A Study of AC676 for the Treatment of Relapsed/Refractory B-Cell Malignancies

Study Overview
=================
Brief Summary
-----------------
This clinical trial is evaluating a drug called AC676 in participants with Relapsed/Refractory B-cell Malignancies. The main goals of the study are to: Identify the recommended dose of AC676 that can be given safely to participants Evaluate the safety profile of AC676 Evaluate the pharmacokinetics of AC676 Evaluate the effectiveness of AC676

Detailed Description
-----------------
AC676-001 is a Phase I, first-in-human, open-label, multi-center dose-escalation study of AC676 given as a single agent. AC676 is an investigational medicinal product that is an orally bioavailable BTK degrader for the treatment of B-cell malignancies.

Official Title
-----------------
A Phase I Clinical Study to Evaluate Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Preliminary Anti-Malignancy Activity of AC676 in Patients With Relapsed/Refractory B-cell Malignancies

Conditions
-----------------
Relapsed/Refractory B-cell Malignancies

Intervention / Treatment
-----------------
* Drug: AC676


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Adult male and female patients, at least 18 years-of-age at the time of signature of the informed consent form (ICF). Patients with histologically confirmed relapsed/refractory Chronic Lymphocytic Leukemia (CLL), Small Lymphocytic Lymphoma (SLL), Mantle Cell Lymphoma (MCL), Follicular Lymphoma (FL), non-GCB Diffuse Large B-cell Lymphoma (DLBCL), Marginal Zone Lymphoma (MZL), or Waldenström Macroglobulinemia (WM). Must have received at least 2 prior systemic therapies or have no other therapies to provide significant clinical benefit in the opinion of the Investigator or who are not amenable (intolerability, patient choice) to standard therapies. Exclusion Criteria: Patients who meet any of the following criteria will be excluded from study entry: Treatment with any of the following: Small molecule anti-cancer drugs within 5 half-lives or 2 days (whichever is longer, not to exceed 14 days). Systemic chemotherapy within 14 days. Radiation therapy within 14 days Biologics (Antibodies) treatment within 28 days, Radioimmunoconjugates or toxin conjugates within 12 weeks. Prior Chimeric antigen receptor (CAR) T cell therapy (and prior use of immunoglobulin replacement therapy to treat associated adverse events) within 3 months. For patients with DLBCL, no prior CAR- T therapy is allowed. Autologous or allogenic stem cell transplant within 100 days and must not have ongoing graft-versus-host disease (GVHD) and no ongoing therapy to treat GVHD. History of central nervous system lymphoma/leukemia in remission for less than 2 years. Medical history of active bleeding within 2 months prior to study entry, or susceptible to bleeding by the judgement of investigator.

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
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AC676 Dose Escalation<br>Participants will receive an assigned dose of AC676 in a 28-days cycle. | Drug: AC676<br>* AC676 will be given orally (PO) on a 28-day cycle.<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of dose limiting toxicities (DLTs) from AC676 monotherapy |  | From cycle 1 day 1 to Cycle 1 day 28. Cycles are 28 days. | 
| Incidence of treatment-emergent adverse events (TEAEs) and clinically significant Grade 3 or higher laboratory abnormalities using CTCAE v5.0 criteria. |  | Approximately 18 months | 
| Maximum tolerated dose (MTD) and/or recommended Phase II dose (RP2D) |  | Approximately 18 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetic Analysis: area under the plasma concentration-time curve over the dosing interval (AUC(0-inf)) |  | Up to approximately 20 weeks | 
| Pharmacokinetic Analysis: area under the plasma concentration-time curve from over the dosing interval (AUC(0-tau)) |  | Up to approximately 20 weeks | 
| Pharmacokinetic Analysis: maximum plasma concentration (Cmax) |  | Up to approximately 20 weeks | 
| Pharmacokinetic Analysis: time to maximum plasma concentration (tmax) |  | Up to approximately 20 weeks | 
| Pharmacokinetic Analysis: terminal elimination half-life (t1/2) |  | Up to approximately 20 weeks | 
| Objective Response Rate (ORR) in patients receiving AC676 |  | Approximately 18 months | 
| Duration of Response (DOR) in patients receiving AC676 |  | Approximately 18 months | 
| Time to Response (TTR) in patients receiving AC676 |  | Approximately 18 months | 
| Disease Control Rate (DCR) in patients receiving AC676 |  | Approximately 18 months | 
| Progression Free Survival rate (PFS) in patients receiving AC676 |  | Approximately 18 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
AC676, Chronic Lymphocytic Leukemia (CLL), Small Lymphocytic Lymphoma (SLL), Mantle Cell Lymphoma (MCL), Follicular Lymphoma (FL), Non-Germinal Center B-cell (Non-GCB) Diffuse Large B-cell Lymphoma (DLBCL), Marginal Zone Lymphoma (MZL, Waldenström Macroglobulinemia (WM), Non-Hodgkin Lymphoma (NHL), Bruton's tyrosine kinase-BTK, BTK Degrader, AC0676