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

Study Overview
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Brief Summary
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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 tumours with MTAP deficiency. The study consists of several study modules, evaluating the safety, tolerability, PK, pharmacodynamics, and preliminary efficacy of AZD3470 as monotherapy or in combination with other anti-cancer agents.

Detailed Description
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This first time in human, open-label, multi-centre study of AZD3470 in participants with advanced or metastatic solid tumours with MTAP deficiency follows a modular design. Module 1 will include dose escalation and DDI (Part A) and dose optimisation and expansion (Part B). New modules for combination treatments may be added in the future based on emerging data.

Official Title
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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 Patients With Advanced/Metastatic Solid Tumours That Are MTAP Deficient

Conditions
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Advanced Solid Tumours That Are MTAP Deficient

Intervention / Treatment
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* Drug: AZD3470


Participation Criteria
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Eligibility Criteria
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Principal 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 tumour 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 tumour type. All participants are required to have had at least one prior line of treatment in the recurrent or metastatic setting. MTAP deficient tumours defined as evidence of homozygous deletion of one or more exons of the MTAP gene in tumour tissue AND/OR loss of MTAP expression in the tumour 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 Tumours (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. Principal Exclusion Criteria: Spinal cord compression or symptomatic and unstable brain metastases or leptomeningeal disease. Allogenic 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 active 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Sequential Assignment
Interventional Model Description: This is a FTiH (first time in human), modular Phase I/IIa, open-label, multi-centre study of AZD3470, in participants with MTAP deficient advanced/metastatic solid tumours. 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 dose escalation and DDI cohorts and Part B consisting of dose optimisation and expansion cohorts.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AZD3470 Monotherapy<br>Part A dose escalation and DDI and Part B dose optimisation and expansion in varying doses of AZD3470 | Drug: AZD3470<br>* AZD3470 is a novel, potent and selective, second-generation, methylthioadenosine (MTA)-selective, small molecule inhibitor of PRMT5.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | 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 evaluation period (defined as 21 days after the 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 Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Radiological response assessed by the Investigator evaluated according to RECIST v1.1 - ORR (Objective Response Rate) | Proportion of patients who have a confirmed complete or partial radiological response 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 until date of documented disease progression per Tumour 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 tumour size | Best percentage change from baseline in TL (target lesion) tumour 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 (nonrandomised study parts) or date of randomisation (randomised 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 tumour 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 (nonrandomised study parts) or date of randomisation (randomised 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 (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) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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solid tumour, MTAP deficient