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

NCT03754179 | Unknown Phase 1

• 1 other identifier: 2017-BN-004
• Study Type: interventional
• Target: 63
• Locations: 1 country
• Sites: 1

Brief 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 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.

Conditions

Melanoma

Keywords

autophagy; dabrafenib; hydroxychloroquine; trametinib; melanoma; rechallenge

Outcome Measures

Primary Outcomes (2)

• 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)

  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 \[Eisenhauer 2009\]).

  2 years

Secondary Outcomes (15)

• Ph. 1: objective response rate (ORR) of DAB, TRA and HCQ

  1 year

• Ph. 1: progression-free survival (PFS) on DAB, TRA and HCQ

  1 year

• Ph. 1: overall survival (OS) on DAB, TRA and HCQ

  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

  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

  2 years

Study Arms (3)

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.

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

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.

Drug: Dabrafenib; Drug: Trametinib; Drug: Hydroxychloroquine

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

Also known as: Tafinlar, DAB

Arm A phase 2; Arm B phase 2; Phase 1

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

Also known as: Mekinist, TRA

Arm A phase 2; Arm B phase 2; Phase 1

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

Also known as: Plaquenil, HCQ

Arm A phase 2; Arm B phase 2; Phase 1

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• ≥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.
• 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

You may not qualify if:

• 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.
• 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.

Sponsors & Collaborators

• Universitair Ziekenhuis Brussel: lead
• University Hospital, Ghent: collaborator

Study Sites (1)

UZ Brussel

Jette, Brabant, 1090, Belgium

RECRUITING

MeSH Terms

Conditions

Melanoma

Interventions

dabrafenib; trametinib; Hydroxychloroquine

Condition Hierarchy (Ancestors)

Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Neoplasms by Site; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Chloroquine; Aminoquinolines; Quinolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• Bart Neyns, MD PhD

  Universitair Ziekenhuis Brussel

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Bart Neyns, MD PhD

CONTACT

+32 2 477 54 47; bart.neyns@uzbrussel.be

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 16, 2018
• First Posted: November 27, 2018
• Study Start: January 23, 2018
• Primary Completion: December 1, 2021
• Study Completion: July 1, 2022
• Last Updated: April 28, 2021

Record last verified: 2021-04

Locations

BE (1)