A Multicenter, Phase 1, Open-label, Dose-escalation and Expansion Study of AZD0486, a Bispecific Antibody Targeting CD19 in Subjects With B-Cell Non-Hodgkin Lymphoma
Overview
- Phase
- Phase 1
- Intervention
- AZD0486 IV
- Conditions
- B-cell Non Hodgkin Lymphoma
- Sponsor
- AstraZeneca
- Enrollment
- 317
- Locations
- 28
- Primary Endpoint
- Area under the concentration versus time curve from time zero to the last quantifiable time point prior to the next dose (AUClast)
- Status
- Recruiting
- Last Updated
- last month
Overview
Brief Summary
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 B-cell non-Hodgkin lymphoma (B-NHL).
Detailed Description
This dose escalation and optimization study, is evaluating the safety, tolerability, PK, PD and clinical activity of AZD0486 monotherapy.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Biopsy proven B-NHL, including DLBCL, HGBL, or FL.
- •Relapsed/refractory cohorts:
- •In order to be eligible subjects must have received at least 2 prior lines of therapy and not be candidates for treatment regimens known to provide clinical benefit in B-NHL. CAR T-naive subjects are allowed if they have declined, are considered ineligible for, or do not have timely access to CAR T cell therapies.
- •1L FL cohorts: Subject has biopsy-proven FL Grade 1-3a per WHO 2016 classification, Stage II-IV, FL International Prognostic Index 2-5 that has not been treated with prior systemic lymphoma-directed therapy and requires initiation of treatment based on GELF criteria. Radiation to localized disease prior to study entry is allowed if \>14 days from first dose.
- •All Cohorts:
- •Subject has an Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤
- •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
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 active central nervous system (CNS) involvement by their B-NHL. --Subjects may be eligible with a distant history of CNS involvement that has been adequately treated with no evidence of recurrence within last 6 months from screening.
- •Subject has a history of leukemic presentation of their B-NHL (\>5,000 circulating lymphoma cells/uL in the peripheral blood).
- •Subject has history or presence of clinically significant CNS pathology
- •Subject has CNS involvement from active or history of autoimmune disease.
- •Subject received CD19 CAR T therapy within 3 months prior to first dose.
- •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.
Arms & Interventions
AZD0486 Monotherapy Dose Escalation in Subjects with B-NHL
AZD0486 monotherapy will be administered intravenously on day 1 and 15 of 28 day cycles for a maximum of 2 years or until discontinuation criteria are met. Depending on cohort, subjects may receive priming or step-up dosing administered weekly during cycle 1 before reaching the target dose. Additional cohorts may be opened where subjects receive weekly dosing during Cycles 1-2. 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
Intervention: AZD0486 IV
Outcomes
Primary Outcomes
Area under the concentration versus time curve from time zero to the last quantifiable time point prior to the next dose (AUClast)
Time Frame: 4 Weeks
Area under the serum concentration-time curve from time zero to time of last measurable concentration.
Incidence of subjects with Dose-limiting toxicities (DLT)
Time Frame: 28 days
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.
Incidence of subjects with adverse events (AEs) and/or serious adverse events (SAEs)
Time Frame: From screening until 90 Days after end of treatment
The incidence, timing, seriousness, and relationship to study treatment of adverse events will be evaluated.
Maximum Observed Serum Concentration of AZD0486 (Cmax)
Time Frame: 4 Weeks
The maximum observed serum concentration on a concentration time curve.
Apparent terminal half-life (t1/2) of AZD0486
Time Frame: From screening until 90 Days after end of treatment
Terminal half-life (t1/2,) will be determined after infusion in Cycle 1 using non-compartmental methods.
Secondary Outcomes
- Anti-Lymphoma Activity by Duration of Objective Response (DOR)(48 months)
- Anti-Lymphoma Activity by Clinical Benefit Rate(48 months)
- Anti-Lymphoma Activity by Objective Response Rate (ORR)(48 months)
- Anti-Lymphoma Activity by Progression-Free Survival (PFS)(48 months)