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Dabrafenib and Trametinib for BRAF-inhibitor Pretreated Patients

Primary Purpose

Malignant Melanoma

Status
Completed
Phase
Phase 2
Locations
Belgium
Study Type
Interventional
Intervention
Dabrafenib + Trametinib
Sponsored by
Universitair Ziekenhuis Brussel
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Malignant Melanoma focused on measuring BRAF V600, Rechallenge, Combination, Dabrafenib, Trametinib

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • UZ Brussel

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Dabrafenib + trametinib

Arm Description

Single arm study with dabrafenib + trametinib combination therapy

Outcomes

Primary Outcome Measures

Overall response rate

Secondary Outcome Measures

Progression-free survival
Overall Survival
Number of Participants with Adverse Events as a Measure of Safety and Tolerability
Detect adverse events

Full Information

First Posted
October 15, 2014
Last Updated
January 22, 2019
Sponsor
Universitair Ziekenhuis Brussel
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1. Study Identification

Unique Protocol Identification Number
NCT02296996
Brief Title
Dabrafenib and Trametinib for BRAF-inhibitor Pretreated Patients
Official Title
A Phase II Clinical Trial on the Combination of Dabrafenib and Trametinib for BRAF-inhibitor Pretreated Patients With Advanced BRAF V600 Mutant Melanoma
Study Type
Interventional

2. Study Status

Record Verification Date
January 2019
Overall Recruitment Status
Completed
Study Start Date
October 2014 (undefined)
Primary Completion Date
December 2017 (Actual)
Study Completion Date
December 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Universitair Ziekenhuis Brussel

4. Oversight

Data Monitoring Committee
No

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Malignant Melanoma
Keywords
BRAF V600, Rechallenge, Combination, Dabrafenib, Trametinib

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
25 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Dabrafenib + trametinib
Arm Type
Experimental
Arm Description
Single arm study with dabrafenib + trametinib combination therapy
Intervention Type
Drug
Intervention Name(s)
Dabrafenib + Trametinib
Primary Outcome Measure Information:
Title
Overall response rate
Time Frame
Participants will be monitored until progression, with an expected average of 6 months
Secondary Outcome Measure Information:
Title
Progression-free survival
Time Frame
Participants will be monitored until progression, with an expected average of 6 months
Title
Overall Survival
Time Frame
2 years
Title
Number of Participants with Adverse Events as a Measure of Safety and Tolerability
Description
Detect adverse events
Time Frame
Participants will be monitored until progression, with an expected average of 6 months
Other Pre-specified Outcome Measures:
Title
Tumour-specific cfDNA levels
Description
To explore if tumor specific cfDNA levels can be used as a monitoring tool to detect early progression of disease
Time Frame
Participants will be monitored until progression, with an expected average of 6 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: 18 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. 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. An Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2 [Oken, 1982]. Refer to Appendix 1 for details. Adequate baseline organ function as defined in Table 2. Exclusion Criteria: 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); 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. Uncorrectable electrolyte abnormalities (e.g. hypokalaemia, hypomagnesaemia, hypocalcaemia), long QT syndrome or taking medicinal products known to prolong the QT interval. 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 pregnant or nursing. Interstitial lung disease or pneumonitis 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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Neyns Bart, MD, PhD
Organizational Affiliation
Universitair Ziekenhuis Brussel
Official's Role
Principal Investigator
Facility Information:
Facility Name
UZ Brussel
City
Brussels
ZIP/Postal Code
1090
Country
Belgium

12. IPD Sharing Statement

Citations:
PubMed Identifier
28268064
Citation
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.
Results Reference
derived

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Dabrafenib and Trametinib for BRAF-inhibitor Pretreated Patients

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