Clinical trial NCT03787602: Navtemadlin (KRT-232) With or Without Anti-PD-1/Anti-PD-L1 for the Treatment of Patients With Merkel Cell Carcinoma
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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Merkel Cell Carcinoma
Keywords: navtemadlin (KRT-232)
Lead sponsor: Kartos Therapeutics, Inc.
Sponsor class: INDUSTRY
First posted: 2018-12-26
Enrollment: 115
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility criteria: 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)

Primary outcomes:
measure: Cohort 1 Part 1: To determine the KRT-232 RP2D.
timeFrame: 10 Weeks
measure: 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
timeFrame: 10 Weeks
measure: Cohort 2 Part 1: To determine the KRT-232 RP2D in combination with avelumab
timeFrame: 28 Days
measure: Cohort 2 Part 2: To determine the objective response rate (ORR) in treatment-naïve subjects with p53WT MCC
timeFrame: 10 Weeks
measure: 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.
timeFrame: 10 Weeks
measure: 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.
timeFrame: 10 Weeks
Secondary outcomes:
measure: To determine the confirmed ORR based on investigator assessment.
timeFrame: 1 year after last subject enrolled.
measure: To determine the duration of response (DoR)
timeFrame: 1 year after last subject enrolled
measure: To determine Progression-free survival (PFS)
timeFrame: 1 year after last subject enrolled
measure: To determine overall survival (OS)
timeFrame: 1 year after last subject enrolled
measure: To determine clinical benefit rate (CBR)
timeFrame: 1 year after last subject enrolled.
Other outcomes:
Locations:
city: Aurora
country: United States
facility: University of Colorado Anschutz Medical Campus
state: Colorado
city: Miami
country: United States
facility: Miami Cancer Institute
state: Florida
city: Tampa
country: United States
facility: Moffitt
state: Florida
city: Chicago
country: United States
facility: Northwestern Memorial Hospital
state: Illinois
city: Louisville
country: United States
facility: Norton Healthcare
state: Kentucky
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Dana-Farber Cancer Institute
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: New York
country: United States
facility: Memorial Sloan-Kettering Cancer Center
state: New York
city: New York
country: United States
facility: Mount Sinai Hospital
state: New York
city: Philadelphia
country: United States
facility: Fox Chase Cancer Center
state: Pennsylvania
city: Pittsburgh
country: United States
facility: UPMC Hillman Cancer Center
state: Pennsylvania
city: Houston
country: United States
facility: University of Texas MD Anderson
state: Texas
city: Fairfax
country: United States
facility: Inova Health Care Services
state: Virginia
city: Woolloongabba
country: Australia
facility: Princess Alexandra Hospital Oncology
city: Blumenau
country: Brazil
facility: Centro Catarinense de Pesquisa (CECAP) - Hospital Santa Catarina de Blumenau
city: Brasília
country: Brazil
facility: Instituto Nacional do Cancer
city: Curitiba
country: Brazil
facility: Centro Intergado de Oncologia
city: Ijuí
country: Brazil
facility: Centro de Pesquisa Clinica em Oncologia
city: Itajai
country: Brazil
facility: Clinica De Neoplasias Litoral
city: São Paulo
country: Brazil
facility: Hospital Paulistano
city: Toronto
country: Canada
facility: Princess Margaret Cancer Centre
city: Bordeaux
country: France
facility: CHU de Bordeaux- Hopital Saint-Andre
city: Gif-sur-Yvette
country: France
facility: AP-HP Universite Paris Saclay
city: Lille
country: France
facility: CHU de Lille
city: Lyon
country: France
facility: CHU Lyon-Sud
city: Marseille
country: France
facility: Hôpital de la Timone. Aix-Marseille Université
city: Montpellier
country: France
facility: CHU Montpellier
city: Nantes
country: France
facility: CHU de Nantes
city: Paris
country: France
facility: Hôpital Saint Louis - APHP
city: Tours
country: France
facility: CHU de Tours
city: Berlin
country: Germany
facility: Vivantes Network for Health Gmb, Neukölln Clinic
city: Erlangen
country: Germany
facility: Universitätsklinikum Erlangen
city: Essen
country: Germany
facility: Universitätsklinikum Essen (AöR)
city: Heidelberg
country: Germany
facility: Nationales Centrum für Tumorerkrankungen NCT
city: Köln
country: Germany
facility: Uniklinik Koln
city: Rostock
country: Germany
facility: Universitätsklinik Rostock
city: Tübingen
country: Germany
facility: Universitats-Hautklinik Tubingen
city: Candiolo
country: Italy
facility: Institute for Cancer Research and Treatment
city: Napoli
country: Italy
facility: Istituto Nazionale Tumori IRCCS Fondazione Pascale
city: Ravenna
country: Italy
facility: AUSL della Romagna
city: Siena
country: Italy
facility: AOUS Le Scotte
city: Verona
country: Italy
facility: OSP Civile Maggiore Borgo Trento
city: Goyang-si
country: Korea, Republic of
facility: National Cancer Center
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Seoul
country: Korea, Republic of
facility: Severance Hospital Yonsei University Health System
city: Groningen
country: Netherlands
facility: University Medical Center Groningen
city: Barcelona
country: Spain
facility: Hospital Duran i Reynals
city: Madrid
country: Spain
facility: Hospital General Universitario Gregorio Marañn (Madrid)
city: Pamplona
country: Spain
facility: Complejo Hospitalario de Navarra
city: Valencia
country: Spain
facility: Fundacio Investigao Hospital General Universitario de Valencia
Study officials:
References: