A Phase I/II Study of AZD0466 as Monotherapy or in Combination With Anticancer Agents in Advanced Non-Hodgkin Lymphoma

A Modular Phase I/II, Open-label, Dose Escalation and Expansion, Multicentre Study to Assess the Safety, Tolerability, Pharmacokinetics, and Preliminary Efficacy of AZD0466 as Monotherapy or in Combination With Anticancer Agents in Patients With Advanced Non-Hodgkin Lymphoma.

This study evaluates the safety, tolerability, PK, and preliminary efficacy of AZD0466 as monotherapy or in combination with other anticancer agents in patients with advanced NHL

Study Overview

• Status: Terminated
• Conditions: Non-Hodgkin Lymphoma
• Intervention / Treatment: Drug: AZD0466

Detailed Description

This is a modular Phase I/II, open-label, dose escalation and expansion, multicentre Study. The study consists of individual modules, each evaluating the safety and tolerability of AZD0466 as monotherapy or with a specific combination treatment. The initial components are the core protocol, which contains information applicable to all modules, and Module 1.

Module 1 will evaluate the safety, tolerability, PK, and preliminary efficacy of AZD0466 monotherapy and will include 2 parts. Part A dose escalation and Part B dose expansion cohorts. Part A will enrol patients with advanced B-NHL and once the RP2D has been determined, Part B may open to further explore the preliminary anticancer efficacy of AZD0466 monotherapy in patients with selected lymphoid malignancies.

Part A: Phase 1 dose setting to assess the safety and tolerability and determine dose(s) and schedule(s) to be evaluated in Part B.

Part B: Phase 1b/2a dose expansion to assess the efficacy of AZD0466 in 3 select patient populations: relapsed/refractory (R/R) mantle cell lymphoma (MCL) (Cohort B1), R/R follicular lymphoma (FL) or marginal zone lymphoma (MZL) (Cohort B2), and R/R diffuse large B-cell lymphoma (DLBCL) (Cohort B3).

• Study Type: Interventional
• Enrollment (Actual): 7
• Phase: Phase 1

Contacts and Locations

Study Locations

• Australia
  • Heidelberg, Australia, 3084
    • Research Site
• France
  • Lille Cedex, France, 59037
    • Research Site
• Italy
  • Milan, Italy, 20141
    • Research Site
• Korea, Republic of
  • Seoul, Korea, Republic of, 06591
    • Research Site
  • Seoul, Korea, Republic of, 110-744
    • Research Site
• Portugal
  • Porto, Portugal, 4200-072
    • Research Site
• Spain
  • Palma de Mallorca, Spain, 07010
    • Research Site
  • Pamplona, Spain, 31008
    • Research Site
  • Salamanca, Spain, 37007
    • Research Site
• United States
  • California
    • Duarte, California, United States, 91010
      • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 130 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria- Core

• Patient must be aged ≥ 18 years at the time of signing the informed consent. In some countries, parental consent may be required in addition to an assent form for patients who are 18 years of age.
• Patient must have histologically documented diagnosis of B-cell non-Hodgkin lymphoma (B-NHL) as defined by a B-cell neoplasm in the World Health Organisation classification scheme except as noted in the exclusion criteria.
• Patient has relapsed after or failed to respond to at least 2 but no more than 5 prior systemic treatment regimens (including investigational therapy) and for whom there is no available therapy expected to improve survival (eg, standard chemotherapy, autologous stem cell transplantation (SCT), chimeric antigen receptor T cell (CAR-T) cell therapy).

• Documented active disease requiring treatment that is relapsed or refractory defined as:

  • Recurrence/relapse of disease after response to prior line(s) of therapy.
  • Progressive disease (refractory) on/after completion of the treatment regimen preceding entry into the study.

• Must have at least one measurable, fluorodeoxyglucose positron emission tomography (FDG-PET) avid lesion (except for MZL), based on bi-dimensional assessment on PET and computed tomography (CT)/magnetic resonance imaging (MRI) scan. A measurable lesion is defined as:

  • For nodal lesions: longest diameter > 1.5 cm
  • For extranodal lesions: longest diameter > 1 cm
• Eastern Cooperative Oncology Group (ECOG) performance status score ≤ 2. Performance status must not have deteriorated by ≥ 2 levels within 2 weeks after providing informed consent.
• Adequate haematologic, hepatic, and renal function
• Adequate cardiac function as demonstrated by left ventricular ejection fraction > 50% on screening cardiac multigated acquisition, magnetic resonance imaging, or echocardiogram.
• Women of childbearing potential and men should use protocol defined contraceptive measures.
• Willing and able to participate in all required study evaluations and procedures including receiving IV administration of study intervention and admission to the hospital, when required, for administration of study treatment and monitoring.
• All patients must be willing to undergo an incisional or excisional lymph node or tissue biopsy or to provide a lymph node or tissue biopsy from the most recent available archival tissue.
• For inclusion in the genetic component of the study, patients must fulfil protocol defined criteria.

Inclusion Criteria- Module 1

Additional Inclusion Criteria for Cohort B1 (R/R mantle cell lymphoma [MCL]):

• Histologically confirmed MCL, with documentation of monoclonal B cells that have a chromosome translocation t(11;14)(q13;q32) and/or overexpress cyclin D1, as assessed by Investigator or local pathologist.
• Must have relapsed after or failed to respond to at least 2 prior lines of treatment, including one anti-CD20 monoclonal antibody (mAb) and a Bruton's tyrosine kinase inhibitor.

Additional Inclusion Criteria for Cohort B2 (R/R FL or MZL):

• Histologically confirmed diagnosis of FL Grade 1, 2, or 3a OR histologically confirmed MZL including splenic, nodal, and extranodal subtypes, as assessed by Investigator or local pathologist.
• For FL patients: Previously received at least 2 prior systemic treatment regimens (including anti-CD20 mAb and an alkylating agent).
• For MZL patients: Previously received at least 2 prior lines of systemic therapy including at least one anti-CD20 mAb-directed regimen either as monotherapy or as chemoimmunotherapy (Helicobacter pylori eradication and radiation therapy alone will not be considered a systemic treatment regimen).

Additional Inclusion Criteria for Cohort B3 (R/R DLBCL):

• Histologically confirmed DLBCL (including transformed FL) OR FL Grade 3b.
• Must have received 2 lines of systemic therapy including at least one anti-CD20 mAb-directed regimen and must have failed or are ineligible for stem cell transplantation (if indicated per local institutional guidelines).

Exclusion Criteria- Core

• Diagnosis of post-transplant lymphoproliferative disease, Richter's transformation, Burkitt's lymphoma, Burkitt-like lymphoma, lymphoblastic lymphoma/leukaemia, chronic lymphocytic leukaemia, small lymphocytic lymphoma.
• High risk of TLS according to Howard modification of Cairo-Bishop criteria and/or the presence of bulky disease.
• Unresolved toxicity from prior anticancer therapy. Patients with Grade 2 neuropathy or Grade 2 alopecia are eligible.
• Active idiopathic thrombocytopenic purpura.
• Active central nervous system (CNS) involvement by lymphoma, leptomeningeal disease or spinal cord compression.
• Known history of infection with human immunodeficiency virus.
• Known serologic status reflecting active hepatitis B or C infection; concurrent infection with cytomegalovirus (CMV).
• Patients must be tested for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and those with active infection in accordance with local testing guidelines will be excluded.
• Any evidence of severe or uncontrolled systemic diseases; current unstable or uncompensated respiratory or cardiac conditions; uncontrolled hypertension; history of, or active, bleeding diatheses; uncontrolled active systemic fungal, bacterial, or other infection.
• Any of the following cardiac criteria at screening: patients with a history of myocarditis within one year of study entry, or heart failure; mean resting corrected QT interval (QTcF) ≥ 470 msec obtained from 3 electrocardiograms (ECGs), in the absence of a cardiac pacemaker; any factors that increase the risk of QTc prolongation or risk of arrhythmic events; any clinically important abnormalities in rhythm, conduction or morphology of resting ECG.
• History of another life-threatening malignancy ≤ 2 years prior to first dose of study intervention.
• Any of the following currently or in the 6 months prior to the first dose of study intervention: coronary artery bypass graft; angioplasty; vascular stent; myocardial infarction; angina pectoris; haemorrhagic or thrombotic stroke, including transient ischaemic attacks or any other CNS bleeding.
• Treatment with any of the following: radiotherapy less than 2 weeks prior to the first dose of study intervention; any investigational agents or study drugs from a previous clinical study within ≤ 14 days or 5 half-lives prior to the first dose of study intervention; any other chemotherapy, immunotherapy, immunosuppressant medication or anticancer agents within 21 days of the first dose of study intervention; Prior allogenic haematopoietic stem cell transplantation (HSCT) within 6 months from the first dose of study intervention (patients > 6 months after allogenic HSCT are eligible in the absence of active graft-versus host disease and concomitant immune-suppressive therapy). Eligible patients must have stopped immunosuppression at least 2 months prior to study entry; prior cellular therapies such as CAR-T and/or autologous HSCT within 3 months prior to the first dose of study intervention; major surgery ≤ 21 days, or minor surgical procedures ≤ 7 days, prior to the first dose of study intervention; prescription or non-prescription drugs or other products known to be sensitive substrates of BCRP, OCT2, OAT3, OATP1B1, OATP1B3, CYP2B6, CYP2C8, CYP2C9 or CYP2D6, or reversible moderate or strong cytochrome 3A (CYP3A) inhibitors, which cannot be discontinued within 5 half-lives of the first dose of study intervention and withheld throughout the study until 14 days after the last dose of AZD0466; moderate or strong mechanism-based inhibitors or inducers of CYP3A4 which cannot be discontinued within 5 half-lives plus 12 days of the drug prior to the first dose of study intervention and withheld until 14 days after the last dose of AZD0466; concurrent anticoagulation therapy, including aspirin, which cannot be stopped; medications with known risk of Torsades de Pointes within 5 half-lives of the first dose of study intervention and continuing until 5 half-lives after the last dose of AZD0466.
• Administration of a live, attenuated vaccine within 4 weeks before first dose of study intervention.
• Administration of inactivated vaccines or protein/RNA immunogen vaccines.
• Patients with a known hypersensitivity to polyethylene glycol, pegylated products, or drugs with a similar chemical structure or class to AZD0466 or other BH3 mimetic.

Exclusion Criteria- Module 1

Additional Exclusion Criteria for Cohort B1:

- Patients with known blastoid or pleiomorphic variant at study entry/most recent relapse.

Additional Exclusion Criteria for Cohort B2:

• Histologically confirmed diagnosis of FL grade 3B.
• Known transformation to aggressive lymphoma, eg, large cell lymphoma.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

8

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part A (Dose Escalation): Dose Level (DL)-1; Participants with advanced R/R B-NHL will receive AZD0466 on day 1 , day 4, day 8 day 15, day 22 of cycle 1 and day 1, day 8 day 15, day 22 of cycle 2 and beyond until maximum 2 years or until disease progression, initiation of alternative anticancer therapy, unacceptable toxicity, withdrawal of consent, or other reasons to discontinue study intervention, whichever occurs first.	Drug: AZD0466; All patients will receive treatment with the investigational product AZD0466 via intravenous infusion.
Experimental: Part A (Dose Escalation): DL1; Participants with advanced R/R B-NHL will receive AZD0466 on day 1 , day 4, day 8 day 15, day 22 of cycle 1 and day 1, day 8 day 15, day 22 of cycle 2 and beyond until maximum 2 years or until disease progression, initiation of alternative anticancer therapy, unacceptable toxicity, withdrawal of consent, or other reasons to discontinue study intervention, whichever occurs first.	Drug: AZD0466; All patients will receive treatment with the investigational product AZD0466 via intravenous infusion.
Experimental: Part A (Dose Escalation): DL2; Participants with advanced R/R B-NHL will receive AZD0466 on day 1 , day 4, day 8 day 15, day 22 of cycle 1 and day 1, day 8 day 15, day 22 of cycle 2 and beyond until maximum 2 years or until disease progression, initiation of alternative anticancer therapy, unacceptable toxicity, withdrawal of consent, or other reasons to discontinue study intervention, whichever occurs first.	Drug: AZD0466; All patients will receive treatment with the investigational product AZD0466 via intravenous infusion.
Experimental: Part A (Dose Escalation): DL3; Participants with advanced R/R B-NHL will receive AZD0466 on day 1 , day 4, day 8 day 15, day 22 of cycle 1 and day 1, day 8 day 15, day 22 of cycle 2 and beyond until maximum 2 years or until disease progression, initiation of alternative anticancer therapy, unacceptable toxicity, withdrawal of consent, or other reasons to discontinue study intervention, whichever occurs first.	Drug: AZD0466; All patients will receive treatment with the investigational product AZD0466 via intravenous infusion.
Experimental: Part A (Dose Escalation): DL4; Participants with advanced R/R B-NHL will receive AZD0466 on day 1 , day 4, day 8 day 15, day 22 of cycle 1 and day 1, day 8 day 15, day 22 of cycle 2 and beyond until maximum 2 years or until disease progression, initiation of alternative anticancer therapy, unacceptable toxicity, withdrawal of consent, or other reasons to discontinue study intervention, whichever occurs first.	Drug: AZD0466; All patients will receive treatment with the investigational product AZD0466 via intravenous infusion.
Experimental: Part B (Dose Expansion): Cohort B1 (R/R MCL); Participants with advanced R/R MCL will receive AZD0466 at the recommended phase 2 dose (RP2D) until maximum 2 years or until disease progression, initiation of alternative anticancer therapy, unacceptable toxicity, withdrawal of consent, or other reasons to discontinue study intervention, whichever occurs first.	Drug: AZD0466; All patients will receive treatment with the investigational product AZD0466 via intravenous infusion.
Experimental: Part B (Dose Expansion): Cohort B2 (R/R FL or MZL); Participants with advanced R/R FL or MZL will receive AZD0466 at the recommended phase 2 dose (RP2D) until maximum 2 years or until disease progression, initiation of alternative anticancer therapy, unacceptable toxicity, withdrawal of consent, or other reasons to discontinue study intervention, whichever occurs first.	Drug: AZD0466; All patients will receive treatment with the investigational product AZD0466 via intravenous infusion.
Experimental: Part B (Dose Expansion): Cohort B3 (R/R DLBCL); Participants with advanced R/R DLBCL will receive AZD0466 at the recommended phase 2 dose (RP2D) until maximum 2 years or until disease progression, initiation of alternative anticancer therapy, unacceptable toxicity, withdrawal of consent, or other reasons to discontinue study intervention, whichever occurs first.	Drug: AZD0466; All patients will receive treatment with the investigational product AZD0466 via intravenous infusion.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Adverse Events (AE)	The safety and the tolerability of AZD0466 in patients with relapsed/ refractory B-cell non-Hodgkin lymphoma (R/R B-NHL) was evaluated.	Day 1 to Follow-up (30 days post last dose or up to the day prior to start of subsequent cancer therapy) up to approximately 1 year 1 month
Number of Participants With Dose Limiting Toxicity (DLT)	The DLT of AZD0466 in participants with R/R B-NHL was evaluated.	Day 1 to end of Cycle 1 (28 days treatment cycle)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part A: Maximum Observed Plasma (Peak) Drug Concentration (Cmax) of AZD4320	The Cmax of AZD4320 was assessed to characterise the pharmacokinetic (PK) profile of AZD0466.	Cycle 1 Day 8, Cycle 2 Day 1
Part A: Time to Reach Peak or Maximum Observed Concentration or Response Following Drug Administration (Tmax) of AZD4320	The tmax of AZD4320 was assessed to characterise the Pk profile of AZD0466.	Cycle 1 Day 8, Cycle 2 Day 1
Part A: Terminal Rate Constant, Estimated by Log-linear Least Squares Regression of the Terminal Part of the Concentration-time Curve (λz) of AZD4320	The λz of AZD4320 was assessed to characterise the Pk profile of AZD0466.	Cycle 1 Day 8 (Study Day 8), Cycle 2 Day 1 (Study Day 22)
Part A: Half-life Associated With Terminal Slope (λz) of a Semi-logarithmic Concentration-time Curve (t1/2λz) of AZD4320	The t1/2λz of AZD4320 was assessed to characterise Pk profile of AZD0466.	Cycle 1 Day 8, Cycle 2 Day 1
Part A: Partial Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours After the Start of Infusion (AUC0-24) of AZD4320	The AUC0-24 of AZD4320 was assessed to characterise the Pk profile of AZD0466.	Cycle 1 Day 8, Cycle 2 Day 1
Part A: Partial Area Under the Plasma Concentration-time Curve From Time 0 to 72 Hours After the Start of Infusion (AUC0-72) of AZD4320	The AUC0-72 of AZD4320 was assessed to characterise the Pk profile of AZD0466.	Cycle 1 Day 8
Part A: Area Under the Plasma Concentration-curve From Time 0 to the Last Quantifiable Concentration (AUClast) of AZD4320	The AUClast of AZD4320 was assessed to characterise the Pk profile of AZD0466	Cycle 1 Day 8, Cycle 2 Day 1
Part A: Time of Last Observed (Quantifiable) Concentration (Tlast) of AZD4320	The tlast of AZD4320 was assessed to characterise the Pk profile of AZD0466	Cycle 1 Day 8, Cycle 2 Day 1
Part A: Concentration Prior to Dosing (Ctrough) of AZD4320	The Ctrough of AZD4320 was assessed to characterise the Pk profile of AZD0466	Cycle 2 Day 1
Part A:Area Under the Plasma Concentration-time Curve From Time 0 to Time of Last Quantifiable Analyte Concentration Divided by the Dose Administered (Dose Normalised AUClast) of AZD4320	The Dose normalised AUClast of total AZD4320 was assessed to characterise the Pk profile of AZD0466	Cycle 1 Day 8, Cycle 2 Day 1
Part A: Area Under the Plasma Concentration-time Curve From Time 0 to 72 Hours After the Start of Infusion (Dose Normalised AUC0-72) of AZD4320	The Dose normalised AUC0-72 of total AZD4320 was assessed to characterise the Pk profile of AZD0466	Cycle 1 Day 8
Part A: Maximum Observed Plasma (Peak) Drug Concentration Divided by the Dose Administered (Dose Normalised Cmax) of AZD4320	The Dose normalised Cmax of total AZD4320 was assessed to characterise the Pk profile of AZD0466	Cycle 1 Day 8, Cycle 2 Day 1

Collaborators and Investigators

• Sponsor: AstraZeneca

Publications and helpful links

Helpful Links

• D8242C00001_CSP_Redacted
• D8242C00001_CSR Synopsis_Redacted
• D8242C00001_SAP_Redacted

Study record dates

Study Major Dates

• Study Start (Actual): July 5, 2022
• Primary Completion (Actual): August 17, 2023
• Study Completion (Actual): August 17, 2023

Study Registration Dates

• First Submitted: January 5, 2022
• First Submitted That Met QC Criteria: January 5, 2022
• First Posted (Actual): January 25, 2022

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: November 19, 2024
• Last Verified: November 1, 2024

More Information

Terms related to this study

• Keywords: Dose Escalation; Open-label,; Dose Expansion,; Multicentre Study; Anticancer; Pegylated poly-L-lysine dendrimer
• Additional Relevant MeSH Terms: Neoplasms; Immune System Diseases; Neoplasms by Histologic Type; Lymphatic Diseases; Lymphoproliferative Disorders; Immunoproliferative Disorders; Lymphoma; Lymphoma, Non-Hodgkin
• Other Study ID Numbers: D8242C00001; 2021-003410-39 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. 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 shared.

IPD Sharing Time Frame

AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please refer to our disclosure commitment at:

https://astrazenecagrouptrials.pharmacm.com /ST/Submission/Disclosure.

IPD Sharing Access Criteria

When a request has been approved AstraZeneca will provide access to the de-identified individual patientlevel data in an approved sponsored tool. Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at:

https://astrazenecagrouptrials.pharmacm.com /ST/Submission/Disclosure.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No