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

NCT03745989 | Completed Phase 1 Results FDA Drug

• 2 other identifiers: 8353-014MK-8353-014
• Study Type: interventional
• Target: 30
• Locations: 3 countries
• Sites: 5

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.

Conditions

Solid Tumors

Keywords

advanced/metastatic; solid tumors; Selumetinib

Outcome Measures

Primary Outcomes (3)

• 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 Outcomes (6)

• Area Under the Plasma Concentration-Time Curve for MK-8353 From Time 0 to 12 Hours

  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

  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

  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

  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

  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

Study Arms (1)

MK-8353 and Selumetinib Dose Escalation

EXPERIMENTAL

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; Drug: Selumetinib

Interventions

MK-8353 DRUG

Participants will receive MK-8353 orally twice daily (BID), escalated sequentially from 50 mg to 250 mg.

MK-8353 and Selumetinib Dose Escalation

Selumetinib DRUG

Participants will receive selumetinib orally BID, escalated sequentially from 25 mg to 75 mg.

Also known as: MK-5618

MK-8353 and Selumetinib Dose Escalation

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Merck Sharp & Dohme LLC: lead

Study Sites (5)

Florida Cancer Specialists ( Site 7000)

Sarasota, Florida, 34232, United States

Location

Next Oncology ( Site 0001)

San Antonio, Texas, 78229, United States

Location

BC Cancer-Vancouver Center ( Site 0011)

Vancouver, British Columbia, V5Z 4E6, Canada

Location

Princess Margaret Cancer Centre ( Site 0012)

Toronto, Ontario, M5G 2M9, Canada

Location

Istituto Oncologica della Svizzera Italiana (IOSI) ( Site 0020)

Bellinzona, Canton Ticino, 6500, Switzerland

Location

Related Publications (1)

• 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.

  PMID: 37040046 RESULT

Related Links

• Merck Oncology Clinical Trials Information

MeSH Terms

Conditions

Neoplasm Metastasis

Interventions

MK-8353; AZD 6244

Condition Hierarchy (Ancestors)

Neoplastic Processes; Neoplasms; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Results Point of Contact

• Title: Senior Vice President, Global Clinical Development
• Organization: Merck Sharp & Dohme Corp.

ClinicalTrialsDisclosure@merck.com

1-800-672-6372

Study Officials

• Medical Director

  Merck Sharp & Dohme LLC

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: 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.

Study Record Dates

• First Submitted: November 16, 2018
• First Posted: November 19, 2018
• Study Start: February 22, 2019
• Primary Completion: March 19, 2021
• Study Completion: March 19, 2021
• Last Updated: July 27, 2023
• Results First Posted: January 25, 2023

Record last verified: 2023-07

Data Sharing

• IPD Sharing: Will share

Locations

US (2); CA (2); CH (1)