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Navtemadlin (KRT-232) With or Without Anti-PD-1/Anti-PD-L1 for the Treatment of Patients With Merkel Cell Carcinoma

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ClinicalTrials.gov Identifier: NCT03787602
Recruitment Status : Recruiting
First Posted : December 26, 2018
Last Update Posted : March 2, 2023
Sponsor:
Information provided by (Responsible Party):
Kartos Therapeutics, Inc.

Study Description
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Brief Summary:
This study evaluates KRT-232, a novel oral small molecule inhibitor of MDM2, for the treatment of patients with Merkel Cell Carcinoma (MCC) who have failed treatment with at least one anti-PD-1 or anti-PD-L1 immunotherapy or in combination with avelumab in MCC patients who are anti-PD-1 or anti-PD-L1 treatment naïve. Inhibition of MDM2 is a novel mechanism of action in MCC.

Condition or disease Intervention/treatment Phase
Merkel Cell Carcinoma Drug: KRT-232 Drug: Avelumab Phase 1 Phase 2

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 115 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1b/2, Open-Label Study Evaluating the Safety and Efficacy of KRT-232 in Patients With p53 Wild-Type (p53WT) Merkel Cell Carcinoma (MCC) Who Have Failed Anti-PD-1 or Anti-PD-L1 Immunotherapy, or in Combination With Avelumab in MCC Patients Who Are Anti-PD-1 or Anti-PD-L1 Treatment Naïve
Actual Study Start Date : March 19, 2019
Estimated Primary Completion Date : November 2024
Estimated Study Completion Date : August 2025

Resource links provided by the National Library of Medicine

Drug Information available for: Avelumab

Arms and Interventions
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Arm Intervention/treatment
Experimental: Cohort 1, Arm 1
KRT-232 will be administered orally, once daily (QD) on Days 1-7 in a 21-day cycle.
 Drug: KRT-232
KRT-232 is an experimental MDM2 anticancer drug taken by mouth.
Other Name: navtemadlin
Experimental: Cohort 1, Arm 1b
KRT-232 will be administered orally, once daily (QD) on Days 1-5 in a 23-day cycle.
 Drug: KRT-232
KRT-232 is an experimental MDM2 anticancer drug taken by mouth.
Other Name: navtemadlin
Experimental: Cohort 1, Arm 2b
KRT-232 will be administered orally, once daily (QD) on Days 1-5 in a 28-day cycle.
 Drug: KRT-232
KRT-232 is an experimental MDM2 anticancer drug taken by mouth.
Other Name: navtemadlin
Experimental: Cohort 1, Arm 3
KRT-232 will be administered orally, once daily (QD) on Days 1-7 in a 21-day cycle.
 Drug: KRT-232
KRT-232 is an experimental MDM2 anticancer drug taken by mouth.
Other Name: navtemadlin
Experimental: Cohort 1, Arm 5
KRT-232 will be administered orally, once daily (QD) on Days 1-7 in a 28-day cycle.
 Drug: KRT-232
KRT-232 is an experimental MDM2 anticancer drug taken by mouth.
Other Name: navtemadlin
Experimental: Cohort 1 Expansion
KRT-232 will be administered orally, once daily (QD) per Cohort 1 RP2D dose and schedule.
 Drug: KRT-232
KRT-232 is an experimental MDM2 anticancer drug taken by mouth.
Other Name: navtemadlin
Experimental: Cohort 2, Arm 1 KRT-232 in combination with avelumab
KRT-232 will be administered orally, once daily (QD) on Days 1-5, in combination with avelumab 800 mg IV on Day 1 and 15 in a 28-day cycle.
 Drug: KRT-232
KRT-232 is an experimental MDM2 anticancer drug taken by mouth.
Other Name: navtemadlin

Drug: Avelumab
Avelumab is a PD-L1 blocking antibody anticancer drug administered by intravenous infusion.
Other Name: Bavencio
Experimental: Cohort 2, Arm 2 KRT-232 in combination with avelumab
KRT-232 will be administered orally, once daily (QD) on Days 1-7, in combination with avelumab 800 mg IV on Day 1 and 15 in a 28-day cycle.
 Drug: KRT-232
KRT-232 is an experimental MDM2 anticancer drug taken by mouth.
Other Name: navtemadlin

Drug: Avelumab
Avelumab is a PD-L1 blocking antibody anticancer drug administered by intravenous infusion.
Other Name: Bavencio
Experimental: Cohort 2 Expansion
KRT-232 will be administered orally, once daily (QD) per RP2D dose and schedule, in combination with avelumab 800 mg IV on Day 1 and 15 in a 28-day cycle.
 Drug: KRT-232
KRT-232 is an experimental MDM2 anticancer drug taken by mouth.
Other Name: navtemadlin

Drug: Avelumab
Avelumab is a PD-L1 blocking antibody anticancer drug administered by intravenous infusion.
Other Name: Bavencio
Experimental: Cohort 3
KRT-232 will be administered orally, once daily (QD) per Cohort 1 RP2D dose and schedule.
 Drug: KRT-232
KRT-232 is an experimental MDM2 anticancer drug taken by mouth.
Other Name: navtemadlin
Experimental: Cohort 4
KRT-232 will be administered orally, once daily (QD) per Cohort 1 RP2D dose and schedule.
 Drug: KRT-232
KRT-232 is an experimental MDM2 anticancer drug taken by mouth.
Other Name: navtemadlin


Outcome Measures
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Primary Outcome Measures :
  1. Cohort 1 Part 1: To determine the KRT-232 RP2D. [ Time Frame: 10 Weeks ]
    The Safety Review Committee (SRC) will determine RP2D for expansion based on safety and tolerability of each arm.

  2. Cohort 1 Part 2: To determine the objective response rate (ORR) in subjects with p53WT MCC who have failed anti-PD-1 or anti-PDL-1 immunotherapy [ Time Frame: 10 Weeks ]
    ORR will be assessed per RECIST criteria version 1.1 after all subjects have been treated at the RP2D of KRT 232 and completed the second response assessment.

  3. Cohort 2 Part 1: To determine the KRT-232 RP2D in combination with avelumab [ Time Frame: 28 Days ]
    DLTs will be used to establish the MTD of KRT-232 in combination with avelumab. SRC will determine the RP2D based on the safety of combination of KRT-232 with avelumab.

  4. Cohort 2 Part 2: To determine the objective response rate (ORR) in treatment-naïve subjects with p53WT MCC [ Time Frame: 10 Weeks ]
    ORR will be assessed per RECIST criteria version 1.1 after all 30 subjects have been treated at the RP2D of in combination with avelumab and have completed the second response assessment.

  5. Cohort 3: To determine the confirmed overall response rate (ORR) based on IRC assessments in subjects with p53WT MCC are chemotherapy naive and have failed anti-PD-1/PD-L. [ Time Frame: 10 Weeks ]
    ORR will be assessed per RECIST criteria 1.1 by IRC.

  6. Cohort 4: To determine the confirmed overall response rate (ORR) based on IRC assessments in subjects with p53WT MCC who have failed anti-PD-1 or anti-PDL-1 immunotherapy and have had least 1 line of prior chemotherapy. [ Time Frame: 10 Weeks ]
    ORR will be assessed per RECIST criteria 1.1 by IRC.


Secondary Outcome Measures :
  1. To determine the confirmed ORR based on investigator assessment. [ Time Frame: 1 year after last subject enrolled. ]
    ORR will be assessed per RECIST criteria 1.1 by investigators.

  2. To determine the duration of response (DoR) [ Time Frame: 1 year after last subject enrolled ]
    Time from documentation of response (CR or PR as determined by RECIST 1.1) until disease progression.

  3. To determine Progression-free survival (PFS) [ Time Frame: 1 year after last subject enrolled ]
    Time from initial treatment until disease progression.

  4. To determine overall survival (OS) [ Time Frame: 1 year after last subject enrolled ]
    Time from initial treatment until death from any cause.

  5. To determine clinical benefit rate (CBR) [ Time Frame: 1 year after last subject enrolled. ]
    PR, CR or stable disease that last at least 10 weeks, per IRC or investigator assessment.


Eligibility Criteria
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Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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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:

  • For Cohort 1, 3 and 4 patients must have failed treatment with at least one PD-1 inhibitor or PD-L1 inhibitor for metastatic MCC
  • For Cohort 2, patients must not have received any anti-PD-1 or anti-PD-L1 therapy
  • For Cohort 3, patients must not have received any prior chemotherapy
  • For Cohort 4, patients must have received at least one prior line of chemotherapy
  • ECOG performance status of 0 to 1
  • Histologically confirmed MCC. Disease must be measurable, with at least 1 measurable lesion by RECIST 1.1
  • MCC expressing p53WT based on any CLIA or test approved by local health authority or a validated test (Cohort 1 and 2)
  • MCC expressing p53WT based Central Lab test (Cohort 3 and 4)
  • Adequate hematological, hepatic, and renal functions

Exclusion Criteria:

  • For Cohort 2, subjects must not have autoimmune disease, medical conditions requiring systemic immunosuppression, prior stem cell transplant, or active infection with HBV or HCV.
  • Patients previously treated with MDM2 antagonist therapies or p53-directed therapies
  • History of major organ transplant
  • Patients with known central nervous system (CNS) metastases that are previously untreated
  • Grade 2 or higher QTc prolongation (>480 milli-seconds per NCI-CTCAE criteria, version 5.0)
Contacts and Locations
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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): NCT03787602


Contacts
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Contact: John Mei 650-542-0136 jmei@kartosthera.com
Contact: Emily Houlihan 401-954-8042 ehoulihan@kartosthera.com

Locations
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Sponsors and Collaborators
Kartos Therapeutics, Inc.
More Information
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Responsible Party: Kartos Therapeutics, Inc.
ClinicalTrials.gov Identifier: NCT03787602    
Other Study ID Numbers: KRT-232-103
First Posted: December 26, 2018    Key Record Dates
Last Update Posted: March 2, 2023
Last Verified: February 2023

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Kartos Therapeutics, Inc.:
navtemadlin (KRT-232)
Additional relevant MeSH terms:
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Carcinoma, Merkel Cell
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Polyomavirus Infections
DNA Virus Infections
Virus Diseases
Infections
Tumor Virus Infections
 Carcinoma, Neuroendocrine
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Adenocarcinoma
Neoplasms, Nerve Tissue
Avelumab
Antineoplastic Agents, Immunological
Antineoplastic Agents