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Hodgkin Lymphoma

In Part A, participants with Relapsed/Refractory classical Hodgkin Lymphoma (cHL) will take AZD3470 tablets orally until PD, unacceptable toxicity, or withdrawal of consent.

In Part B, adult and adolescent participants with r/r cHL will take AZD3470 tablets orally until PD, unacceptable toxicity, or withdrawal of consent.

AZD3470 is a novel, potent and selective, secondgeneration, Methylthioadenosine (MTA)-selective, small molecule inhibitor of PRMT5.

AZD3470

AstraZeneca Clinical Study Information Center

This study is designed to evaluate the safety, tolerability, PK and preliminary efficacy following oral administration of AZD3470 as a monotherapy, and in combination with other anticancer agents in participants with haematologic malignancies.

This is a FTiH modular, Phase I/II, open-label, multicentre, dose escalation and expansion study in participants with r/r haematologic malignancies. The study is designed to evaluate the safety, tolerability, PK and preliminary efficacy following oral administration of AZD3470 as a monotherapy, and in combination with other anticancer agents in participants with haematologic malignancies.

This study will follow a modular protocol design evaluating AZD3470 as monotherapy and in combination with other anticancer agents. New cohorts (including further monotherapy expansion) and new modules for combination treatments may be added as protocol amendments in the future based on emerging supportive preclinical and/or clinical data.

Module 1 Part A includes a dose escalation of AZD3470 monotherapy in participants with r/r haematologic malignancies, initially focused on r/r cHL. Dose escalation cohorts will evaluate the safety, tolerability, PK, and preliminary efficacy in participants with r/r cHL.

Module 1 Part B optimization/expansion cohorts may be opened at selected dose levels. These cohorts will further characterise the safety, PK, and preliminary efficacy of AZD3470 to support dose optimization. Both adult and adolescent participants with r/r cHL will be eligible for this part of the study. Adolescent participants will only be enrolled once there is sufficient PK and safety data in adults. A preliminary effect of food on AZD3470 pharmacokinetics will be explored in this part of the study.

The protocol may be amended in the future to incorporate further expansion of cHL at the RP2D, additional monotherapy cohorts in other hematologic malignancies, and/or additional modules investigating AZD3470 in combination with other anticancer agents.

AZD3470 as Monotherapy and in Combination With Anticancer Agents in Participants With Relapsed/Refractory Haematologic Malignancies.

A Modular Phase I/II, Open-label, Multicentre Study to Evaluate the Safety, Tolerability, and Efficacy of AZD3470, a PRMT5 Inhibitor, as Monotherapy and in Combination With Anticancer Agent(s) in Participants With Relapsed/Refractory Haematologic Malignancies

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.

AEs: Number of patients with adverse events by system organ class and preferred term.

SAEs: Number of patients with serious adverse events by system organ class and preferred term.

In the Dose Escalation cohorts in Part A, the number of participants with at least 1 dose-limiting toxicity (DLT), which is any toxicity defined as a DLT in the Clinical Study Protocol

ORR is defined as the proportion of participants who have a CR or PR and CRR is defined as the proportion of participants who have a CR.

Assessment of ORR/CRR will be done according to the Lugano Classification for cHL.

The time from the date of first documented response until the date of documented progression as assessed by the investigator according to the Lugano classification for cHL, or death due to any cause

Time from date of first dose (non- randomised study parts) or date of randomization (randomised study parts) until progression as assessed by the investigator according to the Lugano Classification for cHL, or death due to any cause.

Time from date of first dose (non-randomised study parts) or date of randomization (randomised study parts) until the date of death due to any cause.

Assessed to characterize the plasma PK profile of AZD3470.

Assessed to characterize the urine PK profile of AZD3470.

Preliminary food effect on plasma PK of AZD3470 administered as a monotherapy in participants enrolled in dose expansion.

AstraZeneca

Part A dose escalation and DDI and Part B dose optimisation and expansion in varying doses of AZD3470

AZD3470 is a novel, potent and selective, second-generation, methylthioadenosine (MTA)-selective, small molecule inhibitor of PRMT5.

This is a first time in human (FTiH) Phase I/IIa, open-label, multi-centre study of AZD3470 in participants with advanced or metastatic solid tumours with MTAP deficiency. The study consists of several study modules, evaluating the safety, tolerability, PK, pharmacodynamics, and preliminary efficacy of AZD3470 as monotherapy or in combination with other anti-cancer agents.

This first time in human, open-label, multi-centre study of AZD3470 in participants with advanced or metastatic solid tumours with MTAP deficiency follows a modular design. Module 1 will include dose escalation and DDI (Part A) and dose optimisation and expansion (Part B). New modules for combination treatments may be added in the future based on emerging data.

This is a FTiH (first time in human), modular Phase I/IIa, open-label, multi-centre study of AZD3470, in participants with MTAP deficient advanced/metastatic solid tumours. The study consists of individual modules, each evaluating safety and tolerability of AZD3470 dosed as a monotherapy or in combination with specific treatments. Module 1 describes AZD3470 monotherapy, and will have at least two parts. Part A dose escalation and DDI cohorts and Part B consisting of dose optimisation and expansion cohorts.

A Study of AZD3470, a PRMT5 Inhibitor, in Patients With MTAP Deficient Advanced/Metastatic Solid Tumours

PRIMROSE: A Modular Phase I/IIa, Multi-centre, Dose Escalation, and Expansion Study of AZD3470, a MTA Cooperative PRMT5 Inhibitor, as Monotherapy and in Combination With Anticancer Agents in Patients With Advanced/Metastatic Solid Tumours That Are MTAP Deficient

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

Incidence of dose-limiting toxicities (DLT) as determined by number of patients with at least 1 dose-limiting toxicity (DLT). DLT is defined as an AE (adverse event) or abnormal laboratory value that occurs during the DLT evaluation period (defined as 21 days after the start of study intervention) that is assessed as unrelated to the disease, intercurrent illness, or concomitant medications and meets any DLT criteria defined in the clinical study protocol

Proportion of patients who have a confirmed complete or partial radiological response by the Investigator according to RECIST v1.1

DoR - the time from date of first documented objective response until date of documented disease progression per Tumour RECIST v1.1 as assessed by the Investigator at local site or death due to any cause.

Best percentage change from baseline in TL (target lesion) tumour size is based on the RECIST 1.1. TL measurements as assessed by the Investigator.

PFS - defined as time from date of first dose (nonrandomised study parts) or date of randomisation (randomised study parts) until progression per RECIST v1.1 as assessed by the Investigator at local site, or death due to any cause.

DCR at 12 weeks defined as the percentage of participants who have a confirmed CR (complete response) or PR (partial response) or who have SD (stable disease) per RECIST 1.1 as assessed by the Investigator at local site and derived from the raw tumour data for at least 11 weeks after date of first dose to allow for an early assessment within the assessment window.

Overall Survival (OS) - defined as time from date of first dose (nonrandomised study parts) or date of randomisation (randomised study parts) until the date of death due to any cause.

Part A (Dose escalation) Measurement of PK parameters: Area under the concentration time curve (AUC).

Part A (Dose escalation) Measurement of PK parameters: Maximum observed plasma concentration of the study drug (C-max).

Part A (Dose escalation) Measurement of PK parameters: Terminal elimination half-life (t 1/2)

Part A (Dose escalation) Measurement of PK parameters: amount of AZD3470 excreted in urine (Ae).

Part A (Dose escalation) Measurement of PK parameters: renal clearance (Clr).

Part A (DDI)- Plasma geometric mean ratio (Maximum observed plasma concentration of the study drug (C-max)) of Midazolam evaluated with and without AZD3470

Part A (DDI) - Plasma geometric mean ratio (Area under the concentration time curve (AUC)) of Midazolam evaluated with and without AZD3470

Part A (DDI)- Plasma geometric mean ratio (Maximum observed plasma concentration of the study drug (C-max)) of Dextromethorphan evaluated with and without AZD3470

Part A (DDI) - Plasma geometric mean ratio (Area under the concentration time curve (AUC)) of Dextromethorphan evaluated with and without AZD3470

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
AZD3470 as Monotherapy and in Combination With Anticancer Agents in Participants With Relapsed/Refractory Haematologic Malignancies.	NCT06137144	Lymphoma Non-Hodgkin Hodgkin Lymphom...	AZD3470	15 Years - 130 Years	AstraZeneca
A Study of AZD3470, a PRMT5 Inhibitor, in Patients With MTAP Deficient Advanced/Metastatic Solid Tumours	NCT06130553	Advanced Solid ...	AZD3470	18 Years -	AstraZeneca
AZD3470 as Monotherapy and in Combination With Anticancer Agents in Participants With Relapsed/Refractory Haematologic Malignancies.	NCT06137144	Lymphoma Non-Hodgkin Hodgkin Lymphom...	AZD3470	15 Years - 130 Years	AstraZeneca

Spots Global Cancer Trial Database for mtap deficient