B-cell Non Hodgkin Lymphoma, Diffuse Large B Cell Lymphoma, Follicular Lymphoma, High-grade B-cell Lymphoma
Conditions
Keywords
NHL, DLBCL, HGBL, CD19, FL
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.
Interventions
DRUGAZD0486 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
Sponsors
AstraZeneca
Study design
Allocation
NA
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Adult subjects with B-NHL who will be enrolled into cohorts of incrementally increasing doses. Escalation is dependent upon ongoing review of emerging data by the Safety Monitoring Group (SMG).
Eligibility
Sex/Gender
ALL
Age
18 Years to 130 Years
Healthy volunteers
No
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 ≤ 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 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. * Subject has a history of major cardiac abnormalities. * If female, subject must not be pregnant or breastfeeding.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of subjects with Dose-limiting toxicities (DLT) | 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) | 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) | 4 Weeks | The maximum observed serum concentration on a concentration time curve. |
| Area under the concentration versus time curve from time zero to the last quantifiable time point prior to the next dose (AUClast) | 4 Weeks | Area under the serum concentration-time curve from time zero to time of last measurable concentration. |
| Apparent terminal half-life (t1/2) of AZD0486 | 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
| Measure | Time frame | Description |
|---|---|---|
| Anti-Lymphoma Activity by Objective Response Rate (ORR) | 48 months | Objective response rate is defined as the proportion of subjects with a confirmed partial or complete response to treatment |
| Anti-Lymphoma Activity by Progression-Free Survival (PFS) | 48 months | Progression-free survival time is defined as the time from the first dose of AZD0486 to progression or death, whichever occurs first |
| Anti-Lymphoma Activity by Duration of Objective Response (DOR) | 48 months | 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 |
| Anti-Lymphoma Activity by Clinical Benefit Rate | 48 months | 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 |
Countries
Australia, Japan, South Korea, Taiwan, United States
Contacts
STUDY_DIRECTORDavid Sermer, MD
AstraZeneca
Outcome results
None listed