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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


Phase 2
16 Years
N/A
Open (Enrolling)
Both
Melanoma

Thank you

Trial Information

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


Study Drug Administration:

If you are found to be eligible to take part in this study, you will take both GSK2118436
and GSK1120212 together.

You will take 2 capsules of GSK1120212 by mouth once a day. You will take 2 capsules of
GSK2118436 by mouth 2 times every day (1 time in the morning and 1 time in the evening,
about 12 hours apart - a total of 4 capsules a day). If you experience severe side effects,
your doctor or the research team may lower the dose of the drug(s).

You should take the study drugs with about 1 cup (8 ounces) of room-temperature water. You
should not eat or drink anything besides water for at least 1 hour before and 2 hours after
you take the study drugs.

You will be given a study drug diary to record the times and doses that you take the study
drugs. You should bring the diary to each study visit.

Study Visits:

On Day 1 of Cycle 1:

- Your medical history will be recorded, including any symptoms you may be having. (if it
was not recorded in the previous 7 days)

- Your weight, vital signs, and performance status will be recorded.

- You will have a physical exam (if one was not performed in the previous 7 days).

- Blood (about 2 teaspoons) will be collected for routine tests (if this was not
performed in the previous 7 days).

- You will be asked about any drugs you may be taking, how you are feeling, and if you
have had any side effects.

- You will have a blood draw this visit for research purposes.

On Days 8 of Cycle 1:

- Your weight, vital signs, and performance status will be recorded.

- Blood (about 4 tablespoons) will be drawn for biomarker testing.

- You will be asked about any drugs or herbal supplements that you may be taking.

- You will be asked about any drugs you may be taking, how you are feeling, and if you
have had any side effects.

On Day 15 of Cycle 1:

- You will have a physical exam.

- Your weight, vital signs, and performance status will be recorded.

- You will have an ECG.

- Blood (about 2 teaspoons) will be collected for routine tests.

- Blood (about 4 tablespoons) will be drawn for biomarker testing.

- You will be asked about any drugs you may be taking, how you are feeling, and if you
have had any side effects.

On Day 1 of Cycles 2 and beyond:

- You will have a physical exam.

- Your weight, vital signs, and performance status will be recorded.

- Blood (about 2 teaspoons) will be collected for routine tests.

- You will be asked about any drugs you may be taking, how you are feeling, and if you
have had any side effects

- Blood (about 4 tablespoons) will be drawn for biomarker testing on day 1 of Cycle 2 and
4. If your disease worsens, blood (about 4 tablespoons) will also be drawn at that
time.

Every 8 weeks (2 cycles) from the time of the start of the treatment, you will have an
x-ray, a CT scan, an MRI scan, a skin exam, and/or a bone scan to check the status of the
disease.

Every 12 weeks, you will have an ECHO performed.

If at any point during the study you have any symptoms or signs of a serious skin, eye, or
heart side effect, you may be referred to a dermatologist or an ophthalmologist, or you may
have an ECG and ECHO to check your heart's health.

Length of Study:

You may continue taking the study drugs for as long as the study doctor thinks it is in your
best interest. You will no longer be able to take the study drugs if the disease gets
worse, you start having other health problems, or intolerable side effects occur.

Your participation on the study will be over once you have completed the end-of-study visit.

End-of-Study Visit:

You will have an end-of-study visit within 4 weeks after your last dose of study drugs. The
following tests and procedures will be performed:

- You will have a physical exam.

- Your weight, vital signs, and performance status will be recorded.

- You will have an ECG.

- Blood (about 2 teaspoons) will be collected for routine tests.

- You will have an x-ray, computed tomography (CT) scan, magnetic resonance imaging (MRI)
scan, and/or bone scan to check the status of the disease if you are taken off the
study for any other reason than the disease getting worse.

- Blood (about 4 tablespoons) will be drawn for biomarker testing.

- You will have the same kind of mandatory biopsy that you did at screening. You may be
allowed to continue receiving the study drugs until the time of this biopsy (up to 2
days) even if the disease is not showing a response to the study drugs. Your doctor
and/or the study team will discuss this with you.

This is an investigational study. Neither GSK2118436 nor GSK1120212 are FDA approved or
commercially available. They are currently being used for research purposes only.

Up to 30 patients will take part in this study. All will be enrolled at MD Anderson.


Inclusion Criteria:



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. Patients must have easily accessible tumor for biopsy.

5. Patients must have measurable disease, defined by Response Evaluation Criteria In
Solid Tumors (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. The Eastern Cooperative Oncology Group (ECOG) performance status 0-2

9. Patients must have organ and marrow function as defined below: · absolute neutrophil
count >/= 1,500/mcL · platelets >/= 75,000/mcL · total bilirubin institutional upper limit of normal: no restriction to serum bilirubin level if
Gilbert's syndrome is diagnosed or suspected · aspartate aminotransferase (AST or
SGOT) and alanine aminotransferase (ALT or SGPT) limit of normal · creatinine creatinine clearance >/= 60 mL/min/1.73 m^2 for patients with creatinine levels above
1.3 times institutional upper limit of normal

10. Ability to understand and the willingness to sign a written informed consent
document.

11. 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).

12. 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.

13. (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.

Exclusion Criteria:

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
performed.

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 National Cancer Institute's Common Toxicity Criteria
for Adverse Events (NCI-CTCAE) version 4 Grade 1 from previous anti-cancer therapy
except alopecia and peripheral neuropathy, for which 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, unless 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. Untreated asymptomatic brain metastasis
less than 10 mm will be allowed if no steroid and anti-epileptic drugs are used.

11. History of acute coronary syndromes (including myocardial infarction and unstable
angina), coronary angioplasty, or stenting within the past 6 months.

12. QTc interval >/= 480 msec (>/= 500 msec for subjects with Bundle Branch Block).

13. Uncontrolled arrhythmias. • Subjects with controlled atrial fibrillation for >1 month
prior to study Day 1 are eligible.

14. Class II, III, or IV heart failure as defined by the New York Heart Association
(NYHA) functional classification system.

15. Abnormal cardiac valve morphology (subjects with minimal abnormalities can be entered
on study if deemed not clinically significant)

16. 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.

17. Pregnant or lactating female.

18. Unwillingness or inability to follow the procedures required in the protocol.

19. Uncontrolled diabetes, hypertension or other medical conditions that may interfere
with assessment of toxicity

20. Subjects with known glucose 6 phosphate dehydrogenase (G6PD) deficiency.

Type of Study:

Interventional

Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Overall Response Rate (ORR)

Outcome Description:

Overall response rate defined as percentage of subjects with a confirmed complete response (CR) or a partial response (PR) at any time as per RECIST 1.1 criteria.

Outcome Time Frame:

8 weeks

Safety Issue:

No

Principal Investigator

Kevin B. Kim, MD,BA

Investigator Role:

Principal Investigator

Investigator Affiliation:

UT MD Anderson Cancer Center

Authority:

United States: Food and Drug Administration

Study ID:

2011-0579

NCT ID:

NCT01619774

Start Date:

September 2012

Completion Date:

Related Keywords:

  • Melanoma
  • Melanoma
  • Metastatic melanoma
  • Refractory or Resistant to BRAF Inhibitor
  • Advanced melanoma
  • GSK2118436
  • GSK1120212
  • Melanoma

Name

Location

UT MD Andreson Cancer CenterHouston, Texas  77030