Dabrafenib and Trametinib for BRAF-inhibitor Pretreated Patients

NCT02296996 | Completed Phase 2

• 1 other identifier: UZB-BN- 2013-001
• Study Type: interventional
• Target: 25
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Malignant Melanoma

Keywords

BRAF V600; Rechallenge; Combination; Dabrafenib; Trametinib

Outcome Measures

Primary Outcomes (1)

• Overall response rate

  Participants will be monitored until progression, with an expected average of 6 months

Secondary Outcomes (3)

• Progression-free survival

  Participants will be monitored until progression, with an expected average of 6 months

• Overall Survival

  2 years

• Number of Participants with Adverse Events as a Measure of Safety and Tolerability

  Participants will be monitored until progression, with an expected average of 6 months

Other Outcomes (1)

• Tumour-specific cfDNA levels

  Participants will be monitored until progression, with an expected average of 6 months

Study Arms (1)

Dabrafenib + trametinib

EXPERIMENTAL

Single arm study with dabrafenib + trametinib combination therapy

Drug: Dabrafenib + Trametinib

Interventions

Dabrafenib + Trametinib DRUG

Dabrafenib + trametinib

Eligibility Criteria

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

You may qualify if:

• years of age and signed written informed consent.
• Histologically confirmed cutaneous melanoma that is either Stage IIIC (unresectable) or Stage IV (metastatic), and determined to be BRAF V600E/K mutation-positive.
• 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.
• 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.
• The presence of at least one measurable lesion per RECIST, version 1.1 \[Eisenhauer, 2009\]).
• 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.
• Subjects with ocular melanoma are not eligible.
• 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.
• 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.

You may not qualify if:

• Grade 4 or repetitive grade 3 adverse event(s) related to prior treatment with a BRAF- and/or MEK inhibitor.
• Any contra-indication for evaluation by whole body CT and MRI 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 as described in Section 6 or requires any of these medications during treatment.
• 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.
• 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).
• 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
• No enzyme inducing anticonvulsants for ≥ 4 weeks prior to recruitment
• 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);

Sponsors & Collaborators

• Universitair Ziekenhuis Brussel: lead

Study Sites (1)

UZ Brussel

Brussels, 1090, Belgium

Location

Related Publications (1)

• 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.

  PMID: 28268064 DERIVED

MeSH Terms

Conditions

Melanoma

Interventions

dabrafenib; trametinib

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

Study Officials

• Neyns Bart, MD, PhD

  Universitair Ziekenhuis Brussel

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Bart Neyns, MD PhD

Study Record Dates

• First Submitted: October 15, 2014
• First Posted: November 21, 2014
• Study Start: October 1, 2014
• Primary Completion: December 1, 2017
• Study Completion: December 1, 2017
• Last Updated: January 23, 2019

Record last verified: 2019-01

Locations

BE (1)