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

Study Overview
=================
Brief 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.

Detailed 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.

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

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

Intervention / Treatment
-----------------
* Drug: AS-1763
* Drug: AS-1763


Participation Criteria
=================
Eligibility Criteria
-----------------
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 × 10⁹/L Platelet count ≥50 × 10⁹/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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose Escalation<br>Dose escalation (3+3 design) and determination of MTD and DLTs CLL/SLL or B-cell NHL patients previously treated with ≥2 lines of systemic therapy will self-administer AS-1763 oral tablet at multiple dose levels twice daily for 24 cycles (1 cycle = 28 days). | Drug: AS-1763<br>* oral tablet, twice daily<br>|
| Experimental: Dose Expansion Cohort 1<br>CLL/SLL patients previously treated with ≥2 lines of systemic therapy will self-administer AS-1763 oral tablet for 24 cycles (1 cycle = 28 days). Dose levels will be determined based on the result of dose escalation part. | Drug: AS-1763<br>* oral tablet, twice daily<br>|
| Experimental: Dose Expansion Cohort 2<br>B-cell NHL patients previously treated with ≥2 lines of systemic therapy will self-administer AS-1763 oral tablet for 24 cycles (1 cycle = 28 days). Dose levels will be determined based on the result of dose escalation part. | Drug: AS-1763<br>* oral tablet, twice daily<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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) | 
| Overall response rate (ORR) as assessed by safety monitoring committee (SMC) | Dose expansion | Up to 24 cycles (1 cycle = 28 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of patients with adverse events (AEs) and clinical laboratory abnormalities | Dose escalation, dose expansion | Up to 24 cycles (1 cycle = 28 days) | 
| Area under the plasma concentration versus time curve (AUC) of AS-1763 | Dose escalation, dose expansion | Up to 24 cycles (1 cycle = 28 days) | 
| Peak Plasma Concentration (Cmax) of AS-1763 | Dose escalation, dose expansion | Up to 24 cycles (1 cycle = 28 days) | 
| Time to maximum plasma concentration (tmax) of AS-1763 | Dose escalation, dose expansion | Up to 24 cycles (1 cycle = 28 days) | 
| ORR as assessed by investigator | Dose escalation, dose expansion | Up to 24 cycles (1 cycle = 28 days) | 
| Best overall response as assessed by investigator and SMC | Dose expansion | Up to 24 cycles (1 cycle = 28 days) | 
| Duration of response as assessed by the investigator and SMC | Dose expansion | Up to 24 cycles (1 cycle = 28 days) | 
| Progression free survival as assessed by the investigator and SMC | Dose expansion | Up to 24 cycles (1 cycle = 28 days) | 
| Overall survival | Dose expansion | Up to 4 years |