A study of dabrafenib with trametinib in patients with melanoma

Phase 1

• Conditions: patients with metastatic and unresectable stage III or IV melanoma harbouring an activating BRAF mutation; MedDRA version: 18.0Level: HLTClassification code 10027156Term: Skin melanomas (excl ocular)System Organ Class: 100000004864; Therapeutic area: Diseases [C] - Cancer [C04]

• Registration Number: EUCTR2012-004577-12-ES
• Lead Sponsor: GlaxoSmithKline, S.A.

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Study Start: 2015-02-16
• Last Update Posted: 6 February 2017

Recruitment & Eligibility

• Status: ot Recruiting
• Sex: All
• Target Recruitment: 54

Inclusion Criteria

Patients eligible for enrolment in the study must meet all of the following criteria:
1.Signed written informed consent;
2. >=18 years of age;
3.Histologically confirmed cutaneous melanoma that is either Stage IIIc (unresectable) or Stage IV (metastatic) (according to American Joint Committee on Cancer (AJCC) staging 7th edition).
4.BRAF V600E/K mutation-positive confirmed by a local laboratory.
5.Accessible melanoma tumours for biopsies (locally advanced primary melanoma or metastases)
6.Measurable disease according to Response Evaluation Criteria in Solid Tumours (RECIST 1.1) (Eisenhauer et al. 2009) on not biopsied lesions. Refer to protocol section 7.3.3.1 for the definition of a measureable lesion.
7.All prior anti-cancer treatment-related toxicities (except alopecia) must be less than or equal to Grade 1 according to the Common Terminology Criteria for Adverse Events version 4 (CTCAE version 4.0) at the time of randomisation.
8.Able to swallow and retain orally administered medication and does not have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels.
9.Women of childbearing potential must have a negative serum pregnancy test within 14 days prior to randomisation and agree to use effective contraception, as defined in Section 7.4.3.1, throughout the treatment period, and for 4 months after the last dose of study treatment.
10.Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 or 1. Refer to Appendix 1 for details.
11.Adequate baseline organ function as defined in Table 2 (Refer to protocl page 22).
12.In France, a patient will be eligible for inclusion in this study only if either affiliated to, or a beneficiary of, a social security category.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 44
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 10

Exclusion Criteria

Patients meeting any of the following criteria must not be enrolled in the study:
1.Prior treatment with a BRAF or MEK inhibitor
2.Any major surgery, extensive radiotherapy, chemotherapy with delayed toxicity, biologic therapy, or immunotherapy within 21 days prior to randomisation and/or daily or weekly chemotherapy without the potential for delayed toxicity within 14 days prior to randomisation.
3.Taken an investigational drug within 28 days or 5 half-lives (minimum 14 days), whichever is shorter, prior to randomisation
4.Current use of a prohibited medication as described in Section 6.2.
5.Refusal of tumour and skin biopsies.
6.History of another malignancy.
Exception: Patients, who have been disease-free for 3 years, or patients with a history of completely resected non-melanoma skin cancer, and/or patients with indolent second malignancies are eligible.
7.Any serious and/or unstable pre-existing medical conditions (aside from malignancy exceptions specified above), psychiatric disorders, or other conditions that could interfere with the patient?s safety, obtaining informed consent, or compliance with study procedures.
8.Known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), or Hepatitis C Virus (HCV) infection (with the exception of chronic or cleared HBV and HCV infection which will be allowed).
9.A history of glucose-6-phosphate dehydrogenase (G6PD) deficiency.
10.Brain metastases are excluded unless:
a.All known lesions were previously treated with surgery or stereotactic surgery (whole-brain radiation is not allowed unless given after definitive treatment with surgery or stereotactic surgery), OR
b.Brain lesion(s), if still present, must be confirmed stable (i.e., no increase in lesion size) for ? 12 weeks prior to randomisation (stability must be confirmed with two consecutive magnetic resonance image (MRI) or computed tomography (CT) scans with contrast, AND
c.Asymptomatic with no corticosteroid requirements for ? 4 weeks prior to randomisation, AND
d.No enzyme inducing anticonvulsants for ? 4 weeks prior to randomisation
In addition, for patients that had brain metastases but currently have no evidence of disease (NED), NED for ?12 weeks is required and must be confirmed by two consecutive scans, separated by ?6 weeks, prior to randomisation.
11.A history or evidence of cardiovascular risk including any of the following:
a.LVEF < LLN
b.A QT interval corrected for heart rate using the Bazett?s formula (QTcB; Appendix 3) ?480 msec;
c.A history or evidence of current clinically significant uncontrolled arrhythmias;
Exception: Patients with atrial fibrillation controlled for > 30 days prior to randomisation are eligible.
d.A history (within 6 months prior to randomisation) of acute coronary syndromes (including myocardial infarction or unstable angina), 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);
f.Treatment refractory hypertension defined as a blood pressure of systolic> 140 mmHg and/or diastolic > 90 mm Hg which cannot be controlled by anti-hypertensive therapy;
g.Patients with intra-cardiac defibrillators or permanent pacemakers;
h.Known cardiac metastases;
i.Abnormal cardiac valve morphology (?grade 2) documented by echocardiogram (patients with grade 1 abnormalities [i.e., mild regurgitation/stenosis] can be entered on study). Patients with moderate valvular thickening should not be e

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: To evaluate biomarkers linked to treatment response, resistance and toxicity including skin toxicity when dabrafenib and trametinib combination is given upfront or as monotherapy before the combination treatment.;Secondary Objective: - To evaluate the clinical response (ORR)<br>- To characterise the safety profile of dabrafenib and trametinib in monotherapy and/or in combination including incidences of squamous cell carcinoma (SCC) and other proliferative cutaneous lesions as well as the papulo-pustular rash.<br>- To evaluate dabrafenib, trametinib and combination exposures in connection to clinical response and toxicity.;Primary end point(s): Percentage Change of Erk phosphorylation score from baseline;Timepoint(s) of evaluation of this end point: Screening, weeks 2, 8, 10 and at disease progression.

Secondary Outcome Measures

Name	Time	Method
Secondary end point(s): - Overall response rate (ORR; defined as the percentage of patients with a confirmed complete response [CR] or partial response [PR] at any time per Response Evaluation Criteria in Solid Tumours [RECIST], version 1.1.<br>- Safety as measured by clinical assessments including vital signs and physical examinations, ECOG performance status, 12-lead electrocardiograms (ECG), echocardiogram (ECHO), chemistry and haematology laboratory values, incidence of squamous cell carcinoma and keratoacanthoma (KA), and adverse events (AEs) graded according to the Common Terminology Criteria for Adverse Events (CTC-AE), version 4.0<br>- Plasma PK/PD evaluation;Timepoint(s) of evaluation of this end point: - ORR: Week 8 and every 8 weeks thereafter through week 56 and then every 12 weeks thereafter until determination of progressive disease<br>- Safety: every 4 until disease progression.<br>- PK/PD: at weeks 2, 8 , 10 and disease progression.