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.

Status

Terminated

Phases

Phase 1

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT05205161

Enrollment

Registered

2022-01-25

Start date

2022-07-05

Completion date

2023-08-17

Last updated

2025-01-07

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Non-Hodgkin Lymphoma

Keywords

Open-label,, Dose Escalation, Dose Expansion,, Multicentre Study, Anticancer, Pegylated poly-L-lysine dendrimer

Brief summary

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

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).

Interventions

DRUGAZD0466

All patients will receive treatment with the investigational product AZD0466 via intravenous infusion.

Study design

Allocation

NON_RANDOMIZED

Intervention model

SEQUENTIAL

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to 130 Years

Healthy volunteers

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).

Design outcomes

Primary

Measure	Time frame	Description
Number of Participants With Adverse Events (AE)	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	The safety and the tolerability of AZD0466 in patients with relapsed/ refractory B-cell non-Hodgkin lymphoma (R/R B-NHL) was evaluated.
Number of Participants With Dose Limiting Toxicity (DLT)	Day 1 to end of Cycle 1 (28 days treatment cycle)	The DLT of AZD0466 in participants with R/R B-NHL was evaluated.

Secondary

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

Countries

Australia, France, Italy, Portugal, South Korea, Spain, United States

Participant flow

Recruitment details

Participants were enrolled in the study from 05July 2022 (First subject in) to 17 August 2023 (Last subject last visit) at 24 sites in 8 countries.

Pre-assignment details

Participants meeting the inclusion criteria were enrolled in the study. All the assessments were performed as per the schedule of the assessments.

Participants by arm

Arm	Count
600 mg of AZD0466 Participants received 600mg of AZ0466 in Part A of the treatment	3
1200 mg of AZD0466 Participants received 1200mg of AZD0466 in Part A of the treatment	3
2400 mg of AZD0466 Participants received 2400mg of AZD0466 in Part A of the treatment	1
Total	7

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002
Overall Study	Study terminated by sponsor	3	3	1

Baseline characteristics

Characteristic	600 mg of AZD0466	1200 mg of AZD0466	2400 mg of AZD0466	Total
Age, Continuous	62.7 Years STANDARD_DEVIATION 7	44.0 Years STANDARD_DEVIATION 16.1	NA Years	57.0 Years STANDARD_DEVIATION 16.9
Race/Ethnicity, Customized Asian	2 Participants	0 Participants	0 Participants	2 Participants
Race/Ethnicity, Customized Not Hispanic or Latino	3 Participants	2 Participants	0 Participants	5 Participants
Race/Ethnicity, Customized Not Reported	0 Participants	1 Participants	0 Participants	1 Participants
Race/Ethnicity, Customized Other	1 Participants	0 Participants	1 Participants	1 Participants
Race/Ethnicity, Customized White	0 Participants	2 Participants	0 Participants	2 Participants
Sex/Gender, Customized Female	0 Participants	0 Participants	0 Participants	0 Participants
Sex/Gender, Customized Male	3 Participants	2 Participants	0 Participants	5 Participants
Sex/Gender, Customized Other	0 Participants	1 Participants	1 Participants	2 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk
deaths Total, all-cause mortality	0 / 3	0 / 3	0 / 1
other Total, other adverse events	3 / 3	3 / 3	1 / 1
serious Total, serious adverse events	0 / 3	0 / 3	1 / 1

Outcome results

Primary

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.

Time frame: 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

Population: The safety analysis included all participants who received at least one dose of AZD0466.

Arm	Measure	Group	Value (NUMBER)
600mg of AZD0466	Number of Participants With Adverse Events (AE)	Any AE	3 Participants
600mg of AZD0466	Number of Participants With Adverse Events (AE)	Any possibly related AE	2 Participants
600mg of AZD0466	Number of Participants With Adverse Events (AE)	Any AE of >= CTCAE grade 3	1 Participants
600mg of AZD0466	Number of Participants With Adverse Events (AE)	Any Serious Adverse events (SAE)	0 Participants
600mg of AZD0466	Number of Participants With Adverse Events (AE)	Any possibly related SAE	0 Participants
600mg of AZD0466	Number of Participants With Adverse Events (AE)	Any SAE with outcome death	0 Participants
600mg of AZD0466	Number of Participants With Adverse Events (AE)	Any SAE of >= CTCAE grade 3	0 Participants
600mg of AZD0466	Number of Participants With Adverse Events (AE)	Any Adverse event of Special interest	0 Participants
600mg of AZD0466	Number of Participants With Adverse Events (AE)	Any AE leading to discontinuation of AZD0466	0 Participants
600mg of AZD0466	Number of Participants With Adverse Events (AE)	Any AE leading to AZD0466 drug interruption	0 Participants
600mg of AZD0466	Number of Participants With Adverse Events (AE)	Any AE leading to AZD0466 dose reduction	0 Participants
600mg of AZD0466	Number of Participants With Adverse Events (AE)	Any possibly related deaths	0 Participants
1200 mg of AZD0466	Number of Participants With Adverse Events (AE)	Any possibly related deaths	0 Participants
1200 mg of AZD0466	Number of Participants With Adverse Events (AE)	Any AE	3 Participants
1200 mg of AZD0466	Number of Participants With Adverse Events (AE)	Any SAE of >= CTCAE grade 3	0 Participants
1200 mg of AZD0466	Number of Participants With Adverse Events (AE)	Any AE leading to discontinuation of AZD0466	1 Participants
1200 mg of AZD0466	Number of Participants With Adverse Events (AE)	Any possibly related AE	3 Participants
1200 mg of AZD0466	Number of Participants With Adverse Events (AE)	Any SAE with outcome death	0 Participants
1200 mg of AZD0466	Number of Participants With Adverse Events (AE)	Any AE leading to AZD0466 dose reduction	0 Participants
1200 mg of AZD0466	Number of Participants With Adverse Events (AE)	Any AE of >= CTCAE grade 3	2 Participants
1200 mg of AZD0466	Number of Participants With Adverse Events (AE)	Any Adverse event of Special interest	1 Participants
1200 mg of AZD0466	Number of Participants With Adverse Events (AE)	Any possibly related SAE	0 Participants
1200 mg of AZD0466	Number of Participants With Adverse Events (AE)	Any Serious Adverse events (SAE)	0 Participants
1200 mg of AZD0466	Number of Participants With Adverse Events (AE)	Any AE leading to AZD0466 drug interruption	0 Participants
2400 mg of AZD0466	Number of Participants With Adverse Events (AE)	Any Serious Adverse events (SAE)	1 Participants
2400 mg of AZD0466	Number of Participants With Adverse Events (AE)	Any possibly related SAE	1 Participants
2400 mg of AZD0466	Number of Participants With Adverse Events (AE)	Any AE leading to AZD0466 drug interruption	0 Participants
2400 mg of AZD0466	Number of Participants With Adverse Events (AE)	Any SAE with outcome death	0 Participants
2400 mg of AZD0466	Number of Participants With Adverse Events (AE)	Any SAE of >= CTCAE grade 3	1 Participants
2400 mg of AZD0466	Number of Participants With Adverse Events (AE)	Any Adverse event of Special interest	0 Participants
2400 mg of AZD0466	Number of Participants With Adverse Events (AE)	Any AE leading to AZD0466 dose reduction	0 Participants
2400 mg of AZD0466	Number of Participants With Adverse Events (AE)	Any AE	1 Participants
2400 mg of AZD0466	Number of Participants With Adverse Events (AE)	Any possibly related AE	1 Participants
2400 mg of AZD0466	Number of Participants With Adverse Events (AE)	Any AE leading to discontinuation of AZD0466	1 Participants
2400 mg of AZD0466	Number of Participants With Adverse Events (AE)	Any AE of >= CTCAE grade 3	1 Participants
2400 mg of AZD0466	Number of Participants With Adverse Events (AE)	Any possibly related deaths	0 Participants

Primary

Number of Participants With Dose Limiting Toxicity (DLT)

The DLT of AZD0466 in participants with R/R B-NHL was evaluated.

Time frame: Day 1 to end of Cycle 1 (28 days treatment cycle)

Population: The safety analysis included all participants who received at least one dose of AZD0466.

Arm	Measure	Value (NUMBER)
600mg of AZD0466	Number of Participants With Dose Limiting Toxicity (DLT)	0 Participants
1200 mg of AZD0466	Number of Participants With Dose Limiting Toxicity (DLT)	0 Participants
2400 mg of AZD0466	Number of Participants With Dose Limiting Toxicity (DLT)	1 Participants

Secondary