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

NCT03787602 | Unknown Phase 1 FDA Drug

• 1 other identifier: KRT-232-103
• Study Type: interventional
• Target: 115
• Locations: 10 countries
• Sites: 51

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.

Conditions

Merkel Cell Carcinoma

Keywords

navtemadlin (KRT-232)

Outcome Measures

Primary Outcomes (6)

• Cohort 1 Part 1: To determine the KRT-232 RP2D.

  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

  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

  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

  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.

  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.

  ORR will be assessed per RECIST criteria 1.1 by IRC.

  10 Weeks

Secondary Outcomes (5)

• To determine the confirmed ORR based on investigator assessment.

  1 year after last subject enrolled.

• To determine the duration of response (DoR)

  1 year after last subject enrolled

• To determine Progression-free survival (PFS)

  1 year after last subject enrolled

• To determine overall survival (OS)

  1 year after last subject enrolled

• To determine clinical benefit rate (CBR)

  1 year after last subject enrolled.

Study Arms (11)

Cohort 1, Arm 1

EXPERIMENTAL

KRT-232 will be administered orally, once daily (QD) on Days 1-7 in a 21-day cycle.

Drug: KRT-232

Cohort 1, Arm 1b

EXPERIMENTAL

KRT-232 will be administered orally, once daily (QD) on Days 1-5 in a 23-day cycle.

Drug: KRT-232

Cohort 1, Arm 2b

EXPERIMENTAL

KRT-232 will be administered orally, once daily (QD) on Days 1-5 in a 28-day cycle.

Drug: KRT-232

Cohort 1, Arm 3

EXPERIMENTAL

KRT-232 will be administered orally, once daily (QD) on Days 1-7 in a 21-day cycle.

Drug: KRT-232

Cohort 1, Arm 5

EXPERIMENTAL

KRT-232 will be administered orally, once daily (QD) on Days 1-7 in a 28-day cycle.

Drug: KRT-232

Cohort 1 Expansion

EXPERIMENTAL

KRT-232 will be administered orally, once daily (QD) per Cohort 1 RP2D dose and schedule.

Drug: KRT-232

Cohort 2, Arm 1 KRT-232 in combination with avelumab

EXPERIMENTAL

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; Drug: Avelumab

Cohort 2, Arm 2 KRT-232 in combination with avelumab

EXPERIMENTAL

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; Drug: Avelumab

Cohort 2 Expansion

EXPERIMENTAL

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; Drug: Avelumab

Cohort 3

EXPERIMENTAL

KRT-232 will be administered orally, once daily (QD) per Cohort 1 RP2D dose and schedule.

Drug: KRT-232

Cohort 4

EXPERIMENTAL

KRT-232 will be administered orally, once daily (QD) per Cohort 1 RP2D dose and schedule.

Drug: KRT-232

Interventions

KRT-232 DRUG

KRT-232 is an experimental MDM2 anticancer drug taken by mouth.

Also known as: navtemadlin

Cohort 1 Expansion; Cohort 1, Arm 1; Cohort 1, Arm 1b; Cohort 1, Arm 2b; Cohort 1, Arm 3; Cohort 1, Arm 5; Cohort 2 Expansion; Cohort 2, Arm 1 KRT-232 in combination with avelumab; Cohort 2, Arm 2 KRT-232 in combination with avelumab; Cohort 3; Cohort 4

Avelumab DRUG

Avelumab is a PD-L1 blocking antibody anticancer drug administered by intravenous infusion.

Also known as: Bavencio

Cohort 2 Expansion; Cohort 2, Arm 1 KRT-232 in combination with avelumab; Cohort 2, Arm 2 KRT-232 in combination with avelumab

Eligibility Criteria

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

You may qualify if:

• 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

You may not qualify if:

• 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)

Sponsors & Collaborators

• Kartos Therapeutics, Inc.: lead

Study Sites (51)

University of Colorado Anschutz Medical Campus

Aurora, Colorado, 80045, United States

RECRUITING

Miami Cancer Institute

Miami, Florida, 33176, United States

RECRUITING

Moffitt

Tampa, Florida, 33612, United States

RECRUITING

Northwestern Memorial Hospital

Chicago, Illinois, 60612, United States

RECRUITING

Norton Healthcare

Louisville, Kentucky, 40202, United States

RECRUITING

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

RECRUITING

Dana-Farber Cancer Institute

Boston, Massachusetts, 02215-5418, United States

RECRUITING

University of Michigan

Ann Arbor, Michigan, 48109, United States

RECRUITING

Memorial Sloan-Kettering Cancer Center

New York, New York, 10021, United States

RECRUITING

Mount Sinai Hospital

New York, New York, 10029, United States

RECRUITING

Fox Chase Cancer Center

Philadelphia, Pennsylvania, 19111-2434, United States

ACTIVE NOT RECRUITING

UPMC Hillman Cancer Center

Pittsburgh, Pennsylvania, 15232, United States

RECRUITING

University of Texas MD Anderson

Houston, Texas, 77030, United States

RECRUITING

Inova Health Care Services

Fairfax, Virginia, 22031, United States

RECRUITING

Princess Alexandra Hospital Oncology

Woolloongabba, Australia

RECRUITING

Centro Catarinense de Pesquisa (CECAP) - Hospital Santa Catarina de Blumenau

Blumenau, Brazil

RECRUITING

Instituto Nacional do Cancer

Brasília, Brazil

RECRUITING

Centro Intergado de Oncologia

Curitiba, Brazil

RECRUITING

Centro de Pesquisa Clinica em Oncologia

Ijuí, Brazil

RECRUITING

Clinica De Neoplasias Litoral

Itajaí, Brazil

RECRUITING

Hospital Paulistano

São Paulo, Brazil

RECRUITING

Princess Margaret Cancer Centre

Toronto, Canada

RECRUITING

CHU de Bordeaux- Hopital Saint-Andre

Bordeaux, France

RECRUITING

AP-HP Universite Paris Saclay

Gif-sur-Yvette, France

RECRUITING

CHU de Lille

Lille, France

RECRUITING

CHU Lyon-Sud

Lyon, France

RECRUITING

Hôpital de la Timone. Aix-Marseille Université

Marseille, Cedex 5, France

RECRUITING

CHU Montpellier

Montpellier, France

RECRUITING

CHU de Nantes

Nantes, France

RECRUITING

Hôpital Saint Louis - APHP

Paris, France

RECRUITING

CHU de Tours

Tours, France

RECRUITING

Vivantes Network for Health Gmb, Neukölln Clinic

Berlin, Germany

RECRUITING

Uniklinik Koln

Cologne, Germany

RECRUITING

Universitätsklinikum Erlangen

Erlangen, Germany

RECRUITING

Universitätsklinikum Essen (AöR)

Essen, Germany

RECRUITING

Nationales Centrum für Tumorerkrankungen NCT

Heidelberg, Germany

RECRUITING

Universitätsklinik Rostock

Rostock, Germany

RECRUITING

Universitats-Hautklinik Tubingen

Tübingen, Germany

RECRUITING

Institute for Cancer Research and Treatment

Candiolo, Italy

RECRUITING

Istituto Nazionale Tumori IRCCS Fondazione Pascale

Napoli, Italy

RECRUITING

AUSL della Romagna

Ravenna, Italy

RECRUITING

AOUS Le Scotte

Siena, Italy

RECRUITING

OSP Civile Maggiore Borgo Trento

Verona, Italy

RECRUITING

University Medical Center Groningen

Groningen, Netherlands

RECRUITING

National Cancer Center

Goyang-si, South Korea

RECRUITING

Seoul National University Hospital

Seoul, South Korea

RECRUITING

Severance Hospital Yonsei University Health System

Seoul, South Korea

RECRUITING

Hospital Duran i Reynals

Barcelona, Spain

RECRUITING

Hospital General Universitario Gregorio Marañn (Madrid)

Madrid, Spain

RECRUITING

Complejo Hospitalario de Navarra

Pamplona, Spain

RECRUITING

Fundacio Investigao Hospital General Universitario de Valencia

Valencia, Spain

RECRUITING

MeSH Terms

Conditions

Carcinoma, Merkel Cell

Interventions

navtemadlin; 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsulfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; avelumab

Condition Hierarchy (Ancestors)

Polyomavirus Infections; DNA Virus Infections; Virus Diseases; Infections; Tumor Virus Infections; Carcinoma, Neuroendocrine; Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue

Central Study Contacts

John Mei

CONTACT

650-542-0136; jmei@kartosthera.com

Emily Houlihan

CONTACT

401-954-8042; ehoulihan@kartosthera.com

Study Design

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

Study Record Dates

• First Submitted: December 6, 2018
• First Posted: December 26, 2018
• Study Start: March 19, 2019
• Primary Completion: November 1, 2024
• Study Completion: August 1, 2025
• Last Updated: March 2, 2023

Record last verified: 2023-02

Locations

NL (1); AU (1); IT (5); DE (7); ES (4); KR (3); CA (1); FR (9); US (14); BR (6)