Safety and Efficacy of KRT-232 in Combination With Acalabrutinib in Subjects With R/R DLBCL or R/R CLL

Study Overview
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Brief Summary
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This study evaluates KRT-232, a novel oral small molecule inhibitor of MDM2, combined with acalabrutinib for the treatment of adults with Diffuse Large B-Cell Lymphoma and Chronic Lymphocytic Leukemia. Participants must be relapsed/refractory (having failed prior therapy)

Official Title
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An Open-Label, Multicenter, Phase 1b/2 Study of the Safety and Efficacy of KRT-232 in Combination With Acalabrutinib in Subjects With Relapsed/Refractory Diffuse Large B-cell Lymphoma or Relapsed/Refractory Chronic Lymphocytic Leukemia

Conditions
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Diffuse Large B Cell Lymphoma, Chronic Lymphocytic Leukemia, Non Hodgkin Lymphoma

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Cohort 1: Confirmed diagnosis of TP53wt DLBCL (WHO); R/R DLBCL after at least 2 prior lines of treatment or 1 prior for patients who are ineligible for stem cell transplant Cohort 2: Confirmed diagnosis of TP53wt CLL (iwCLL); R/R CLL after at least 1 prior line of treatment ECOG 0 to 2 Adequate hematologic, hepatic, and renal functions. Exclusion Criteria: Prior treatment with any MDM2 inhibitor Prior treatment with any BTK inhibitor

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: An Open-label, Phase 1b/2 Study of KRT-232 in combination with acalabrutinib in Subjects with B-cell Non-Hodgkin Lymphoma
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1 (R/R DLBCL)<br>KRT-232 will be administered orally, once daily (QD), on days 1-7 in a 28-day cycle. Acalabrutinib at 100 mg twice a day (BID) continuously starting on Day 1 in a 28-day cycle. | Drug: KRT-232<br>* KRT-232 is an experimental MDM2 inhibitor anticancer drug taken by mouth<br>Drug: acalabrutinib<br>* acalabrutinib is a BTK inhibitor anticancer drug taken by mouth<br>* Other names: ACP-196;|
| Experimental: Cohort 2 (R/R CLL)<br>KRT-232 will be administered orally, once daily (QD), on days 1-7 in a 28-day cycle. Acalabrutinib at 100 mg twice a day (BID) continuously starting on Day 1 in a 28-day cycle. | Drug: KRT-232<br>* KRT-232 is an experimental MDM2 inhibitor anticancer drug taken by mouth<br>Drug: acalabrutinib<br>* acalabrutinib is a BTK inhibitor anticancer drug taken by mouth<br>* Other names: ACP-196;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Primary Objective Phase 1b:To determine the KRT-232 maximum tolerated dose/ maximum administered dose (MTD/MAD) and recommended Phase 2 Dose (RP2D) in combination with acalabrutinib in subjects with R/R DLBCL or R/R CLL | Endpoint/Outcome Measures: Dose-limiting toxicities will be used to establish the MTD/MAD of KRT-232 in combination with acalabrutinib. The Safety Review Committee will determine the RP2D based on safety data of the combination of KRT-232 and acalabrutinib. | 56 Days | 
| Primary Objective Phase 2: Cohort 1: To determine the complete response (CR) | Endpoint/Outcome Measures: Cohort 1: The proportion of subjects with CR as assessed by investigators per the Lugano Classification. | 1 Year | 
| Primary Objective Phase 2: Cohort 2: To determine the rate of CR/complete remission with incomplete hematologic recovery (CRi) rate in R/R CLL | Endpoint/Outcome Measures: Cohort 2: The proportion of subjects with CR/CRi as assessed by investigators per iwCLL Response Criteria. | 1 Year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1b Secondary Objective: Pharmacokinetic (PK) profile | Endpoint/Outcome Measures: Will be measured using liquid chromatography/tandem mass spectrometric method. Standard descriptive methods (point estimates and confidence intervals, scatterplots) will be used to summarize the baseline levels and the changes from baseline (i.e. after treatment). The individual PK parameter from a single dose will be estimated maximum concentration (Cmax). | Baseline, 1, 2, 4, 6 and 24 hours post dose on days 1 and 2 of cycle 1 (each cycle is 28 days); Baseline and 2 hours post dose on day 1 and 24 hours post dose on day 8 of cycle 2 | 
| Phase 1b Secondary Objective: Pharmacokinetic (PK) profile | Endpoint/Outcome Measures: Will be measured using liquid chromatography/tandem mass spectrometric method. Standard descriptive methods (point estimates and confidence intervals, scatterplots) will be used to summarize the baseline levels and the changes from baseline (i.e. after treatment). The individual PK parameters from a single dose will be area under the curve (AUC). | Baseline, 1, 2, 4, 6 and 24 hours post dose on days 1 and 2 of cycle 1 (each cycle is 28 days); Baseline and 2 hours post dose on day 1 and 24 hours post dose on day 8 of cycle 2 | 
| Phase 1b Secondary Objective: Pharmacokinetic (PK) profile | Endpoint/Outcome Measures: Will be measured using liquid chromatography/tandem mass spectrometric method. Standard descriptive methods (point estimates and confidence intervals, scatterplots) will be used to summarize the baseline levels and the changes from baseline (i.e. after treatment). The individual PK parameters from a single dose will be half-life (T1/2). | Baseline, 1, 2, 4, 6 and 24 hours post dose on days 1 and 2 of cycle 1 (each cycle is 28 days); Baseline and 2 hours post dose on day 1 and 24 hours post dose on day 8 of cycle 2 | 
| Phase 1b Secondary Objective: Pharmacokinetic (PK) profile | Endpoint/Outcome Measures: Will be measured using liquid chromatography/tandem mass spectrometric method. Standard descriptive methods (point estimates and confidence intervals, scatterplots) will be used to summarize the baseline levels and the changes from baseline (i.e. after treatment). The individual PK parameter from a single dose will be apparent clearance. | Baseline, 1, 2, 4, 6 and 24 hours post dose on days 1 and 2 of cycle 1 (each cycle is 28 days); Baseline and 2 hours post dose on day 1 and 24 hours post dose on day 8 of cycle 2 | 
| Phase 1b Secondary Objective: Pharmacokinetic (PK) profile | Endpoint/Outcome Measures: Will be measured using liquid chromatography/tandem mass spectrometric method. Standard descriptive methods (point estimates and confidence intervals, scatterplots) will be used to summarize the baseline levels and the changes from baseline (i.e. after treatment). The individual PK parameters from a single dose will be apparent volume of distribution using non-compartmental or compartmental PK methods with the software WinNonlin. | Baseline, 1, 2, 4, 6 and 24 hours post dose on days 1 and 2 of cycle 1 (each cycle is 28 days); Baseline and 2 hours post dose on day 1 and 24 hours post dose on day 8 of cycle 2 | 
| Phase 2 Secondary Objective: Cohort 1 (R/R DLBCL): To determine the overall response rate (ORR) for R/R DLBCL subjects. | Endpoint/Outcome Measures: The proportion of subjects who achieve a partial response (PR) or better at any time point while on study. | 2 Years | 
| Phase 2 Secondary Objective: Cohort 2 (R/R CLL): To determine the ORR for R/R CLL subjects | Endpoint/Outcome Measures: The proportion of subjects who achieve a PR or better at any time point while on study, as assessed by iwCLL Response Criteria | 2 Years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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navtemadlin