A Phase I/II Study of AZD4512 Monotherapy or in Combination With Anticancer Agents in Participants With Relapsed/Refractory B-cell Non-Hodgkin Lymphoma

Official title

A Modular Phase I/II Open-label, Multicenter Study to Evaluate the Safety, Pharmacokinetics, Pharmacodynamics, Immunogenicity, and Efficacy of AZD4512 Monotherapy or in Combination With Other Anticancer Agent(s), in Participants With Relapsed/Refractory B-cell Non-Hodgkin Lymphoma (B-NHL) (Lumi-NHL)

Overview

This is a Phase I/II open-label, global multicenter study to evaluate the safety and efficacy of AZD4512 monotherapy or in combination with other anticancer agent(s), in participants with Relapsed/Refractory B-cell Non-Hodgkin Lymphoma (B-NHL).

Detailed description

Study D9890C00001 (Lumi-NHL) is modular study designed to evaluate the safety, pharmacokinetics, pharmacodynamics, immunogenicity, and efficacy of AZD4512 monotherapy or in combination with other anticancer agent(s), in participants with Relapsed/Refractory B-NHL. Module 1 aims to study AZD4512 monotherapy at in participants in R/R B-NHL who have been exposed to at least 2 prior lines of therapy.

Additional modules in specific B-NHL subtypes with AZD4512 as monotherapy or in combination with other anticancer agent(s) may be added in the future

Interventions

• Drug AZD4512
  AZD4512 is an antibody-drug conjugate targeting cluster of differentiation 22 (CD22) that will be administered via IV infusion

Primary outcome measures

• Percentage of participants with dose-limiting toxicities (DLTs) [Time frame: Up to 4 weeks]
• Frequency, duration, severity of Treatment-Emergent Adverse Events (TEAEs) and Treatment-Related Adverse Events (TRAEs) and Serious Adverse Events (SAEs) [Time frame: From the first dose up to and including 30 (+7) days after the last dose of study treatment , but prior to subsequent cancer therapy]
• Frequency of SAEs/AEs leading to discontinuation of AZD4512 [Time frame: From the first dose up to and including 30 (+7) days after the last dose of study treatment , but prior to subsequent cancer therapy]
• Number of participants with clinically significant alterations in vitals signs and abnormal laboratory parameters [Time frame: From the first dose up to and including 30 (+7) days after the last dose of study treatment , but prior to subsequent cancer therapy]

Secondary outcome measures (12)

• Objective response rate (ORR) [Time frame: Up to 2 years]
• Complete response (CR) rate [Time frame: Up to 2 years]
• Duration of response (DoR) [Time frame: Up to 2 years]
• Progression-free survival (PFS) [Time frame: Up to 2 years]
• Overall survival (OS) [Time frame: Up to 2 years]
• Area Under plasma concentration-time Curve (AUC) of AZD4512, total antibody and total unconjugated warhead [Time frame: Up to 2 years]
• Observed plasma (peak) drug concentration (Cmax) of AZD4512, total antibody and total unconjugated warhead [Time frame: Up to 2 years]
• Trough concentration (Ctrough) of AZD4512, total antibody and total unconjugated warhead [Time frame: Up to 2 years]
• Half life of AZD4512, total antibody and total unconjugated warhead [Time frame: Up to 2 years]
• Time to reach peak or maximum observed concentration (tmax) of AZD4512, total antibody and total unconjugated warhead [Time frame: Up to 2 years]
• Total clearance of AZD4512, total antibody and total unconjugated warhead [Time frame: Up to 2 years]
• The number and percentage of participants who develop anti-drug antibodies (ADAs) [Time frame: Up to 2 years]

Eligibility criteria

Inclusion criteria

• Eligible patients must be adults (≥18 years)
• Documented histologically confirmed diagnosis of B-cell non-Hodgkin lymphoma (B-NHL) as per World Health Organization (WHO) 2022 classification. In the dose escalation phase, any B-NHL subtype is allowed (excluding some subtypes), while the backfill phase restricts inclusion to defined subtypes: large B-cell lymphomas (as defined as Diffuse large B-cell lymphoma (DLBCL), Grade 3b Follicular lymphoma (FL), high-grade B-cell lymphoma (HGBCL) NOS, DLBCL/HGBCL with MYC and BCL2 rearrangements, primary mediastinal Large B-cell lymphoma, T-cell/histiocyte-rich LBCL, and transformed indolent lymphoma) and mantle cell lymphoma.
• Patients must have relapsed or refractory disease after at least two prior lines of systemic therapy and lack additional standard options with established benefit:

A)LBCL patients must have progressed after both anti-CD20 and at least one systemic chemotherapy regimen, and have considered-or be ineligible for-CAR-T, T cell engager, and stem cell transplant modalities.

B) Mantle cell lymphoma (MCL) patients must have had anti-CD20 and Bruton's Tyrosine Kinase (BTK) inhibitor.

Additional criteria include measurable disease by Lugano 2014, Eastern Cooperative Oncology Group (ECOG) performance status ≤2, and adequate organ and bone marrow function (as specified by blood counts, cardiac ejection fraction, renal and hepatic parameters, and coagulation indices).

Exclusion criteria

• Patients are excluded if they have a diagnosis of post-transplant lymphoproliferative disease, Richter's transformation, Burkitt's lymphoma, or chronic lymphocytic leukemia (CLL)/ Small lymphocytic lymphoma (SLL), Waldenstrom Macroglobulinemia/ Lymphoplasmacytic Lymphoma, or if they have active Central nervous system (CNS) involvement from their B-NHL. Exclusion also applies to those who have received Chimeric antigen receptor-T (CAR-T) or T cell engager therapies within 90 days prior to Cycle 1 Day 1 (C1D1), any investigational drug or other systemic anticancer therapies (except low-dose corticosteroids) within 21 days or 5 half-lives, and curative radiation within 14 days (localized palliative radiotherapy is allowed).
• Other exclusions include allogeneic Hematopoietic stem cell transplantation (HSCT) within 180 days (unless stable without active (graft-versus-host disease) GVHD for ≥2 months), autologous HSCT within 90 days (unless resolved toxicities), major surgery within 28 days, use of strong CYP3A inhibitors within 14 days or 5 half-lives before the dosing date, use of QTc-prolonging agents within 5 half-lives before the dosing date, or other malignancies within two years. Patients with unresolved ≥ Grade 2 AEs from prior therapy (except specified tolerable conditions), serious uncontrolled medical conditions, active infection within 14 days, or history/suspicion of significant interstitial lung disease/pneumonitis are also excluded.
• Females who are pregnant or breastfeeding are not eligible.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Sequential

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 8 centers

• Research Site — Irvine
• Research Site — Jacksonville
• Research Site — Rochester
• Research Site — New York
• Research Site — New York
• Research Site — Cleveland
• Research Site — Myrtle Beach
• Research Site — Franklin

Italy · 3 centers

• Research Site — Bologna
• Research Site — Milan
• Research Site — Milan

China · 2 centers

• Research Site — Chengdu
• Research Site — Guangzhou

Japan · 2 centers

• Research Site — Bunkyō City
• Research Site — Kōtoku

South Korea · 2 centers

• Research Site — Seoul
• Research Site — Seoul

Taiwan · 2 centers

• Research Site — Taichung
• Research Site — Taipei

United Kingdom · 2 centers

• Research Site — London
• Research Site — Newcastle upon Tyne

Australia · 1 center

• Research Site — Melbourne

Identifiers

NCT: NCT07123454 · D9890C00001

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗