None listed
Conditions
Sponsors
Kartos Therapeutics Inc.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Adults =18 years of age; 2. Patient population: Cohort 1 (R/R DLBCL): a) Histologically confirmed diagnosis of de novo or transformed TP53^wt ABC (non-GCB) or GCB DLBCL based on 2016 WHO Classification; i) Phase 2: 25 or more subjects with non-GCB and 10 or more subjects with double-expressor lymphoma will be enrolled as described in Section 10.2 of the study protocol; b) R/R DLBCL which has been treated with at least 2 prior lines of systemic therapy or at least 1 prior line of systemic therapy in subjects who are ineligible for hematopoietic stem cell transplantation (autologous or allogeneic) for reasons other than active disease; c) At least 1 measurable site of disease on computed tomography (CT) (defined as >1.5 cm in longest transverse diameter of a lesion [LDi]) and clearly measurable in 2 perpendicular dimensions); Cohort 2 (R/R CLL/SLL): d) Histologically confirmed diagnosis of TP53^wt CLL according to iw CLL/SLL criteria; e) Previously treated with at least 1 prior regimen according to current guidelines; f) Active disease meeting at least 1 of the iwCLL 2008 criteria for requiring treatment; 3. ECOG performance status of 0 to 2; 4. Adequate hematologic function within 7 days (Phase 1b) or 28 days (Phase 2) prior to first dose, independent of growth factor support for at least 7 days with the exception of pegylated G-CSF which require at least 14 days, defined as: a) Absolute neutrophil count (ANC) =1,000/mm^3; b) Platelet count =50,000/mm^3; 5. Adequate hepatic function within within 7 days (Phase 1b) or 28 days (Phase 2) prior to first dose defined as: a) Total bilirubin = 2.0 x upper limit of normal (ULN). Subjects with known Gilbert's syndrome or disease-related hemolysis must have a total bilirubin =3.0 X ULN; b) Aspartate transaminase/serum glutamic oxaloacetic transaminase (AST/SGOT) and alanine transaminase/serum glutamic pyruvic transaminase (ALT/SGPT) =2.5 ULN; 6. Adequate renal function within within 7 days (Phase 1b) or 28 days (Phase 2) prior to the first dose defined as an estimated creatinine clearance =30 mL/min by Cockcroft Gault; 7. Female subjects of childbearing potential and their male partners, or male subjects who have female partners of childbearing potential must both use an highly effective contraception method during the study. The use of condoms by male sexual partners not practicing abstinence is mandatory, regardless of vasectomy status. In addition, after the last dose of study drug, female subjects must continue to use a highly effective method of contraception for 1 month and 1 week and male subjects must continue to use a highly effective method of contraception for 3 months and 1 week. A woman is considered of childbearing potential (ie, fertile, following menarche and until becoming post-menopausal) unless permanently sterile. Note: Marketed drugs administered concomitantly in this study may have different contraception requirements, including required duration of contraception use. The contraception requirements in the local prescribing guidelines must be followed for all concomitant drugs administered in this study. Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 34 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 51
Exclusion criteria
Exclusion criteria: 1. Subjects with a history of CNS involvement; 2. Any recent prior therapy meeting one or more of the following criter: a) Concurrent anticancer treatment, such as chemotherapy, cytoreductive therapy, immune therapy, or cytokine therapy: i) DLBCL: Within 14 days prior to the first dose of study treatment; ii) CLL/SLL: Within 28 days prior to the first dose of study treatment; b) Allogeneic stem cell transplant within the last 6 months, or active graft versus host disease following allogeneic transplant, or autologous stem cell transplant within 3 months prior to the first dose of study treatment; c) Subjects who have received immunosuppressive therapy for graft-versus-host disease within 6 months prior to first dose of study treatment; 3. Subjects previously treated with MDM2 antagonist therapies; 4. Subjects previously treated with a BTK inhibitor; 5. Subjects with a history of bleeding diathesis or major hemorrhage within 6 months prior to first dose of study treatment; 6. History of stroke or intracranial hemorrhage within 6 months before first dose of study drug; 7. Participation in another interventional clinical study within the past 4 weeks of the first dose of study treatment (participation in observational studies is permitted); 8. Uncontrolled intercurrent illness including but not limited to clinically significant cardiac disease (New York Heart Association Class III or IV); symptomatic congestive heart failure, unstable angina pectoris; unstable ventricular arrhythmia; or psychiatric illness/social situations that would limit compliance with study requirements; 9. Grade 2 or higher QTc prolongation (>480 milliseconds per National Cancer Institute Common Terminology of Adverse Events [v 5.0]); 10. Malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach; or extensive small bowel resection that is likely to affect absorption; symptomatic inflammatory bowel disease, or partial or complete bowel obstruction; or gastric restrictions and bariatric surgery, such as gastric bypass or difficulty swallowing which may hamper compliance with study treatment; 11. Subjects with uncontrolled bacterial, fungal, parasitic, or viral infection. Subjects with acute bacterial infections requiring antibiotic use should not enroll until the infection is stable in the judgement of the treating physician; these subjects may be on antibiotics at time of enrollment; 12. Subjects with active fever (temperature higher than 38.2°C [100.8°F]) within 14 days prior to the first dose of study treatment; 13. Subjects with active hepatitis B virus (HBV) or hepatitis C virus (HCV); 14. Known history of HIV; 15. Requires or receiving anticoagulation with warfarin or equivalent vitamin K antagonists (eg, preprohormone) within 7 days of first dose of study drug; 16. Phase 1 only: Requires treatment with a strong and/or moderate CYP3A inhibitor/inducer within 7 days prior to first dose of study drug; 17. Phase 2 only: Requires treatment with a strong CYP3A inhibitor/inducer within 7 days prior to first dose of study drug; 18. Requires treatment with proton-pump inhibitors (eg, omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole). Subjects receiving proton-pump inhibitors who switch to H2-receptor antagonists or antacids are eligible for enrollment to this study provided the proton pump inhibitor is discontinued at least 5 days prior to first dose of study drug; 19. Other mali
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main 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 (Cohort 1) or R/R CLL/SLL (Cohort 2) - To determine the safety and tolerability of KRT-232 in combination with acalabrutinib in subjects with R/R DLBCL (Cohort 1) or R/R CLL/SLL (Cohort 2) Phase II: - Cohort 1 (R/R DLBCL): To determine the complete response (CR) rate in R/R DLBCL. - Cohort 2 (R/R CLL/SLL): To determine the rate of CR/complete remission with incomplete hematologic recovery (CRi) in R/R CLL/SLL.;Secondary Objective: Phase Ib: - To monitor the PK of KRT-232 and acalabrutinib Phase II: - Cohort 1 (R/R DLBCL): To determine the overall response rate (ORR) for R/R DLBCL subjects - Cohort 2 (R/R CLL/SLL): To determine the ORR for R/R CLL/SLL subjects - To evaluate the duration of response (DOR) among subjects who achieve a response of PR or better by cohort. - Cohort 2 (R/R CLL/SLL): To determine the rate of measurable residual disease (MRD) - To determine the safety and tolerability of KRT-232 in combination with acalabrutinib - To monitor the PK of KRT-232 and acalabrutinib using sparse sampling.;Primary end point(s): Phase Ib: 1. 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; 2. Analyses of the safety endpoints will include the following measurements or assessments: physical examinations, laboratory tests, adverse events (AEs), serious AEs (SAEs), electrocardiograms (ECGs), and vital signs. Phase II: 1. The proportion of subjects with CR as assessed by investigators per the Lugano Classification; 2. The proportion of subjects with CR/CRi as assessed by investigators per iwCLL Response Criteria.;Timepoint(s) of evaluation of this end point: Phase 1b: 1-2. Throughout | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Phase 1b: 1. KRT-232, acyl glucuronide metabolite (M1), acalabrutinib, and metabolite ACP-5862 pharmacokinetic (PK) parameters will be determined, including but not limited to: • Maximum observed concentration (C^max) • Minimum observed concentration (C^min) • Area under the plasma concentration-time curve (AUC) • Time of maximum plasma concentration Phase II: 1. The proportion of subjects who achieve a partial response (PR) or better at any time point while on study, as assessed by Lugano Classification; 2. The proportion of subjects who achieve a PR or better at any time point while on study, as assessed by iwCLL Response Criteria; 3. Median DOR (Kaplan-Meier estimate) defined as the time from the first observation of response to disease progression or death; 4. The proportion of subject who achieve MRD negativity either in peripheral blood or bone marrow by flow cytometry and DNA sequencing; 5. Analyses of the safety endpoints will include the following measurements or assessments: physical examinations, laboratory tests, adverse events (AEs), serious AEs (SAEs), electrocardiograms (ECGs), and vital signs; 6. KRT-232, acyl glucuronide metabolite (M1), acalabrutinib, and metabolite ACP-5862 plasma concentrations will be monitored using sparse sampling.;Timepoint(s) of evaluation of this end point: Phase 1b: 1. Throughout the study Phase II: 1-6. Throughout the study | — |
Countries
Australia, Belgium, Czechia, Czech Republic, France, Hungary, Italy, Korea, Republic of, Poland, Portugal, Switzerland, United Kingdom
Contacts
Public ContactJohn Mei
Kartos Therapeutics, Inc.
Outcome results
None listed