A Study of the Safety and Activity of the MEK Inhibitor Given Together With the AKT Inhibitor to Patients With Multiple Myeloma or Solid Tumor Cancers
- Registration Number
- NCT01476137
- Lead Sponsor
- GlaxoSmithKline
- Brief Summary
The purpose of this study is to determine whether the MEK inhibitor and the AKT inhibitor can be given in combination and if the combination is effective treatment for patients with solid tumors, including breast cancer and endometrial cancer, and for patients with multiple myeloma.
- Detailed Description
This is an open-label, two part, Phase I/II study to investigate the safety, pharmacokinetics, pharmacodynamics, and clinical activity of the MEK inhibitor GSK1120212 administered in combination with the AKT inhibitor GSK2110183 in subjects with solid tumors and multiple myeloma.
In Part 1, the safety and tolerability of a range of doses for GSK1120212 and GSK2110183 dosed in combination will be investigated; pharmacokinetics will also be analyzed to determine whether there is a drug-drug interaction between GSK1120212 and GSK2110183 when dosed in combination.
The second part of the study will focus on evaluation of the clinical efficacy of the combination as well as the pharmacodynamic response in subjects with proteasome-refractory multiple myeloma (Part 2A) or solid tumors, putatively endometrial and triple negative breast cancer (Part 2B).
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 335
Not provided
- Chemotherapy, radiotherapy, immunotherapy or other anti-cancer therapy including investigational drugs within 14 days prior to the first dose of any one of the investigational drugs described in this study.
- History of an allogenic stem cell transplant. Subjects with a history of an autologous stem cell transplant are NOT excluded from Part 2A if they meet Part 2A inclusion criteria.
- Current use of prohibited medication during treatment with GSK1120212 and/ or GSK 2110183.
- History of Type 1 diabetes.
- Anticoagulants are permitted only if the subject meets PTT and INR entry criteria. Their use must be monitored in accordance with local institutional practice.
- Presence of active gastrointestinal disease or other condition that could affect gastrointestinal absorption (eg, malabsorption syndrome) or predispose subject to gastrointestinal ulceration.
- Evidence of mucosal or internal bleeding.
- Any major surgery within the last 4 weeks.
- Any serious or unstable pre-existing medical, psychiatric, or other condition (including lab abnormalities) that could interfere with the subject's safety or providing informed consent.
- Known active infection requiring parenteral or oral anti-infective treatment.
- Evidence of severe or uncontrolled systemic diseases (eg, unstable or uncompensated respiratory, hepatic, renal or cardiac disease, unstable hypertension).
- Subjects with brain metastases are excluded if their brain metastases are: symptomatic, treated (surgery, radiation therapy) but not clinically and radiologically stable one month after therapy (as assessed by at least 2 distinct contrast enhanced MRI or CT scans over at least a one month period) OR asymptomatic and untreated but > 1 cm in the longest dimension.
Subjects with small (less than or equal to 1cm in the longest dimension), asymptomatic brain metastases that do not need immediate therapy can be enrolled. Subjects with solid tumors on a stable (ie, unchanged) dose of corticosteroids for more than one month, or those who have been off corticosteroids for at least 2 weeks can be enrolled. Subjects must also be off of enzyme-inducing anticonvulsants for more than 4 weeks.
- Subjects with leptomeningeal disease are excluded.
- QTcF interval greater than or equal to 470msecs.
- Subjects with bundle branch block (BBB) or pacemaker.
- Other clinically significant ECG abnormalities including 2nd degree (Type II) or 3rd degree atrioventricular (AV) block.
- History of myocardial infarction, acute coronary syndromes (including unstable angina), coronary angioplasty, or stenting or bypass grafting within 6 months of Screening.
- Class II, III or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system.
- Known hypersensitivity to any of the components of the study treatment.
- Pregnant or lactating female.
- Any malignancy related to HIV or solid organ transplant; history of known HIV, history of known HBV surface antigen positivity (subjects with documented laboratory evidence of HBV clearance may be enrolled) or positive HCV antibody.
- History or current evidence/ risk of retinal vein occlusion (RVO) or central serous retinopathy (CSR): history of RVO or CSR, or predisposing factors to RVO or CSR at the time of screening (eg, uncontrolled glaucoma or ocular hypertension, uncontrolled systemic disease such as hypertension, diabetes mellitus, or history of hyperviscosity or hypercoagulability syndromes); visible retinal pathology as assessed by ophthalmic exam that is considered a risk factor for RVO or CSR, such as evidence of new optic disc cupping, evidence of new visual field defects, intraocular pressure (IOP) > 24mmHg.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Part 1: Cohort 4a GSK1120212 GSK1120212 2mg + GSK2110183 125mg Part 2A: GSK1120212 2mg GSK1120212 Maximum tolerated dose of GSK1120212 as determined in prior single-agent trials Part 1: Cohort 1 GSK1120212 GSK1120212 1.5mg + GSK2110183 50mg Part 2A; GSK2110183 125mg GSK2110183 GSK2110183 125mg Part 2A and 2B: GSK1120212 + GSK2110183 Dose Combination 2 GSK1120212 One of two dose combination levels (GSK1120212+GSK2110183) based on data from Part 1 of the trial Part 2A and 2B: GSK1120212 + GSK2110183 Dose Combination 2 GSK2110183 One of two dose combination levels (GSK1120212+GSK2110183) based on data from Part 1 of the trial Part 1: Cohort 3b GSK1120212 GSK1120212 1.5mg + GSK2110183 125mg Part 2A and 2B: GSK1120212 + GSK2110183 Dose Combination 1 GSK1120212 One of two dose combination levels (GSK1120212+GSK2110183) based on data from Part 1 of the trial Part 2A: GSK2110183 MTD GSK2110183 Maximum tolerated dose (MTD) as determined in ongoing single agent trial PKB115340 Part 1: Cohort 1 GSK2110183 GSK1120212 1.5mg + GSK2110183 50mg Part 1: Cohort 2 GSK1120212 GSK1120212 1.5mg + GSK2110183 100mg Part 1: Cohort 3a GSK1120212 GSK1120212 2mg + GSK2110183 100mg Part 1: Cohort 4a GSK2110183 GSK1120212 2mg + GSK2110183 125mg Part 2A and 2B: GSK1120212 + GSK2110183 Dose Combination 1 GSK2110183 One of two dose combination levels (GSK1120212+GSK2110183) based on data from Part 1 of the trial Part 1: Cohort 3a GSK2110183 GSK1120212 2mg + GSK2110183 100mg Part 1: Cohort 3b GSK2110183 GSK1120212 1.5mg + GSK2110183 125mg Part 1: Cohort 2 GSK2110183 GSK1120212 1.5mg + GSK2110183 100mg
- Primary Outcome Measures
Name Time Method Part 2A: Number of patients whose disease responds to study drugs, as determined by Overall Response Rate (ORR) Every four weeks for up to one year. Defined as stringent complete response, complete response, very good partial response, or partial response, using the International Myeloma Working Group (IMWG) Uniform Response Criteria for Multiple Myeloma
Part 1: Safety and tolerability in first 4 weeks as determined by the number of patients with adverse events, serious adverse events, dose reductions or delays, withdrawals due to toxicities and changes in lab values and vital signs from baseline Weekly during first four weeks. Adverse events, serious adverse events, dose reductions or delays, withdrawals due to toxicities and changes in laboratory values and vital signs
Part 1: Safety and tolerability in continuation as determined by the number of patients with adverse events, serious adverse events, dose reductions or delays, withdrawals due to toxicities and changes in lab values and vital signs from baseline Every four weeks for up to one year. Adverse events, serious adverse events, dose reductions or delays, withdrawals due to toxicities and changes in laboratory values and vital signs
Part 2B: Number of patients whose disease responds to study drugs, as determined by Overall response rate (ORR) Until disease progression or for up to one year. Defined as confirmed complete response or confirmed partial response rate, using Response Evaluation Criteria in Solid Tumors (RECIST) v 1.1
- Secondary Outcome Measures
Name Time Method Part 1: Profile of pharmacokinetic parameters following repeat-dose administration of GSK1120212 and GSK2110183 in combination versus repeat-dose administration of monotherapy GSK2110183 and GSK1120212 Day 15 and Day 29 at predose and 1h, 2h, 3h, 4h, 6h, 8h 11h, 18h and 24h postdose Parameters include: AUC(0-tau), Ctau, Cmax, and tmax
Part 2B: Number of patients whose disease responds to study drugs, as shown by PFS; duration of response; change from baseline measures in biomarkers in the PI3K/ATK and MAPK pathways; genetic alterations in PI3K/AKT/RAS/RAF pathway Every 8 weeks PFS is defined as the interval between date of randomization and the earliest date of disease progression or death due to any cause; duration of response is defined as the time from first documented evidence of complete or partial response until time of first documented disease progression or death due to any cause; biomarkers in the PI3K/AKT and MAPK pathways, eg phosphS6RP, p-ERK, pPRAS40, pAKT measured in tumor tissue.
Part 2A: Number of patients whose disease responds to study drugs, as shown by PFS; duration of response; change from baseline measures in biomarkers in the PI3K/ATK and MAPK pathways; genetic alterations in PI3K/AKT/RAS/RAF pathway Every 4 weeks Progression-free survival (PFS) is defined as the interval between date of randomization and the earliest date of disease progression or death due to any cause; duration of response is defined as the time from first documented evidence of response until time of first documented disease progression; biomarkers in the PI3K/AKT and MAPK pathways, eg pS6RP, pAKT, p-ERK, pRAS40, as measured in bone marrow aspirates/biopsies.
Trial Locations
- Locations (1)
GSK Investigational Site
🇺🇸San Antonio, Texas, United States