Clinical trial NCT04594642: A Study of AZD0486 in Subjects With B-Cell Non-Hodgkin Lymphoma
Official title: 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
Conditions: B-cell Non Hodgkin Lymphoma
Diffuse Large B Cell Lymphoma
High-grade B-cell Lymphoma
Follicular Lymphoma
Keywords: NHL
DLBCL
HGBL
CD19
FL
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
First posted: 2020-10-20
Enrollment: 317
Sex: ALL
Minimum age (years): 18
Maximum age (years): 130
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
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).
Primary purpose: TREATMENT

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.

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 ≤ 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.

Primary outcomes:
measure: Incidence of subjects with Dose-limiting toxicities (DLT)
timeFrame: 28 days
measure: Incidence of subjects with adverse events (AEs) and/or serious adverse events (SAEs)
timeFrame: From screening until 90 Days after end of treatment
measure: Maximum Observed Serum Concentration of AZD0486 (Cmax)
timeFrame: 4 Weeks
measure: Area under the concentration versus time curve from time zero to the last quantifiable time point prior to the next dose (AUClast)
timeFrame: 4 Weeks
measure: Apparent terminal half-life (t1/2) of AZD0486
timeFrame: From screening until 90 Days after end of treatment
Secondary outcomes:
measure: Anti-Lymphoma Activity by Objective Response Rate (ORR)
timeFrame: 48 months
measure: Anti-Lymphoma Activity by Progression-Free Survival (PFS)
timeFrame: 48 months
measure: Anti-Lymphoma Activity by Duration of Objective Response (DOR)
timeFrame: 48 months
measure: Anti-Lymphoma Activity by Clinical Benefit Rate
timeFrame: 48 months
Other outcomes:
Locations:
city: Tampa
country: United States
facility: Research Site
state: Florida
city: Louisville
country: United States
facility: Research Site
state: Kentucky
city: New Brunswick
country: United States
facility: Research Site
state: New Jersey
city: Charlotte
country: United States
facility: Research Site
state: North Carolina
city: Columbus
country: United States
facility: Research Site
state: Ohio
city: Portland
country: United States
facility: Research Site
state: Oregon
city: Pittsburgh
country: United States
facility: Research Site
state: Pennsylvania
city: Austin
country: United States
facility: Research Site
state: Texas
city: Houston
country: United States
facility: Research Site
state: Texas
city: Milwaukee
country: United States
facility: Research Site
state: Wisconsin
city: Bedford Park
country: Australia
facility: Research Site
city: Heidelberg
country: Australia
facility: Research Site
city: Hobart
country: Australia
facility: Research Site
city: Melbourne
country: Australia
facility: Research Site
city: Chuo-ku
country: Japan
facility: Research Site
city: Koto-ku
country: Japan
facility: Research Site
city: Nagoya-shi
country: Japan
facility: Research Site
city: Yamagata-shi
country: Japan
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Kaohsiung City
country: Taiwan
facility: Research Site
city: Kweishan
country: Taiwan
facility: Research Site
city: Tainan
country: Taiwan
facility: Research Site
city: Taipei
country: Taiwan
facility: Research Site
Study officials:
affiliation: AstraZeneca
name: David Sermer, MD
role: STUDY_DIRECTOR
References: