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|NCT01619774 : An Open-Label Phase II Study of the Combination of GSK2118436 and GSK1120212 in Patients With Metastatic Melanoma Which is Refractory or Resistant to BRAF Inhibitor|
|Ages||Min: 16 Years Max: N/A|
1. Capable of giving written informed consent, which includes compliance with the
requirements and restrictions listed in the consent form.
2. Patients must have histologically or cytologically confirmed Stage IV or recurrent or
unresectable Stage III melanoma.
3. BRAF mutation-positive melanoma (i.e., V600E, V600K or V600D)
4. For Cohort A, patients must have easily accessible tumor for a mandatory biopsy. This
is not required for patients enrolled on Cohort B.
5. Patients must have measurable disease, defined by RECIST 1.1
6. Patients must have tumor lesions which is refractory or resistant to a selective BRAF
inhibitor (RO5185426 or GSK2118436).
7. Age >/= 16 years.
8. ECOG performance status 0-1
9. Patients must have organ and marrow function as defined below: · absolute neutrophil
count >/= 1,500/mcL · platelets >/= 75,000/mcL · total bilirubin = 1.5 ×
institutional upper limit of normal: no restriction to serum bilirubin level if
Gilbert's syndrome is diagnosed or suspected · AST(SGOT)/ALT(SGPT) = 2.5 ×
institutional upper limit of normal, (= 3x upper limit of normal for AST and ALT
for those subjects with liver metastasis) · creatinine = 1.3 × institutional upper
limit of normal OR · creatinine clearance >/= 60 mL/min/1.73 m2 for patients with
creatinine levels above 1.3 X institutional upper limit of normal.
10. Ability to understand and the willingness to sign a written informed consent
11. For Cohort B, patients must have at least 1 measureable parenchymal brain metastasis
of at least 10 mm in the greatest diameter and no greater than 40 mm diameter. There
must be at least one parenchymal brain metastasis that has not received any previous
locally-directed treatment (i.e. surgery or radiation), or that has progressed after
prior treatment for the brain metastases (i.e. surgery or radiation).
12. Male subjects must agree to use contraception, this criterion must be followed from
the time of the first dose of study medication until 4 weeks after the last dose of
study medication. However, it is advised that contraception be used for a total of 16
weeks following the last dose (based on the lifecycle of sperm).
13. A female subject is eligible to participate if she is of: Non-childbearing potential
defined as pre-menopausal females with a documented tubal ligation or hysterectomy;
or postmenopausal defined as 12 months of spontaneous amenorrhea [in questionable
cases a blood sample with simultaneous follicle stimulating hormone (FSH) > 40 MlU/mL
and estradiol < 40 pg/mL (<140 pmol/L) is confirmatory]. Females on hormone
replacement therapy (HRT) and whose menopausal status is in doubt will be required to
use contraception if they wish to continue their HRT during the study. Following
confirmation of their post-menopausal status, they can resume use of HRT during the
study without use of a contraceptive method.
14. (cont' from Inclusion #12) • Child-bearing potential and agrees to use one of the
contraception methods listed in Section 7.1.1 for an appropriate period of time (as
determined by the product label or investigator) prior to the start of dosing to
sufficiently minimize the risk of pregnancy at that point. Female subjects must agree
to use contraception until 4 weeks after the last dose of study medication, and must
have a negative serum pregnancy test within 14 days prior to the start of dosing.
Note: Oral contraceptives are not reliable due to potential drug-drug interaction.
1. Currently receiving cancer therapy (chemotherapy, radiation therapy, immunotherapy,
or biologic therapy) except a selective RAF inhibitor.
2. Patients must not have previously received a selective BRAF inhibitor (RO5185426,
GSK2118436) and a selective MEK inhibitor (AZD6244, GSK1120212) concurrently.
3. Received an investigational anti-cancer drug within four weeks or five half-lives
(whichever is shorter) of study drug administration, other than BRAF inhibitor--at
least 14 days must have passed between the last dose of the prior investigational
anti-cancer drug and the first dose of study drug. However, there is no required
washout period for any BRAF inhibitors at least until the baseline biopsy is
4. Current use of a prohibited medication or requires any of these medications during
treatment with study drug.
5. Any major surgery, within the last 3 weeks. Radiotherapy, or immunotherapy within the
last 2 weeks.
6. Unresolved toxicity greater than NCI-CTCAE v4 Grade 1 from previous anti-cancer
therapy except alopecia and peripheral neuropathy, for which = grade 2 toxicity is
allowed to participate.
7. Presence of rheumatoid arthritis.
8. History of retinal vein occlusion or central serous retinopathy, or predisposing
factors to retinal vein occlusion or central serous retinopathy (e.g. uncontrolled
glaucoma or ocular hypertension, uncontrolled systemic disease such as hypertension,
diabetes mellitus, or history of hyperviscosity or hypercoagulability syndromes).
9. Presence of active gastrointestinal disease or other condition that will interfere
significantly with the absorption, distribution, metabolism, or excretion of drugs.
10. Brain Metastases a. For cohort A, patients will be excluded if they have brain
metastases, unless they have been previously treated brain metastases with surgery or
stereotactic radiosurgery and the disease has been confirmed stable (i.e., no
increase in lesion size) for at least 4 weeks with MRI scans using contrast prior to
Day 1. Subjects are not permitted to receive enzyme-inducing anti-epileptic drugs
and/or steroids to control symptoms/signs of brain metastases. Patients previously
treated with whole brain radiation therapy must have confirmed stable disease for at
least 12 weeks prior to starting treatment. However, untreated asymptomatic brain
metastasis less than 10 mm will be allowed if no steroid and anti-epileptic drugs are
11. 10 (con't) b. For cohort B, patients may not have any evidence of leptomeningeal
disease. Use of corticosteroids is permitted as long as the dose of steroids required
for symptom control has been stable or decreasing for at least 3 weeks prior to the
first dose of study treatment.
12. History of acute coronary syndromes (including myocardial infarction and unstable
angina), coronary angioplasty, or stenting within the past 6 months.
13. QTc interval >/= 480 msec (>/= 500 msec for subjects with Bundle Branch Block).
14. Uncontrolled arrhythmias. • Subjects with controlled atrial fibrillation for >1 month
prior to study Day 1 are eligible.
15. Class II, III, or IV heart failure as defined by the New York Heart Association
(NYHA) functional classification system.
16. Abnormal cardiac valve morphology (subjects with minimal abnormalities can be entered
on study if deemed not clinically significant)
17. Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs
chemically related to the study drugs, or excipients. NOTE: To date there are no
known FDA approved drugs chemically related to GSK2118436 or GSK1120212.
18. Pregnant or lactating female.
19. Unwillingness or inability to follow the procedures required in the protocol.
20. Uncontrolled diabetes, hypertension or other medical conditions that may interfere
with assessment of toxicity
21. Subjects with known glucose 6 phosphate dehydrogenase (G6PD) deficiency.
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