MelanomaPhase 1/2COMBI-R2NCT03754179
Dabrafenib/Trametinib/Hydroxychloroquine for Advanced Pretreated BRAF V600 Mutant Melanoma
A Phase 1/2 study testing Dabrafenib, Trametinib and Hydroxychloroquine in people with Melanoma, run by Universitair Ziekenhuis Brussel at 1 site in Belgium.
Trial summary
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… Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Melanoma
- What is being tested?
- Dabrafenib, Trametinib and Hydroxychloroquine
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 63 participants
- Where
- 1 siteBelgium
- Study dates
- 23 Jan 2018to 1 Jul 2022
- Phase
- Phase 1/2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- ≥18 years of age.
- Signed written informed consent.
- Histologically confirmed cutaneous melanoma that is either unresectable AJCC (American Joint Committee on Cancer) stage III or stage IV, and previously determined to be BRAF V600 mutation-positive.
- Subjects must have failed at least two prior systemic anti-cancer treatments for AJCC (American Joint Committee on Cancer) unresectable stage III or stage IV melanoma that must have included: a. Treatment with a BRAF inhibitor (including but not limited to dabrafenib, vemurafenib, encorafenib or other experimental BRAF inhibitors) in combination with a MEK inhibitor (including but not limited to trametinib, cobimetinib, binimetinib or other experimental MEK inhibitors) and progression of disease per Response Evaluation Criteria In Solid Tumors (RECIST), version 1.1 must have been documented during this treatment; b. Treatment with anti-CTLA4 (cytotoxic T-lymphocyt antigen 4) antibodies (ipilimumab or other experimental anti-CTLA4 antibodies), anti-PD1 (programmed cell death 1) antibodies (pembrolizumab, nivolumab or other experimental anti-PD1 antibodies), anti-PDL1 (programmed cell death ligand 1) antibodies and progression of disease per RECIST, version 1.1 or per immune related response criteria must have been documented during this treatment.
- The presence of at least one measurable lesion per RECIST, version 1.1.
- Interval between the date of the last administration of prior therapy for melanoma and the date of recruitment: a. ≥ 12 weeks following the date of the last administration of a BRAF with or without MEK inhibitor; b. ≥ 12 weeks following the date of the first administration and ≥4 weeks following the date of the last administration of ipilimumab, or an anti-PD1, or anti-PD-L1 therapy; c. ≥ 4 weeks following the date of the last administration of chemotherapy (≥ 6 weeks in case of a nitrosurea or mitomycin C containing regimen); d. ≥ 4 weeks following major surgery or extensive radiotherapy.
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- All prior anti-cancer treatment-related toxicities (except alopecia and laboratory values as listed on Table 1) must be ≤ grade 1 according to the Common Terminology Criteria for Adverse Events version 4 (CTCAE version 4.0; National Cancer Institute [NCI] 2009) at the time of recruitment.
- Able to swallow and retain oral medication and must not have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels.
- Women of childbearing potential must have a negative serum pregnancy test within 14 days prior to recruitment and agree to use effective contraception throughout the treatment period, and for 16 weeks after the last dose of study treatment.
- Men with a female partner of childbearing potential must have either had a prior vasectomy or agree to use effective contraception from 14 days prior to administration of the first dose of study treatment, throughout the treatment period, and for 16 weeks after the last dose of study treatment.
- An Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2.
- Adequate baseline organ function as defined as follows: Absolute neutrophil count: ≥ 1.2 x 103/mm3 - Hemoglobin: ≥ 9.0 g/dL - Platelet count: ≥ 75 x 103/mm3 - prothrombin time/international normalized ratio and activated partial thromboplastin time: ≤ 1.5 x ULN - Albumin: ≥ 2.5 g/dL - Total bilirubin: ≤ 1.5 x ULN - aspartate aminotransferase and alanine aminotransferase - ≤ 2.5 x ULN - Calculated creatinine clearance - ≥ 50 mL/min (by use of the Cockroft-Gault formula) - Left ventricular ejection fraction ≥ lower limit of normal by transthoracic echocardiogram
Who cannot join
- No Belgian medical insurance
- Subjects with uveal or mucosal melanoma.
- Prior treatment with hydroxychloroquine, chloroquine or other quinine derivatives.
- Grade 4 or repetitive grade 3 adverse event(s) related to prior treatment with a BRAF and/or a MEK inhibitor.
- Any contra-indication for evaluation by whole body PET/CT (positron emission tomography/computed tomography) and MRI (magnetic resonance imaging) of the brain.
- Taken an investigational drug within 28 days or 5 half-lives (minimum 14 days), whichever is shorter, prior to recruitment.
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- Current use of a prohibited medication (macrolides, azoles).
- History of another malignancy with exception of subjects who have been disease-free for 3 years (i.e. subjects with second malignancies that are indolent or definitively treated at least 3 years ago) or subjects with a history of completely resected non-melanoma skin cancer.
- Any serious or unstable pre-existing medical conditions (aside from malignancy exceptions specified above), psychiatric disorders, or other conditions that could interfere with the subject's safety, obtaining informed consent, or compliance with study procedures.
- Known Human Immunodeficiency Virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV) infection (subjects with laboratory evidence of cleared HBV and HCV infection will be permitted).
- A history of glucose-6-phosphate dehydrogenase (G6PD) deficiency, psoriasis and/or porphyria.
- No enzyme inducing anticonvulsants for ≥ 4 weeks prior to recruitment.
- A history or evidence of cardiovascular risk including any of the following: a. Current left ventricular ejection fraction < lower limit of normal; b. A QT interval corrected for heart rate using the Bazett's formula (QTcB) ≥480 ms; c. A history or evidence of current clinically significant uncontrolled arrhythmias with exception of subjects with atrial fibrillation controlled for >30 days prior to recruitment are eligible; d. A history (within 6 months prior to recruitment) of acute coronary syndromes (including myocardial infarction or unstable angina), or coronary angioplasty; e. A history or evidence of current ≥ class II congestive heart failure as defined by the New York Heart Association (NYHA) guidelines (Appendix 4: New York Heart Association (NYHA) Guidelines); f. Treatment refractory hypertension defined as a blood pressure of systolic >140 mmHg and/or diastolic > 90 mm Hg which cannot be controlled by antihypertensive therapy; g. Patients with intra-cardiac defibrillators or permanent pacemakers; h. Known cardiac metastases; i. Abnormal cardiac valve morphology (≥ grade 2) documented by echocardiogram (subjects with grade 1 abnormalities [i.e., mild regurgitation/stenosis] can be entered on study). Subjects with moderate valvular thickening should not be entered on study.
- Uncorrectable electrolyte abnormalities (e.g. hypokalaemia, hypomagnesaemia, hypocalcaemia), long QT syndrome or taking other medicinal products known to prolong the QT interval.
- A history or current evidence/risk of retinal vein occlusion (RVO) or central serous retinopathy (CSR) including: a. Presence of predisposing factors to RVO or CSR (e.g., uncontrolled glaucoma or ocular hypertension, uncontrolled hypertension, uncontrolled diabetes mellitus, or a history of hyperviscosity or hypercoagulability syndromes); b. Visible retinal pathology as assessed by ophthalmologic examination that is considered a risk factor for RVO or CSR such as: i. Evidence of new optic disc cupping; ii. Evidence of new visual field defects on automated perimetry; iii. Intraocular pressure >21 mmHg as measured by tonography.
- Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to the study treatments, their excipients, and/or dimethyl sulfoxide (DMSO).
- Females who are nursing.
Trial locations and contacts
1 site in 1 country.
Belgium1 site, 1 recruiting
- Recruiting
UZ Brussel
Jette, Brabant, 1090
Bart Neyns, Phd,Md, 0032(0)2477 64 15, bart.neyns@uzbrussel.be
Bart Neyns, Phd,Md
About this study
Official title: A lead-in Phase I Followed by a Phase II Clinical Trial on the Combination of Dabrafenib, Trametinib and the Autophagy Inhibitor Hydroxychloroquine in BRAF/MEK Inhibitor-pretreated Patients With Advanced BRAF V600 Mutant Melanoma
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.
Read the detailed description
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.
- Conditions
- Melanoma
- Being tested
- Dabrafenib, Trametinib, Hydroxychloroquine
- Keywords
- autophagy, dabrafenib, hydroxychloroquine, trametinib, melanoma, rechallenge
- Medical subject headings
- Melanoma
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
DabrafenibDrug
Also called Tafinlar, DAB
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
TrametinibDrug
Also called Mekinist, TRA
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
Also called Plaquenil, HCQ
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 group | Role | What they receive |
|---|---|---|
| Arm A phase 2 | Experimental | 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. Receives: Drug: Dabrafenib; Drug: Trametinib; Drug: Hydroxychloroquine |
| Arm B phase 2 | Active comparator | 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 Receives: Drug: Dabrafenib; Drug: Trametinib; Drug: Hydroxychloroquine |
| Phase 1 | Experimental | 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. Receives: Drug: Dabrafenib; Drug: Trametinib; Drug: Hydroxychloroquine |
What is being measured
The primary outcome is the main question the study is designed to answer.
Ph. 1: incidence of adverse events of DAB, TRA and HCQ
Adverse events graded by the Common Terminology Criteria of Adverse Events version 4 (CTCAE v4)
Measured: 1 year
Ph. 2 Arm A: objective response rate (ORR) of DAB, TRA and HCQ
Objective response rate (ORR; defined as the percentage of subjects with a confirmed complete response [CR] or partial response [PR] at any time per Response Evaluation Criteria in Solid Tumors [RECIST], version 1.1 [Eisenhauer 2009]).
Measured: 2 years
Secondary outcomes (15)
Ph. 1: objective response rate (ORR) of DAB, TRA and HCQ
Objective response rate (ORR; defined as the percentage of subjects with a confirmed complete response [CR] or partial response [PR] at any time per Response Evaluation Criteria in Solid Tumors [RECIST], version 1.1 [Eisenhauer 2009]).
Measured: 1 year
Ph. 1: progression-free survival (PFS) on DAB, TRA and HCQ
Progression-free survival (PFS; defined as the time from treatment initiation until the earliest date of disease progression or death due to any cause)
Measured: 1 year
Ph. 1: overall survival (OS) on DAB, TRA and HCQ
Overall survival (OS; defined as the time from treatment initiation until the date of death due to any cause).
Measured: 1 year
Ph. 1: value of BRAF V600 mutant circulating tumor DNA (ctDNA) as a predictive and/or prognostic marker during treatment DAB, TRA and HCQ
Copy number of BRAF V600 mutant ctDNA as measured by quantitative Polymerase Chain Reaction (qPCR)
Measured: 1 year
Ph. 2 Arm B: objective response rate 1 (ORR 1) of DAB and TRA prior to the addition of HCQ at progression of disease
Objective response rate 1 (ORR 1; defined as the percentage of subjects with a confirmed complete response [CR] or partial response [PR] prior to the addition of hydroxychloroquine at any time per Response Evaluation Criteria in Solid Tumors [RECIST], version 1.1 [Eisenhauer 2009]).
Measured: 2 years
Ph. 2 Arm B: objective response rate 2 (ORR 2) of DAB and TRA following the addition of HCQ at progression of disease
Objective response rate 2 (ORR 2; defined as the percentage of subjects with a confirmed complete response [CR] or partial response [PR] following the addition of hydroxychloroquine at any time per Response Evaluation Criteria in Solid Tumors [RECIST], version 1.1 [Eisenhauer 2009]).
Measured: 2 years
Ph. 2 Arm A: progression-free survival (PFS) on DAB, TRA and HCQ
Progression-free survival (PFS; defined as the time from randomization until the earliest date of disease progression or death due to any cause)
Measured: 2 years
Ph. 2 Arm A: overall survival (OS) on DAB, TRA and HCQ
Overall survival (OS; defined as the time from randomization until the date of death due to any cause).
Measured: 2 years
Ph. 2 Arm B: progression-free survival 1 (PFS 1) on DAB and TRA prior to the addition of HCQ
Progression-free survival 1 (PFS 1; defined as the time from randomization until the earliest date of disease progression or death due to any cause whilst treated with dabrafenib and trametinib)
Measured: 2 years
Ph. 2 Arm B: progression-free survival 2 (PFS 2) on DAB and TRA following the addition of HCQ
Progression-free survival 2 (PFS 2; defined as the time from addition of hydroxychloroquine to dabrafenib and trametinib until the earliest date of disease progression or death due to any cause)
Measured: 2 years
Ph. 2 Arm B: overall survival 1 (OS 1) on DAB and TRA prior to the addition of HCQ
Overall survival 1 (OS 1; defined as the time from randomization until death due to any cause whilst treated with dabrafenib and trametinib)
Measured: 2 years
Ph. 2 Arm B: overall survival 2 (OS 2) on DAB and TRA following the addition of HCQ
Overall survival 2 (OS 2; defined as the time from addition of hydroxychloroquine to dabrafenib and trametinib until death due to any cause)
Measured: 2 years
Ph. 2 Arm B: overall survival 3 (OS 3) on DAB and TRA following the addition of HCQ
Overall survival 3 (OS 3; defined as the time from randomization until death).
Measured: 2 years
Ph. 2 Arm A and B: incidence of adverse events of DAB, TRA and HCQ
Adverse events graded by the Common Terminology Criteria of Adverse Events version 4 (CTCAE v4)
Measured: 2 years
Ph. 2 Arm A and B: value of BRAF V600 mutant circulating tumor DNA (ctDNA) as a predictive and/or prognostic marker during treatment with DAB, TRA and HCQ
Copy number of BRAF V600 mutant ctDNA as measured by quantitative Polymerase Chain Reaction (qPCR) in plasma
Measured: 2 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted27 Nov 2018
- Study start23 Jan 2018
- Primary completion1 Dec 2021 (estimated)
- Study completion1 Jul 2022 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for MelanomaStudies of the same condition, open and under way.
- More trials run by Universitair Ziekenhuis BrusselThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 63 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Universitair Ziekenhuis Brussel
- Sponsor type
- University, hospital or other
- Collaborators
- University Hospital, Ghent
- Responsible party
- Sponsor
- Investigators
- Bart Neyns, MD PhD, Principal investigator, Universitair Ziekenhuis Brussel
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03754179
- Sponsor's protocol ID
- 2017-BN-004
- Acronym
- COMBI-R2
- Status last verified
- Apr 2021
- First submitted
- 16 Nov 2018
- Last updated
- 28 Apr 2021
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Undecided
Study at a glance
From the registry record, last updated by the sponsor on 28 Apr 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A lead-in Phase I Followed by a Phase II Clinical Trial on the Combination of Dabrafenib, Trametinib and the Autophagy Inhibitor Hydroxychloroquine in BRAF/MEK Inhibitor-pretreated Patients With Advanced BRAF V600 Mutant Melanoma
- ClinicalTrials.gov ID
- NCT03754179
- Acronym / sponsor ID
- COMBI-R2 / 2017-BN-004
- Conditions
- Melanoma
- Keywords
- autophagy, dabrafenib, hydroxychloroquine, trametinib, melanoma, rechallenge
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 63 participants (estimated)
- Lead sponsor
- Universitair Ziekenhuis BrusselUniversity, hospital or other
- Collaborators
- University Hospital, Ghent
- Study start
- 23 Jan 2018 (actual)
- Primary completion
- 1 Dec 2021 (estimated)
- Study completion
- 1 Jul 2022 (estimated)
- First posted
- 27 Nov 2018 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Arm A phase 2 | Experimental | Drug: Dabrafenib, Drug: Trametinib, Drug: HydroxychloroquinePatients 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. |
| Arm B phase 2 | Active comparator | Drug: Dabrafenib, Drug: Trametinib, Drug: HydroxychloroquinePatients 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 |
| Phase 1 | Experimental | Drug: Dabrafenib, Drug: Trametinib, Drug: HydroxychloroquinePatients 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. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (12 listed)
- ≥18 years of age.
- Signed written informed consent.
- Histologically confirmed cutaneous melanoma that is either unresectable AJCC (American Joint Committee on Cancer) stage III or stage IV, and previously determined to be BRAF V600 mutation-positive.
- Subjects must have failed at least two prior systemic anti-cancer treatments for AJCC (American Joint Committee on Cancer) unresectable stage III or stage IV melanoma that must have included: a. Treatment with a BRAF inhibitor (including but not limited to dabrafenib, vemurafenib, encorafenib or other experimental BRAF inhibitors) in combination with a MEK inhibitor (including but not limited to trametinib, cobimetinib, binimetinib or other experimental MEK inhibitors) and progression of disease per Response Evaluation Criteria In Solid Tumors (RECIST), version 1.1 must have been documented during this treatment; b. Treatment with anti-CTLA4 (cytotoxic T-lymphocyt antigen 4) antibodies (ipilimumab or other experimental anti-CTLA4 antibodies), anti-PD1 (programmed cell death 1) antibodies (pembrolizumab, nivolumab or other experimental anti-PD1 antibodies), anti-PDL1 (programmed cell death ligand 1) antibodies and progression of disease per RECIST, version 1.1 or per immune related response criteria must have been documented during this treatment.
- The presence of at least one measurable lesion per RECIST, version 1.1.
Key exclusion criteria (17 listed)
- No Belgian medical insurance
- Subjects with uveal or mucosal melanoma.
- Prior treatment with hydroxychloroquine, chloroquine or other quinine derivatives.
- Grade 4 or repetitive grade 3 adverse event(s) related to prior treatment with a BRAF and/or a MEK inhibitor.
- Any contra-indication for evaluation by whole body PET/CT (positron emission tomography/computed tomography) and MRI (magnetic resonance imaging) of the brain.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| DabrafenibAlso: Tafinlar, DABUpfront 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 | Drug | Arm A phase 2, Arm B phase 2, Phase 1 |
| TrametinibAlso: Mekinist, TRAUpfront 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 | Drug | Arm A phase 2, Arm B phase 2, Phase 1 |
| HydroxychloroquineAlso: Plaquenil, HCQUpfront 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 | Drug | Arm A phase 2, Arm B phase 2, Phase 1 |
Primary outcome
Ph. 1: incidence of adverse events of DAB, TRA and HCQ
Time frame: 1 year
Adverse events graded by the Common Terminology Criteria of Adverse Events version 4 (CTCAE v4)
Ph. 2 Arm A: objective response rate (ORR) of DAB, TRA and HCQ
Time frame: 2 years
Objective response rate (ORR; defined as the percentage of subjects with a confirmed complete response [CR] or partial response [PR] at any time per Response Evaluation Criteria in Solid Tumors [RECIST], version 1.1 [Eisenhauer 2009]).
15 secondary outcomes
Ph. 1: objective response rate (ORR) of DAB, TRA and HCQ
Time frame: 1 year
Ph. 1: progression-free survival (PFS) on DAB, TRA and HCQ
Time frame: 1 year
Ph. 1: overall survival (OS) on DAB, TRA and HCQ
Time frame: 1 year
Ph. 1: value of BRAF V600 mutant circulating tumor DNA (ctDNA) as a predictive and/or prognostic marker during treatment DAB, TRA and HCQ
Time frame: 1 year
Ph. 2 Arm B: objective response rate 1 (ORR 1) of DAB and TRA prior to the addition of HCQ at progression of disease
Time frame: 2 years
Ph. 2 Arm B: objective response rate 2 (ORR 2) of DAB and TRA following the addition of HCQ at progression of disease
Time frame: 2 years
Ph. 2 Arm A: progression-free survival (PFS) on DAB, TRA and HCQ
Time frame: 2 years
Ph. 2 Arm A: overall survival (OS) on DAB, TRA and HCQ
Time frame: 2 years
Ph. 2 Arm B: progression-free survival 1 (PFS 1) on DAB and TRA prior to the addition of HCQ
Time frame: 2 years
Ph. 2 Arm B: progression-free survival 2 (PFS 2) on DAB and TRA following the addition of HCQ
Time frame: 2 years
Ph. 2 Arm B: overall survival 1 (OS 1) on DAB and TRA prior to the addition of HCQ
Time frame: 2 years
Ph. 2 Arm B: overall survival 2 (OS 2) on DAB and TRA following the addition of HCQ
Time frame: 2 years
Ph. 2 Arm B: overall survival 3 (OS 3) on DAB and TRA following the addition of HCQ
Time frame: 2 years
Ph. 2 Arm A and B: incidence of adverse events of DAB, TRA and HCQ
Time frame: 2 years
Ph. 2 Arm A and B: value of BRAF V600 mutant circulating tumor DNA (ctDNA) as a predictive and/or prognostic marker during treatment with DAB, TRA and HCQ
Time frame: 2 years
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 28 Apr 2021.
- Individual participant dataSharing planned: Undecided
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Bart Neyns, MD PhD principal investigator
Universitair Ziekenhuis Brussel
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing Dabrafenib, Trametinib and Hydroxychloroquine in people with Melanoma, run by Universitair Ziekenhuis Brussel at 1 site in Belgium.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 12 inclusion and 17 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 28 Apr 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Belgium. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Bart Neyns, MD PhD (+32 2 477 54 47, bart.neyns@uzbrussel.be), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Ph. 1: incidence of adverse events of DAB, TRA and HCQ (time frame: 1 year). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 28 Apr 2021.