Purpose

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.

Condition

Eligibility

Eligible Ages
Over 18 Years
Eligible Sex
All
Accepts Healthy Volunteers
No

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 Design

Phase
Phase 1/Phase 2
Study Type
Interventional
Allocation
N/A
Intervention Model
Sequential Assignment
Intervention Model Description
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
Primary Purpose
Treatment
Masking
None (Open Label)

Arm Groups

ArmDescriptionAssigned Intervention
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

Recruiting Locations

Research Site
San Francisco, California 94143

Research Site
New Haven, Connecticut 06510

Research Site
Baltimore, Maryland 21231

Research Site
Portland, Oregon 97239

Research Site
Pittsburgh, Pennsylvania 15232

Research Site
Providence, Rhode Island 02903

Research Site
Fairfax, Virginia 22031

More Details

Status
Recruiting
Sponsor
AstraZeneca

Study Contact

AstraZeneca Clinical Study Information Center
1-877-240-9479
information.center@astrazeneca.com

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.

Notice

Study information shown on this site is derived from ClinicalTrials.gov (a public registry operated by the National Institutes of Health). The listing of studies provided is not certain to be all studies for which you might be eligible. Furthermore, study eligibility requirements can be difficult to understand and may change over time, so it is wise to speak with your medical care provider and individual research study teams when making decisions related to participation.