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

February 28, 2023 updated by: Kartos Therapeutics, Inc.

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

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.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Anticipated)

115

Phase

  • Phase 2
  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

  • Australia
      • Woolloongabba, Australia
        • Recruiting
        • Princess Alexandra Hospital Oncology
  • Brazil
      • Blumenau, Brazil
        • Recruiting
        • Centro Catarinense de Pesquisa (CECAP) - Hospital Santa Catarina de Blumenau
      • Brasília, Brazil
        • Recruiting
        • Instituto Nacional do Cancer
      • Curitiba, Brazil
        • Recruiting
        • Centro Intergado de Oncologia
      • Ijuí, Brazil
        • Recruiting
        • Centro de Pesquisa Clinica em Oncologia
      • Itajai, Brazil
        • Recruiting
        • Clinica de Neoplasias Litoral
      • São Paulo, Brazil
        • Recruiting
        • Hospital Paulistano
  • Canada
      • Toronto, Canada
        • Recruiting
        • Princess Margaret Cancer Centre
  • France
      • Bordeaux, France
        • Recruiting
        • CHU de Bordeaux- Hopital Saint-Andre
      • Gif-sur-Yvette, France
        • Recruiting
        • AP-HP Universite Paris Saclay
      • Lille, France
        • Recruiting
        • CHU de Lille
      • Lyon, France
        • Recruiting
        • CHU Lyon-Sud
      • Marseille, France, Cedex 5
        • Recruiting
        • Hôpital de la Timone. Aix-Marseille Université
      • Montpellier, France
        • Recruiting
        • CHU Montpellier
      • Nantes, France
        • Recruiting
        • CHU de Nantes
      • Paris, France
        • Recruiting
        • Hôpital Saint Louis - APHP
      • Tours, France
        • Recruiting
        • CHU de Tours
  • Germany
      • Berlin, Germany
        • Recruiting
        • Vivantes Network for Health Gmb, Neukölln Clinic
      • Erlangen, Germany
        • Recruiting
        • Universitätsklinikum Erlangen
      • Essen, Germany
        • Recruiting
        • Universitätsklinikum Essen (AöR)
      • Heidelberg, Germany
        • Recruiting
        • Nationales Centrum für Tumorerkrankungen NCT
      • Köln, Germany
        • Recruiting
        • Uniklinik Koln
      • Rostock, Germany
        • Recruiting
        • Universitätsklinik Rostock
      • Tübingen, Germany
        • Recruiting
        • Universitäts-Hautklinik Tübingen
  • Italy
      • Candiolo, Italy
        • Recruiting
        • Institute for Cancer Research and Treatment
      • Napoli, Italy
        • Recruiting
        • Istituto Nazionale Tumori IRCCS Fondazione Pascale
      • Ravenna, Italy
        • Recruiting
        • AUSL della Romagna
      • Siena, Italy
        • Recruiting
        • AOUS Le Scotte
      • Verona, Italy
        • Recruiting
        • OSP Civile Maggiore Borgo Trento
  • Korea, Republic of
      • Goyang-si, Korea, Republic of
        • Recruiting
        • National Cancer Center
      • Seoul, Korea, Republic of
        • Recruiting
        • Seoul National University Hospital
      • Seoul, Korea, Republic of
        • Recruiting
        • Severance Hospital Yonsei University Health System
  • Netherlands
      • Groningen, Netherlands
        • Recruiting
        • University Medical Center Groningen
  • Spain
      • Barcelona, Spain
        • Recruiting
        • Hospital Duran i Reynals
      • Madrid, Spain
        • Recruiting
        • Hospital General Universitario Gregorio Marañn (Madrid)
      • Pamplona, Spain
        • Recruiting
        • Complejo Hospitalario de Navarra
      • Valencia, Spain
        • Recruiting
        • Fundacio Investigao Hospital General Universitario de Valencia
  • United States
    • Colorado
      • Aurora, Colorado, United States, 80045
        • Recruiting
        • University of Colorado Anschutz Medical Campus
    • Florida
      • Miami, Florida, United States, 33176
        • Recruiting
        • Miami Cancer Institute
      • Tampa, Florida, United States, 33612
        • Recruiting
        • Moffitt
    • Illinois
      • Chicago, Illinois, United States, 60612
        • Recruiting
        • Northwestern Memorial Hospital
    • Kentucky
      • Louisville, Kentucky, United States, 40202
        • Recruiting
        • Norton Healthcare
        • Contact:
          • Norton Cancer Institute Research
    • Massachusetts
      • Boston, Massachusetts, United States, 02114
        • Recruiting
        • Massachusetts General Hospital
      • Boston, Massachusetts, United States, 02215-5418
        • Recruiting
        • Dana-Farber Cancer Institute
    • Michigan
      • Ann Arbor, Michigan, United States, 48109
        • Recruiting
        • University of Michigan
    • New York
      • New York, New York, United States, 10021
        • Recruiting
        • Memorial Sloan-Kettering Cancer Center
      • New York, New York, United States, 10029
        • Recruiting
        • Mount Sinai Hospital
    • Pennsylvania
      • Philadelphia, Pennsylvania, United States, 19111-2434
        • Active, not recruiting
        • Fox Chase Cancer Center
      • Pittsburgh, Pennsylvania, United States, 15232
        • Recruiting
        • UPMC Hillman Cancer Center
    • Texas
      • Houston, Texas, United States, 77030
        • Recruiting
        • University of Texas MD Anderson
    • Virginia
      • Fairfax, Virginia, United States, 22031
        • Recruiting
        • Inova Health Care Services

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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)

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
10 Weeks
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.
10 Weeks
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.
28 Days
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.
10 Weeks
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.
10 Weeks
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.
10 Weeks

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
1 year after last subject enrolled.
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.
1 year after last subject enrolled
To determine Progression-free survival (PFS)
Time Frame: 1 year after last subject enrolled
Time from initial treatment until disease progression.
1 year after last subject enrolled
To determine overall survival (OS)
Time Frame: 1 year after last subject enrolled
Time from initial treatment until death from any cause.
1 year after last subject enrolled
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.
1 year after last subject enrolled.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Kartos Therapeutics, Inc.

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

March 19, 2019

Primary Completion (Anticipated)

November 1, 2024

Study Completion (Anticipated)

August 1, 2025

Study Registration Dates

First Submitted

December 6, 2018

First Submitted That Met QC Criteria

December 21, 2018

First Posted (Actual)

December 26, 2018

Study Record Updates

Last Update Posted (Actual)

March 2, 2023

Last Update Submitted That Met QC Criteria

February 28, 2023

Last Verified

February 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • KRT-232-103

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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