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Trametinib

Protein Kinase Inhibitors

Enzyme Inhibitors

Eligible subjects will receive doses of GSK525762 with a starting dose of 40 milligrams (mg), or 60 mg in combination with trametinib with a starting dose of 1 mg or 1.5 mg or 2 mg, administered orally once daily. Dose escalation will continue until the maximally-tolerated dose combination (MTC) is reached. Once the MTC is reached, subjects will be enrolled in expansion cohort and will receive a fixed dose combination.

Eligible subjects with small cell lung cancer (SCLC) will receive their Part 2 dose as the dose combination of GSK525762 with trametinib selected at the end of Part 1.

Eligible subjects with Ras-mutated colorectal cancer (RMCRC) will receive their Part 2 dose as the dose combination of GSK525762 with trametinib selected at the end of Part 1.

Eligible subjects with Ras-mutated non small cell lung cancer (RMNSCLC) will receive their Part 2 dose as the dose combination of GSK525762 with trametinib selected at the end of Part 1.

Eligible subjects with Ras-mutated pancreatic adenocarcinoma (RMPAC) will receive their Part 2 dose as the dose combination of GSK525762 with trametinib selected at the end of Part 1.

Eligible subjects with Ras-pathway activated solid tumors (RAST) will receive their Part 2 dose as the dose combination of GSK525762 with trametinib selected at the end of Part 1.

GSK525762 Besylate film coated tablets will be available as a 20 mg tablet strength, yellowish pink in color, round and biconvex with no markings. It will be administered with 240mL of liquid.

GSK525762 Besylate tablets

Trametinib film coated tablets will be available as 0.5 mg and 2 mg dose strengths. Trametinib 0.5 mg will be yellow colored, modified oval, biconvex, tablets with 'GS' debossed on one face and 'TFC' on the opposing face.

Trametinib 2 mg will be pink colored, round, biconvex tablets with 'GS' debossed on one face and 'HMJ' on the opposing face. Doses will be taken at least 1 hour before or at least 2 hours after a meal.

Trametinib tablets

GSK Clinical Trials

GSK525762 is a novel inhibitor of bromodomain and extraterminal (BET) proteins. Trametinib is a potent inhibitor of the mitogen-activated protein kinase proteins (MEK1 and MEK2). GSK525762 and trametinib are critical for growth and survival of tumor cells. This will be the first study demonstrating the synergistic effect of BET inhibitor and MEK inhibitor administered together against tumor cell growth. This study aims to evaluate the safety, tolerability, PK, PD, and preliminary efficacy of combination of GSK525762 and trametinib when administered concomitantly to subjects with small cell lung cancer (SCLC) and rat sarcoma virus oncogene homolog (Ras) mutated solid tumors. The study will be conducted in two parts; part 1 will consists of dose escalation and dose expansion cohorts and part 2 will consists of four disease specific cohorts (SCLC, Ras-mutated adenocarcinoma \[RMAC\] of the colon \[Ras-mutated colorectal cancer {RMCRC}\] and/or rectum, Ras-mutated non small cell lung cancer \[RMNSCLC\], Ras-mutated pancreatic adenocarcinoma \[RMPAC\]) and an optional "basket" cohort (Ras-pathway activated solid tumors \[RAST\]). Part 1 will focus on selection of the Part 2 dose based on safety/tolerability, PK, PD, and efficacy. Part 2 will investigate the overall response rate and clinical response. The total duration of study will be approximately three years (nine to twelve months for part 1 and two years for part 2). Approximately 138-156 subjects will be enrolled in the study.

A sequential combined therapy of GSK525762 plus trametinib will be given to the subjects. Subjects will receive escalating doses in part 1 and the dose combination selected at the end of part 1 will be provided in part 2.

This will be an open-label study. Hence, masking will not be performed.

A Dose Escalation Study to Investigate the Safety, Pharmacokinetics (PK), Pharmacodynamics (PD), and Clinical Activity of GSK525762 Plus Trametinib in Subjects With Solid Tumors

A Phase I/II Open-Label, Dose Escalation Study to Investigate the Safety, Pharmacokinetics, Pharmacodynamics, and Clinical Activity of GSK525762 Plus Trametinib in Subjects With Small Cell Lung Cancer and Ras-Mutated Solid Tumors

An AE is any untoward medical occurrence in a subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. Any untoward event resulting in death, life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, congenital anomaly/birth defect or any other situation according to medical or scientific judgement will be categorized as SAE.

DLT is defined by the occurrence of severe toxicities during the first cycle of cancer therapy. An event will be considered a DLT if it occurs within the first 21 days of treatment and meets the DLT criteria.

Blood samples will be collected at the indicated time points for pharmacokinetic analysis and concentration of GSK525762 and trametinib will be determined in plasma.

The pERK levels will be assessed in pre-therapy and on-therapy tumor samples.

The circulating protein or RNA biomarkers including to monocyte chemoattractant protein-1 (MCP-1) will be assessed in pre-therapy and on-therapy blood samples.

The transcriptional levels and MAP kinase signaling will be assessed in pre-therapy and on-therapy tumor and/or blood samples.

ORR is defined as the percentage of subjects with a confirmed complete response (CR) or partial response (PR) at any time as per disease-specific criteria.

DCR is defined as the percentage of subjects with a confirmed CR, PR, or SD at any time as per disease-specific criteria.

The DOR is defined as, in the subset of subjects who show a confirmed CR or PR, the time from first documented evidence of CR or PR until the first documented sign of disease progression or death.

ORR is defined as the percentage of subjects with a confirmed CR or PR at any time as per disease-specific criteria.

Clinical response is defined as confirmed ORR as per standard evaluation criteria. ORR is the percentage of subjects with a confirmed CR or PR at any time as per disease-specific criteria.

Dose reductions or delays will be evaluated until the end of treatment.

Withdrawals will be collected until the end of treatment.

Clinical chemistry parameters will be analyzed as a measure of safety.

Hematology parameters will be analyzed as a measure of safety.

Urinalysis will be carried out as a measure of safety.

Systolic and diastolic blood pressure will be measured in semi-supine position after 5 minutes of rest.

Pulse rate will be measured in a semi-supine position after 5 minutes of rest..

Respiratory rate will be measured in a semi-supine position after 5 minutes of rest.

Body temperature will be measured in a semi-supine position after 5 minutes of rest.

Triplicate 12-lead ECGs will be obtained at each time point using an ECG machine to measure PR, QRS, QT, and Corrected QT interval (QTc).

Echocardiography (ECHO) or multigated acquisition (MUGA) scan will be performed to assess cardiotoxicity and GI effects will be monitored.

Blood samples will be collected at the indicated time points for pharmacokinetic analysis and concentration of GSK525762 AND TRAMETINIB will be determined in plasma.

The circulating protein or RNA biomarkers including to MCP-1 will be assessed in pre-therapy and on-therapy blood samples.

Subjects will be evaluated for dose reductions and delays. An event will be considered a DLT if it occurs within the first 21 days of treatment and meets the DLT criteria.

Pulse rate will be measured in a semi-supine position after 5 minutes of rest.

Triplicate 12-lead ECGs will be obtained at each time point using an ECG machine to measure PR, QRS, QT, and QTc.

ORR is defined as the percentage of subjects with a CR or PR at any time as per disease-specific criteria.

PFS defined as the time from first dose of study treatment until the disease progression or death due to any cause.

Plasma samples will be collected at the indicated time points to measure concentrations of GSK525762 and its relevant metabolite(s) and trametinib following repeat dose oral administration.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
A Dose Escalation Study to Investigate the Safety, Pharmacokinetics (PK), Pharmacodynamics (PD), and Clinical Activity of GSK525762 Plus Trametinib in Subjects With Solid Tumors	NCT03266159	Solid Tumours	GSK525762 Besyl... Trametinib tabl...	18 Years -	GlaxoSmithKline
A Dose Escalation Study to Investigate the Safety, Pharmacokinetics (PK), Pharmacodynamics (PD), and Clinical Activity of GSK525762 Plus Trametinib in Subjects With Solid Tumors	NCT03266159	Solid Tumours	GSK525762 Besyl... Trametinib tabl...	18 Years -	GlaxoSmithKline

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