Neoplasms

Respiratory Tract (Lung and Bronchial) Diseases

All Conditions

Rare Diseases

Small Cell Lung Carcinoma

Lung Neoplasms

Small Cell Lung Cancer

Antineoplastic Agents

All Drugs and Chemicals

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.

GlaxoSmithKline

Oculocerebral Syndrome With Hypopigmentation

Pharmaceutical Solutions

Anti-Infective Agents

Itraconazole

Rifampin

Hydroxyitraconazole

Trichostatin A

Clotrimazole

Miconazole

Antifungal Agents

Cytochrome P-450 Enzyme Inhibitors

Hormones

Hormone Antagonists

Cytochrome P-450 CYP3A Inhibitors

Anti-Bacterial Agents

Antibiotics, Antitubercular

Antitubercular Agents

Subjects will receive a single dose of GSK525762 10 mg on Day 1 followed by 200 mg Itraconazole two times a day (BID) on Day 3. On Day 4 to Day 6 inclusive subjects will receive a single dose of itraconazole 200 mg in the morning. On Day 7 subjects will receive a single dose of GSK525762 5 mg one hour after receiving 200 mg dose of itraconazole. On day 8 and 9 subjects will receive a single dose of 200 mg itraconazole in the morning.

Subjects will receive a single dose of GSK525762 10 mg on day 1 followed by 200 mg Itraconazole BID on day 3. On day 4 to day 6 inclusive subjects will receive a single dose of itraconazole 200 mg in the morning. On day 7 subjects will receive a single dose of GSK525762 5 mg or GSK525762 10 mg one hour after receiving 200 mg dose of itraconazole. On day 8 and 9 subjects will receive a single dose of 200 mg itraconazole in the morning.

Subjects will receive a single dose of GSK525762 10 mg on day 1. From day 3 to 17 inclusive, subjects will receive a single dose of 600 mg rifampicin in fasting conditions. On day 18 subjects will receive single dose of GSK525762 either 20 or 30 mg along with 600 mg dose of rifampicin. On day 19 subjects will receive a single dose of rifampicin 600 mg.

GSK525762 is available as a film-coated, white to slightly colored round, biconvex tablets with no markings. It is available in unit dose strength of 5 mg.

GSK525762 Besylate Tablets

Itraconazole is available as a clear yellow solution with unit dose strength of 10 mg/mL

Itraconazole 200 mg

Rifampicin is available as a red capsule with printed markings and as a 300 mg unit dose strength.

Rifampicin 300 mg

This is a Phase I, single center, two-part, randomized, open label, cross-over study. Part 1 of this study will evaluate the PK, safety, and tolerability of GSK525762 when administered alone and when co-administered following repeat dosing of itraconazole, a known strong inhibitor of Cytochrome P450 3A4 (CYP3A4) and a Para-glycoprotein (Pgp) inhibitor. Part 1 will consist of 2 Cohorts with preliminary PK and safety data obtained from Cohort 1 informing Cohort 2. Part 2 (one Cohort) of the study will evaluate the PK, safety, and tolerability of GSK525762 when administered alone and when co-administered following repeat dosing of rifampicin, a known potent inducer of CYP3A4. In vitro inhibition data indicate CYP3A4 may be the major route of clearance for GSK525762 and co-administration of drug therapies which modulate CYP3A4 (i.e.CYP3A4 inhibitors and inducers) is likely to alter the exposure of GSK525762 (i.e. increase or decrease exposure, respectively). The data generated from this current study to justify exclusion criteria on concomitant medications which affect CYP3A4 or Pgp and also inform potential dose modification in case of co-administration with medication affecting CYP3A4 activity. All subjects will undergo a screening visit within 28 days of the first dose of study drug followed by one treatment period and a follow-up visit 7-10 days after the last dose of GSK525762. Subjects in Part 1 will participate in the study for up to 45 days and subjects in Part 2 will participate for up to 56 days.

A Cross-over Study to Evaluate the Effect of Itraconazole and Rifampicin on the Pharmacokinetics (PK) of GSK525762 in Healthy Female Subjects of Non Child Bearing Potential

A Single Center, Two Part, Randomized, Open Label Cross-over Study to Evaluate the Effect of Itraconazole and Rifampicin on the Pharmacokinetics of GSK525762 in Healthy Female Subjects of Non Child Bearing Potential

IPD for this study is available via the Clinical Study Data Request site.

An AE is any untoward medical occurrence in a clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the 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

Blood samples will be collected at screening, pre dose (Day 1), and post dose on Day 3,Day 6 and at follow-up visit to analyze platelet counts, red blood cells (RBC) count, white blood cells (WBC) count (absolute), haemoglobin, hematocrit and differential WBC count ( neutrophils, lymphocytes, monocytes, eosinophils, and basophils).

Blood samples will be collected at screening, pre dose (Day 1), and post dose on Day 3,Day 6 and at follow-up visit to analyze blood urea nitrogen (BUN), creatinine, glucose (fasting), sodium, c peptide, potassium, chloride, magnesium, ionized calcium, aspartate aminotransferase (AST/SGOT), alanine aminotransferase (ALT/SGPT), alkaline phosphatase (ALP) levels, gamma-glutamyltransferase (GGT), total and direct bilirubin, total carbon dioxide, total protein and albumin

Urine samples will be collected at screening, pre dose (Day 1), and post dose on Day 3,Day 6 and at follow-up visit to analyze specific gravity, pH, glucose, protein, blood and ketone bodies by dipstick method, microscopic examination (if blood or protein is abnormal) WBCs, RBCs, hyaline casts, granular casts and cellular casts.

ECGs will be measured in supine position after 5 minutes rest using a standard 12-lead ECG machine that automatically calculates the HR and measures PR, QRS, QT and QTcF intervals.

Systolic and diastolic blood pressure will be measured on each day in supine or semi-supine position after 5 minutes rest.

Heart rate will be measured on each day in supine or semi-supine position after 5 minutes rest.

An AE is any untoward medical occurrence in a clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the 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.

Blood samples will be collected at screening, pre dose (Day 1), and post dose on Day 3,Day 4, Day 17 and at follow-up to analyze platelet counts, RBC count, WBC count (absolute), haemoglobin, hematocrit and differential WBC count ( neutrophils, lymphocytes, monocytes, eosinophils, and basophils).

Blood samples will be collected at screening, pre dose (Day 1), and post dose on Day 3,Day 4, Day 17 and at follow-up visit to analyze BUN, creatinine, glucose (fasting), sodium, c peptide, potassium, chloride, magnesium, ionized calcium, AST/SGOT, ALT/SGPT, ALP levels, GGT, total and direct bilirubin, total carbon dioxide, total protein and albumin

Urine samples will be collected at screening, pre dose (Day 1), and post dose on Day 3,Day 4, Day 17 and at follow-up visit to analyze specific gravity, pH, glucose, protein, blood and ketone bodies by dipstick method, microscopic examination (if blood or protein is abnormal) WBCs, RBCs, hyaline casts, granular casts and cellular casts.

On Day 1 and Day 18 ECGs will be measured in supine position after 5 minutes rest at screening, pre-dose, 1 hr, 24 hr and 48 hrs.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
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 Cross-over Study to Evaluate the Effect of Itraconazole and Rifampicin on the Pharmacokinetics (PK) of GSK525762 in Healthy Female Subjects of Non Child Bearing Potential	NCT02706535	Drug Interactio... Neoplasms	GSK525762 Besyl... Itraconazole 20... Rifampicin 300 ...	18 Years - 70 Years	GlaxoSmithKline
A Cross-over Study to Evaluate the Effect of Itraconazole and Rifampicin on the Pharmacokinetics (PK) of GSK525762 in Healthy Female Subjects of Non Child Bearing Potential	NCT02706535	Drug Interactio... Neoplasms	GSK525762 Besyl... Itraconazole 20... Rifampicin 300 ...	18 Years - 70 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

Spots Global Cancer Trial Database for gsk525762 besylate tablets