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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

Sponsor
Kartos Therapeutics, Inc. (Industry)
Overall Status
Recruiting
CT.gov ID
NCT03787602
Collaborator
(none)
115
Enrollment
39
Locations
11
Arms
76.5
Anticipated Duration (Months)
2.9
Patients Per Site
0
Patients Per Site Per Month

Study Details

Study Description

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
Phase 1/Phase 2

Study Design

Study Type:
Interventional
Anticipated 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 :
Mar 19, 2019
Anticipated Primary Completion Date :
Nov 1, 2024
Anticipated Study Completion Date :
Aug 1, 2025

Arms and Interventions

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 Names:
  • 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 Names:
  • 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 Names:
  • 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 Names:
  • 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 Names:
  • 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 Names:
  • 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 Names:
  • navtemadlin

    • Drug: Avelumab
    Avelumab is a PD-L1 blocking antibody anticancer drug administered by intravenous infusion.
    Other Names:
  • 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 Names:
  • navtemadlin

    • Drug: Avelumab
    Avelumab is a PD-L1 blocking antibody anticancer drug administered by intravenous infusion.
    Other Names:
  • 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 Names:
  • navtemadlin

    • Drug: Avelumab
    Avelumab is a PD-L1 blocking antibody anticancer drug administered by intravenous infusion.
    Other Names:
  • 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 Names:
  • 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 Names:
  • navtemadlin

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Cohort 1 Part 1: To determine the KRT-232 RP2D. [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 [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 [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 [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. [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. [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. [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) [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) [1 year after last subject enrolled]

      Time from initial treatment until disease progression.

    4. To determine overall survival (OS) [1 year after last subject enrolled]

      Time from initial treatment until death from any cause.

    5. To determine clinical benefit rate (CBR) [1 year after last subject enrolled.]

      PR, CR or stable disease that last at least 10 weeks, per IRC or investigator assessment.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    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

    Locations

    Site City State Country Postal Code
    1 University of Colorado Anschutz Medical Campus Aurora Colorado United States 80045
    2 Miami Cancer Institute Miami Florida United States 33176
    3 Moffitt Tampa Florida United States 33612
    4 Northwestern Memorial Hospital Chicago Illinois United States 60612
    5 Norton Healthcare Louisville Kentucky United States 40202
    6 Massachusetts General Hospital Boston Massachusetts United States 02114
    7 Dana-Farber Cancer Institute Boston Massachusetts United States 02215-5418
    8 University of Michigan Ann Arbor Michigan United States 48109
    9 Memorial Sloan-Kettering Cancer Center New York New York United States 10021
    10 Mount Sinai Hospital New York New York United States 10029
    11 Fox Chase Cancer Center Philadelphia Pennsylvania United States 19111-2434
    12 UPMC Hillman Cancer Center Pittsburgh Pennsylvania United States 15232
    13 University of Texas MD Anderson Houston Texas United States 77030
    14 Inova Health Care Services Fairfax Virginia United States 22031
    15 Princess Alexandra Hospital Oncology Woolloongabba Australia
    16 CHU de Bordeaux- Hopital Saint-Andre Bordeaux France
    17 AP-HP Universite Paris Saclay Gif-sur-Yvette France
    18 CHU de Lille Lille France
    19 Hôpital de la Timone. Aix-Marseille Université Marseille France Cedex 5
    20 CHU de Nantes Nantes France
    21 Hôpital Saint Louis - APHP Paris France
    22 Vivantes Network for Health Gmb, Neukölln Clinic Berlin Germany
    23 Universitätsklinikum Erlangen Erlangen Germany
    24 Universitätsklinikum Essen (AöR) Essen Germany
    25 Nationales Centrum für Tumorerkrankungen NCT Heidelberg Germany
    26 Uniklinik Koln Köln Germany
    27 Universitätsklinik Rostock Rostock Germany
    28 Universitats-Hautklinik Tubingen Tübingen Germany
    29 Istituto Nazionale Tumori IRCCS Fondazione Pascale Napoli Italy
    30 AUSL della Romagna Ravenna Italy
    31 AOUS Le Scotte Siena Italy
    32 OSP Civile Maggiore Borgo Trento Verona Italy
    33 National Cancer Center Goyang-si Korea, Republic of
    34 Seoul National University Hospital Seoul Korea, Republic of
    35 Severance Hospital Yonsei University Health System Seoul Korea, Republic of
    36 Hospital Duran i Reynals Barcelona Spain
    37 Hospital General Universitario Gregorio Marañn (Madrid) Madrid Spain
    38 Complejo Hospitalario de Navarra Pamplona Spain
    39 Fundacio Investigao Hospital General Universitario de Valencia Valencia Spain

    Sponsors and Collaborators

    • Kartos Therapeutics, Inc.

    Investigators

    None specified.

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Kartos Therapeutics, Inc.
    ClinicalTrials.gov Identifier:
    NCT03787602
    Other Study ID Numbers:
    • KRT-232-103
    First Posted:
    Dec 26, 2018
    Last Update Posted:
    Aug 4, 2022
    Last Verified:
    Aug 1, 2022
    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:
    Carcinoma, Merkel Cell
    Carcinoma
    Avelumab

    Study Results

    No Results Posted as of Aug 4, 2022