A Study of AZD0486 in Subjects With Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma

Study Overview
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Brief Summary
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This phase 1 study will investigate the safety, tolerability, pharmacokinetic, pharmacodynamic, and clinical activity of AZD0486, a CD19 x CD3 T-cell engaging bispecific antibody, in subjects with relapsed or refractory B-cell non-Hodgkin lymphoma (B-NHL) who have received 2 or more prior lines of therapy.

Detailed Description
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The study consists of 3 parts. Part 1 Arm A is a dose escalation study allowing the assessment of safety, tolerability, PK and PD profiles of single-agent AZD0486. Part 2 Arm B will evaluate the MTD (or RP2D) of AZD0486 monotherapy in subjects with biopsy proven RR DLBCL and HGBL. This will be initiated once expansion dose has been selected based on data from Part 1 Arm A. Part 2 Arm C evaluate the MTD (or RP2D) of AZD0486 monotherapy in subjects with biopsy proven RR FL. Arm C will be initiated once the expansion dose for FL has been selected based on data from the Monotherapy Dose Escalation (Part 1, Arm A). The expansion dose and dosing frequency for Part 2 will be chosen by the SMG based on safety, tolerability, and PK/PD data collected during the dose escalation portion of the study.

Official Title
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A Multicenter, Phase 1, Open-label, Dose-escalation and Expansion Study of AZD0486, a Bispecific Antibody Targeting CD19 in Subjects With Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma

Conditions
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B-cell Non Hodgkin Lymphoma, Diffuse Large B Cell Lymphoma, High-grade B-cell Lymphoma, Follicular Lymphoma

Intervention / Treatment
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* Drug: AZD0486 IV


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Biopsy proven B-NHL, including DLBCL, HGBL, or FL. For Arm B Only: Subject has biopsy proven DLBCL or HGBL For Arm C only: Subject has biopsy proven FL Subject has received at least 2 lines of therapy to which the subject has been either refractory or has subsequently relapsed. In order to be eligible for this study subjects must not be candidates for treatment regimens known to provide clinical benefit in B-NHL. Subject has an Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤ 2. Subject must have adequate liver, bone marrow and kidney function (eGFR ≥ 50 mL/min). Subject must have locally confirmed CD19 positivity (must be documented after time of progression from last CD19-targeted therapy, if received) Subject must have at least 1 measurable disease site Subject must have ANC >/= 1000/mm3, platelets >/= 50,000 mm3, hemoglobin >/= 8.0 g/dL. Transfusion and/or growth factor are allowed but counts must be stable for at least 72 hours afterwards prior to screening Subject must have a total bilirubin <1.5x ULN, AST/ALT < 3xULN Exclusion Criteria: Subject has been diagnosed with or treated for another malignancy whose natural history or treatment may interfere with the safety or efficacy assessment of the investigational regimen. Subject has a history of central nervous system (CNS) involvement by their B-NHL Subject has a history of leukemic presentation of their B-NHL. Subject has history or presence of clinically significant CNS pathology Subject has CNS involvement from active or history of autoimmune disease. Subject experienced Grade ≥ 3 cytokine release syndrome (CRS) following prior T-cell engager (TCE) or CAR T-cell therapy. Subject experienced Grade ≥ 2 neurotoxicity/immune effector cell-associated neurotoxicity syndrome (ICANS) following prior TCE or CAR T-cell therapy. Subject has received a peripheral autologous stem cell transplant (SCT) within 12 weeks, or an allogeneic SCT within 1 year of the first dose of study drug treatment or has received an SCT and requires ongoing immunosuppressive therapy. Subjects with human immunodeficiency virus (HIV) infection, or subjects with chronic or active infection with hepatitis B virus (HBV) or hepatitis C virus (HCV). HIV-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial. Subjects with chronic HBV may be enrolled if the HBV viral load is undetectable on suppressive therapy, or if the subject has a documented cure. Subjects with HCV who have a documented cure may be enrolled. Subject has a history of major cardiac abnormalities. If female, subject must not be pregnant or breastfeeding.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 130 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
Interventional Model Description: The study will consist of 2 parts; In the monotherapy dose escalation part (Part 1, Arm A), adult subjects with RR B-NHL who have received 2 or more prior lines of therapy will be enrolled into cohorts of incrementally increasing doses. Dose escalation will proceed based on emerging safety, efficacy, and PK/PD data and after review by safety monitoring group (SMG) The monotherapy dose expansion in refractory or relapsed (RR) diffuse large B-cell lymphoma (DLBCL)/ high-grade B-cell lymphoma (HGBL) (Part 2, Arm B) or RR follicular lymphoma (FL) (Grade 1-3a) (Part 2, Arm C) will be initiated after MTD (or RP2D) has been selected based on data from Part 1, Arm A. Arm B and Arm C will evaluate the MTD (or RP2D) of AZD0486 in subjects with RR DLBCL/HGBL or RR FL to evaluate safety, tolerability, and the relationship between pharmacodynamic markers and PK, safety and clinical response
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1, Arm A: AZD0486 Monotherapy Dose Escalation in Subjects with RR B-NHL<br>AZD0486 monotherapy will be administered intravenously on day 1 and 15 of 28 day cycles for a maximum of 24 cycles or until disease progression. Depending on cohort, subjects may receive priming or step-up dosing during cycle 1 before reaching the target dose. While on study, subjects will be monitored for safety and efficacy with periodic disease assessment with PET/CT. If subject achieves two consecutive CRs after completing C6, then they may be eligible for monthly dosing | Drug: AZD0486 IV<br>* AZD0486 is a bispecific antibody targeting CD19 on tumor cells and CD3 on T-cells leading to T cell-mediated cytotoxicity of malignant B cells<br>* Other names: TNB-486;|
| Experimental: Part 2, Arm B: Monotherapy Dose Expansion in Subjects with RR DLBCL/HGBL<br>An expansion cohort in subjects with DLBCL or HGBL will be enrolled after RP2D is established. | Drug: AZD0486 IV<br>* AZD0486 is a bispecific antibody targeting CD19 on tumor cells and CD3 on T-cells leading to T cell-mediated cytotoxicity of malignant B cells<br>* Other names: TNB-486;|
| Experimental: Part 2, Arm C: Monotherapy Dose Expansion in Subjects with RR FL<br>An expansion cohort in subjects with FL will be enrolled after RP2D is established. | Drug: AZD0486 IV<br>* AZD0486 is a bispecific antibody targeting CD19 on tumor cells and CD3 on T-cells leading to T cell-mediated cytotoxicity of malignant B cells<br>* Other names: TNB-486;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of subjects with Dose-limiting toxicities (DLT) | A DLT is defined as a TEAE that is not unequivocally due to the subject's underlying malignancy or other extraneous cause. DLT evaluable subjects are defined as those subjects who receive either the target dose of AZD0486 or priming dose(s) in any step-up dose schedule and are assessed for toxicities for the 28-day evaluation period. The NCI-CTCAE version 5.0 will be used (except for CRS and NT). A DLT will be evaluated as Non-hematologic, Hematologic, Cytokine Release Syndrome (CRS), or neurotoxicity. | 28 days | 
| Incidence of subjects with adverse events (AEs) and/or serious adverse events (SAEs) | The incidence, timing, seriousness, and relationship to study treatment of adverse events will be evaluated. | From screening until 90 Days after end of treatment | 
| Maximum Observed Serum Concentration of AZD0486 (Cmax) | The maximum observed serum concentration on a concentration time curve. | 4 weeks | 
| Area under the concentration versus time curve from time zero to the last quantifiable time point prior to the next dose (AUClast) | Area under the serum concentration-time curve from time zero to time of last measurable concentration. | 4 weeks | 
| Apparent terminal half-life (t1/2) of AZD0486 | Terminal half-life (t1/2,) will be determined after infusion in Cycle 1 using non-compartmental methods. | From screening until 90 Days after end of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Anti-Lymphoma Activity by Objective Response Rate (ORR) | Objective response rate is defined as the proportion of subjects with a confirmed partial or complete response to treatment | 48 months | 
| Anti-Lymphoma Activity by Progression-Free Survival (PFS) | Progression-free survival time is defined as the time from the first dose of AZD0486 to progression or death, whichever occurs first | 48 months | 
| Anti-Lymphoma Activity by Duration of Objective Response (DOR) | The duration of objective response for a subject is defined as the time from the initial objective response to disease progression or death, whichever occurs first | 48 months | 
| Anti-Lymphoma Activity by Clinical Benefit Rate | Clinical benefit rate is defined as the proportion of subjects with a confirmed complete response, partial response or minor response, or stable disease for at least 24 weeks after responding to treatment | 48 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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NHL, DLBCL, HGBL, CD19, FL