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

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

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.

Study Overview

• Status: Recruiting
• Conditions: Follicular Lymphoma; Diffuse Large B Cell Lymphoma; High-grade B-cell Lymphoma; B-cell Non Hodgkin Lymphoma
• Intervention / Treatment: Drug: AZD0486 IV

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 116
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: AstraZeneca Clinical Study Information Center; Phone Number: 1-877-240-9479; Email: information.center@astrazeneca.com

Study Locations

• Australia
  • Heidelberg, Australia, 3084
    • Not yet recruiting
    • Research Site
  • Hobart, Australia, 7000
    • Not yet recruiting
    • Research Site
  • Melbourne, Australia, 3004
    • Recruiting
    • Research Site
• Japan
  • Chuo-ku, Japan, 104-0045
    • Recruiting
    • Research Site
  • Koto-ku, Japan, 135-8550
    • Recruiting
    • Research Site
  • Nagoya-shi, Japan, 460-0001
    • Recruiting
    • Research Site
  • Yamagata-shi, Japan, 990-9585
    • Not yet recruiting
    • Research Site
• Korea, Republic of
  • Seoul, Korea, Republic of, 05505
    • Recruiting
    • Research Site
  • Seoul, Korea, Republic of, 06591
    • Recruiting
    • Research Site
  • Seoul, Korea, Republic of, 06351
    • Recruiting
    • Research Site
  • Seoul, Korea, Republic of, 03080
    • Recruiting
    • Research Site
  • Seoul, Korea, Republic of, 120-752
    • Recruiting
    • Research Site
• Taiwan
  • Kaohsiung City, Taiwan, 833401
    • Not yet recruiting
    • Research Site
  • Kweishan, Taiwan, 333
    • Not yet recruiting
    • Research Site
  • Tainan, Taiwan, 704
    • Not yet recruiting
    • Research Site
  • Taipei, Taiwan, 10002
    • Not yet recruiting
    • Research Site
• United States
  • Florida
    • Tampa, Florida, United States, 33612
      • Recruiting
      • Research Site
  • Kentucky
    • Louisville, Kentucky, United States, 40207
      • Recruiting
      • Research Site
  • New Jersey
    • New Brunswick, New Jersey, United States, 08901
      • Recruiting
      • Research Site
  • North Carolina
    • Charlotte, North Carolina, United States, 28204
      • Recruiting
      • Research Site
  • Ohio
    • Columbus, Ohio, United States, 43210
      • Recruiting
      • Research Site
  • Oregon
    • Portland, Oregon, United States, 97239
      • Not yet recruiting
      • Research Site
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15237
      • Recruiting
      • Research Site
  • Texas
    • Austin, Texas, United States, 78704
      • Recruiting
      • Research Site
    • Houston, Texas, United States, 77030
      • Recruiting
      • Research Site
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Recruiting
      • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 78 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part 2, Arm B: Monotherapy Dose Expansion in Subjects with RR DLBCL/HGBL; An expansion cohort in subjects with DLBCL or HGBL will be enrolled after RP2D is established.	Drug: AZD0486 IV; 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; Other Names: TNB-486
Experimental: Part 2, Arm C: Monotherapy Dose Expansion in Subjects with RR FL; An expansion cohort in subjects with FL will be enrolled after RP2D is established.	Drug: AZD0486 IV; 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; Other Names: TNB-486
Experimental: Part 1, Arm A: AZD0486 Monotherapy Dose Escalation in Subjects with RR B-NHL; 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; 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; Other Names: TNB-486

What is the study measuring?

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 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
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

Collaborators and Investigators

• Sponsor: AstraZeneca
• Investigators: Study Director: David Sermer, MD, AstraZeneca

Study record dates

Study Major Dates

• Study Start (Actual): March 2, 2021
• Primary Completion (Estimated): January 22, 2027
• Study Completion (Estimated): January 22, 2027

Study Registration Dates

• First Submitted: October 13, 2020
• First Submitted That Met QC Criteria: October 13, 2020
• First Posted (Actual): October 20, 2020

Study Record Updates

• Last Update Posted (Actual): March 29, 2024
• Last Update Submitted That Met QC Criteria: March 28, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: DLBCL; NHL; FL; CD19; HGBL
• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma; Lymphoma, B-Cell; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Non-Hodgkin
• Other Study ID Numbers: D7400C00006

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal Vivli.org. All requests will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

"Yes", indicates that AZ are accepting requests for IPD, but this does not mean all requests will be approved.

Supporting

IPD Sharing Time Frame

AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA/PhRMA Data-Sharing Principles. For details of our timelines, please refer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

Access Criteria:

• IPD Sharing Access Criteria: When a request has been approved AstraZeneca will provide access to the anonymized individual patient-level data via secure research environment Vivli.org. A Signed Data Usage Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No