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

Chronic Lymphocytic Leukemia Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04502394
• Other study ID #: KRT-232-111
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: February 23, 2021
• Est. completion date: March 2024

Study information

• Verified date: August 2022
• 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, 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)

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 84
• Est. completion date: March 2024
• Est. primary completion date: October 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Chronic Lymphocytic Leukemia
• Diffuse Large B Cell Lymphoma
• Leukemia
• Leukemia, Lymphocytic, Chronic, B-Cell
• Leukemia, Lymphoid
• Lymphoma
• Lymphoma, B-Cell
• Lymphoma, Large B-Cell, Diffuse
• Non Hodgkin Lymphoma

Intervention

Drug:
• KRT-232
KRT-232 is an experimental MDM2 inhibitor anticancer drug taken by mouth
• acalabrutinib
acalabrutinib is a BTK inhibitor anticancer drug taken by mouth

Locations

Country	Name	City	State
Australia	Royal Adelaide Hospital	Adelaide
Australia	Eastern Health - Box Hill Hospital	Box Hill
Australia	Barwon Health	Geelong
Australia	Royal Perth Hospital	Perth
Belgium	Antwerp University Hospital (UZA)	Edegem
Belgium	Jessa Ziekenhuis	Hasselt
Belgium	University Hospital (UZ) Leuven	Leuven
Czechia	Fakultni Nemocnice Hradec Kralove	Nový Hradec Králové
Czechia	Fakultni nemocnice Ostrava	Ostrava
Czechia	Vseobecna fakultni nemocnice v Praze	Prague
France	CHU de Nantes - Hôtel-Dieu	Nantes
France	Centre Henri Becquerel	Rouen
France	CHRU de Tours - Hôpital Bretonneau	Tours
Italy	Centro Riferimento Oncologico - Aviano	Aviano
Italy	Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori	Meldola
Italy	ASST Grande Ospedale Metropolitano Niguarda	Milano
Italy	IRCCS Ospedale San Raffaele	Milano
Italy	Fondazione IRCCS Policlinico San Matteo	Pavia
Italy	Centro Ricerche Cliniche di Verona s.r.l.	Verona
Korea, Republic of	National Cancer Center	Goyang
Korea, Republic of	Gachon University Gil Medical Center	Incheon
Korea, Republic of	Samsung Medical Center	Seoul
Korea, Republic of	Seoul National University Hospital	Seoul
Korea, Republic of	Seoul St. Mary's Hospital	Seoul
Korea, Republic of	Severance Hospital, Yonsei University Health System	Seoul
Poland	Copernicus PL Sp. z o.o., Wojewodzkie Centrum Onkologii	Gdansk
Poland	Uniwersyteckie Centrum Kliniczne, Klinika Hematologii i Transplantologii	Gdansk
Poland	Narodowy Instytut Onkologii im. Marii Sklodowskiej-Curie - Panstwowy Instytut Badawczy, Oddzial w Gliwicach - Klinika Transplantacji Szpiku i Onkohematologii	Gliwice
Poland	Szpital Uniwersytecki Krakow - Oddzial Kliniczny Hematologii	Krakow
Poland	Pratia MCM Krakow	Kraków
Poland	Uniwersytecki Szpital Kliniczny im. Jana Mikulicza Radeckiego we Wroclawiu	Wroclaw
Portugal	Hospital de Braga	Braga
Portugal	Centro Hospitalar Universitario de Lisboa Norte - Hospital de Santa Maria	Lisboa
Portugal	Champalimaud Cancer Center	Lisbon
Portugal	Instituto Portugues de Oncologia do Porto Francisco Gentil, EPE	Porto
Portugal	Centro Hospitalar de Vila Nova de Gaia/Espinho EPE	Vila Nova de Gaia
Switzerland	Kantonsspital St. Gallen	Saint Gallen
United Kingdom	St James's University Hospital	Leeds
United Kingdom	King's College Hospital	London
United Kingdom	Royal Marsden Foundation Trust	London
United Kingdom	University Hospital Southampton NHS Foundation Trust	Southampton
United States	University of Cincinnati	Cincinnati	Ohio
United States	The Ohio State University Comprehensive Cancer Center	Columbus	Ohio
United States	UT Southwestern Medical Center	Dallas	Texas
United States	Goshen Center for Cancer Care	Goshen	Indiana

Sponsors (1)

Lead Sponsor	Collaborator
Kartos Therapeutics, Inc.

Countries where clinical trial is conducted

United States,  Australia,  Belgium,  Czechia,  France,  Italy,  Korea, Republic of,  Poland,  Portugal,  Switzerland,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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