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A Study of MK-0482 as Monotherapy and in Combination With Pembrolizumab (MK-3475) in Participants With Advanced Solid Tumors (MK-0482-001)

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ClinicalTrials.gov Identifier: NCT03918278
Recruitment Status : Not yet recruiting
First Posted : April 17, 2019
Last Update Posted : May 13, 2019
Sponsor:
Information provided by (Responsible Party):
Merck Sharp & Dohme Corp.

Brief Summary:
This is a dose escalation study to determine the safety and pharmacokinetics of MK-0482 as monotherapy and in combination with pembrolizumab (MK-3475) in participants with advanced solid tumors for which there is no available therapy which may convey clinical benefit.

Condition or disease Intervention/treatment Phase
Neoplasms Biological: MK-0482 Biological: pembrolizumab Phase 1

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 85 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1b, Open-Label, Dose Escalation Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of MK-0482 as Monotherapy and in Combination With Pembrolizumab in Participants With Advanced/Metastatic Solid Tumors.
Estimated Study Start Date : June 17, 2019
Estimated Primary Completion Date : October 11, 2021
Estimated Study Completion Date : October 11, 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: MK-0482 Monotherapy
Participants receive escalating doses of MK-0482 via intravenous (IV) infusion on Day 1 of each 21-day cycle (Q3W) for up to 35 administrations (up to approximately 2 years).
Biological: MK-0482
IV infusion

Experimental: MK-0482 + Pembrolizumab Combination Therapy
Participants receive escalating doses of MK-0482 via IV infusion + pembrolizumab 200 mg via IV infusion on Day 1 of each 21-day cycle (Q3W) for up to 35 administrations (up to approximately 2 years).
Biological: MK-0482
IV infusion

Biological: pembrolizumab
IV infusion
Other Names:
  • MK-3475
  • KEYTRUDA®




Primary Outcome Measures :
  1. Number of Participants Who Experience a Dose-Limiting Toxicity (DLT) Graded Using National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 [ Time Frame: Cycle 1 (Up to 21 days) ]
    DLTs were defined as any of the following toxicities assessed by the investigator as treatment (Tx)-related: Grade (Gr)4 nonhematologic toxicity; Gr4 hematologic toxicity lasting ≥7 days, except thrombocytopenia; Gr4 thrombocytopenia of any duration; Gr3 thrombocytopenia associated with clinically-significant bleeding; nonhematologic adverse event (AE) ≥Gr3 in severity, with exceptions; Gr3/4 alanine transaminase, aspartate transaminase, and/or bilirubin laboratory values, with exceptions; Gr3/4 nonhematologic laboratory abnormality if: clinically significant medical intervention is required or if abnormality leads to hospitalization, persists for >1 week or results in drug-induced liver injury with exceptions; Gr3/4 febrile neutropenia; >2 week-delay in starting Cycle 2 due to Tx-related toxicity; Tx-related toxicity resulting in Tx discontinuation during Cycle 1; missing >25% of the MK-0482 and/or pembrolizumab doses during Cycle 1 resulting from Tx-related AE; or Gr5 toxicity.

  2. Number of Participants Who Experience at Least One Adverse Event (AE) [ Time Frame: Up to approximately 27 months ]
    An AE is defined as any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. The number of participants who experience at least one AE will be presented.

  3. Number of Participants Who Discontinue Study Treatment Due to an Adverse Event (AE) [ Time Frame: Up to approximately 24 months ]
    The number of participants who discontinue study treatment due to an AE will be presented.


Secondary Outcome Measures :
  1. Minimum Serum Concentration (Cmin) of MK-0482 When Administered as Monotherapy [ Time Frame: At designated time points (Up to approximately 25 months) ]
    Blood samples will be obtained at designated time points for the assessment of MK-0482 Cmin (Cycle 1 Day 1: Predose and at end of administration [up to approximately 60 minutes after the start of administration]; Cycle 1 Days 2, 4, 8 and 15: Once daily; Cycles 2, 4, 6, 8 and every 4 cycles thereafter: Predose and at end of administration [up to approximately 60 minutes after the start of administration]; and at end of treatment/discontinuation [Up to approximately 25 months]). Each cycle is 21 days.

  2. Minimum Serum Concentration (Cmin) of MK-0482 When Administered in Combination with Pembrolizumab [ Time Frame: At designated time points (Up to approximately 25 months) ]
    Blood samples will be obtained at designated time points for the assessment of MK-0482 Cmin (Cycle 1 Day 1: Predose and at end of administration [up to approximately 60 minutes after the start of administration]; Cycle 1 Days 2, 4, 8 and 15: Once daily; Cycles 2, 4, 6, 8 and every 4 cycles thereafter: Predose and at end of administration [up to approximately 60 minutes after the start of administration]; and at end of treatment/discontinuation [Up to approximately 25 months]). Each cycle is 21 days.

  3. Maximum Serum Concentration (Cmax) of MK-0482 When Administered as Monotherapy [ Time Frame: At designated time points (Up to approximately 25 months) ]
    Blood samples will be obtained at designated time points for the assessment of MK-0482 Cmax (Cycle 1 Day 1: Predose and at end of administration [up to approximately 60 minutes after the start of administration]; Cycle 1 Days 2, 4, 8 and 15: Once daily; Cycles 2, 4, 6, 8 and every 4 cycles thereafter: Predose and at end of administration [up to approximately 60 minutes after the start of administration]; and at end of treatment/discontinuation [Up to approximately 25 months]). Each cycle is 21 days.

  4. Maximum Serum Concentration (Cmax) of MK-0482 When Administered in Combination with Pembrolizumab [ Time Frame: At designated time points (Up to approximately 25 months) ]
    Blood samples will be obtained at designated time points for the assessment of MK-0482 Cmax (Cycle 1 Day 1: Predose and at end of administration [up to approximately 60 minutes after the start of administration]; Cycle 1 Days 2, 4, 8 and 15: Once daily; Cycles 2, 4, 6, 8 and every 4 cycles thereafter: Predose and at end of administration [up to approximately 60 minutes after the start of administration]; and at end of treatment/discontinuation [Up to approximately 25 months]). Each cycle is 21 days.

  5. Area Under the Concentration-Time Curve (AUC) of MK-0482 When Administered as Monotherapy [ Time Frame: At designated time points (Up to approximately 25 months) ]
    Blood samples will be obtained at designated time points for the assessment of MK-0482 AUC (Cycle 1 Day 1: Predose and at end of administration [up to approximately 60 minutes after the start of administration]; Cycle 1 Days 2, 4, 8 and 15: Once daily; Cycles 2, 4, 6, 8 and every 4 cycles thereafter: Predose and at end of administration [up to approximately 60 minutes after the start of administration]; and at end of treatment/discontinuation [Up to approximately 25 months]). Each cycle is 21 days.

  6. Area Under the Concentration-Time Curve (AUC) of MK-0482 When Administered in Combination with Pembrolizumab [ Time Frame: At designated time points (Up to approximately 25 months) ]
    Blood samples will be obtained at designated time points for the assessment of MK-0482 AUC (Cycle 1 Day 1: Predose and at end of administration [up to approximately 60 minutes after the start of administration]; Cycle 1 Days 2, 4, 8 and 15: Once daily; Cycles 2, 4, 6, 8 and every 4 cycles thereafter: Predose and at end of administration [up to approximately 60 minutes after the start of administration]; and at end of treatment/discontinuation [Up to approximately 25 months]). Each cycle is 21 days.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Has histologically-or cytologically-confirmed advanced/metastatic solid tumors by pathology report and have received, or been intolerant to, or been ineligible for, all treatments known to confer clinical benefit
  • Has measurable disease by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as assessed by the local site investigator/radiology
  • Has provided an evaluable baseline tumor tissue sample
  • Has ≥1 discrete malignant lesions that are amenable to biopsy
  • Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1
  • A female participant is eligible to participate if she is not pregnant or breastfeeding, and ≥1 of the following conditions applies: is not a woman of childbearing potential (WOCBP) OR is using a contraceptive method that is highly effective or is abstinent from heterosexual intercourse as their preferred and usual lifestyle during the intervention period and for ≥120 days after the last dose of study treatment
  • Has a negative highly sensitive pregnancy test within 72 hours before the first dose of study treatment
  • Human immunodeficiency virus (HIV) infected participants must have well controlled HIV on anti-retroviral therapy (ART)

Exclusion Criteria:

  • Has a history of a second malignancy, unless potentially curative treatment has been completed with no evidence of recurrence for ≥2 years
  • Has a known additional malignancy that is progressing or has required active treatment within the past 2 years; with the exception of basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (eg, breast carcinoma, cervical cancer in situ) that have undergone potentially curative therapy
  • Has known active central nervous system metastases and/or carcinomatous meningitis
  • Has had a severe hypersensitivity reaction to treatment with a monoclonal antibody (mAb) and/or any component of pembrolizumab (MK-3475) or MK-0482
  • Has received any prior immunotherapy and was discontinued from that treatment due to a Grade 3 or higher immune-related adverse event (irAE)
  • Has an active infection requiring systemic therapy
  • Has a history of interstitial lung disease
  • Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis
  • Has an active autoimmune disease that has required systemic treatment in the past 2 years
  • HIV-infected participants with a history of Kaposi's sarcoma and/or Multicentric Castleman's Disease
  • Has known Hepatitis B or C infection
  • Has received prior systemic anticancer therapy, definitive radiotherapy, including investigational agents within 4 weeks (2 weeks for palliative radiation) prior to the first dose of study treatment
  • Has not recovered from all radiation-related toxicities to Grade 1 or less
  • Surgeries that required general anesthesia must be completed ≥2 weeks before first study treatment administration. Surgery requiring regional/epidural anesthesia must be completed ≥72 hours before first study treatment
  • Has received a live vaccine within 30 days prior to the first dose of study treatment
  • Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 28 days prior to the first dose of study treatment.
  • Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior the first dose of study treatment
  • 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
  • Has had an allogeneic tissue/solid organ transplant in the last 5 years or has evidence of graft-versus-host disease

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03918278


Sponsors and Collaborators
Merck Sharp & Dohme Corp.
Investigators
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Study Director: Medical Director Merck Sharp & Dohme Corp.

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Responsible Party: Merck Sharp & Dohme Corp.
ClinicalTrials.gov Identifier: NCT03918278     History of Changes
Other Study ID Numbers: 0482-001
MK-0482-001 ( Other Identifier: Merck Protocol Number )
First Posted: April 17, 2019    Key Record Dates
Last Update Posted: May 13, 2019
Last Verified: May 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf
URL: http://engagezone.msd.com/ds_documentation.php

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
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Pembrolizumab
Antineoplastic Agents, Immunological
Antineoplastic Agents