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

Study Overview
=================
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.

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

Conditions
-----------------
Merkel Cell Carcinoma

Intervention / Treatment
-----------------
* Drug: KRT-232
* Drug: Avelumab


Participation Criteria
=================
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)

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1, Arm 1<br>KRT-232 will be administered orally, once daily (QD) on Days 1-7 in a 21-day cycle. | Drug: KRT-232<br>* KRT-232 is an experimental MDM2 anticancer drug taken by mouth.<br>* Other names: navtemadlin;|
| Experimental: Cohort 1, Arm 1b<br>KRT-232 will be administered orally, once daily (QD) on Days 1-5 in a 23-day cycle. | Drug: KRT-232<br>* KRT-232 is an experimental MDM2 anticancer drug taken by mouth.<br>* Other names: navtemadlin;|
| Experimental: Cohort 1, Arm 2b<br>KRT-232 will be administered orally, once daily (QD) on Days 1-5 in a 28-day cycle. | Drug: KRT-232<br>* KRT-232 is an experimental MDM2 anticancer drug taken by mouth.<br>* Other names: navtemadlin;|
| Experimental: Cohort 1, Arm 3<br>KRT-232 will be administered orally, once daily (QD) on Days 1-7 in a 21-day cycle. | Drug: KRT-232<br>* KRT-232 is an experimental MDM2 anticancer drug taken by mouth.<br>* Other names: navtemadlin;|
| Experimental: Cohort 1, Arm 5<br>KRT-232 will be administered orally, once daily (QD) on Days 1-7 in a 28-day cycle. | Drug: KRT-232<br>* KRT-232 is an experimental MDM2 anticancer drug taken by mouth.<br>* Other names: navtemadlin;|
| Experimental: Cohort 1 Expansion<br>KRT-232 will be administered orally, once daily (QD) per Cohort 1 RP2D dose and schedule. | Drug: KRT-232<br>* KRT-232 is an experimental MDM2 anticancer drug taken by mouth.<br>* Other names: navtemadlin;|
| Experimental: Cohort 2, Arm 1 KRT-232 in combination with avelumab<br>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<br>* KRT-232 is an experimental MDM2 anticancer drug taken by mouth.<br>* Other names: navtemadlin;Drug: Avelumab<br>* Avelumab is a PD-L1 blocking antibody anticancer drug administered by intravenous infusion.<br>* Other names: Bavencio;|
| Experimental: Cohort 2, Arm 2 KRT-232 in combination with avelumab<br>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<br>* KRT-232 is an experimental MDM2 anticancer drug taken by mouth.<br>* Other names: navtemadlin;Drug: Avelumab<br>* Avelumab is a PD-L1 blocking antibody anticancer drug administered by intravenous infusion.<br>* Other names: Bavencio;|
| Experimental: Cohort 2 Expansion<br>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<br>* KRT-232 is an experimental MDM2 anticancer drug taken by mouth.<br>* Other names: navtemadlin;Drug: Avelumab<br>* Avelumab is a PD-L1 blocking antibody anticancer drug administered by intravenous infusion.<br>* Other names: Bavencio;|
| Experimental: Cohort 3<br>KRT-232 will be administered orally, once daily (QD) per Cohort 1 RP2D dose and schedule. | Drug: KRT-232<br>* KRT-232 is an experimental MDM2 anticancer drug taken by mouth.<br>* Other names: navtemadlin;|
| Experimental: Cohort 4<br>KRT-232 will be administered orally, once daily (QD) per Cohort 1 RP2D dose and schedule. | Drug: KRT-232<br>* KRT-232 is an experimental MDM2 anticancer drug taken by mouth.<br>* 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. | 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 Outcome Measures

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

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
navtemadlin (KRT-232)