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

Merkel Cell Carcinoma Clinical Trial

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03787602
• Other study ID #: KRT-232-103
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: March 19, 2019
• Est. completion date: August 2025

Study information

• Verified date: February 2023
• Source: Kartos Therapeutics, Inc.
• Contact: John Mei
• Phone: 650-542-0136
• Email: jmei[@]kartosthera.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 115
• Est. completion date: August 2025
• Est. primary completion date: November 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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)

Related Conditions & MeSH terms

• Carcinoma
• Carcinoma, Merkel Cell
• Merkel Cell Carcinoma

Intervention

Drug:
• KRT-232
KRT-232 is an experimental MDM2 anticancer drug taken by mouth.
• Avelumab
Avelumab is a PD-L1 blocking antibody anticancer drug administered by intravenous infusion.

Locations

Country	Name	City	State
Australia	Princess Alexandra Hospital Oncology	Woolloongabba
Brazil	Centro Catarinense de Pesquisa (CECAP) - Hospital Santa Catarina de Blumenau	Blumenau
Brazil	Instituto Nacional do Cancer	Brasília
Brazil	Centro Intergado de Oncologia	Curitiba
Brazil	Centro de Pesquisa Clinica em Oncologia	Ijuí
Brazil	Clinica De Neoplasias Litoral	Itajai
Brazil	Hospital Paulistano	São Paulo
Canada	Princess Margaret Cancer Centre	Toronto
France	CHU de Bordeaux- Hopital Saint-Andre	Bordeaux
France	AP-HP Universite Paris Saclay	Gif-sur-Yvette
France	CHU de Lille	Lille
France	CHU Lyon-Sud	Lyon
France	Hôpital de la Timone. Aix-Marseille Université	Marseille
France	CHU Montpellier	Montpellier
France	CHU de Nantes	Nantes
France	Hôpital Saint Louis - APHP	Paris
France	CHU de Tours	Tours
Germany	Vivantes Network for Health Gmb, Neukölln Clinic	Berlin
Germany	Universitätsklinikum Erlangen	Erlangen
Germany	Universitätsklinikum Essen (AöR)	Essen
Germany	Nationales Centrum für Tumorerkrankungen NCT	Heidelberg
Germany	Uniklinik Koln	Köln
Germany	Universitätsklinik Rostock	Rostock
Germany	Universitats-Hautklinik Tubingen	Tübingen
Italy	Institute for Cancer Research and Treatment	Candiolo
Italy	Istituto Nazionale Tumori IRCCS Fondazione Pascale	Napoli
Italy	AUSL della Romagna	Ravenna
Italy	AOUS Le Scotte	Siena
Italy	OSP Civile Maggiore Borgo Trento	Verona
Korea, Republic of	National Cancer Center	Goyang-si
Korea, Republic of	Seoul National University Hospital	Seoul
Korea, Republic of	Severance Hospital Yonsei University Health System	Seoul
Netherlands	University Medical Center Groningen	Groningen
Spain	Hospital Duran i Reynals	Barcelona
Spain	Hospital General Universitario Gregorio Marañn (Madrid)	Madrid
Spain	Complejo Hospitalario de Navarra	Pamplona
Spain	Fundacio Investigao Hospital General Universitario de Valencia	Valencia
United States	University of Michigan	Ann Arbor	Michigan
United States	University of Colorado Anschutz Medical Campus	Aurora	Colorado
United States	Dana-Farber Cancer Institute	Boston	Massachusetts
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	Northwestern Memorial Hospital	Chicago	Illinois
United States	Inova Health Care Services	Fairfax	Virginia
United States	University of Texas MD Anderson	Houston	Texas
United States	Norton Healthcare	Louisville	Kentucky
United States	Miami Cancer Institute	Miami	Florida
United States	Memorial Sloan-Kettering Cancer Center	New York	New York
United States	Mount Sinai Hospital	New York	New York
United States	Fox Chase Cancer Center	Philadelphia	Pennsylvania
United States	UPMC Hillman Cancer Center	Pittsburgh	Pennsylvania
United States	Moffitt	Tampa	Florida

Sponsors (1)

Lead Sponsor	Collaborator
Kartos Therapeutics, Inc.

Countries where clinical trial is conducted

United States,  Australia,  Brazil,  Canada,  France,  Germany,  Italy,  Korea, Republic of,  Netherlands,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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	To determine the confirmed ORR based on investigator assessment.	ORR will be assessed per RECIST criteria 1.1 by investigators.	1 year after last subject enrolled.
Secondary	To determine the duration of response (DoR)	Time from documentation of response (CR or PR as determined by RECIST 1.1) until disease progression.	1 year after last subject enrolled
Secondary	To determine Progression-free survival (PFS)	Time from initial treatment until disease progression.	1 year after last subject enrolled
Secondary	To determine overall survival (OS)	Time from initial treatment until death from any cause.	1 year after last subject enrolled
Secondary	To determine clinical benefit rate (CBR)	PR, CR or stable disease that last at least 10 weeks, per IRC or investigator assessment.	1 year after last subject enrolled.