Study of MK-8353 + Selumetinib in Advanced/Metastatic Solid Tumors (MK-8353-014)

Study Overview
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Brief Summary
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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
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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.

Official Title
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Phase 1b Open-label Study of MK-8353 in Combination With Selumetinib (MK-5618) in Participants With Advanced/Metastatic Solid Tumors

Conditions
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Solid Tumors

Intervention / Treatment
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* Drug: MK-8353
* Drug: Selumetinib


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Sequential Assignment
Interventional 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.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MK-8353 and Selumetinib Dose Escalation<br>Participants will receive a combination MK-8353 and selumetinib for 4 days on and 3 days off until disease progression or discontinuation. MK-8353 will be escalated sequentially from 50 mg to 250 mg based on pharmacokinetic and safety data. Selumetinib will be escalated sequentially from 25 mg to 75 mg based on pharmacokinetic and safety data. Doses may be adjusted downward sequentially based on tolerability | Drug: MK-8353<br>* Participants will receive MK-8353 orally twice daily (BID), escalated sequentially from 50 mg to 250 mg.<br>Drug: Selumetinib<br>* Participants will receive selumetinib orally BID, escalated sequentially from 25 mg to 75 mg.<br>* Other names: MK-5618;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Experiencing Dose Limiting Toxicities | A dose limiting toxicity (DLT) is defined as any hematologic or non-hematologic toxicity ≥Grade 3 per National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.0. The occurrence of any of the designated toxicities during Cycle 1 (3-week cycle) were considered a DLT, if assessed by the investigator to be possibly, probably, or definitely related to study treatment administration. The number of participants experiencing DLTs was assessed. | Cycle 1 (3-week Cycle) (Up to 3 weeks) | 
| Number of Participants Experiencing Adverse Events | An adverse event (AE) is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. 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 study intervention. The number of participants experiencing AEs was assessed. |  90 days after last treatment dose (up to  45 weeks) | 
| Number of Participants Discontinuing Study Treatment Due to AEs | An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. 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 study intervention. The number of participants discontinuing study treatment due to AEs was assessed. | Up to  33 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Plasma Concentration-Time Curve for MK-8353 From Time 0 to 12 Hours | Blood samples were collected to determine the area under the curve from time 0 to 12 hours (AUC0-12). AUC is a measure of the amount of drug in the blood over time. | 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 | 
| AUC0-12 for Selumetinib | Blood samples were collected to determine the AUC0-12. AUC is a measure of the amount of drug in the blood over time. | 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 | 
| Minimum Observed Plasma Concentration for MK-8353 | Blood samples were collected to determine the minimum observed plasma concentration (Cmin) which is the minimum amount of drug in the plasma after the dose is given. In cases where Cmin values were below the limit of quantification (BLOQ), arithmetic mean (percent coefficient of variation [%CV]) was reported instead of geometric mean (percent geometric coefficient of variation [%GCV]), since geometric mean (%GCV) was not calculable. In cases where all Cmin values were BLOQ, mean was not calculable and indicated as NA. | 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 | 
| Cmin for Selumetinib | Blood samples were collected to determine the Cmin which is the minimum amount of drug in the plasma after the dose is given. In cases where Cmin values were BLOQ, arithmetic mean (%CV) was reported instead of geometric mean (%GCV), since geometric mean (%GCV) was not calculable. In cases where all Cmin values were BLOQ, mean was not calculable and indicated as NA. | 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 | 
| Maximum Observed Plasma Concentration for MK-8353 | Blood samples were collected to determine the maximum observed plasma concentration (Cmax) which is the measure of the maximum amount of drug in the plasma after the dose is given. | 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 | 
| Cmax for Selumetinib | Blood samples were collected to determine the Cmax which is the measure of the maximum amount of drug in the plasma after the dose is given. | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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advanced/metastatic, solid tumors, Selumetinib