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
A Study of AZD0486 in Subjects with B-Cell Non-Hodgkin Lymphoma
Misaki Masako
Syneos Health Japan K.K.
10F Umeda Daibiru, 3-3-10 Umeda, Kita-ku, Osaka
+81-90-1790-0384
TNB486.001@syneoshealth.com
Misaki Masako
Syneos Health Japan K.K.
10F Umeda Daibiru, 3-3-10 Umeda, Kita-ku, Osaka
+81-90-1790-0384
TNB486.001@syneoshealth.com
Not Recruiting
Aug. 25, 2023
Sept. 12, 2023
226
Interventional
single arm study
open(masking not used)
uncontrolled control
single assignment
treatment purpose
- Subject is between 18 and 80 years of age at the time of ICF signing. Those subjects >80 years of age may enroll in elderly cohorts.
- Biopsy proven B-NHL, including DLBCL, HGBL, or FL.
- For RR cohorts: 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 the RR cohorts in this study subjects must 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.
For 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. The last dose of radiation should not be within 14 days prior to the first dose of AZD0486. The subject should have recovered from all radiation-induced toxicity prior to the first dose of AZD0486.
- Subject has an Eastern Cooperative Oncology Group (ECOG) Performance Status of <= 2.
- 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.
- Subject must have an eGFR >= 50mL/min as estimated by the MRD formula.
- Subject is capable of understanding and complying with the parameters as outlined in the protocol and able to sign informed consent.
- 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 active central nervous system (CNS) involvement by their B-NHL.
- Subject has a history of leukemic presentation (>5,000 circulating lymphoma cells/micro L in the peripheral blood) of their B-NHL.
- Subject has a 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 following prior TCE or CAR T-cell therapy.
- Subject has received another investigational drug within 5x T1/2 (of this agent) within 28 days of enrollment, whichever is shorter.
- 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.
- Subject received CD19 CAR T therapy within 3 months prior to first dose.
- Subject requires chronic immunosuppressive therapy (including steroids >10mg prednisone/day). A short course of corticosteroids for symptom and disease control prior to first dose of study treatment is allowed. Immunosuppressive therapy must be discontinued 14 days or 5 half-lives prior to the first dose of study treatment (whichever is shorter).
- Subject has any medical or psychiatric condition which, in the opinion of Investigator or medical monitor, places subject at an unacceptable high risk of toxicity or could interfere with successful or safe delivery of therapy or evaluation of drug in subject safety or study results.
- Subject has received any therapy to treat cancer (including radiation, chemotherapy biologics or cellular therapies) or undergone a major surgical procedure within 14 days (or within 5 half-lives of an anti-cancer drug prior to first dose of study treatment, whichever is shorter. For RR disease only: The administration of debulking chemotherapy outside of this washout period to reduce the risk of TLS or CRS / NT in subjects with bulky disease is permitted.
- Subject has known serious infection requiring treatment.
- 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.
- Subject has unresolved AEs >= Grade 2 from prior anticancer therapy except for:
Alopecia, Peripheral neuropathy, Anemia or thrombocytopenia
18age old over
No limit
Both
B-Cell Non-Hodgkin Lymphoma
In the Japan cohorts, the subjects will receive a AZD0486 target dose of 7200 micro g, 15000 micro g, 25000 micro g or 37500 micro g in a SUD approach during Cycle 1, or Cycle 1 and 2. Dosing will continue thereafter Q2W on Days 1 and 15, in 28-day cycles. Additional cohorts may be opened where subjects receive weekly dosing during Cycles 1-2. AZD0486 may continue for up to two years of treatment or until the criteria for discontinuation are met.
Activity: The activity endpoints include objective response rate (ORR, defined as CR + PR), clinical benefit rate (CBR; defined as CR + PR + MR + SD for 24 weeks), overall survival (OS), progression-free survival (PFS), time to progression (TTP), time to response (TTR), and duration of objective response (DOR).
Pharmacokinetic: Concentrations of AZD0486 and antidrug antibody (ADA) will be determined at designated time points throughout the study. Values for the PK parameters of AZD0486 including the Cmax, the time to Cmax (Tmax), AUC from time 0 to the time of the last measurable concentration (AUCt), clearance (CL), the terminal phase elimination rate constant, and terminal half-life (t1/2,) will be determined after infusion in Cycle 1 using non-compartmental methods.
Exploratory Research Variables: Exploratory research will be conducted to study exposure-response relationships via biomarker relationships with PK, safety, and clinical activity.
Safety: Adverse events, laboratory profiles, physical exams, and vital signs will be assessed throughout the study. Adverse events will be graded according to the NCI CTCAE, version 5.0.
Adverse events will be collected until the 90-day post-last treatment visit or until a new line of therapy is initiated, whichever occurs earlier.
AstraZeneca Pharmaceuticals LP
National Hospital Organization Nagoya Medical Center IRB
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.
