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

Sponsor
GlaxoSmithKline
Study ID
NCT03266159
Phase
PHASE2
Status
Withdrawn

Conditions

  • Solid Tumours

Eligibility Criteria

Sex
ALL
Age
18 Years - N/A
Healthy Volunteers
Not accepted

Interventions

  • GSK525762 Besylate tablets — DRUG
    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.
  • Trametinib tablets — DRUG
    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.

Study Details

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.

Key Dates

Start date
Nov 27, 2017
Status verified
Dec 2017
Primary completion
Aug 19, 2020
Completion
Aug 19, 2020

Study Design

Enrollment
0 participants (actual)
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT

Arms

  • Experimental: Part 1: Subjects receiving GSK525762 + trametinib
    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.
  • Experimental: Part 2: Subjects with SCLC receiving GSK525762+ trametinib
    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.
  • Experimental: Part 2: Subjects with RMCRC receiving GSK525762+ trametini
    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.
  • Experimental: Part 2: Subjects with RMNSCLC receiving GSK525762+ trametinib
    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.
  • Experimental: Part 2: Subjects with RMPAC receiving GSK525762+ trametinib
    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.
  • Experimental: Part 2: Subjects with RAST receiving GSK525762+ trametinib
    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.

Primary Outcome Measure

Part 1: Number of subjects with adverse events (AEs) and serious adverse events (SAEs) [ Time Frame: Up to 12 months ]

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