A Dose-Escalation and Expansion Study of BGB-16673 in Participants With B-Cell Malignancies

Study Overview
=================
Brief Summary
-----------------
Study consists of two main parts to explore BGB-16673 recommended dosing, a Part 1 monotherapy dose finding comprised of monotherapy dose escalation and monotherapy safety expansion of selected doses, and a part 2 (dose expansion cohorts)

Official Title
-----------------
A Phase 1/2, Open-Label, Dose-Escalation and -Expansion Study of the Bruton Tyrosine Kinase Targeted Protein Degrader BGB-16673 in Patients With B-Cell Malignancies

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

Intervention / Treatment
-----------------
* Drug: BGB-16673


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria : Confirmed diagnosis (per World Health Organization (WHO) guidelines, unless otherwise noted) of one of the following: Marginal Zone Lymphoma (MZL) (Part 1a 1b, and 1c only), Follicular Lymphoma (FL) (Part 1a and 1c only), R/R MCL (parts 1a, 1b, and 2 only), R/R CLL/SLL (Parts 1a, 1b, and 2), WM (Part 1a and 1c only), DLBCL (Part 1a and 1c only), or >2 treatments per the Richter's transformation to DLBCL (Part 1a and 1c only). Participants who have previously received a covalently-binding BTK inhibitor in any line of therapy must have received treatment with the BTK inhibitor for ≥ 8 weeks (unless reason for discontinuation is intolerance). For dose-finding and dose-expansion, participants who had previously received a covalently-binding BTK inhibitor as monotherapy or in combination with other anticancer agents are eligible for the study if they meet any of the following criteria: discontinued the previous BTK inhibitor due to disease progression, experienced disease progression after completing treatment with a BTK inhibitor or discontinued the BTK inhibitor due to toxicity or intolerance. Measurable disease by radiographic assessment or serum IgM level (WM only) Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 2 participants enrolling in the dose finding phase of the study may be previously treated with a BTKi or may be naïve to BTKi therapy depending on the diagnosis and country of enrollment; participants with CLL/SLL or MCL enrolling in the expansion cohorts (Part 2) must have been treated with a BTKi in a prior line of therapy. Exclusion Criteria: Prior malignancy (other than the disease under study) within the past 2 years, except for curatively treated basal or squamous skin cancer, superficial bladder cancer, carcinoma in situ of the cervix or breast, or localized Gleason score ≤ 6 prostate cancer Requires ongoing systemic treatment for any other malignancy Requires ongoing systemic (defined as ≥ 10 mg/day of prednisone or equivalent) corticosteroid treatment. Current or history of central nervous system involvement including the brain, spinal cord, leptomeninges, and cerebrospinal fluid (as documented by imaging, cytology, or biopsy) by B-cell malignancy, regardless of whether participants had received treatment for central nervous system disease Known active plasma cell neoplasm, prolymphocytic leukemia, T-cell lymphoma, Burkitt lymphoma, acquired immunodeficiency syndrome (AIDS)-related B-cell lymphoma, Castleman disease, post-transplant lymphoproliferative disorders, hairy cell leukemia, GCB DLBCL, EBV+ DLBCL NOS, primary DLBCL of the central nervous system (CNS), primary cutaneous DLBCL - leg type, DLBCL associated with chronic inflammation, primary mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, ALK+ large B-cell lymphoma, primary effusion lymphoma, high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements, high-grade B-cell lymphoma - NOS, B-cell lymphoma unclassifiable with features intermediate between DLBCL and classical Hodgkin lymphoma, or history of or currently suspected Richter's transformation of an indolent lymphoma to an aggressive histology (only participants with Richter Transformation to DLBCL are eligible for Part 1a and 1c). Note: Other protocol defined Inclusion/Exclusion criteria may apply.

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: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1a (Monotherapy Dose Escalation)<br>Dose escalation in selected R/R B-Cell malignancies to inform safety, tolerability and MTD. | Drug: BGB-16673<br>* Orally administered<br>|
| Experimental: Part 1b (Monotherapy Safety Expansion)<br>Additional participants with selected R/R B-Cell malignancies will be enrolled at selected doses to help inform the selection of the recommended phase two dose (RP2D). | Drug: BGB-16673<br>* Orally administered<br>|
| Experimental: Part 1c (Additional Monotherapy Safety Expansion)<br>After RP2D is determined, additional safety data will be collected to confirm RP2D for participants with selected B-cell malignancies not being evaluated in Part 2 | Drug: BGB-16673<br>* Orally administered<br>|
| Experimental: Part 2 (Monotherapy Dose Expansion)<br>The totality of the data from Part 1a and Part 1b will be used to further evaluate the safety and efficacy of BGB-16673 at the recommended dose(s) for Part 2 expansion in specific histologies. | Drug: BGB-16673<br>* Orally administered<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) with adverse events leading to discontinuation, and Adverse Events (AEs) graded according NCI-CTCAE V5. | TEAE is defined as an AE that had an onset date or a worsening in severity from baseline (pretreatment) on or after the date of the first dose of the study drug and up to 30 days after the last dose of study treatment or the initiation of a new anticancer therapy, whichever is earlier | approximately 3 years | 
| Recommended Phase 2 Dose (RP2D) of BGB-16673 | RP2D is the recommended dose for further evaluation in Part 2, determined based on the totality of the available clinical safety, clinical efficacy, pharmacokinetics (PK), and pharmacodynamic data in Part 1. | approximately 3 years | 
| Maximum Tolerated Dose (MTD) of BGB-16673 | determined by the sponsor based on the Safety Monitoring Committee's recommendation considering the totality of the available clinical safety, clinical efficacy, pharmacokinetics (PK), and pharmacodynamic data | approximately 3 years | 
| Part 2: Overall response rate (ORR) in Relapsed/Refractory Mantle Cell Lymphoma (R/R MCL) Participants | according to the Independent Review Committee (IRC) assessment based on best overall response of PR or better as determined by Lugano criteria | approximately 3 years | 
| Part 2: ORR in relapsed/refractory chronic/small lymphocytic lymphoma (R/R CLL/SLL) Participants | as assessed by investigators based on overall response of PR-L or better as determined by the International Workshop on Chronic Lymphocytic Leukemia (iwCLL )criteria | approximately 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Single Dose Maximum observed plasma concentration (Cmax) of BGB-16673 | Collected for both Part 1 and Part 2 | Day 1 pre-dose and 2, 4, 6,8,24, 48 and 72 hours post-dose (approximately 2 years) | 
| Single Dose Minimum observed plasma concentration (Cmin) of BGB-16673 | Collected for both Part 1 and Part 2 | Day 1 pre-dose and 2, 4, 6,8,24, 48 and 72 hours post-dose (approximately 2 years) | 
| Single Dose Time to reach Cmax (tmax) of BGB-16673 | Collected for both Part 1 and Part 2 | Day 1 pre-dose and 2, 4, 6,8,24, 48 and 72 hours post-dose (approximately 2 years) | 
| Single Dose Time to reach half of Cmax (T1/2) of BGB-16673 | Collected for both Part 1 and Part 2 | Day 1 pre-dose and 2, 4, 6,8,24, 48 and 72 hours post-dose (approximately 2 years) | 
| Single Dose Area under the plasma concentration-time curve (AUC) of BGB-16673 | Collected for both Part 1 and Part 2 | Day 1 pre-dose and 2, 4, 6,8,24, 48 and 72 hours post-dose (approximately 2 years) | 
| Single Dose apparent total clearance of drug from plasma after oral administration (CL/F) of BGB-16673 | Collected for both Part 1 and Part 2 | Day 1 pre-dose and 2, 4, 6,8,24, 48 and 72 hours post-dose (approximately 2 years) | 
| Single Dose apparent volume of distribution (Vz/F) of BGB-16673 | Collected for both Part 1 and Part 2 | Day 1 pre-dose and 2, 4, 6,8,24, 48 and 72 hours post-dose (approximately 2 years) | 
| Single Dose accumulation ratios of BGB-16673 | Collected for both Part 1 and Part 2 | Day 1 pre-dose and 2, 4, 6,8,24, 48 and 72 hours post-dose (approximately 2 years) | 
| Steady State Maximum observed plasma concentration (Cmax) of BGB-16673 | Collected for both Part 1 and Part 2 | Day 1 pre-dose and 2, 4, 6,8,24, 48 and 72 hours post-dose (approximately 2 years) | 
| Steady State minimum observed plasma concentration (Cmin) of BGB-16673 | Collected for both Part 1 and Part 2 | Day 1 pre-dose and 2, 4, 6,8,24, 48 and 72 hours post-dose (approximately 2 years) | 
| Steady State Time to reach Cmax (tmax) of BGB-16673 | Collected for both Part 1 and Part 2 | Day 1 pre-dose and 2, 4, 6,8,24, 48 and 72 hours post-dose (approximately 2 years) | 
| Steady State Time to reach half of Cmax (T1/2) of BGB-16673 | Collected for both Part 1 and Part 2 | Day 1 pre-dose and 2, 4, 6,8,24, 48 and 72 hours post-dose (approximately 2 years) | 
| Steady State Area under the plasma concentration-time curve (AUC) of BGB-16673 | Collected for both Part 1 and Part 2 | Day 1 pre-dose and 2, 4, 6,8,24, 48 and 72 hours post-dose (approximately 2 years) | 
| Steady State apparent total clearance of drug from plasma after oral administration (CL/F) of BGB-16673 | Collected for both Part 1 and Part 2 | Day 1 pre-dose and 2, 4, 6,8,24, 48 and 72 hours post-dose (approximately 2 years) | 
| Steady State apparent volume of distribution (Vz/F) of BGB-16673 | Collected for both Part 1 and Part 2 | Day 1 pre-dose and 2, 4, 6,8,24, 48 and 72 hours post-dose (approximately 2 years) | 
| Bruton's tyrosine kinase (BTK) protein degradation in peripheral blood after BGB-16673 monotherapy | Collected for both Part 1 and Part 2 | Day 1 pre-dose and 8 hours post-dose (approximately 2 years) | 
| Part 1: Overall response rate (ORR) | defined as the proportion of participants whose best overall response is better than stable disease. | approximately 3 years | 
| Part 1: Number of Waldenström Macroglobulinemia (WM) Participants with major response rate (MRR) | MRR is defined as the proportion of participants whose best overall response (BOR) is partial response (PR) or better (PR, very good partial response (VGPR), or complete response (CR)). | approximately 3 years | 
| Part 2: Number of R/R MCL Participants with overall response rate (ORR) | defined as the proportion of participants whose best overall response is better than stable | approximately 3 years | 
| Part 2: Number of R/R CLL/SLL Participants with overall response rate (ORR) | defined as the proportion of participants whose best overall response is better than stable | approximately 3 years | 
| Part 2: Duration of Response (DOR) for R/R MCL Participants | DOR is defined as the time from the date that response criteria are first met to the date that progressive disease is objectively documented or death, whichever comes first [as assessed by the investigator and the IRC. | approximately 3 years | 
| Part 2: Duration of Response (DOR) for R/R CLL/SLL Participants | DOR is defined as the time from the date that response criteria are first met to the date that progressive disease is objectively documented or death, whichever comes first [as assessed by the investigator and the IRC. | approximately 3 years | 
| Part 2: Time to Response (TTR) for R/R MCL Participants | TTR is defined as the time from study treatment start to date of the earliest qualifying response (partial response or better), as assessed by IRC and the investigator | approximately 3 years | 
| Part 2: Time to Response (TTR) for R/R CLL/SLL Participants | TTR is defined as the time from study treatment start to date of the earliest qualifying response (partial response or better), as assessed by IRC and the investigator | approximately 3 years | 
| Part 2: Progression- Free Survival (PFS) for R/R MCL Participants | PFS is defined as the time from first dose until first documentation of progression or death, whichever comes first, as assessed by IRC and the investigator | approximately 3 years | 
| Part 2: Progression- Free Survival (PFS) for R/R CLL/SLL Participants | PFS is defined as the time from first dose until first documentation of progression or death, whichever comes first, as assessed by IRC and the investigator | approximately 3 years | 
| Part 2: Overall Survival (OS) for R/R MCL Participants | OS is defined as the time from first study drug administration to the date of death due to any cause | approximately 3 years | 
| Part 2: Overall Survival (OS) for R/R CLL/SLL Participants | OS is defined as the time from first study drug administration to the date of death due to any cause | approximately 3 years | 
| Part 2: Participant-reported outcomes (PRO) in R/R MCL participants via National Comprehensive Cancer Network/Functional Assessment of Cancer Therapy Lymphoma Cancer Symptom Index - 18 (NFLymSI-18) | The NFlymSI-18 is a participant-reported outcome questionnaire that is developed to measure disease-specific symptoms and/or treatment-related concerns in participants with advanced lymphoma | approximately 3 years |