Clinical trial NCT03745989: Study of MK-8353 + Selumetinib in Advanced/Metastatic Solid Tumors (MK-8353-014)
Official title: Phase 1b Open-label Study of MK-8353 in Combination With Selumetinib (MK-5618) in Participants With Advanced/Metastatic Solid Tumors
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Solid Tumors
Keywords: advanced/metastatic
solid tumors
Selumetinib
Lead sponsor: Merck Sharp & Dohme LLC
Sponsor class: INDUSTRY
First posted: 2018-11-19
Enrollment: 30
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SEQUENTIAL
Intervention model description: Groups of participants are assigned to receive interventions based on prior milestones being reached in the study, such as in some dose escalation and adaptive design studies.
Primary purpose: TREATMENT

Brief summary: This is a multicenter, worldwide, open-label study of MK-8353 in combination with selumetinib in participants with histologically or cytologically confirmed diagnosis of advanced solid tumor. This study will evaluate the safety, tolerability, and exploratory efficacy of MK-8353 in combination with selumetinib.

Detailed description: As specified by Phase 1 protocol-flexible language, modifications to the dose or dosing regimen can be made to achieve the scientific goals of the trial objectives and/or ensure appropriate safety of the trial participants. The proposed doses may be adjusted based on evaluation of safety, tolerability, and pharmacokinetic data.

Eligibility criteria: Inclusion Criteria:

* Have a histologically- or cytologically-documented, locally-advanced or metastatic solid tumor by pathology report and have received, or been intolerant to, all treatment known to confer clinical benefit.
* Provide an archival or newly obtained tumor tissue sample and blood samples for assessment of proto-oncogene rat sarcoma virus (RAS)/rapidly accelerated fibrosarcoma (RAF) mutation and for biomarker analysis.
* Have at least 1 measurable lesion as defined by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) on imaging studies (computed tomography \[CT\] or magnetic resonance imaging \[MRI\]) as assessed by the investigator/local radiology review.
* Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale. (Obtain within 7 days prior to first dose of study treatment.)
* Have the ability to swallow and retain oral medication.
* Demonstrate adequate organ function.
* Male participants must agree to use an acceptable contraception during the treatment period and for at least 120 days after the last dose of study intervention and refrain from donating sperm during this period.
* Female participants must not be pregnant, not breastfeeding, and either not a woman of childbearing potential (WOCBP) or a WOCBP who agrees to follow the study's contraceptive guidance during the treatment period and for at least 120 days, after the last dose of study intervention.

Exclusion Criteria:

* Have had chemotherapy, definitive radiation, or biological cancer therapy within 4 weeks (2 weeks for palliative radiation) prior to the first dose of study treatment, or has not recovered to National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 or better from any AEs that were due to cancer therapeutics administered more than 4 weeks earlier (this includes participants with previous immunomodulatory therapy with residual immune-related AEs).
* Have clinically active central nervous system metastases and/or carcinomatous meningitis.
* Have an active infection requiring therapy.
* Have known human immunodeficiency virus (HIV) and/or Hepatitis B or C infections, or known to be positive for Hepatitis B antigen (HBsAg)/ Hepatitis B virus (HBV) deoxyribonucleic acid (DNA) or Hepatitis C Antibody or ribonucleic acid (RNA).
* Have clinically significant cardiovascular disease as defined by study criteria.
* Have a history of thromboembolic or cerebrovascular events within 6 months prior to treatment start, including transient ischemic attacks (TIAs), cerebrovascular accidents (CVAs), deep vein thrombosis, or pulmonary embolism.
* Have neuromuscular disorders associated with an elevated creatine kinase (e.g., inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy).
* Have one or more study-defined ophthalmological findings/conditions.
* Have a known history of Gilbert's Syndrome.
* Have a history or current evidence of a gastrointestinal (GI) condition (e.g., inflammatory bowel disease, Crohn's disease, ulcerative colitis) or impaired liver function or diseases that in the opinion of the investigator may significantly alter the absorption or metabolism of oral medications.
* Have a known psychiatric or substance abuse disorder, or any other cognitive disorder that would interfere with the participant's ability to cooperate with the requirements of the study.
* Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the study, starting with the Screening Visit through 120 days after the last dose of study treatment.
* Received prior therapy with a mitogen activated protein kinase (MEK) inhibitor (e.g., cobimetinib, trametinib), or an extracellular signal-regulated kinase (ERK) inhibitor (e.g., MK-8353, GCD-0994, ulixertinib), or a proto-oncogene BRAF inhibitor (e.g., dabrafenib, vemurafenib).
* Is currently participating and receiving study treatment in a study of an investigational agent or has participated and received study treatment in a study of an investigational agent or has used an investigational device within 28 days of administration of selumetinib.
* Have a history of allergic reactions attributed to compounds of similar chemical or biologic composition to agents and/or excipients used in the study.
* A WOCBP who has a positive urine pregnancy test within 24 hours before the first dose of study treatment

Primary outcomes:
measure: Number of Participants Experiencing Dose Limiting Toxicities
timeFrame: Cycle 1 (3-week Cycle) (Up to 3 weeks)
measure: Number of Participants Experiencing Adverse Events
timeFrame: ~90 days after last treatment dose (up to ~45 weeks)
measure: Number of Participants Discontinuing Study Treatment Due to AEs
timeFrame: Up to ~33 weeks
Secondary outcomes:
measure: Area Under the Plasma Concentration-Time Curve for MK-8353 From Time 0 to 12 Hours
timeFrame: Study Days 1 and 4 of Cycle 1 (3-week cycle) at pre-dose and at 1, 2, 4, 6 hours, and between 8 and 12 hours post-dose
measure: AUC0-12 for Selumetinib
timeFrame: Study Days 1 and 4 of Cycle 1 (3-week cycle) at pre-dose and at 1, 2, 4, 6 hours, and between 8 and 12 hours post-dose
measure: Minimum Observed Plasma Concentration for MK-8353
timeFrame: Study Days 1 and 4 of Cycles 1 and 2 (3-week cycles). For Cycle 1, pre-dose and at 1, 2, 4, 6 hours, and between 8 and 12 hours post-dose; and for Cycle 2 pre-dose, and at 1 and 4 hours post-dose
measure: Cmin for Selumetinib
timeFrame: Study Days 1 and 4 of Cycles 1 and 2 (3-week cycles). For Cycle 1, pre-dose and at 1, 2, 4, 6 hours, and between 8 and 12 hours post-dose; and for Cycle 2 pre-dose, and at 1 and 4 hours post-dose
measure: Maximum Observed Plasma Concentration for MK-8353
timeFrame: Study Days 1 and 4 of Cycle 1 (3-week cycle) at pre-dose and at 1, 2, 4, 6 hours, and between 8 and 12 hours post-dose
measure: Cmax for Selumetinib
timeFrame: Study Days 1 and 4 of Cycle 1 (3-week cycle) at pre-dose and at 1, 2, 4, 6 hours, and between 8 and 12 hours post-dose
Other outcomes:
Locations:
city: Sarasota
country: United States
facility: Florida Cancer Specialists ( Site 7000)
state: Florida
city: San Antonio
country: United States
facility: Next Oncology ( Site 0001)
state: Texas
city: Vancouver
country: Canada
facility: BC Cancer-Vancouver Center ( Site 0011)
state: British Columbia
city: Toronto
country: Canada
facility: Princess Margaret Cancer Centre ( Site 0012)
state: Ontario
city: Bellinzona
country: Switzerland
facility: Istituto Oncologica della Svizzera Italiana (IOSI) ( Site 0020)
state: Ticino
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: Stathis A, Tolcher AW, Wang JS, Renouf DJ, Chen LC, Suttner LH, Freshwater T, Webber AL, Nayak T, Siu LL. Results of an open-label phase 1b study of the ERK inhibitor MK-8353 plus the MEK inhibitor selumetinib in patients with advanced or metastatic solid tumors. Invest New Drugs. 2023 Jun;41(3):380-390. doi: 10.1007/s10637-022-01326-3. Epub 2023 Apr 11.