Lead-in phase 1 safety trial followed by asymmetrically randomized open- label, double-arm, two-stage, multicenter, phase 2 clinical trial.
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.
Phase 1
Patients will be screened and if found eligible treated with the combination of standard dosing of dabrafenib (150 mg twice daily) and trametinib (2 mg once daily) with the autophagy inhibitor hydroxychloroquine (200 mg twice daily). Treatment will continue until disease progression, unacceptable treatment related toxicity or patient's refusal to continue study treatment. Throughout their study participation, patients will be continuously monitored for safety and evaluated for tumor response every 8 weeks or sooner if there is clinical suspicion of progressive disease.
Six patients will be included for this phase 1 trial with incidence of adverse events as primary endpoint and ORR (objective response rate), PFS (progression-free survival), OS (overall survival, per RECIST v1.1 \[Response Evaluation Criteria for Solid Tumors\]) and value of ctDNA (circulating tumor DNA) as secondary endpoints.
Phase 2
Patients will be screened and if found eligible asymmetrically randomized to treatment with the combination of standard dosing of dabrafenib (150 mg twice daily) and trametinib (2 mg once daily) with the autophagy inhibitor hydroxychloroquine (200 mg twice daily) (arm A, investigational arm) or treatment with standard dosing of dabrafenib (150 mg twice daily) and trametinib (2 mg once daily) (arm B, contemporary control arm). Stratification will occur according to baseline lactate dehydrogenase level. Treatment will continue until disease progression, unacceptable treatment related toxicity or patient's refusal to continue study treatment. However, at disease progression in arm B (dabrafenib plus trametinib), hydroxychloroquine (200 mg twice daily) will be added to the standard treatment and treatment will be continued until disease progression, unacceptable treatment related toxicity or patient's refusal to continue study treatment.
Throughout their study participation, patients will be continuously monitored for safety and evaluated for tumor response every 8 weeks or sooner if there is clinical suspicion of progressive disease.
Primary endpoint is ORR (objective response rate) in arm A, secondary endpoints are ORR (objective response rate) in arm B and PFS (progression-free survival), OS (overall survival), incidence of adverse events and value of ctDNA (circulating tumor DNA) in both arms.
