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)
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
84
KRT-232 is an experimental MDM2 inhibitor anticancer drug taken by mouth
acalabrutinib is a BTK inhibitor anticancer drug taken by mouth
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.
Time frame: 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.
Time frame: 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.
Time frame: 1 Year
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).
Time frame: 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).
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Goshen Center for Cancer Care
Goshen, Indiana, United States
RECRUITINGUniversity of Cincinnati
Cincinnati, Ohio, United States
RECRUITINGThe Ohio State University Comprehensive Cancer Center
Columbus, Ohio, United States
RECRUITINGUT Southwestern Medical Center
Dallas, Texas, United States
RECRUITINGRoyal Adelaide Hospital
Adelaide, Australia
RECRUITINGEastern Health - Box Hill Hospital
Box Hill, Australia
RECRUITINGBarwon Health
Geelong, Australia
RECRUITINGRoyal Perth Hospital
Perth, Australia
RECRUITINGAntwerp University Hospital (UZA)
Edegem, Belgium
RECRUITINGJessa Ziekenhuis
Hasselt, Belgium
RECRUITING...and 35 more locations
Time frame: 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).
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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
Time frame: 2 Years