AS-1763 in Patients With Previously Treated CLL/SLL or Non-Hodgkin Lymphoma

Chronic Lymphocytic Leukemia Clinical Trial

Official title:

A Phase 1b Study of Oral AS-1763 in Patients With Previously Treated Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma or Non-Hodgkin Lymphoma

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05602363
• Other study ID #: C1763102
• Status: Recruiting
• Phase: Phase 1
• Start date: August 1, 2023
• Est. completion date: September 2027

Study information

• Verified date: February 2024
• Source: Carna Biosciences, Inc.
• Contact: Akinori Arimura, PhD
• Phone: 650-636-4603
• Email: clinical_us[@]dd.carnabio.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is an open-label, multi-center Phase 1b clinical study of oral AS-1763 in patients with CLL/SLL or B-cell NHL who have failed or are intolerant to ≥2 lines of systemic therapy.

Description:

This study consists of 2 parts.

Dose escalation part will enroll up to 27 patients to evaluate safety profile and tolerance of AS-1763 using 3+3 design. The starting dose of AS-1763 in oral tablet form is 100 mg twice daily (200 mg/day). Dose escalation will continue up to the planned maximum dose level or until the maximum tolerated dose (MTD) has been identified.

Dose expansion part will enroll up to 48 CLL/SLL patients (Cohort 1) and up to 35 NHL patients (Cohort 2). The first 30 patients in each cohort will be allocated to three dose levels (n=10 at each dose level) which will be selected based on the data from dose escalation. Preliminary efficacy and safety data from the first 30 patients in one of cohorts will be used to identify the provisional recommended Phase 2 dose (RP2D) level. Thereafter, up to a further 18 patients for Cohort 1 and up to a further 5 patients for Cohort 2 will be enrolled and allocated to the provisional RP2D level.

Study assessments will continue for 24 cycles (1 cycle = 28 days) or until disease progression, occurrence of unacceptable toxicity, or discontinuation because of other reasons. Patients will then be followed for survival status for a further 2 years.

RP2D will be determined based on all the data generated in the study.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 110
• Est. completion date: September 2027
• Est. primary completion date: September 2027
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Age =18 years

• Provided written informed consent

• Histologically confirmed B-cell malignancy, including CLL/SLL, WM, MCL, MZL, or FL. Patients must have failed or are intolerant to =2 prior lines of systemic therapy

• ECOG Performance Status 0 to 2

• Absolute neutrophil count =0.75 × 10?/L

• Platelet count =50 × 10?/L

• Hemoglobin =8 g/dL

• Adequate hepatic function

• Adequate renal function

• Ability to swallow tablets and comply with study requirements for the duration of study participation.

• Male and female patients of reproductive potential: Willing to observe conventional and effective birth control methods

Exclusion Criteria:

• Transformed disease (eg, Richter's transformation) prior to or during Screening

• Investigational agent or anticancer therapy within 5 half-lives before the planned start of AS-1763, except therapeutic monoclonal antibody treatment which must be discontinued at least 4 weeks before the start of AS-1763. Current treatment with investigational therapy or planned investigational therapy which would be concurrent with this study.

• Requiring therapeutic anticoagulation with warfarin.

• Current treatment with certain strong cytochrome P450 3A4 (CYP3A4) inhibitors or inducers

• Treatment with proton pump inhibitors within 7 days before first dose of AS-1763

• Current treatment with strong P-glycoprotein inhibitors or strong breast cancer resistance protein (BCRP) inhibitors.

• Refractory to transfusion support.

• Major surgery within 4 weeks before planned start of AS-1763.

• Radiotherapy with a limited field of radiation for palliation within 7 days of the first dose of study treatment

• Any unresolved toxicities from prior therapy greater than National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 5.0 Grade 2 at the time of starting study treatment except for alopecia.

• History of allogeneic or autologous stem cell transplant or chimeric antigen receptor T-cell (CAR-T) therapy within the last 30 days.

• Active second malignancy unless in remission with life expectancy >2 years

• Known central nervous system (CNS) involvement by systemic lymphoma. Patients with previous treatment for CNS involvement who are neurologically stable and without evidence of disease may be eligible if a compelling clinical rationale is provided by the investigator and with documented Sponsor approval.

• Active uncontrolled autoimmune cytopenia (eg, autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura) where new therapy introduced or concomitant therapy escalated within the 4 weeks before study enrollment is required to maintain adequate blood counts.

• Clinically significant, uncontrolled cardiac, cardiovascular disease or history of myocardial infarction within 6 months before planned start of AS-1763, or prolongation of the QT interval corrected for heart rate using Fridericia's Formula (QTcF) >470 msec on at least 2 of 3 consecutive ECGs, and mean QTcF >470 msec on all 3 ECGs, during Screening.

• Active uncontrolled systemic bacterial, viral, fungal, or parasitic infection

• Positive for human immunodeficiency virus (HIV). For patients with unknown HIV status, HIV testing will be performed at Screening.

• Clinically significant active malabsorption syndrome or other condition likely to affect gastrointestinal absorption of AS-1763

• Pregnant or lactating.

• Known hypersensitivity to any component or excipient of AS-1763.

• Prior treatment with AS-1763 or other noncovalent BTKi such as pirtobrutinib or nemtabrutinib

Related Conditions & MeSH terms

• B-cell Malignancy
• Chronic Lymphocytic Leukemia
• Follicular Lymphoma
• Leukemia
• Leukemia, Lymphocytic, Chronic, B-Cell
• Leukemia, Lymphoid
• Lymphoma
• Lymphoma, Mantle-Cell
• Lymphoma, Non-Hodgkin
• Mantle Cell Lymphoma
• Marginal Zone Lymphoma
• Non-Hodgkin Lymphoma
• Small Lymphocytic Lymphoma
• Waldenstrom Macroglobulinemia

Intervention

Drug:
• AS-1763
oral tablet, twice daily

Locations

Country	Name	City	State
United States	University of Maryland Medical Center - Greenebaum Comprehensive Cancer Center	Baltimore	Maryland
United States	University of Texas MD Anderson Cancer Center	Houston	Texas
United States	Mount Sinai Comprehensive Cancer Center	Miami Beach	Florida
United States	The Medical College of Wisconsin	Milwaukee	Wisconsin
United States	UC Irvine Health	Orange	California
United States	Moffitt Cancer Center	Tampa	Florida
United States	Clinical Research Alliance, Inc.	Westbury	New York
United States	University of Massachusetts Memorial Medical Center	Worcester	Massachusetts

Sponsors (1)

Lead Sponsor	Collaborator
Carna Biosciences, Inc.

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Proportion of patients with BTK and PLCG2 gene mutation before and after disease progression	Dose escalation, dose expansion	Up to 24 cycles (1 cycle = 28 days)
Primary	Number of patients with dose limiting toxicities (DLTs) and determination of maximum tolerated dose (MTD)	Dose escalation	Up to 24 cycles (1 cycle = 28 days)
Primary	Overall response rate (ORR) as assessed by investigator	Dose expansion	Up to 24 cycles (1 cycle = 28 days)
Secondary	Number of patients with adverse events (AEs) and clinical laboratory abnormalities	Dose escalation, dose expansion	Up to 24 cycles (1 cycle = 28 days)
Secondary	Area under the plasma concentration versus time curve (AUC) of AS-1763	Dose escalation, dose expansion	Up to 24 cycles (1 cycle = 28 days)
Secondary	Peak Plasma Concentration (Cmax) of AS-1763	Dose escalation, dose expansion	Up to 24 cycles (1 cycle = 28 days)
Secondary	Time to maximum plasma concentration (tmax) of AS-1763	Dose escalation, dose expansion	Up to 24 cycles (1 cycle = 28 days)
Secondary	ORR as assessed by investigator	Dose escalation	Up to 24 cycles (1 cycle = 28 days)
Secondary	Best overall response as assessed by investigator	Dose expansion	Up to 24 cycles (1 cycle = 28 days)
Secondary	Duration of response as assessed by investigator	Dose expansion	Up to 24 cycles (1 cycle = 28 days)
Secondary	Progression free survival as assessed by investigator	Dose expansion	Up to 24 cycles (1 cycle = 28 days)
Secondary	Overall survival	Dose expansion	Up to 4 years