Navtemadlin (KRT-232) With or Without Anti-PD-1/Anti-PD-L1 for the Treatment of Patients With Merkel Cell Carcinoma
- Registration Number
- NCT03787602
- Lead Sponsor
- Kartos Therapeutics, Inc.
- 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.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 115
- 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
- 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 & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Cohort 2, Arm 1 KRT-232 in combination with avelumab KRT-232 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. Cohort 1 Expansion KRT-232 KRT-232 will be administered orally, once daily (QD) per Cohort 1 RP2D dose and schedule. Cohort 1, Arm 1b KRT-232 KRT-232 will be administered orally, once daily (QD) on Days 1-5 in a 23-day cycle. Cohort 1, Arm 1 KRT-232 KRT-232 will be administered orally, once daily (QD) on Days 1-7 in a 21-day cycle. Cohort 1, Arm 2b KRT-232 KRT-232 will be administered orally, once daily (QD) on Days 1-5 in a 28-day cycle. Cohort 1, Arm 3 KRT-232 KRT-232 will be administered orally, once daily (QD) on Days 1-7 in a 21-day cycle. Cohort 1, Arm 5 KRT-232 KRT-232 will be administered orally, once daily (QD) on Days 1-7 in a 28-day cycle. Cohort 2, Arm 2 KRT-232 in combination with avelumab KRT-232 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. Cohort 4 KRT-232 KRT-232 will be administered orally, once daily (QD) per Cohort 1 RP2D dose and schedule. Cohort 3 KRT-232 KRT-232 will be administered orally, once daily (QD) per Cohort 1 RP2D dose and schedule. Cohort 2 Expansion KRT-232 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. Cohort 2, Arm 1 KRT-232 in combination with avelumab 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. Cohort 2, Arm 2 KRT-232 in combination with avelumab 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. Cohort 2 Expansion Avelumab 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.
- Primary Outcome Measures
Name Time Method 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.
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.
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.
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.
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.
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
Name Time Method 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.
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.
To determine Progression-free survival (PFS) 1 year after last subject enrolled Time from initial treatment until disease progression.
To determine overall survival (OS) 1 year after last subject enrolled Time from initial treatment until death from any cause.
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.
Trial Locations
- Locations (51)
CHU de Bordeaux- Hopital Saint-Andre
🇫🇷Bordeaux, France
Hôpital de la Timone. Aix-Marseille Université
🇫🇷Marseille, France
CHU Montpellier
🇫🇷Montpellier, France
Nationales Centrum für Tumorerkrankungen NCT
🇩🇪Heidelberg, Germany
Hôpital Saint Louis - APHP
🇫🇷Paris, France
CHU Lyon-Sud
🇫🇷Lyon, France
Universitätsklinikum Erlangen
🇩🇪Erlangen, Germany
Seoul National University Hospital
🇰🇷Seoul, Korea, Republic of
UPMC Hillman Cancer Center
🇺🇸Pittsburgh, Pennsylvania, United States
Fox Chase Cancer Center
🇺🇸Philadelphia, Pennsylvania, United States
Inova Health Care Services
🇺🇸Fairfax, Virginia, United States
Memorial Sloan-Kettering Cancer Center
🇺🇸New York, New York, United States
AUSL della Romagna
🇮🇹Ravenna, Italy
Universitätsklinikum Essen (AöR)
🇩🇪Essen, Germany
AOUS Le Scotte
🇮🇹Siena, Italy
Uniklinik Koln
🇩🇪Köln, Germany
Universitätsklinik Rostock
🇩🇪Rostock, Germany
Istituto Nazionale Tumori IRCCS Fondazione Pascale
🇮🇹Napoli, Italy
Fundacio Investigao Hospital General Universitario de Valencia
🇪🇸Valencia, Spain
National Cancer Center
🇰🇷Goyang-si, Korea, Republic of
Complejo Hospitalario de Navarra
🇪🇸Pamplona, Spain
University Medical Center Groningen
🇳🇱Groningen, Netherlands
Centro de Pesquisa Clinica em Oncologia
🇧🇷Ijuí, Brazil
Vivantes Network for Health Gmb, Neukölln Clinic
🇩🇪Berlin, Germany
Mount Sinai Hospital
🇺🇸New York, New York, United States
Princess Alexandra Hospital Oncology
🇦🇺Woolloongabba, Australia
Centro Intergado de Oncologia
🇧🇷Curitiba, Brazil
Northwestern Memorial Hospital
🇺🇸Chicago, Illinois, United States
Centro Catarinense de Pesquisa (CECAP) - Hospital Santa Catarina de Blumenau
🇧🇷Blumenau, Brazil
Instituto Nacional do Cancer
🇧🇷Brasília, Brazil
Clinica De Neoplasias Litoral
🇧🇷Itajai, Brazil
Hospital Duran i Reynals
🇪🇸Barcelona, Spain
University of Colorado Anschutz Medical Campus
🇺🇸Aurora, Colorado, United States
Dana-Farber Cancer Institute
🇺🇸Boston, Massachusetts, United States
Miami Cancer Institute
🇺🇸Miami, Florida, United States
Moffitt
🇺🇸Tampa, Florida, United States
Massachusetts General Hospital
🇺🇸Boston, Massachusetts, United States
University of Michigan
🇺🇸Ann Arbor, Michigan, United States
Norton Healthcare
🇺🇸Louisville, Kentucky, United States
University of Texas MD Anderson
🇺🇸Houston, Texas, United States
Hospital Paulistano
🇧🇷São Paulo, Brazil
CHU de Lille
🇫🇷Lille, France
AP-HP Universite Paris Saclay
🇫🇷Gif-sur-Yvette, France
Princess Margaret Cancer Centre
🇨🇦Toronto, Canada
CHU de Nantes
🇫🇷Nantes, France
CHU de Tours
🇫🇷Tours, France
Institute for Cancer Research and Treatment
🇮🇹Candiolo, Italy
OSP Civile Maggiore Borgo Trento
🇮🇹Verona, Italy
Universitats-Hautklinik Tubingen
🇩🇪Tübingen, Germany
Severance Hospital Yonsei University Health System
🇰🇷Seoul, Korea, Republic of
Hospital General Universitario Gregorio Marañn (Madrid)
🇪🇸Madrid, Spain