Overview Study details Eligibility Things to know Research Study plan

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Overview Study details Eligibility Things to know Research Study plan

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

PHASE1PHASE2RECRUITING

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 details:

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.

Eligibility criteria

Researchers look for people who fit a certain description, called eligibility criteria. See if you qualify.

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.

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.

Eligibility

Age eligible for study : NA

Healthy volunteers accepted : No

Gender eligible for study: ALL

Things to know

Study dates

Study start:

Primary completion:

Study completion finish:

Study type

TREATMENT

Phase

PHASE1PHASE2

Study ID

NCT06130553

Intervention or treatment

DRUG: AZD3470

Conditions

Advanced Solid Tumors That Are MTAP Deficient

Condition: Advanced Solid Tumors That Are MTAP Deficient
DRUG: AZD3470
Melbourne, Australia
Sponsor: AstraZeneca

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Research sites nearby

Closest Location:

Research Site

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Research Site
Melbourne, Australia

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Who is running the clinical trial?

AstraZeneca

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?

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
EXPERIMENTAL: Module 2: AZD3470 in combination with Dato-DXd Varying doses of AZD3470 in combination with Dato-Dxd	Drug: AZD3470, Drug: Datopotamab deruxtecan
EXPERIMENTAL: Module 2: Dato-DXd alone Control arm	Drug: Datopotamab deruxtecan

What is the study measuring?

Primary Outcome

Measure	Description	Time Frame
Incidence of adverse events (AEs) and serious adverse events (SAEs)	Number of participants with AEs and SAEs	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	From first dose of study treatment until the end of Cycle 1 (each cycle is 21 days)

Secondary Outcome

Measure	Description	Time Frame
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	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.	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	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).
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.	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.	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.	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).	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	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	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)	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)	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 drug-drug interaction (DDI) - Measurement of PK parameters of Midazolam: Cmax	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 (DDI) - Measurement of PK parameters of Midazolam: AUC	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	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	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 pharmacodynamic backfill cohorts - Measurement of SDMA in tumor.	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.

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References

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

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