Neoplasms

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Gland and Hormone Related Diseases

All Conditions

Rare Diseases

Ovarian Neoplasms

Carcinoma, Ovarian Epithelial

Ovarian Cancer

Ovarian Epithelial Cancer

All Drugs and Chemicals

Fluorodeoxyglucose F18

Three to six patients on a medium dose of GSK2141795 for four weeks

Nine to eighteen subjects on a low, medium or high dose of GSK2141795 for four weeks

GSK2141795 is an oral, low nanomolar pan-AKT kinase inhibitor that demonstrates activity in hematologic and solid tumor cell lines. It also delays tumor growth in a dose dependent manner in solid tumor xenograft mouse models

GSK2141795

GSK Clinical Trials

The purpose of this study is to explore the potential dose response relationship between the pharmacokinetics of GSK2141795 and \[18F\] FDG PET pharmacodynamic markers of glucose metabolism in tumor tissue. Three to six subjects will be enrolled in each cohort and dosed with repeat escalating doses of GSK2141795. \[18F\] FDG PET imaging and optional tumor biopsies will be done prior to initiation of dosing and sequentially at select time points during the first five weeks of dosing. The maximal dose of a given schedule evaluated in this study will not exceed the maximal tolerated dose established in the first-time-in-human trial PCS112689 for the same schedule.

An Open Label Study To Investigate the Pharmacokinetics and Pharmacodynamics of Repeat Escalating Doses of the Oral AKT Inhibitor GSK2141795 by 18F FDG PET Analysis in Subjects With Ovarian Cancer

GlaxoSmithKline

Skin and Connective Tissue Diseases

Blood and Lymph Conditions

Immune System Diseases

Breast Neoplasms

Lymphoma

Lymphosarcoma

Oral GSK214179 given daily to patients with cancer. Groups of approximately three patients will receive GSK2141795 at increasing doses until a maximum tolerated dose is identified.

This study is a first time in human, Phase I, open-label, dose-escalation study of the oral AKT inhibitor GSK2141795 in subjects with solid tumors or lymphomas.

A Phase I, Open-Label, First-Time-In-Human Study of the Oral AKT Inhibitor GSK2141795

A Phase I, Open-Label, Two-Stage Study to Investigate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of the Oral AKT Inhibitor GSK2141795 in Subjects With Solid Tumors or Lymphomas

Melanoma

Neuroendocrine Tumors

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Nerve Tissue

Nevus, Pigmented

Nevus

Nevi and Melanomas

Skin Neoplasms

Skin Diseases

Neuroendocrine Tumor

Neuroepithelioma

Antineoplastic Agents

Trametinib

Protein Kinase Inhibitors

Enzyme Inhibitors

Trametinib (GSK1120212)

* Oral
* 2 mg
* Daily
* Number of Cycles: until progression or unacceptable toxicity develops

GSK2141795

* Oral
* 25 mg
* Daily
* Number of Cycles: until progression or unacceptable toxicity develops

Trametinib is a highly selective allosteric inhibitor of MEK1 and MEK2 activation and kinase activity.

Trametinib (GSK1120212)

GSK 2141795 is an ATP competitive subnanomolar pan-AKT inhibitor. In order to measure the true potency of GSK 2141795, potency (Ki\*) values were determined in a filter binding assay using lower enzyme concentrations (0.1, 0.7, and 0.2 nM for human AKT1, AKT2, and AKT3, respectively). Using a sandwich ELISA, GSK 2141795 inhibited phosphorylation of GSK-3β in BT474 and LNCaP cell lines with EC50 values of 143 and 34 nM, respectively. Since phosphorylation of GSK-3β can be modulated by other enzymes (PKA, PKC, and RSK),cellular activity of GSK 2141795 was evaluated using a phospho-PRAS40 ELISA. GSK 2141795 inhibited the phosphorylation of PRAS40 with EC50 values of 39 and 55 nM for BT474 and LNCaP cells, respectively.

Adil Daud, M.D.

This is a multicenter phase II clinical study of trametinib in combination with GSK2141795 in patients with BRAF wild-type mutation melanoma. All patients will receive continuous dosing of trametinib (2 mg) in combination with GSK2141795 (25 mg) oral daily until progression of disease, withdrawal of consent, or the development of intolerable treatment associated toxicity. Imaging (CT or MRI) will be performed within 7 days prior to day 1 of Odd Cycles, starting with Cycle 3.

Patients may continue treatment with trametinib in combination with GSK2141795 on trial until disease progression or the development of unacceptable toxicity that does not improve with maximal supportive care or dose reduction per protocol.

Treatment-associated adverse events will be assessed based on clinical and laboratory findings using the Common Toxicity Criteria for Adverse Events, version 4.0. Adverse event (AE) assessments will be performed every week through cycle 3 day 1, and on day 1 for every cycle thereafter. AEs and Serious adverse events (SAE)s will be monitored by UCSF's Data Safety Monitoring Committee.

Safety assessments will include medical history, physical examination, Complete Blood Count (CBC) with differential, chemistries panel, thyroid function and pregnancy tests, ECGs, and ophthalmology evaluations. Screening assessments will also include a transthoracic echocardiogram or multiple-gated acquisition (MUGA) scan, and brain imaging.

It is estimated that 48 patients will complete the study.

Trametinib With GSK2141795 in BRAF Wild-type Melanoma

Phase II Clinical Trial of the MEK Inhibitor Trametinib With the AKT Inhibitor GSK2141795 in BRAF Wild-type Melanoma

Only those participants who have measurable disease present at baseline, have received at least one cycle of therapy, and have had their disease re-evaluated will be considered evaluable for response These participants will have their response classified according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1) method, where the baseline target lesion sum of longest diameter (LD) will be used as reference by which to characterize the objective tumor response. An objective response is defined as an overall response of complete response (CR), partial response (PR), or stable disease (SD) with a confirmatory scan or evaluation at time of final disease response determination.

Time from randomization to objective tumor progression or death. Participants who die without documentation of disease progression and before it was time to conduct the first tumor reassessment, will be considered inevaluable or not assessed adequately

Time from treatment initiation until objective tumor progression observed. Only those participants who have measurable disease present at baseline, have received at least one cycle of therapy, and have had their disease re-evaluated will be considered evaluable for response. Participants who exhibit objective disease progression prior to the end of Cycle 1 will be considered evaluable. Response will also be considered inevaluable for any participants receiving treatment (regardless of how much was received) who did not have any follow-up assessment completed before initiation of alternative treatment or participants who die without documentation of disease progression and before it was time to conduct the first tumor reassessment, will be considered inevaluable or not assessed adequately

National Comprehensive Cancer Network

Adil Daud

Clinical Professor

Trametinib (GSK1120212)

* Oral, 2 mg Daily
* Number of Cycles: until progression or unacceptable toxicity develops

GSK2141795

* Oral, 25 mg Daily
* Number of Cycles: until progression or unacceptable toxicity develops

Trametinib, GSK2141795

Patients without NRAS exon 1 and 2 mutations

NRAS Wildtype

Patients with NRAS exon 1 and 2 mutations (NRAS mutant) identified by Sanger sequencing or exon-capture next-generation sequencing

NRAS Mutant

Total

Age, Customized

Sex: Female, Male

ECOG status 0

ECOG status 1

ECOG status 2

Participants were rated using the ECOG Performance Status Scale. Status had to be 0 to 2 in order to be eligible for the study.

Grade 0: Normal activity. Fully active, able to carry on all pre-disease performance without restriction

Grade 1: Symptoms, but ambulatory. Restricted in physically strenuous activity, but ambulatory and able to carry out work of a light or sedentary nature (e.g., light housework, office work)

Grade 2: In bed \< 50% of the time. Ambulatory and capable of all self-care, but unable to carry out any work activities. Up and about more than 50% of waking hours

Eastern Cooperative Oncology Group (ECOG) status: 0

Histological confirmation of Malignant Melanoma using the American Joint Committee on Cancer (AJCC) tumor/node/metastasis (TNM) classification and staging system.

M1a: Metastases to skin, soft tissue (including muscle), and/or nonregional lymph nodes

M1b: Lung metastasis, with or without M1a involvement

M1c: Distant metastasis to non-central nervous system (CNS) visceral sites with or without M1a or M1b involvement

Stage

LDH normal

LDH elevated

Lactate Dehydrogenase (LDH) level

Genotype NRAS Q61H

Genotype NRAS Q61K

Genotype NRAS Q61L

Genotype NRAS Q61R

BRAF Wild Type (WT) /NRAS WT

Genotype

Cutaneous

Mucosal

Acral

Uveal

Subtype

Patients with NRAS exon 1 and 2 mutations (NRAS mutant) identified by Sanger sequencing or exon-capture next-generation equencing and patients without these mutations (wild-type (WT)). The sample size for each arm was based on a Simon 2-stage stage design.

Adil Daud, MD

Reported here are a number of participants that achieved the best objective response defined as stable disease

Objective Response Rate (ORR)

Progression-Free Survival of Patients Treated With the Combination of Trametinib and GSK 2141795

Overall Survival of Patients Treated With the Combination of Trametinib and GSK 2141795

The drug combination failed to produce objective responses in participants with either NRAS mutant or NRAS wild-type melanoma in TTP evaluable patient population. No objective responses for progression in TTP specific evaluable participants population were observed so endpoint could not be calculated.

Time-to-Progression (TTP) of Patients Treated With the Combination of Trametinib and GSK 2141795

Number of Severe Adverse Events (Grade 3 and 4) Reported by Patients Related With the Treatment of Trametinib and GSK2141795.

Patients without NRAS (neuroblastoma RAS viral oncogene homolog) exon 1 and 2 mutations

Overall Study

Symptoms and General Pathology

Recurrence

Uterine Cervical Neoplasms

Uterine Neoplasms

Genital Neoplasms, Female

Urogenital Neoplasms

Uterine Cervical Diseases

Uterine Diseases

Genital Diseases, Female

Genital Diseases

Urogenital Diseases

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

GSK1120212 (trametinib) 1.5 mg QD + GSK2141795 50 mg QD in 28 day cycles

Trametinib dose is 1.5 mg orally once per day

GSK1120212 (trametinib)

The dose of GSK2141795 is 50 mg orally once per day

Ursula A. Matulonis, MD

This research study is evaluating the combination of two drugs called GSK1120212 (trametinib) and GSK2141795 as a possible treatment for recurrent or persistent cervical cancer. Trametinib and GSK2141795 are drugs that may stop cancer cells from growing. Trametinib is a MEK inhibitor - it blocks a protein called MEK that is commonly overactive in tumor cells. GSK2141795 is an AKT inhibitor which blocks a pathway in cancer cells that is commonly overactive in tumor cells called the PI3kinase pathway. In this research study, the investigator is looking to see whether the combination of Trametinib and GSK2141795 is useful in treating recurrent and persistent cervical cancer.

Additionally, the investigator is looking to see if participants whose tumors contain a particular genetic make-up will have better response to combination trametinib and GSK2141795. Participants' tumors will be tested for mutations in genes which could make some cancers more susceptible to trametinib and GSK2141795.

Before the research starts (screening): The participant will be asked to undergo some screening tests or procedures to find out if they can be in the research study. Many of these tests and procedures are likely to be part of regular cancer care and may be done even if it turns out that the participant does not take part in the research study. If the participant has had some of these tests or procedures recently, they may or may not have to be repeated.

* A medical history, which includes questions about the participant's health, current medications, and any allergies.
* Physical exam, including height and weight
* An eye exam, by an eye specialist
* Performance status, the investigator will ask the participant questions about how they are able to carry on with your usual activities.
* Vital signs, including blood pressure, pulse, body temperature and respiratory rate
* An assessment of the participant's tumor by CT (Computerized Tomography) scan or MRI (Magnetic Resonance Imaging), of their chest, stomach area, and pelvis.
* Blood tests (approximately 2-3 tablespoons) including hematology, chemistry, liver function, kidney function, blood sugar levels, blood clotting levels
* Electrocardiogram (EKG), a test to check the participant's heart's rhythm
* Echocardiogram (ECHO), a test to check the participant's heart's structure and function.
* Serum pregnancy test if the participant are capable of becoming pregnant

If the results of the above tests show that the participant is eligible to participate in the research study, the participant will begin the study treatment. If the participant does not meet the eligibility criteria, the participant will not be able to participate in this research study.

If these tests show that the participant is eligible to participate in the research study, the participant will begin the study treatment. If the participant does not meet the eligibility criteria, the participant will not be able to participate in this research study.

Additional research procedures to be performed at the time of screening:

- Archival tumor testing: During this study, additional tests will be performed on a sample of the participant's original tumor that has been stored in your institution's tissue banks. These tests will be performed on tumor tissue samples from previous biopsies or surgeries for the participant's cancer. The research done on these samples will involve looking at DNA and proteins in the participant's cancer to see if researchers can learn more about the participant's type of cancer and understand how trametinib and GSK2141795 might work on their tumor. Testing of this sample will not require the participant to undergo any additional procedures.

TISSUE COLLECTIONS/OWNERSHIP: Participation in this protocol involves providing specimen(s) of the participant's tissue. Please know that if the investigator leaves the institution, the research and the tissue might remain at the DF/HCC or might be transferred to another institution.

* Additional Blood tests: Approximately 2 tablespoons of blood will be collected for research testing. This testing will involve looking at DNA and proteins in the participant's blood to compare them with those seen in their cancer. This will be drawn before the participant begin taking the study drug. These research sample collections are a required part of this research study. If the participant does not wish to undergo these procedures, the participant may not participate in this research study.
* Optional pre and post tumor biopsies: Before the participant begin receiving the study drug, your doctor will arrange for a procedure where your tumor will be biopsied. Your entire tumor or part of your tumor might be removed (excisional biopsy) or a small sample of the tumor might be removed using a needle (needle biopsy, fine needle aspirate) with guidance under radiographic studies. This will also occur before the participant begins treatment and between 2-4 weeks after treatment has started.

After the screening procedures confirm that the participant is eligible to participate in the research study:

Study Drugs:

If the participant decides to take part in this research study, the participant will be given a study drug diary for each treatment cycle. The participant will be asked to complete a drug diary to record when they took each dose or to give a reason if the participant did not take the study drugs. At the end of each cycle, the participant should return the pill bottles and all of the remaining pills prior to starting the next cycle. The participant will receive a new set of pills and new diary if the participant is to continue the next cycle.

Clinical Exams: During all cycles the participant will have a physical exam, and will be asked questions about their general health and specific questions about any problems that they might having and any medications the participant may be taking.

The participant can expect the following while they are a participant on this study.

At the beginning of each cycle (one cycle equals 28 days):

* Recording of any health problems, including side effects of the study drugs
* List of medications taken since the last visit
* Physical examination (including measurement of vital signs, such as blood pressure, breathing rate, heart rate, temperature and weight)
* Evaluation of the participant's performance status (the ability to carry on daily activities)
* Blood samples (approximately 2-3 tablespoons of blood will be taken) to evaluate the participant's blood counts, electrolytes, liver function, kidney function and blood sugar levels.
* EKG, a test to check the participant's heart's rhythm. This will be performed at the start on each cycle.

Once a week during the first cycle:

* The participant will be called by a member of the study team to record any health problems, including side effects from the study drugs and any changes in medications.
* Blood samples (approximately 1 teaspoon of blood will be taken) to evaluate their blood sugar levels. This can be done at a lab close to home. If the participant's doctor thinks that their blood sugars need further monitoring, the participant may have continued blood samples drawn to check their blood sugar weekly or daily past the first cycle.

Every 2 cycles:

* Blood samples (approximately 1 teaspoon of blood will be taken) to evaluate the participant's HgbA1C, a test that evaluates their blood sugar levels over a period of time. This can be done at a lab close to home.
* CT scan or MRI of your chest, stomach area, and pelvis to see if the participant's cancer is increasing, decreasing, or staying the same size. If the cancer is decreasing, the participant's doctor may schedule the participant for another CT scan in about one month to check it again.
* ECHO, a test to check the participant's heart's structure and function

At the end of the study:

* Recording of any health problems, including any side effects from the study drugs.
* List of medications taken since the last visit
* Physical examination (including measurement of the participant's vital signs, such as blood pressure, breathing rate, heart rate, temperature, and weight.)
* Evaluation of the participant's performance status (their ability to carry on daily activities).
* Blood samples (approximately 2-3 tablespoons of blood will be taken) to evaluate the participant's blood counts, electrolytes, liver function, kidney function, blood sugar level, and HgbA1C.

After the final dose of the study drug:

The investigator would like to keep track of the participant's medical condition for up to 3 years after the participant completes the study. The investigator would like to do this by calling the participant on the telephone or seeing the participant in clinic for evaluation of their status, disease and current therapy. Keeping in touch with the participant and checking their condition routinely helps us look at the long-term effects of the research study.

GSK1120212+GSK2141795 for Cervical Cancer

A Single Arm, Single Stage Phase II Trial of GSK1120212 and GSK2141795 in Persistent or Recurrent Cervical Cancer

Response rate will be assessed by RECIST version 1.1.

The duration of progression-free (PFS) following initiation of therapy with GSK1120212 (trametinib) and GSK2141795 will be measured.

Toxicity was assessed for this combination by version 4.0 of the NCI Common Terminology Criteria for Adverse Events (CTCAE) in this cohort of patients. Toxicities reported were deemed related to study treatment.

The mutation and co-mutation rates of genes in the PI3K and RAS ERK signaling pathways in recurrent cervical cancer will be interrogated using high throughput targeted mutational analysis on participant tumor samples.

Overall survival will be determined for subjects on this study

Novartis

Dana-Farber Cancer Institute

Principal Investigator

GSK1120212 (trametinib) 1.5 mg QD + GSK2141795 50 mg QD in 28 day cycles

GSK1120212 (trametinib): Trametinib dose is 1.5 mg orally once per day

GSK2141795: The dose of GSK2141795 is 50 mg orally once per day

GSK1120212 (Trametinib) and GSK2141795

Age, Categorical

Race (NIH/OMB)

United States

Region of Enrollment

Dr. Ursula Matulonis

Response rate assessed by RECIST version 1.1.

Response Rate for the Combination of GSK1120212 (Trametinib) and GSK2141795 in Patients With Recurrent or Persistent Cervical Cancer.

PFS events were determined by RECIST 1.1, clinical progression and death.

Duration of Progression-free (PFS)

Toxicity of GSK1120212 (Trametinib) and GSK2141795 as Measured by the Number of Participants With Adverse Events

Adenocarcinoma

Squamous Cell Carcinoma

Mucinous

Observed mutations and amplifications in genes related to PI3K or RAS signaling in the 13 patients with tissue available for testing. One patient did not have archival tissue available for testing, five patients did not have detected alterations.

Mutation and Co-mutation Rates of Genes in the PI3K and RAS ERK Signaling Pathways in Recurrent Cervical Cancer Using High Throughput Targeted Mutational Analysis on Participant Tumor Samples.

Overall Survival

Triple Negative Breast Neoplasms

Dose escalation will proceed until unacceptable toxicity is observed. Dose escalation decisions will take into account all available data, including PK data and the safety profile of prior cohorts and will occur following review of these data by the investigator(s), GSK medical monitor, pharmacokineticist, and statistician.

Enrollment into expansion cohort(s) in Part 2A may begin once a recommended dosing regimen(s) is identified in Part 1A utilizing a once daily continuous dosing schedule for both GSK1120212 and GSK2141795. Enrolment to cohorts utilizing this daily dosing schedule may proceed in parallel with enrolment in Part 1B. Expansion cohort(s) will preferentially enroll subjects with treatment-refractory, measurable and biopsiable triple negative breast cancer or BRAF- wild type melanoma. Subjects selected for enrollment into Part 2A or Part 2B will be tested for PTEN deficiency and must agree to provide paired tumor biopsies (at baseline and once while on- treatment). An additional tumor biopsy at the time of disease progression should also be collected if feasible.

In Part 2A and Part 2B, up to 35 additional subjects per tumor type and schedule (i.e., a total of up to 70 subjects per schedule tested) may be enrolled in a two-stage design to better characterize safety, PK and PD.

GSK1120212

This study is a Phase 1 dose-escalation open-label study to determine the recommended Phase II dose (RP2D) and regimen for the combination of the orally administered MEK inhibitor GSK1120212 and the orally administered AKT kinase inhibitor GSK2141795. The study consists of two parts. Part 1A will identify the maximum tolerated dose (MTD) using a Zone-Based, modified 3 plus 3 dose escalation procedure. The starting dose (Zone 1, Cohort 1) will be 0.5mg GSK1120212 combined with 25mg GSK2141795. Dose escalation will continue based on predefined parameters until a MTD is established. The initial regimen for dose escalation in Part 1A will be continuous oral daily dosing. Once the continuous daily dosing MTD or RP2D has been established in Part 1A, Part 1B will explore alternate dosing schedule(s) in which the dosing schedule may be adjusted for either GSK1120212 or GSK2141795. Dose escalation will proceed using a 3 plus 3 dose escalation procedure until an MTD or RP2D of that alternate schedule is defined. Part 2 will explore further in specific tumor types the safety, tolerability, clinical activity, pharmacokinetic (PK) and pharmacodynamic (PD) properties of the combination of GSK1120212 and GSK2141795 at the recommended dose(s) and regimen(s) identified in Part 1.

Safety, Pharmacokinetics (PK) of AKT and MEK Combination

A Phase I Dose Escalation Open-Label Safety, Pharmacokinetic and Pharmacodynamic Study to Determine the Recommended Phase II Dose of GSK1120212 Dosed in Combination With GSK2141795

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
An Open Label Study To Investigate the Pharmacokinetics and Pharmacodynamics of Repeat Escalating Doses of the Oral AKT Inhibitor GSK2141795 by 18F FDG PET Analysis in Subjects With Ovarian Cancer	NCT01266954	Solid Tumours	GSK2141795	18 Years - 85 Years	GlaxoSmithKline
A Phase I, Open-Label, First-Time-In-Human Study of the Oral AKT Inhibitor GSK2141795	NCT00920257	Cancer	GSK2141795	18 Years -	GlaxoSmithKline
Trametinib With GSK2141795 in BRAF Wild-type Melanoma	NCT01941927	Melanoma	Trametinib (GSK... GSK2141795	18 Years -	University of California, San Francisco
GSK1120212+GSK2141795 for Cervical Cancer	NCT01958112	Cervical Cancer	GSK1120212 (tra... GSK2141795	18 Years -	Dana-Farber Cancer Institute
Safety, Pharmacokinetics (PK) of AKT and MEK Combination	NCT01138085	Cancer	GSK1120212 GSK2141795	18 Years -	GlaxoSmithKline

Spots Global Cancer Trial Database for gsk2141795

Every month we try and update this database with for gsk2141795 cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Spots Global Cancer Trial Database for gsk2141795

Every month we try and update this database with for gsk2141795 cancer trials from around the world to help patients and their families find trials that might be right for them. We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Every month we try and update this database with for gsk2141795 cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.