checkpoint inhibitor therapy. Upfront treatment with dabrafenib 150 mg twice daily, trametinib 2 mg once daily and hydroxychloroquine 200 mg twice daily upfront until disease progression, unacceptable treatment related toxicity or patient's refusal to continue study treatment.
  • Active Comparator: Arm B phase 2
    Patients are eligible if they are diagnosed with BRAF V600 mutant unresectable AJCC (American Joint Committee on Cancer) stage III or IV melanoma and are documented with progression of disease following treatment with a BRAF with or without MEK inhibitor and treatment with an immune checkpoint inhibitor (at least an anti-PD1 \[programmed cell death 1\] antibody). Patients will be considered for study participation not earlier than 12 weeks after the last dosing of the prior BRAF with or without MEK inhibitor therapy and 4 weeks after the last dosing of immune checkpoint inhibitor therapy. Upfront treatment with dabrafenib 150 mg twice daily, trametinib 2 mg once daily until disease progression. At disease progression, add-on of hydroxychloroquine 200 mg twice daily. Treatment until disease progression, unacceptable treatment related toxicity or patient's refusal to continue study treatment
  • Experimental: Phase 1
    Patients are eligible if they are diagnosed with BRAF V600 mutant unresectable AJCC (American Joint Committee on Cancer) stage III or IV melanoma and are documented with progression of disease following treatment with a BRAF with or without MEK inhibitor and treatment with an immune checkpoint inhibitor (at least an anti-PD1 \[programmed cell death 1\] antibody). Patients will be considered for study participation not earlier than 12 weeks after the last dosing of the prior BRAF with or without MEK inhibitor therapy and 4 weeks after the last dosing of immune checkpoint inhibitor therapy. Upfront treatment with dabrafenib 150 mg twice daily, trametinib 2 mg once daily and hydroxychloroquine 200 mg twice daily upfront until disease progression, unacceptable treatment related toxicity or patient's refusal to continue study treatment.

Primary Outcome Measure

Ph. 1: incidence of adverse events of DAB, TRA and HCQ [ Time Frame: 1 year ]

Central Contacts

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