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

Phase 2RecruitingNCT06130553

AstraZeneca234 enrolled

Overview

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.

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. New modules for combination treatments may be added in the future based on emerging data.

Study Type

INTERVENTIONAL

Allocation

Purpose

TREATMENT

Masking

NONE

Enrollment

234

Conditions

Advanced Solid Tumors That Are MTAP Deficient

Interventions

AZD3470DRUG

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

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Principle Inclusion Criteria: * Participant must be at least 18 years of age or the legal age of consent in the jurisdiction in which the study is taking place, at the time of signing the ICF. * Willing to provide archival and/or baseline tumor sample to meet the minimum tissue requirement for central MTAP deficiency testing. * Participants must have received and progressed, are refractory or are intolerant to standard therapy for the specific tumor type. All participants are required to have had at least one prior line of treatment in the recurrent or metastatic setting. * MTAP deficient tumors defined as evidence of homozygous deletion of one or more exons of the MTAP gene in tumor tissue AND/OR loss of MTAP expression in the tumor tissue. * Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 * A minimum life expectance of 12 weeks in the opinion of the Investigator. * Participants must have at least one measurable lesion according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 * Adequate organ and bone marrow reserve function. * Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. Principle Exclusion Criteria: * Spinal cord compression or symptomatic and unstable brain metastases or leptomeningeal disease or primary malignancies of the central nervous system. * Allogeneic organ transplantation. * Any significant laboratory finding or any severe and uncontrolled medical condition. * Any of the following cardiac criteria: * LVEF ≤ 50% * prior or current cardiomyopathy * clinically active cardiovascular disease, or a history of myocardial infarction within the last 6 months * uncontrolled angina or acute coronary syndrome within 6 months * severe valvular heart disease * uncontrolled hypertension * risk of brain perfusion problems. Stroke or transient ischemic attack in the last 6 months, undergone coronary artery bypass graft, angioplasty or vascular stent * chronic heart failure * factors that increase the risk of QTc prolongation or risk of arrhythmic events * Mean resting QTcF \> 470 msec or any clinically important abnormalities in rhythm * Use of therapeutic anti-coagulation for treatment of acute thromboembolic events. * Serologic active hepatitis B or C infection. * Known to have tested positive for Human immunodeficiency virus (HIV). * Confirmed or suspected ILD/pneumonitis or history of (non-infectious) ILD/pneumonitis that required oral or IV steroids or supplemental oxygen * Active gastrointestinal disease or other condition that would interfere with oral therapy. * History of another primary malignancy. * Unresolved toxicities from prior anti-cancer therapy, except alopecia and neuropathy. * Prior treatment with a protein arginine methyltransferase 5 (PRMT5) inhibitor .

Locations (20)

Research Site

San Francisco, California, United States

RECRUITING

Research Site

Outcomes

Primary Outcomes

Incidence of adverse events (AEs) and serious adverse events (SAEs)

Number of participants with AEs and SAEs

Time frame: From time of informed consent to 28 days post last dose of AZD3470

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). DLT is defined as an AE (adverse event) or abnormal laboratory value that occurs during the DLT period (defined as 21 days after 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

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

Secondary Outcomes

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

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

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).

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

DoR - the time from date of first documented objective response (which is subsequently confirmed) 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.

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).

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

Central Contacts

AstraZeneca Clinical Study Information Center

CONTACT

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

Data from ClinicalTrials.gov

This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.

West Hollywood, California, United States

Research Site

New Haven, Connecticut, United States

RECRUITING

Research Site

Baltimore, Maryland, United States

RECRUITING

Research Site

Portland, Oregon, United States

RECRUITING

Research Site

Pittsburgh, Pennsylvania, United States

RECRUITING

Research Site

Providence, Rhode Island, United States

RECRUITING

Research Site

Fairfax, Virginia, United States

RECRUITING

Research Site

Melbourne, Australia

RECRUITING

Research Site

Beijing, China

RECRUITING

...and 10 more locations

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.

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).

Radiological response assessed by the Investigator evaluated according to RECIST v1.1 - PFS (Progression Free Survival)

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.

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).

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

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 tumor data for at least 11 weeks after date of first dose to allow for an early assessment within the assessment window.

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).

Overall Survival (OS)

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.

Time frame: From date of first dose of AZD3470 up until the date of death due to any cause (approximately 2 years).

Module 1 Endpoints Part A (Dose escalation) Measurement of PK parameters: AUC

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