Clinical trial NCT03266159: A Dose Escalation Study to Investigate the Safety, Pharmacokinetics (PK), Pharmacodynamics (PD), and Clinical Activity of GSK525762 Plus Trametinib in Subjects With Solid Tumors
Official title: 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
Study type: INTERVENTIONAL
Overall status: WITHDRAWN
Phase: PHASE2
Conditions: Solid Tumours
Keywords: Dose escalation
Small cell lung cancer
Trametinib
GSK525762
Ras-mutations
BET inhibitor
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2017-08-30
Enrollment: 0
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: 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.
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: Inclusion Criteria:

* Written informed consent provided.
* Males and females 18 years old and greater, at the time of signing the informed consent.
* Histologically- or cytologically confirmed diagnosis of one of the following; Part 1 dose escalation cohorts: Advanced (metastatic or non-resectable) SCLC with any mutational status, or any solid malignancy that demonstrates an activating mutation in Harvey rat sarcoma viral oncogene homolog (HRAS), Kirsten rat sarcoma viral oncogene homolog (KRAS), or neuroblastoma RAS viral (v-ras) oncogene homolog (NRAS); Part 1 dose expansion (PD cohort\[s\]) and part 2: Advanced (metastatic or non-resectable) SCLC with any mutational status, or adenocarcinoma of the colon or rectum, or NSCLC or adenocarcinoma of the pancreas, all of which must demonstrate an activating mutation in HRAS, KRAS, or NRAS; Part 2 "basket" cohort: Advanced (metastatic or non-resectable) solid malignancy that demonstrates Ras pathway activation (including but not limited to activating BRAF/HRAS/KRAS/NRAS mutation, inactivating neurofibromin (NF1) mutation, or evidence of Ras pathway activation by gene expression analysis).
* Disease that did not respond to, or progressed after, at least 1 prior line of therapy, or has no generally-accepted standard therapy (dose escalation cohorts and optional "basket" cohort only).
* Measurable disease during part 1, measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1 is recommended but not required. Subjects enrolled in part 2 must demonstrate measurable disease per RECIST v1.1.
* PD expansion subjects only: Subjects must consent to pre-dosing and on-therapy tumor biopsies and additional sample collection procedures.
* All prior treatment-related toxicities must be National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) v4 \<=Grade 1 (except alopecia \[permitted at any grade\]) and peripheral neuropathy (permitted at \<=Grade 2) at the time of screening.
* Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 1.
* Must have adequate organ function as defined by the following values: Absolute neutrophil count (ANC) \>=1.5 x 10\^9/liter (L); hemoglobin \>=9 grams per deciliter (g/dL) subjects that required transfusion or growth factor need to demonstrate stable hemoglobin for 7 days of 9 g/dL; platelets \>=100 x 10\^9/L; prothrombin time (PT)/International normalized ration (INR) and partial thromboplastin time (PTT) \<=1.5 x upper limit of normal (ULN); albumin \>=2.5 g/dL; total bilirubin \<=1.5 x ULN; aspartate transaminase (AST) \<=2.5 x ULN; alanine transaminase (ALT) \<=2.5 x ULN OR \<5 x ULN; estimated glomerular filtration rate \>=50 milliliter (mL)/minute/1.73 m\^2; ejection fraction\>= lower limit of normal (LLN); troponin \<=ULN
* Able to swallow and retain orally administered medication.
* A female subject is eligible to participate if she is of: Non-childbearing potential; Childbearing potential and agrees to use one of the contraception methods from the time of the screening pregnancy test until at least 7 months after the last dose of study treatment; All female subjects of childbearing potential must have a negative serum pregnancy test \<=7 days prior to first dose of study treatment; Female subjects who are lactating must discontinue nursing prior to the first dose of study treatment and must refrain from nursing throughout the treatment period and for 5 half-lives of GSK525762/trametinib or at least 28 days (whichever is longer) following the last dose of study treatment.
* Male subjects with female partners of childbearing potential must agree to abide by the reproductive guidelines from the first dose of study treatment and for at least 16 weeks after the last dose of study treatment.

Exclusion Criteria:

* Primary malignancy of the central nervous system or malignancies related to human immunodeficiency virus (HIV) or solid organ transplant.
* Prior therapy with any BET inhibitor.
* Recent prior therapy, defined as follows: Any non-biologic anti-cancer drug (either investigational or approved) within 14 days or 5 half-lives, whichever is longer, prior to the first dose of GSK525762 and trametinib; any nitrosoureas or mitomycin C within 42 days prior to the first dose of GSK525762 and trametinib; any biologic anti-cancer agent within 28 days prior to the first dose of GSK525762 and trametinib; any radiotherapy within 14 days or major surgery within 28 days prior to the first dose of GSK525762 and trametinib.
* Therapeutic-dose anticoagulation (e.g., warfarin, heparin) must be discontinued and coagulation parameters must be normalized prior to the first dose of GSK525762 and trametinib. Low dose (prophylactic) low molecular weight heparin or other anticoagulants are permitted.
* Current or planned use of a prohibited medication during treatment with GSK525762 and trametinib.
* Evidence of severe or uncontrolled systemic diseases (e.g., unstable or uncompensated respiratory, hepatic, renal, cardiac disease, or clinically significant bleeding episodes). Any serious and/or unstable pre-existing medical (aside from malignancy) condition, psychiatric disorder, or other conditions that could interfere with subject's safety, obtaining informed consent or compliance to the study procedures, in the opinion of the investigator.
* Symptomatic or untreated leptomeningeal or brain metastases or spinal cord compression. Subjects with a history of central nervous system (CNS) involvement may be enrolled so long as all of the following requirements are met: Subjects must have received definitive therapy for the CNS involvement (e.g., surgery, radiotherapy, or stereotactic radiosurgery \[i.e., gamma knife or equivalent\]); At least 28 days must have elapsed since the CNS-directed therapy; All symptoms and AEs from the CNS-directed therapy must have resolved to \<=Grade 1; Lesion stability must be demonstrated by serial imaging spaced at least 28 days apart; If the subject remains on corticosteroids, the dose must be stable to decreasing for the 28-day interval prior to study Day 1; The subject does not receive any enzyme-inducing anticonvulsants (EIACs) from 14 days prior to study Day 1 until the End of Treatment.
* Cardiac abnormalities as evidenced by any of the following: Baseline QTcF interval \>450 millisecond (msec); Clinically significant conduction abnormalities or arrhythmias; Presence of cardiac pacemaker or defibrillator with a paced ventricular rhythm limiting ECG analysis; History or evidence of current \>=Class II congestive heart failure as defined by New York Heart Association (NYHA); History of acute coronary syndromes (including unstable angina and myocardial infarction), coronary angioplasty, or stenting within the past 3 months. Subjects with a history of stent placement requiring ongoing antithrombotic therapy (e.g., clopidogrel, prasugrel) will not be permitted to enroll.
* Current active liver or biliary disease (with the exception of Gilbert's syndrome or asymptomatic gallstones, liver metastases, or otherwise stable chronic liver disease per investigator assessment).
* Presence of hepatitis B surface antigen (HBsAg) or positive hepatitis C antibody test result at screening or within 3 months prior to first dose of study treatment.
* History of known HIV infection or positive HIV test at screening.
* Any serious known immediate or delayed hypersensitivity reaction(s) to GSK525762 or trametinib, or idiosyncrasy to drugs chemically related to the investigational drugs.
* Subjects with a history of known bleeding disorder(s) or history of clinically significant (as judged by the investigator and medical monitor) hemorrhage (e.g., GI, neurologic, pulmonary) within the past 6 months.
* History of retinal vein occlusion.
* History of pneumonitis or interstitial lung disease.
* Any clinically significant gastrointestinal abnormalities that may alter absorption of oral medications, (e.g., malabsorption syndrome).

Primary outcomes:
measure: Part 1: Number of subjects with adverse events (AEs) and serious adverse events (SAEs)
timeFrame: Up to 12 months
measure: Part 1: Number of subjects with dose limiting toxicities (DLT) as a measure of safety
timeFrame: Up to 12 months
measure: Part 1: Area under the plasma concentration time curve from time 0 to last time of quantifiable concentration (AUC [0-T]) of GSK525762 and trametinib
timeFrame: Pre-dose,30minutes ±5minutes,1 hour±5minutes,2hours±10 minutes,3hours±10minutes, 4hours±15minutes,6±1hour,8±1hour, and 24±2hours at Day1 Week1;Day1 Week3. Pre-dose;1hour±10minutes post-dose at Day1 Week2,Day1 Week 4;every 8 Weeks from Week8 to Week52
measure: Part 1: Pre-dose (trough) concentration at the end of a dosing interval (Ctau) of GSK525762 and trametinib
timeFrame: Pre-dose,30minutes ±5minutes,1 hour±5minutes,2hours±10 minutes,3hours±10minutes, 4hours±15minutes,6±1hour,8±1hour, and 24±2hours at Day1 Week1;Day1 Week3. Pre-dose;1hour±10minutes post-dose at Day1 Week2,Day1 Week 4;every 8 Weeks from Week8 to Week52
measure: Part 1: Maximum observed plasma concentration (Cmax) of GSK525762 and trametinib
timeFrame: Pre-dose,30minutes ±5minutes,1 hour±5minutes,2hours±10 minutes,3hours±10minutes, 4hours±15minutes,6±1hour,8±1hour, and 24±2hours at Day1 Week1;Day1 Week3. Pre-dose;1hour±10minutes post-dose at Day1 Week2,Day1 Week 4;every 8 Weeks from Week8 to Week52
measure: Part 1: Time to Cmax (Tmax) of GSK525762 and trametinib
timeFrame: Pre-dose,30minutes ±5minutes,1 hour±5minutes,2hours±10 minutes,3hours±10minutes, 4hours±15minutes,6±1hour,8±1hour, and 24±2hours at Day1 Week1;Day1 Week3. Pre-dose;1hour±10minutes post-dose at Day1 Week2,Day1 Week 4;every 8 Weeks from Week8 to Week52
measure: Part 1: Change from Baseline in the phosphorylation of extracellular signal-regulated kinase (pERK) levels
timeFrame: Baseline and up to Week 3
measure: Part 1: Change from Baseline circulating protein or ribonucleic acid (RNA) biomarkers
timeFrame: Baseline and up to Week 3
measure: Part 1: Change from Baseline transcriptional levels and mitogen activated protein (MAP) kinase signaling
timeFrame: Baseline and up to Week 3
measure: Part 1: Overall response rate (ORR)
timeFrame: Up to 12 months
measure: Part 1: Disease control rate (DCR)
timeFrame: Up to 12 months
measure: Part 1: Duration of response (DOR)
timeFrame: Up to 12 months
measure: Part 2: ORR
timeFrame: Up to 24 months
measure: Part 2: Clinical response
timeFrame: Up to 24 months
measure: Part 2: Number of subjects with AEs and SAEs
timeFrame: Up to 24 months
measure: Part 2: Number of subjects with dose reductions or delays as a measure of safety
timeFrame: Up to 24 months
measure: Part 2: Number of subjects withdrawals due to toxicities
timeFrame: Up to 24 months
measure: Part 2: Number of subjects with abnormal clinical chemistry laboratory tests
timeFrame: Up to 24 months
measure: Part 2: Number of subjects with abnormal hematology laboratory tests
timeFrame: Up to 24 months
measure: Part 2: Number of subjects with abnormal routine urinalysis laboratory tests
timeFrame: Up to 24 months
measure: Part 2: Number of subjects with abnormal systolic blood pressure (SBP) and diastolic blood pressure (DBP) as a measure of safety
timeFrame: Up to 24 months
measure: Part 2: Number of subjects with abnormal pulse rate
timeFrame: Up to 24 months
measure: Part 2: Number of subjects with abnormal respiratory rate
timeFrame: Up to 24 months
measure: Part 2: Number of subjects with abnormal body temperature
timeFrame: Up to 24 months
measure: Part 2: Number of subjects with abnormal electrocardiogram (ECG) findings
timeFrame: Up to 24 months
measure: Part 2: Number of subjects with cardiotoxicity and gastrointestinal (GI) toxicity
timeFrame: Up to 24 months
measure: Part 2: AUC [0-T] of GSK525762 and trametinib
timeFrame: Pre-dose, and 0.5hour±5 minutes, 1-2 hours, 4-6hours post-dose at Day1 Week 1, Day1 Week3, and every 8 Weeks from Week8 to Week52
measure: Part 2: Ctau of GSK525762 and trametinib
timeFrame: Pre-dose, and 0.5hour±5 minutes, 1-2 hours, 4-6hours post-dose at Day1 Week 1, Day1 Week3, and every 8 Weeks from Week8 to Week52
measure: Part 2: Cmax of GSK525762 and trametinib
timeFrame: Pre-dose, and 0.5hour±5 minutes, 1-2 hours, 4-6hours post-dose at Day1 Week 1, Day1 Week3, and every 8 Weeks from Week8 to Week52
measure: Part 2: Tmax of GSK525762 and trametinib
timeFrame: Pre-dose, and 0.5hour±5 minutes, 1-2 hours, 4-6hours post-dose at Day1 Week 1, Day1 Week3, and every 8 Weeks from Week8 to Week52
measure: Part 2: Change from Baseline in the pERK levels
timeFrame: Baseline and up to Week 3
measure: Part 2: Change from Baseline circulating protein or RNA biomarkers
timeFrame: Baseline and up to Week 3
measure: Part 2: Change from Baseline transcriptional levels and MAP kinase signaling
timeFrame: Baseline and up to Week 3
Secondary outcomes:
measure: Part 1: Number of subjects with AEs and SAEs
timeFrame: Up to 12 months
measure: Part 1: Number of subjects with dose reductions or delays as a measure of safety
timeFrame: Up to 12 months
measure: Part 1: Number of subject withdrawals due to toxicities
timeFrame: Up to 12 months
measure: Part 1: Number of subjects with abnormal clinical chemistry laboratory tests
timeFrame: Up to 12 months
measure: Part 1: Number of subjects with abnormal hematology laboratory tests
timeFrame: Up to 12 months
measure: Part 1: Number of subjects with abnormal routine urinalysis laboratory tests
timeFrame: Up to 12 months
measure: Part 1: Number of subjects with abnormal SBP and DBP as a measure of safety
timeFrame: Up to 12 months
measure: Part 1: Number of subjects with abnormal pulse rate
timeFrame: Up to 12 months
measure: Part 1: Number of subjects with abnormal respiratory rate
timeFrame: Up to 12 months
measure: Part 1: Number of subjects with abnormal body temperature
timeFrame: Up to 12 months
measure: Part 1: Number of subjects with abnormal ECG findings
timeFrame: Up to 12 months
measure: Part 1: Number of subjects with cardiotoxicity and GI toxicity
timeFrame: Up to 12 months
measure: Part 1: (AUC [0-T]) of GSK525762 and trametinib
timeFrame: Pre-dose,30minutes ±5minutes,1 hour±5minutes,2hours±10 minutes,3hours±10minutes, 4hours±15minutes,6±1hour,8±1hour, and 24±2hours at Day1 Week1;Day1 Week3. Pre-dose;1hour±10minutes post-dose at Day1 Week2,Day1 Week 4;every 8 Weeks from Week8 to Week52
measure: Part 1: Ctau of GSK525762 and trametinib
timeFrame: Pre-dose,30minutes ±5minutes,1 hour±5minutes,2hours±10 minutes,3hours±10minutes, 4hours±15minutes,6±1hour,8±1hour, and 24±2hours at Day1 Week1;Day1 Week3. Pre-dose;1hour±10minutes post-dose at Day1 Week2,Day1 Week 4;every 8 Weeks from Week8 to Week52
measure: Part 1: Cmax of GSK525762 and trametinib
timeFrame: Pre-dose,30minutes ±5minutes,1 hour±5minutes,2hours±10 minutes,3hours±10minutes, 4hours±15minutes,6±1hour,8±1hour, and 24±2hours at Day1 Week1;Day1 Week3. Pre-dose;1hour±10minutes post-dose at Day1 Week2,Day1 Week 4;every 8 Weeks from Week8 to Week52
measure: Part 1: Tmax of GSK525762 and trametinib
timeFrame: Pre-dose,30minutes ±5minutes,1 hour±5minutes,2hours±10 minutes,3hours±10minutes, 4hours±15minutes,6±1hour,8±1hour, and 24±2hours at Day1 Week1;Day1 Week3. Pre-dose;1hour±10minutes post-dose at Day1 Week2,Day1 Week 4;every 8 Weeks from Week8 to Week52
measure: Part 1: ORR
timeFrame: Up to 12 months
measure: Part 1: DCR
timeFrame: Up to 12 months
measure: Part 1: DOR
timeFrame: Up to 12 months
measure: Part 1: Progression-free survival (PFS)
timeFrame: Up to 12 months
measure: Part 2: PFS
timeFrame: Up to 24 months
measure: Part 2: DOR
timeFrame: Up to 24 months
measure: Part 2: DCR
timeFrame: Up to 24 months
measure: Part 2 :Concentrations of GSK525762 and its relevant metabolite(s) and trametinib following repeat dose oral administration.
timeFrame: Pre-dose, and 0.5hour±5 minutes, 1-2 hours, 4-6hours post-dose at Day1 Week 1, Day1 Week3, and every 8 Weeks from Week8 to Week52
Other outcomes:
Locations:
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References: