Study for the Evaluation Dabrafenib (Tafinlar) and Trametinib (Mekinist) Plus DNE3 in Patients With Metastatic Melanoma

• Register: ClinicalTrials.gov
• Last refreshed on: 11 May 2015
• Main ID: NCT02087254
• Date of registration: 10/03/2014
• Prospective Registration: No
• Primary sponsor: Cancer Centre of Monoclonal Therapy, LLC
• Public title: Study for the Evaluation Dabrafenib (Tafinlar) and Trametinib (Mekinist) Plus DNE3 in Patients With Metastatic Melanoma
• Scientific title: XTPTC-293-54-for the First Time in Human Studies to Establish the Recommended Dose and Schedule of Oral Dabrafenib, Trametinib and DNE3
• Date of first enrolment: September 2013
• Target sample size: 78
• Recruitment status: Terminated
• URL: http://clinicaltrials.gov/show/NCT02087254
• Study type: Interventional
• Study design: Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
• Phase: Phase 1/Phase 2

Countries of recruitment

Belarus, Germany, Russian Federation, Ukraine

Key inclusion & exclusion criteria

Inclusion Criteria:

- Signed written informed consent

- Recheck the results of histological studies and paraffin blocks

- Histologically confirmed cutaneous melanoma that is either Stage IIIc (unresectable)
or Stage IV (metastatic), and determined to be BRAF V600E or V600K mutation-positive
by the local laboratory.

- Measurable tumor by physical or radiographic examination

- Subjects must not have had more than 1 previous treatment regimen with chemotherapy,
interferon, or IL-2 for metastatic melanoma

- All prior anti-cancer treatment-related toxicities (except alopecia) must be <= Grade
1 according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0
at the time of enrollment

- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

- Adequate baseline organ function as defined by: absolute neutrophil count (ANC) >=
1.2 × 109/L; Hemoglobin >= 9 g/dL; Platelet count >= 100 x 109/L; prothrombin time
(PT) / international normalized ratio (INR) and partial thromboplastin time (PTT) <=
1.5 x upper limit of normal (ULN); Albumin >= 2.5 g/dL; Total bilirubin <= 1.5 x ULN;
aspartate aminotransferase (AST) and alanine transaminase (ALT) <= 2.0 x ULN;
Creatinine <=1.5 mg/mL; Left Ventricular Ejection fraction (LVEF) >= lower limit of
normal (LLN) by ECHO

- Women of childbearing potential must have a negative serum pregnancy test within 7
days prior to randomization and agree to use effective contraception, during the
study, and for 30 days 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 for at least 2 weeks prior to the
first dose of study treatment until 16 weeks after the last dose of study treatment
to allow for clearance of any altered sperm

- Able to swallow and retain orally administered study treatment 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

Exclusion Criteria:

- Prior treatment with a BRAF inhibitor (including but not limited to dabrafenib,
vemurafenib, and XL281/BMS-908662) or a MEK inhibitor (including but not limited to
trametinib, AZD6244, and RDEA119) or ipilimumab or any other agent targeting a T-cell
immunomodulatory pathway (including, but not limited to CTLA-4, PD-1, 4-1BB, OX40,
GITR, CD27, and CD28)

- Any major surgery, extensive radiotherapy, chemotherapy with delayed toxicity,
biologic therapy, or immunotherapy within 21 days prior to randomization and/or daily
or weekly chemotherapy without the potential for delayed toxicity within 14 days
prior to randomization

- 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)

- A history of glucose-6-phosphate dehydrogenase (G6PD) deficiency

- 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)

- Brain lesion(s), if still present, must be confirmed stable (i.e., no increase in
lesion size) for >= 6 weeks prior to randomization (stability must be confirmed with
two consecutive magnetic resonance image (MRI) or computed tomography (CT) scans with
contrast,

- Asymptomatic with no corticosteroid requirements for >= 4 weeks prior to
randomization,

- No enzyme inducing anticonvulsants for >= 4 weeks prior to randomization

- A history or evidence of cardiovascular risk including any of the following LVEF <
LLN for the institution

- A corrected QT interval >=480 msec (e.g. Bazett's formula [QTcB])

- A history or evidence of current clinically significant uncontrolled arrhythmias
(exception: subjects with controlled atrial fibrillation for > 30 days prior to
randomization are eligible)

- A history (within 6 months prior to first dose of study treatment) of acute coronary
syndromes (including myocardial infarction or unstable angina), coronary angioplasty

- A history or evidence of current >=Class II congestive heart failure as defined by
the New York Heart Association (NYHA)

- Treatment refractory hypertension defined as systolic blood pressure >140 millimetres
of mercury (mmHg) and/or diastolic blood pressure >90 mmHg 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

- A history or current evidence/risk of retinal vein occlusion (RVO) or Central serous
retinopathy (CSR) including

- 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), or

- Visible retinal pathology as assessed by ophthalmic examination that is considered a
risk factor for RVO or CSR such as evidence of new optic disc cupping; Evidence of
new visual field defects on automated perimetry; Intraocular pressure >21 mmHg as
measured by tonography

- History of any of the following diseases: inflammatory bowel disease or any other
autoimmune bowel disease; systemic lupus erythematosus; rheumatoid arthritis; or any
autoimmune ocular diseases. Patients with active autoimmune disease or a history of
autoimmune disease other than those mentioned above must be approved by the GSK
medical monitor

- Active pneumonitis or interstitial lung disease

- Lactating female

- History of another malignancy (Exception: Subjects who have been disease-free for 3
years, or subjects with a history of completely resected non-melanoma skin cancer or
successfully treated in situ carcinoma are eligible)

- Any serious and/or unstable pre-existing medical, psychiatric disorder or other
conditions that could interfere with subject's safety, obtaining informed consent or
compliance to the study procedures

- Any prohibited medication

- Administration of an investigational study tr


Age minimum: 18 Years
Age maximum: 80 Years
Gender: Both

Health Condition(s) or Problem(s) studied

Metastatic Melanoma

Melanoma

Intervention(s)

Drug: Trametinib

Drug: Dabrafenib

Biological: DNE3

Primary Outcome(s)

To assess the safety of DNE3 in combination with Dabrafenib and Trametinib and select the optimal dose of DNE3 for the phase II portion in patients with metastasis melanoma (Phase I) [Time Frame: 2 months]

Secondary Outcome(s)

Overall survival (Phase II) [Time Frame: From date of registration to date of death due to any cause, assessed up to 3 years]

Secondary ID(s)

PTC-293-54

XTPTC-293-54

Source(s) of Monetary Support

Please refer to primary and secondary sponsors

Secondary Sponsor(s)

Melanoma Research Foundation

National Cancer Institute (NCI)