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

May 7, 2026 updated by: AstraZeneca

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 Participants With Advanced/Metastatic Solid Tumors That Are MTAP Deficient

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.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

This first time in human, open-label, multi-centre study of AZD3470 in participants with advanced or metastatic solid tumors with MTAP deficiency follows a modular design. Module 1 Part A will include the dose escalation cohorts. Part B will include the dose optimization and expansion cohorts. The purpose of the Phase 2 Module 2 is to evaluate the efficacy and safety of AZD3470 in combination with Dato-DXd versus Dato-DXd alone - dose optimization and expansion. New modules for combination treatments may be added in the future based on emerging data.

Study Type

Interventional

Enrollment (Estimated)

334

Phase

  • Phase 2
  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

  • Australia
      • Melbourne, Australia, 3000
        • Recruiting
        • Research Site
  • China
      • Beijing, China, 100142
        • Recruiting
        • Research Site
      • Chengdu, China, 610041
        • Recruiting
        • Research Site
      • Shanghai, China, 200433
        • Recruiting
        • Research Site
  • France
      • Villejuif, France, 94805
        • Not yet recruiting
        • Research Site
  • Japan
      • Chūōku, Japan, 104-0045
        • Recruiting
        • Research Site
      • Kashiwa, Japan, 227-8577
        • Recruiting
        • Research Site
  • Netherlands
      • Amsterdam, Netherlands, 1066CX
        • Recruiting
        • Research Site
  • South Korea
      • Seoul, South Korea, 03080
        • Recruiting
        • Research Site
      • Seoul, South Korea, 06351
        • Recruiting
        • Research Site
  • Spain
      • Barcelona, Spain, 8035
        • Recruiting
        • Research Site
      • Madrid, Spain, 28027
        • Recruiting
        • Research Site
  • United States
    • California
      • San Francisco, California, United States, 94143
        • Recruiting
        • Research Site
      • West Hollywood, California, United States, 90048
        • Withdrawn
        • Research Site
    • Connecticut
      • New Haven, Connecticut, United States, 06510
        • Recruiting
        • Research Site
    • Maryland
      • Baltimore, Maryland, United States, 21231
        • Recruiting
        • Research Site
    • Oregon
      • Portland, Oregon, United States, 97239
        • Recruiting
        • Research Site
    • Pennsylvania
      • Pittsburgh, Pennsylvania, United States, 15232
        • Recruiting
        • Research Site
    • Rhode Island
      • Providence, Rhode Island, United States, 02903
        • Recruiting
        • Research Site
    • Virginia
      • Fairfax, Virginia, United States, 22031
        • Recruiting
        • Research Site

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

Inclusion Criteria (All Modules) Participants are ≥ 18 years (or the legal age of consent in the jurisdiction) at the time of signing the informed consent form.

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.

Additional Inclusion Criteria (Module 2: Non-squamous NSCLC) Participants have histologically or cytologically confirmed non-squamous NSCLC, Stage IIIB/IIIC not amenable to curative therapy or Stage IV.

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).

Exclusion Criteria (All Modules) Participants have spinal cord compression, or symptomatic and unstable brain metastases, leptomeningeal disease, or primary CNS malignancy. Participants with asymptomatic, radiographically stable brain metastases who do not require steroids (or who have completed definitive therapy and are neurologically stable off steroids, per protocol) may be eligible.

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.

Additional Exclusion Criteria (Module 2 Only) Participants have inaccessible veins and/or inability to place required venous access (e.g., port), per Investigator judgment.

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Sequential Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Module 1: AZD3470 Monotherapy
Part A dose escalation and back-fill cohorts and Part B dose optimization and expansion cohorts of varying doses of AZD3470
Drug: AZD3470
AZD3470 is a novel, potent and selective, second-generation, MTAP-selective, inhibitor of PRMT5.
Experimental: Module 2: AZD3470 in combination with Dato-DXd
Varying doses of AZD3470 in combination with Dato-Dxd
Drug: AZD3470
AZD3470 is a novel, potent and selective, second-generation, MTAP-selective, inhibitor of PRMT5.
Drug: Datopotamab deruxtecan
AZD3470 in combination with Dato-DXd + Dato-Dxd monotherapy
Other Names:
  • Dato-DXd
Experimental: Module 2: Dato-DXd alone
Control arm
Drug: Datopotamab deruxtecan
AZD3470 in combination with Dato-DXd + Dato-Dxd monotherapy
Other Names:
  • Dato-DXd

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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
Time Frame: From time of informed consent to 28 days post last dose of study treatment
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)
Time Frame: From first dose of study treatment until the end of Cycle 1 (each cycle is 21 days)
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
Time Frame: From date of randomization up until progression, or the last evaluable assessment in the absence of progression (approximately 2 years).
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 Outcome Measures

Outcome Measure
Measure Description
Time Frame
Module 1 Endpoints Part A (Dose escalation) Measurement of PK parameters: AUC
Time Frame: At predefined intervals throughout the treatment period (for each patient this is expected to be measured up to approximately 4 weeks)
Part A (Dose escalation) Measurement of PK parameters: Area under the concentration time curve (AUC).
At predefined intervals throughout the treatment period (for each patient this is expected to be measured up to approximately 4 weeks)
Module 1 Endpoints Part A (Dose escalation) Measurement of PK parameters: C-max
Time Frame: At predefined intervals throughout the treatment period (for each patient this is expected to be measured up to approximately 4 weeks)
Part A (Dose escalation) Measurement of PK parameters: Maximum observed plasma concentration of the study drug (C-max).
At predefined intervals throughout the treatment period (for each patient this is expected to be measured up to approximately 4 weeks)
Module 1 Endpoints Part A (Dose escalation) Measurement of PK parameters: half life
Time Frame: At predefined intervals throughout the treatment period (for each patient this is expected to be measured up to approximately 4 weeks)
Part A (Dose escalation) Measurement of PK parameters: Terminal elimination half-life (t 1/2)
At predefined intervals throughout the treatment period (for each patient this is expected to be measured up to approximately 4 weeks)
Module 1 Endpoints Part A (Dose escalation) Measurement of PK parameters: Ae (excreted in urine)
Time Frame: At predefined intervals throughout the treatment period (for each patient this is expected to be measured up to approximately 4 weeks)
Part A (Dose escalation) Measurement of PK parameters: amount of AZD3470 excreted in urine (Ae).
At predefined intervals throughout the treatment period (for each patient this is expected to be measured up to approximately 4 weeks)
Module 1 Endpoints Part A (Dose escalation) Measurement of PK parameters: Clr (renal clearance)
Time Frame: At predefined intervals throughout the treatment period (for each patient this is expected to be measured up to approximately 4 weeks)
Part A (Dose escalation) Measurement of PK parameters: renal clearance (Clr).
At predefined intervals throughout the treatment period (for each patient this is expected to be measured up to approximately 4 weeks)
Module 1 Endpoints Part A (DDI) - Measurement of PK parameters of Midazolam: AUC
Time Frame: At predefined intervals throughout the treatment period (for each patient this is expected to be measured up to approximately 4 weeks)
Part A (DDI) - Plasma geometric mean ratio (Area under the concentration time curve (AUC)) of Midazolam evaluated with and without AZD3470
At predefined intervals throughout the treatment period (for each patient this is expected to be measured up to approximately 4 weeks)
Module 1 Endpoints Part A (DDI) - Measurement of PK parameters of Dextromethorphan: Cmax
Time Frame: At predefined intervals throughout the treatment period (for each patient this is expected to be measured up to approximately 4 weeks)
Part A (DDI)- Plasma geometric mean ratio (Maximum observed plasma concentration of the study drug (C-max)) of Dextromethorphan evaluated with and without AZD3470
At predefined intervals throughout the treatment period (for each patient this is expected to be measured up to approximately 4 weeks)
Module 1 Endpoints Part A (DDI) - Measurement of PK parameters of Dextromethorphan: AUC
Time Frame: At predefined intervals throughout the treatment period (for each patient this is expected to be measured up to approximately 4 weeks)
Part A (DDI) - Plasma geometric mean ratio (Area under the concentration time curve (AUC)) of Dextromethorphan evaluated with and without AZD3470
At predefined intervals throughout the treatment period (for each patient this is expected to be measured up to approximately 4 weeks)
Module 1 Endpoints Part A drug-drug interaction (DDI) - Measurement of PK parameters of Midazolam: Cmax
Time Frame: At predefined intervals throughout the treatment period (for each patient this is expected to be measured up to approximately 4 weeks)
Part A (DDI)- Plasma geometric mean ratio (Maximum observed plasma concentration of the study drug (C-max)) of Midazolam evaluated with and without AZD3470
At predefined intervals throughout the treatment period (for each patient this is expected to be measured up to approximately 4 weeks)
Module 1 Endpoints Part A pharmacodynamic backfill cohorts - Measurement of SDMA in tumor.
Time Frame: From screening baseline timepoint to up to four weeks on treatment timepoint.
Part A pharmacodynamic backfill- Percentage change from baseline tumor SDMA as measured by immunohistochemistry.
From screening baseline timepoint to up to four weeks on treatment timepoint.
All modules: Radiological response assessed by the Investigator evaluated according to RECIST v1.1 - ORR (Objective Response Rate)
Time Frame: From date of first dose of AZD3470 up until progression, or the last evaluable assessment in the absence of progression (approximately 2 years).
Proportion of participants who have a complete or partial radiological response as determined by the Investigator according to RECIST v1.1
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)
Time Frame: From date of first dose of AZD3470 up until progression, or the last evaluable assessment in the absence of progression (approximately 2 years).
DoR - the time from date of first documented objective response until date of documented disease progression per Tumor RECIST v1.1 as assessed by the Investigator at local site or death due to any cause.
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
Time Frame: From date of first dose of AZD3470 up until progression, or the last evaluable assessment in the absence of progression (approximately 2 years).
Best percentage change from baseline in TL (target lesion) tumor size is based on the RECIST 1.1. TL measurements as assessed by the Investigator.
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
Time Frame: From date of first dose/randomization up until progression, or the last evaluable assessment in the absence of progression (approximately 2 years).
PFS - defined as time from date of first dose (nonrandomized study parts) or date of randomization (randomized study parts) until progression per RECIST v1.1 as assessed by the Investigator at local site, or death due to any cause.
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
Time Frame: 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).
DCR at 12 weeks defined as the percentage of participants who have a 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 tumor data for at least 11 weeks after date of first dose to allow for an early assessment within the assessment window.
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).
All modules: Overall Survival (OS)
Time Frame: From date of first dose of AZD3470 up until the date of death due to any cause (approximately 2 years).
Overall Survival (OS) - defined as time from date of first dose (nonrandomized study parts) or date of randomization (randomized study parts) until the date of death due to any cause.
From date of first dose of AZD3470 up until the date of death due to any cause (approximately 2 years).
Module 2: Time to response (TTR)
Time Frame: From randomization until the date of first documented objective response, per RECIST v1.1 as assessed by the investigator
The time from date of randomization until the date of first documented objective response, per RECIST 1.1. as assessed by the investigator
From randomization until the date of first documented objective response, per RECIST v1.1 as assessed by the investigator
Module 2: PK parameters of AZD3470 and Dato-DXd
Time Frame: From C1D1 until EOT/28 Day Follow Up

Measurement of PK parameters:

  • Maximum total plasma concentration Cmax
  • Time to maximum concentration Tmax
  • Area under total plasma concentration curve AUC
From C1D1 until EOT/28 Day Follow Up
Module 2: Presence of ADAs (anti-drug antibody) for Dato-DXd
Time Frame: From C1D1 until EOT/28 Day Follow Up
To evaluate the immunogenicity of Dato-DXd Presence of ADAs (anti-drug antibody) for Dato-DXd
From C1D1 until EOT/28 Day Follow Up

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

AstraZeneca

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

January 18, 2024

Primary Completion (Estimated)

December 4, 2028

Study Completion (Estimated)

December 4, 2028

Study Registration Dates

First Submitted

October 19, 2023

First Submitted That Met QC Criteria

November 8, 2023

First Posted (Actual)

November 14, 2023

Study Record Updates

Last Update Posted (Actual)

May 11, 2026

Last Update Submitted That Met QC Criteria

May 7, 2026

Last Verified

May 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • D9970C00001
  • 165618 (Registry Identifier: IND)

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 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.

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 rerefer 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 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.

IPD Sharing Supporting Information Type

  • STUDY_PROTOCOL
  • SAP

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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