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

This study is currently recruiting participants. (see Contacts and Locations)
Verified July 2014 by M.D. Anderson Cancer Center
Sponsor:
Collaborators:
Cancer Prevention Research Institute of Texas
GlaxoSmithKline
Information provided by (Responsible Party):
M.D. Anderson Cancer Center
ClinicalTrials.gov Identifier:
NCT01619774
First received: June 12, 2012
Last updated: July 1, 2014
Last verified: July 2014
  Purpose

The goal of this clinical research study is to learn if the combination of 2 drugs dabrafenib and trametinib can help to control melanoma that has or has not spread to the brain. The safety of this drug combination will also be studied.

Dabrafenib is designed to block the mutated BRAF protein. This mutation is only found in moles of the skin and in melanoma cells. By blocking the protein, the drug may slow the growth of or kill cancer cells that have the protein.

Trametinib is designed to block certain proteins that cause cancer cells to grow and multiply. This may cause the cancer cells to die.


Condition Intervention Phase
Melanoma
Drug: GSK2118436
Drug: GSK1120212
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: 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

Resource links provided by NLM:


Further study details as provided by M.D. Anderson Cancer Center:

Primary Outcome Measures:
  • Overall Response Rate (ORR) [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]
    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.


Secondary Outcome Measures:
  • Progression-Free Survival (PFS) [ Time Frame: 8 weeks ] [ Designated as safety issue: Yes ]
    Duration of response defined for the subject or subjects with a confirmed complete response (CR) or partial response (PR), as time from the first documented evidence of a CR or PR until the first documented disease progression or death due to any cause. Progression free survival (PFS) estimated and summarized using the method of Kaplan and Meier.


Estimated Enrollment: 45
Study Start Date: September 2012
Estimated Primary Completion Date: September 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: GSK2118436 + GSK1120212
GSK1120212 2 mg by mouth once a day, and GSK2118436 150 mg by mouth 2 times every day (1 time in the morning and 1 time in the evening, about 12 hours apart).
Drug: GSK2118436
Starting dose 150 mg by mouth twice a day.
Drug: GSK1120212
2 mg by mouth daily.

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   16 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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. 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 document.
  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.

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 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 used.
  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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01619774

Contacts
Contact: Michael Davies, MD, PHD, BA 713-792-2921

Locations
United States, Texas
UT MD Andreson Cancer Center Recruiting
Houston, Texas, United States, 77030
Sponsors and Collaborators
M.D. Anderson Cancer Center
Cancer Prevention Research Institute of Texas
GlaxoSmithKline
Investigators
Principal Investigator: Michael Davies, MD, PHD, BA M.D. Anderson Cancer Center
  More Information

Additional Information:
No publications provided

Responsible Party: M.D. Anderson Cancer Center
ClinicalTrials.gov Identifier: NCT01619774     History of Changes
Other Study ID Numbers: 2011-0579, NCI-2012-01222
Study First Received: June 12, 2012
Last Updated: July 1, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by M.D. Anderson Cancer Center:
Melanoma
Metastatic melanoma
Refractory or Resistant to BRAF Inhibitor
Advanced melanoma
GSK2118436
GSK1120212

Additional relevant MeSH terms:
Melanoma
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Nerve Tissue
Nevi and Melanomas

ClinicalTrials.gov processed this record on July 23, 2014