Study to Evaluate Adverse Events, Change in Disease Activity, Movement of Oral ABBV-623 and ABBV-992 Tablets in the Body of Adult Participants With B-cell Cancers

Study Overview
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Brief Summary
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B-cell cancer is an aggressive and rare cancer of a type of immune cells (a white blood cell responsible for fighting infections). The main objective of this study is to evaluate the safety and efficacy of ABBV-623 and ABBV-992 given alone and in combination in treating B-cell cancers. Adverse events, change in disease activity and how the drug moves through the body of adult participants with B-cell cancers will be evaluated. ABBV-623 and ABBV-992 are investigational drugs being developed for the treatment of B-cell cancer. Study doctors assign participants to one of six groups, called treatment arms. Approximately 105 adult participants with a diagnosis of B-cell cancer will be enrolled in the study at approximately 50 sites worldwide. Participants in the combination expansion treatment arms will receive oral tablets of ABBV-623 and/or ABBV-992 once daily for 24 months. All other arms are treated until progression. Participants will attend regular visits during the study at a hospital or clinic. The effect of treatment will be evaluated by medical assessments and blood tests. Adverse events will be collected and assessed throughout the clinical trial.

Official Title
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A Phase 1 First-in-Human, Multicenter, Open-Label Study to Evaluate the Safety, Pharmacokinetics, Pharmacodynamics, and Efficacy of ABBV-623 and ABBV-992 in Subjects With B-cell Malignancies

Conditions
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B-cell Lymphoma

Intervention / Treatment
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* Drug: ABBV-623
* Drug: ABBV-992


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants must have documented diagnosis for one of the following B-cell malignancies: Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL), Mantle Cell Lymphoma (MCL), Marginal Zone Lymphoma (MZL), Waldenström's macroglobulinemia (WM), diffuse large B-cell lymphoma (DLBCL), and follicular lymphoma (FL), with measurable disease requiring treatment. Participants have relapsed or refractory to at least 2 prior systemic therapies. Combination Dose Expansion Only: Participants with documented diagnosis of CLL/SLL with measurable disease requiring treatment per by International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria. Eastern Cooperative Oncology Group performance status of 0 or 1. CLL/SLL, MCL, WM, MZL only: Prior Bruton's tyrosine kinase inhibitor (BTKi) exposure will be allowed if participant did not progress on active treatment and there is no evidence of resistance mutations. Renal, liver and hematological function lab values as determined in the protocol. For participants with prior BTK inhibitor exposure, no evidence of mutations which confer resistance to covalent BTK inhibitors. Exclusion Criteria: Participants with indolent forms of non-Hodgkin lymphoma (NHL) that require immediate cytoreduction. Participants with prior B-cell lymphoma 2 (BCL2) inhibitor (BCL2i) exposure (except for participants in the ABBV-992 monotherapy cohort).

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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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: Monotherapy in Dose Escalation: ABBV-623<br>Participants with Relapsed/Refractory (R/R) B-cell malignancies will receive escalating doses of ABBV-623. | Drug: ABBV-623<br>* Oral Tablets<br>|
| Experimental: Monotherapy in Dose Escalation: ABBV-992<br>Participants with R/R B-cell malignancies will receive escalating doses of ABBV-992. | Drug: ABBV-992<br>* Oral Tablets<br>|
| Experimental: Combination in Dose Escalation<br>Participants with R/R B-cell malignancies will receive escalating doses of ABBV-623 and ABBV-992. | Drug: ABBV-623<br>* Oral Tablets<br>Drug: ABBV-992<br>* Oral Tablets<br>|
| Experimental: Monotherapy in Dose Expansion: ABBV-623<br>Participants with R/R B-cell malignancies will receive ABBV-623 at recommended Phase 2 dose (RP2D) determined in dose escalation phase. | Drug: ABBV-623<br>* Oral Tablets<br>|
| Experimental: Monotherapy in Dose Expansion: ABBV-992<br>Participants with R/R B-cell malignancies will receive ABBV-992 at recommended Phase 2 dose (RP2D) determined in dose escalation phase. | Drug: ABBV-992<br>* Oral Tablets<br>|
| Experimental: Combination in Dose Expansion<br>Participants with R/R chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) will receive ABBV-623 and ABBV-992 at recommended Phase 2 dose (RP2D) determined in dose escalation phase. | Drug: ABBV-623<br>* Oral Tablets<br>Drug: ABBV-992<br>* Oral Tablets<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Adverse Events (AEs) | An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product which does not necessarily have a causal relationship with this treatment. The investigator assesses the relationship of each event to the use of study. A serious adverse event (SAE) is an event that results in death, is life-threatening, requires or prolongs hospitalization, results in a congenital anomaly, persistent or significant disability/incapacity or is an important medical event that, based on medical judgment, may jeopardize the participant and may require medical or surgical intervention to prevent any of the outcomes listed above. | Up to approximately 25 months. | 
| Dose Escalation: Maximum Observed Plasma Concentration (Cmax) of ABBV-623 | The maximum plasma concentration (Cmax; measured in ng/mL) is the highest concentration that ABBV-623 achieves in the blood after administration in a dosing interval. | Up to approximately 96 weeks | 
| Dose Escalation: Area Under the Plasma Concentration- Time Curve (AUC) From Time 0 to the Time of the Last Measurable Concentration of ABBV-623 | The area under the plasma concentration-time curve (AUC; measured in h*ng/mL/mg) is a method of measurement of the total exposure of ABBV-623 in blood plasma. | Up to approximately 96 weeks | 
| Dose Escalation: Maximum Observed Plasma Concentration (Cmax) of ABBV-992 | The maximum plasma concentration (Cmax; measured in ng/mL) is the highest concentration that ABBV-992 achieves in the blood after administration in a dosing interval. | Up to approximately 96 weeks. | 
| Dose Escalation: Area Under the Plasma Concentration- Time Curve (AUC) From Time 0 to the Time of the Last Measurable Concentration of ABBV-992 | The area under the plasma concentration-time curve (AUC; measured in h*ng/mL/mg) is a method of measurement of the total exposure of ABBV-992 in blood plasma. | Up to approximately 96 weeks | 
| Combination Dose Expansion: Overall Response Rate (ORR) (PR or Better by IWCLL Criteria) in Participants With R/R CLL/SLL | ORR is the proportion of R/R CLL/SLL participants achieving a response of PR or better per IWCLL without the use of new anti-cancer therapy. | Up to approximately 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose Escalation in Participants With R/R B-cell Malignancies: Percentage of Participants Achieving a Response of Partial Response (PR) or Better per Disease-Specific Response Criteria (e.g., IWCLL, Lugano, IWWM) | Partial response (PR) as per International Workshop on Chronic Lymphocytic Leukemia (IWCLL) , Lugano, International Workshop on Waldenström's Macroglobulinemia (IWWM) criteria in protocol. | Up to approximately 2 years | 
| Dose Escalation in Participants With R/R B-cell Malignancies: Duration of Response (DOR) for Participants With a Response of PR or Better | Duration of Response (DOR) is defined as the time from the date of the participant's documented first response of PR or better to the date of documented disease progression or death due to the disease, whichever occurs first. | Up to approximately 2 years | 
| Dose Escalation in Participants With R/R B-cell Malignancies: Time to Response (TTR) | Time to response, defined as the length of time from the date of first dose of study drug to the date of first response of PR or better per disease-specific response criteria. | Up to approximately 2 years | 
| Monotherapy Dose Expansion in Participants With R/R B-cell Malignancies: Achievement of a Response of PR or Better | Partial response (PR) as per International Workshop on Chronic Lymphocytic Leukemia (IWCLL) , Lugano, International Workshop on Waldenström's Macroglobulinemia (IWWM) criteria in protocol. | Up to approximately 2 years | 
| Monotherapy Dose Expansion in Participants With R/R B-cell Malignancies: Duration of Response (DOR) for Participants With a Response of PR or Better | Duration of Response (DOR) is defined as the time from the date of the participant's documented first response of PR or better to the date of documented disease progression or death due to the disease, whichever occurs first. | Up to approximately 2 years | 
| Monotherapy Dose Expansion in Participants With R/R B-cell Malignancies: Time to Response (TTR) | Time to response, defined as the length of time from the date of first dose of study drug to the date of first response of PR or better per disease-specific response criteria. | Up to approximately 2 years | 
| Combination Dose Expansion in Participants With CLL/SLL: Achievement of Bone Marrow Undetectable Minimal Residual Disease (uMRD) | Undetectable minimal residual disease (uMRD) is described as less than one myeloma cell per million bone marrow cells. | Up to approximately 6 months | 
| Combination Dose Expansion in Participants With CLL/SLL: Achievement of Bone Marrow Undetectable Minimal Residual Disease (uMRD) | Undetectable minimal residual disease (uMRD) is described as less than one myeloma cell per million bone marrow cells. | Up to approximately 1 Year | 
| Combination Dose Expansion in Participants With CLL/SLL: Percentage of Participants With Achievement of Peripheral Blood uMRD | Peripheral blood Undetectable minimal residual disease (uMRD) is described as less than one CLL cell per 10,000 leukocytes (or below 10^-4) or as specified in the protocol. | Up to approximately 96 weeks | 
| Combination Dose Expansion in Participants With CLL/SLL: Duration of Response for Participants With a Response of PR or Better | Duration of response is defined as the time from the initial objective response to disease progression or death, whichever occurs first. | Up to approximately 2 years | 
| Combination Dose Expansion in Participants With CLL/SLL: Time to Response | Time to response is defined by the time between the date of the first drug intake and the date of the first assessment having documented the response. | Up to approximately 2 years | 
| Combination Dose Expansion in Participants with CLL/SLL: Progression Free Survival | Progression free survival (PFS) is defined as the duration from start of the treatment to disease progression or death (regardless of cause of death), whichever comes first. | Approximately 2 years after study drug discontinuation | 
| Combination Dose Expansion in Participants With CLL/SLL: Overall Survival | Overall Survival is defined as the number of days from the date the participant was randomized to the date of death. | Approximately 2 years after study drug discontinuation | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ABBV-623, ABBV-992, B-cell lymphoma, Cancer, Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL), Mantle Cell Lymphoma (MCL), Marginal Zone Lymphoma (MZL), Waldenström's Macroglobulinemia (WM), Diffuse Large B-cell Lymphoma, Follicular Lymphoma