Dabrafenib and Trametinib for BRAF-inhibitor Pretreated Patients

A Phase II Clinical Trial on the Combination of Dabrafenib and Trametinib for BRAF-inhibitor Pretreated Patients With Advanced BRAF V600 Mutant Melanoma

Patients with BRAF V600 mutant advanced melanoma benefit from treatment with a BRAF-inhibitor (e.g. dabrafenib, vemurafenib) and from combination of a BRAF- and MEK-inhibitor (e.g. dabrafenib and trametinib). Following initial tumor regression, progression is diagnosed in a majority of patients treated with BRAF-inhibitor mono-therapy within the first 12-months of therapy. Various molecular mechanisms that underlie the development of resistance to treatment with a BRAF-inhibitor have been reported. These mechanisms do not include secondary mutations in the BRAF-gene and therefore resistance to BRAF-inhibition could potentially be reversible when selective pressure by BRAF-inhibition is withheld for a sufficient period of time of melanoma progression. This clinical trial protocol addresses the potential renewed anti-tumor activity of combined BRAF- and MEK inhibition with the combination of dabrafenib and trametinib in patients with unresectable AJCC stage III or - IV BRAF V600 mutant melanoma who are documented with progression of disease at least 12 weeks following the last day of dosing of a BRAFinhibitor containing treatment regimen.

Study Overview

• Status: Completed
• Conditions: Malignant Melanoma
• Intervention / Treatment: Drug: Dabrafenib + Trametinib

• Study Type: Interventional
• Enrollment (Actual): 25
• Phase: Phase 2

Contacts and Locations

Study Locations

• Belgium
  • Brussels, Belgium, 1090
    • UZ Brussel

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. 18 years of age and signed written informed consent.
2. Histologically confirmed cutaneous melanoma that is either Stage IIIC (unresectable) or Stage IV (metastatic), and determined to be BRAF V600E/K mutation-positive.

3. Subjects must have failed at least two prior systemic anti-cancer treatments for Stage IIIC (unresectable) or Stage IV (metastatic) melanoma that must have included:

   • Treatment with a BRAF inhibitor (including but not limited to dabrafenib, vemurafenib, and LGX818) and progression of disease per RECIST, version 1.1 [Eisenhauer, 2009] must have been documented during this treatment.
   • Treatment with ipilimumab (or an alternative experimental immunotherapy) and progression of disease per immune related response criteria [Wolchock Clin Cancer Res December 1, 2009 15; 7412] must have been documented during this treatment.
4. Documented progression of disease per RECIST, version 1.1 [Eisenhauer, 2009]) or per immune related response criteria [Wolchock Clin Cancer Res December 1, 2009 15; 7412] if the latest systemic therapy administered was ipilimumab, an anti-PD1 or anti-PD-L1 therapy, or any other experimental immunotherapy.
5. The presence of at least one measurable lesion per RECIST, version 1.1 [Eisenhauer, 2009]).

6. Interval between the date of the last administration of prior therapy for melanoma and the date of recruitment:

   • > 12 weeks following the date of the last administration of a BRAF-inhibitor;
   • > 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;
   • > 4 weeks following the date of the last administration of chemotherapy (> 6 weeks in case of a nitrosurea or mitomycin C containing regimen);
   • > 4 weeks following major surgery or extensive radiotherapy.
7. Subjects with ocular melanoma are not eligible.
8. All prior anti-cancer treatment-related toxicities (except alopecia and laboratory values as listed on Table 2) 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.
9. 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.
10. Women of childbearing potential must have a negative serum pregnancy test within 7 days prior to recruitment and agree to use effective contraception, as defined in Section 7.3.3.1, throughout the treatment period, and for 4 months after the last dose of study treatment.
11. An Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2 [Oken, 1982]. Refer to Appendix 1 for details.
12. Adequate baseline organ function as defined in Table 2.

Exclusion Criteria:

1. Grade 4 or repetitive grade 3 adverse event(s) related to prior treatment with a BRAF- and/or MEK inhibitor.
2. Any contra-indication for evaluation by whole body CT and MRI of the brain.
3. Taken an investigational drug within 28 days or 5 half-lives (minimum 14 days), whichever is shorter, prior to recruitment.
4. Current use of a prohibited medication as described in Section 6 or requires any of these medications during treatment.
5. History of another malignancy, including any malignancy with confirmed activating RAS mutation. Note: Prospective RAS testing is not required. However, if the results of previous RAS testing are known, they must be used in assessing eligibility. Exception: 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) not including malignancy with confirmed activating RAS mutation, or subjects with a history of completely resected non-melanoma skin cancer.
6. 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.
7. 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).
8. Patients with progressive symptoms from active brain metastasis or in need of an increase in corticosteroids dose to control symptoms within 4 weeks prior to recruitment are excluded
9. No enzyme inducing anticonvulsants for ≥ 4 weeks prior to recruitment

10. A history or evidence of cardiovascular risk including any of the following:

    • Current LVEF < LLN
    • A QT interval corrected for heart rate using the Bazett's formula (QTcB; Section 5.6.3.3) ≥480 msec;
    • A history or evidence of current clinically significant uncontrolled arrhythmias; Exception: Subjects with atrial fibrillation controlled for > 30 days prior to recruitment are eligible.
    • A history (within 6 months prior to recruitment) of acute coronary syndromes (including myocardial infarction or unstable angina), coronary angioplasty or stenting;
    • A history or evidence of current ≥Class II congestive heart failure as defined by the New York Heart Association (NYHA) guidelines (Appendix 4);
    • 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;
    • Patients with intra-cardiac defibrillators;
    • 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.
11. Uncorrectable electrolyte abnormalities (e.g. hypokalaemia, hypomagnesaemia, hypocalcaemia), long QT syndrome or taking medicinal products known to prolong the QT interval.
12. Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to the study treatments, their excipients, and/or dimethyl sulfoxide (DMSO).
13. Females who are pregnant or nursing.
14. Interstitial lung disease or pneumonitis
15. Patients with a prior history of central serous retinopathy or retinal vein occlusion are excluded. Patients with a preexisting major ocular pathology are not eligible.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dabrafenib + trametinib; Single arm study with dabrafenib + trametinib combination therapy	Drug: Dabrafenib + Trametinib

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Overall response rate	Participants will be monitored until progression, with an expected average of 6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival		2 years
Progression-free survival		Participants will be monitored until progression, with an expected average of 6 months
Number of Participants with Adverse Events as a Measure of Safety and Tolerability	Detect adverse events	Participants will be monitored until progression, with an expected average of 6 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Tumour-specific cfDNA levels	To explore if tumor specific cfDNA levels can be used as a monitoring tool to detect early progression of disease	Participants will be monitored until progression, with an expected average of 6 months

Collaborators and Investigators

• Sponsor: Universitair Ziekenhuis Brussel
• Investigators: Principal Investigator: Neyns Bart, MD, PhD, Universitair Ziekenhuis Brussel

Publications and helpful links

General Publications

• Schreuer M, Jansen Y, Planken S, Chevolet I, Seremet T, Kruse V, Neyns B. Combination of dabrafenib plus trametinib for BRAF and MEK inhibitor pretreated patients with advanced BRAFV600-mutant melanoma: an open-label, single arm, dual-centre, phase 2 clinical trial. Lancet Oncol. 2017 Apr;18(4):464-472. doi: 10.1016/S1470-2045(17)30171-7. Epub 2017 Mar 4.

Study record dates

Study Major Dates

• Study Start: October 1, 2014
• Primary Completion (Actual): December 1, 2017
• Study Completion (Actual): December 1, 2017

Study Registration Dates

• First Submitted: October 15, 2014
• First Submitted That Met QC Criteria: November 18, 2014
• First Posted (Estimate): November 21, 2014

Study Record Updates

• Last Update Posted (Actual): January 23, 2019
• Last Update Submitted That Met QC Criteria: January 22, 2019
• Last Verified: January 1, 2019

More Information

Terms related to this study

• Keywords: Trametinib; BRAF V600; Combination; Dabrafenib; Rechallenge
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroendocrine Tumors; Nevi and Melanomas; Melanoma; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Trametinib; Dabrafenib
• Other Study ID Numbers: UZB-BN- 2013-001