A Study of AZD3470, a PRMT5 Inhibitor, Given as Monotherapy and in Combination in Patients With MTAP Deficient Advanced/Metastatic Solid Tumors

NCT06130553 | Recruiting Phase 1 FDA Drug

• 2 other identifiers: D9970C00001165618
• Study Type: interventional
• Target: 334
• Locations: 8 countries
• Sites: 21

Brief Summary

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 tumors with MTAP deficiency. The study consists of several study modules, evaluating the safety, tolerability, pharmacokinetic (PK), pharmacodynamics, and preliminary efficacy of AZD3470 as monotherapy or in combination with other anti-cancer agents.

Conditions

Advanced Solid Tumors That Are MTAP Deficient

Keywords

solid tumor; MTAP deficient

Outcome Measures

Primary Outcomes (3)

• All Modules: Incidence of adverse events (AEs) and serious adverse events (SAEs). To determine the RP2D of AZD3470 as monotherapy and in combination with anticancer agents

  Number of participants with AEs and SAEs.

  From time of informed consent to 28 days post last dose of study treatment

• Module 1: Incidence of dose-limiting toxicities (DLT)

  Incidence of dose-limiting toxicities (DLT) as determined by number of patients with at least 1 dose-limiting toxicity (DLT)

  From first dose of study treatment until the end of Cycle 1 (each cycle is 21 days)

• Module 2: Progression Free Survival assessed by the Investigator according to RECIST v1.1

  PFS - defined as time from date of randomization until progression per RECIST v1.1 as assessed by the Investigator at local site, or death due to any cause.

  From date of randomization up until progression, or the last evaluable assessment in the absence of progression (approximately 2 years).

Secondary Outcomes (19)

• All modules: Radiological response assessed by the Investigator evaluated according to RECIST v1.1 - ORR (Objective Response Rate)

  From date of first dose of AZD3470 up until progression, or the last evaluable assessment in the absence of progression (approximately 2 years).

• All modules: Radiological response assessed by the Investigator evaluated according to RECIST v1.1 - DoR (Duration of Response)

  From date of first dose of AZD3470 up until progression, or the last evaluable assessment in the absence of progression (approximately 2 years).

• All modules: Radiological response assessed by the Investigator evaluated according to RECIST v1.1 - Best percentage change in tumor size

  From date of first dose of AZD3470 up until progression, or the last evaluable assessment in the absence of progression (approximately 2 years).

• Module 1: Progression Free Survival assessed by the Investigator evaluated according to RECIST v1.1

  From date of first dose/randomization up until progression, or the last evaluable assessment in the absence of progression (approximately 2 years).

• All modules: Radiological response assessed by the Investigator evaluated according to RECIST v1.1 - DCR (Disease Control Rate) at 12 weeks

  From date of first dose of AZD3470 up until progression, or the last evaluable assessment in the absence of progression (for each patient this is expected to be measured at 12 weeks).

Study Arms (3)

Module 1: AZD3470 Monotherapy

EXPERIMENTAL

Part A dose escalation and back-fill cohorts and Part B dose optimization and expansion cohorts of varying doses of AZD3470

Drug: AZD3470

Module 2: AZD3470 in combination with Dato-DXd

EXPERIMENTAL

Varying doses of AZD3470 in combination with Dato-Dxd

Drug: AZD3470; Drug: Datopotamab deruxtecan

Module 2: Dato-DXd alone

EXPERIMENTAL

Control arm

Drug: Datopotamab deruxtecan

Interventions

Datopotamab deruxtecan DRUG

AZD3470 in combination with Dato-DXd + Dato-Dxd monotherapy

Also known as: Dato-DXd

Module 2: AZD3470 in combination with Dato-DXd; Module 2: Dato-DXd alone

AZD3470 DRUG

AZD3470 is a novel, potent and selective, second-generation, MTAP-selective, inhibitor of PRMT5.

Module 1: AZD3470 Monotherapy; Module 2: AZD3470 in combination with Dato-DXd

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Participants are able to provide written informed consent and are willing and able to comply with study procedures.
• Participants are willing to provide archival and/or newly obtained (baseline) tumor tissue for central testing, including required biomarker assessment(s) (and any module-specific biomarker requirements).
• Participants have tumors meeting the protocol-defined MTAP-deficiency requirement, based on acceptable prior testing and/or central testing per protocol.
• Participants have received prior systemic therapy appropriate for the tumor type and disease stage and have disease progression on or after prior therapy; participants must have had ≥ 1 prior line of systemic treatment in the recurrent/metastatic (advanced) setting.
• Participants have ECOG performance status 0-1. Participants have life expectancy ≥ 12 weeks, in the opinion of the Investigator.
• Participants have measurable disease per RECIST v1.1. Participants have adequate organ and bone marrow function per protocol-defined laboratory/assessment criteria.
• Participants have a treatment-free interval ≥ 3 weeks from prior anticancer therapy before starting study drug (with any additional protocol-defined washout requirements for certain therapies/procedures).
• Contraception use by men and women is consistent with local regulations and protocol-defined requirements.
• Participants have documented radiographic extracranial disease progression while on or after the most recent treatment regimen for advanced/metastatic NSCLC (CNS-only progression is not eligible).
• NSCLC of mixed histology is allowed if not predominantly squamous; no small cell or large cell neuroendocrine components.
• Participants meet one of the following:
• Tumor has a documented EGFR alteration eligible for EGFR-directed therapy (per protocol-defined criteria) and the participant has received prior systemic therapy appropriate for EGFR-altered advanced/metastatic NSCLC (per protocol), OR Tumor is negative for EGFR alterations eligible for EGFR-directed therapy, has no other known actionable genomic alterations for which locally approved/available targeted therapies exist (per protocol-defined criteria), meets any additional protocol-required biomarker criteria for this cohort (as applicable), and the participant has received prior systemic therapy appropriate for non-actionable-alteration advanced/metastatic NSCLC (per protocol).

You may not qualify if:

• Participants have a history of allogeneic organ transplantation. Participants have any clinically significant abnormal laboratory finding or severe and uncontrolled medical condition that, in the Investigator's opinion, makes participation unsafe, including active infection requiring systemic treatment.
• Participants have clinically significant cardiovascular disease or risk factors (including reduced LVEF, cardiomyopathy, clinically active cardiovascular disease, recent major ischemic events or revascularization procedures, uncontrolled angina, severe valvular disease, uncontrolled hypertension, clinically significant heart failure, or recent stroke/TA clinically significant ECG abnormalities, prolonged QTc, or conditions/medications that increase risk of QTc prolongation or arrhythmic events)..
• Participants require therapeutic anticoagulation for treatment of acute thromboembolic events, per protocol.
• Participants have active hepatitis B or hepatitis C infection (including detectable viral load, per protocol-defined testing).
• Participants have known HIV infection. Participants have current ILD/pneumonitis, or a history of (non-infectious) ILD/pneumonitis requiring systemic steroids or supplemental oxygen, or suspected ILD/pneumonitis that cannot be ruled out by screening imaging.
• Participants have active gastrointestinal disease, malabsorption, or other GI condition/surgery that would significantly interfere with oral drug absorption or tolerability.
• Participants have a history of another primary malignancy. Participants have unresolved clinically significant toxicity from prior anticancer therapy (typically Grade ≥ 2).
• Participants have had prior treatment with a PRMT5 inhibitor Participants are pregnant, breastfeeding, or intend to become pregnant during study participation.
• Participants have contraindication to required CNS imaging (brain MRI preferred or CT with contrast).
• Participants have clinically significant corneal disease. Participants have known active tuberculosis infection, per clinical evaluation and local practice.
• Participants have significant third-space fluid (e.g., pleural effusion/ascites) not amenable to required repeated drainage, per Investigator judgment.
• Participants have severe pulmonary function compromise due to intercurrent pulmonary illness (e.g., severe COPD/asthma/restrictive lung disease, recent pulmonary embolism), per protocol.
• Participants have recent radiotherapy that does not meet protocol-defined washout requirements and/or ongoing radiation-related toxicities requiring corticosteroids.
• Participants have had prior treatment with protocol-prohibited anticancer therapies.

Sponsors & Collaborators

• AstraZeneca: lead

Study Sites (21)

Research Site

San Francisco, California, 94143, United States

RECRUITING

Research Site

West Hollywood, California, 90048, United States

WITHDRAWN

Research Site

New Haven, Connecticut, 06510, United States

RECRUITING

Research Site

Baltimore, Maryland, 21231, United States

RECRUITING

Research Site

Portland, Oregon, 97239, United States

RECRUITING

Research Site

Pittsburgh, Pennsylvania, 15232, United States

RECRUITING

Research Site

Providence, Rhode Island, 02903, United States

RECRUITING

Research Site

Fairfax, Virginia, 22031, United States

RECRUITING

Research Site

Melbourne, 3000, Australia

RECRUITING

Research Site

Beijing, 100142, China

RECRUITING

Research Site

Chengdu, 610041, China

RECRUITING

Research Site

Shanghai, 200433, China

RECRUITING

Research Site

Wuhan, 430030, China

NOT YET RECRUITING

Research Site

Villejuif, 94805, France

NOT YET RECRUITING

Research Site

Chūōku, 104-0045, Japan

RECRUITING

Research Site

Kashiwa, 227-8577, Japan

RECRUITING

Research Site

Amsterdam, 1066CX, Netherlands

RECRUITING

Research Site

Seoul, 03080, South Korea

RECRUITING

Research Site

Seoul, 06351, South Korea

RECRUITING

Research Site

Barcelona, 8035, Spain

RECRUITING

Research Site

Madrid, 28027, Spain

RECRUITING

Central Study Contacts

AstraZeneca Clinical Study Information Center

CONTACT

1-877-240-9479; information.center@astrazeneca.com

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: This is a FTiH (first time in human), modular Phase I/IIa, open-label, multi-centre study of AZD3470 as Monotherapy and in Combination with Anti-cancer agents, in participants with MTAP deficient advanced/metastatic solid tumors. 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 consisting of dose escalation cohorts and Part B consisting of optimization and expansion cohorts. Module 2 describes AZD3470 in combination with Dato-DXd and will consist of cohorts of AZD3470 in combination with Dato-DXd and a cohort of Dato-DXd as monotherapy

Study Record Dates

• First Submitted: October 19, 2023
• First Posted: November 14, 2023
• Study Start: January 18, 2024
• Primary Completion (Estimated): December 4, 2028
• Study Completion (Estimated): December 4, 2028
• Last Updated: July 13, 2026

Record last verified: 2026-07

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP
• 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 rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure
• Access Criteria: When a request has been approved AstraZeneca will provide access to the deidentified individual patient-level 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.

Locations

JP (2); AU (1); ES (2); NL (1); CN (4); FR (1); US (8); KR (2)