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

NCT01619774 | Completed Phase 2 Results

• 3 other identifiers: 2011-0579NCI-2012-01222RP120505
• Study Type: interventional
• Target: 28
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Melanoma

Keywords

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

Outcome Measures

Primary Outcomes (2)

• Overall Response Rate (ORR)

  Overall response rate defined as percentage of subjects with a confirmed complete response (CR) or a partial response (PR) at any time as per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. Clinical responses will be evaluated using RECIST 1.1 criteria after every 2 cycles (8 weeks). Complete Response (CR): Disappearance all lesions; pathological lymph nodes reduction in short axis to \<10 mm. Partial Response (PR): \>30% decrease in sum diameters of lesions, reference baseline sum diameters. Progressive Disease (PD): \>20% increase in sum diameters of lesions, reference smallest sum on study (includes baseline sum if smallest on study); relative increase of 20%, sum must also demonstrate absolute increase of \>5 mm; appearance of 1 or \> new lesions considered progression). Stable Disease (SD): Neither sufficient shrinkage for PR nor sufficient increase for PD, reference smallest sum diameters while on study.

  Evaluation every 8 weeks (2 cycles) up to 12 months

• Number of Participants by Response

  Clinical responses evaluated using RECIST 1.1 criteria after every 2 cycles (8 weeks). Complete Response (CR): Disappearance all lesions; pathological lymph nodes reduction in short axis to \<10 mm. Partial Response (PR): \>30% decrease in sum diameters of lesions, reference baseline sum diameters. Progressive Disease (PD): \>20% increase in sum diameters of lesions, reference smallest sum on study (includes baseline sum if smallest on study); relative increase of 20%, sum must also demonstrate absolute increase of \>5 mm; appearance of 1 or \> new lesions considered progression). Stable Disease (SD): Neither sufficient shrinkage for PR nor sufficient increase for PD, reference smallest sum diameters while on study.

  Evaluation every 8 weeks (2 cycles) up to 12 months

Secondary Outcomes (1)

• Progression-Free Survival (PFS)

  Evaluation every 8 weeks (2 cycles) up to 12 months

Study Arms (1)

GSK2118436 + GSK1120212

EXPERIMENTAL

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; Drug: GSK1120212

Interventions

GSK2118436 DRUG

Starting dose 150 mg by mouth twice a day.

GSK2118436 + GSK1120212

GSK1120212 DRUG

2 mg by mouth daily.

GSK2118436 + GSK1120212

Eligibility Criteria

• Age: 16 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.
• Patients must have histologically or cytologically confirmed Stage IV or recurrent or unresectable Stage III melanoma.
• BRAF mutation-positive melanoma (i.e., V600E, V600K or V600D)
• For Cohort A, patients must have easily accessible tumor for a mandatory biopsy. This is not required for patients enrolled on Cohort B.
• Patients must have measurable disease, defined by RECIST 1.1
• Patients must have tumor lesions which is refractory or resistant to a selective BRAF inhibitor (RO5185426 or GSK2118436).
• Age \>/= 16 years.
• Eastern Cooperative Oncology Group (ECOG) performance status 0-1
• 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.
• Ability to understand and the willingness to sign a written informed consent document.
• 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).
• 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).
• 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.

You may not qualify if:

• Currently receiving cancer therapy (chemotherapy, radiation therapy, immunotherapy, or biologic therapy) except a selective RAF inhibitor.
• Patients must not have previously received a selective BRAF inhibitor (RO5185426, GSK2118436) and a selective MEK inhibitor (AZD6244, GSK1120212) concurrently.
• 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.
• Current use of a prohibited medication or requires any of these medications during treatment with study drug.
• Any major surgery, within the last 3 weeks. Radiotherapy, or immunotherapy within the last 2 weeks.
• Unresolved toxicity greater than NCI-Common Toxicity Criteria for Adverse Effects (CTCAE) v4 Grade 1 from previous anti-cancer therapy except alopecia and peripheral neuropathy, for which \</= grade 2 toxicity is allowed to participate.
• Presence of rheumatoid arthritis.
• 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).
• Presence of active gastrointestinal disease or other condition that will interfere significantly with the absorption, distribution, metabolism, or excretion of drugs.
• 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.
• (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.
• History of acute coronary syndromes (including myocardial infarction and unstable angina), coronary angioplasty, or stenting within the past 6 months.
• Corrected QT interval (QTc) \>/= 480 msec (\>/= 500 msec for subjects with Bundle Branch Block).
• Uncontrolled arrhythmias. • Subjects with controlled atrial fibrillation for \>1 month prior to study Day 1 are eligible.
• Class II, III, or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system.

Sponsors & Collaborators

• M.D. Anderson Cancer Center: lead
• Cancer Prevention Research Institute of Texas: collaborator
• GlaxoSmithKline: collaborator

Study Sites (1)

University of Texas MD Anderson Cancer Center

Houston, Texas, 77030, United States

Location

Related Publications (1)

• Chen G, McQuade JL, Panka DJ, Hudgens CW, Amin-Mansour A, Mu XJ, Bahl S, Jane-Valbuena J, Wani KM, Reuben A, Creasy CA, Jiang H, Cooper ZA, Roszik J, Bassett RL Jr, Joon AY, Simpson LM, Mouton RD, Glitza IC, Patel SP, Hwu WJ, Amaria RN, Diab A, Hwu P, Lazar AJ, Wargo JA, Garraway LA, Tetzlaff MT, Sullivan RJ, Kim KB, Davies MA. Clinical, Molecular, and Immune Analysis of Dabrafenib-Trametinib Combination Treatment for BRAF Inhibitor-Refractory Metastatic Melanoma: A Phase 2 Clinical Trial. JAMA Oncol. 2016 Aug 1;2(8):1056-64. doi: 10.1001/jamaoncol.2016.0509.

  PMID: 27124486 DERIVED

Related Links

• University of Texas MD Anderson Cancer Center Website

MeSH Terms

Conditions

Melanoma

Interventions

dabrafenib; trametinib

Condition Hierarchy (Ancestors)

Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Neoplasms by Site; Skin Diseases; Skin and Connective Tissue Diseases

Results Point of Contact

• Title: Michael Davies, Associate Professor, Melanoma Medical Oncology
• Organization: University of Texas (UT) MD Anderson Cancer Center

CR_Study_Registration@mdanderson.org

713-792-7734

Study Officials

• Michael Davies, MD, PHD, BA

  M.D. Anderson Cancer Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 12, 2012
• First Posted: June 14, 2012
• Study Start: September 1, 2012
• Primary Completion: August 1, 2015
• Study Completion: August 1, 2015
• Last Updated: December 12, 2016
• Results First Posted: December 12, 2016

Record last verified: 2016-10

Locations

US (1)