Trial Review

Registering a new trial?

To achieve prospective registration, we recommend submitting your trial for registration at the same time as ethics submission.

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been endorsed by the ANZCTR. Before participating in a study, talk to your health care provider and refer to this information for consumers
Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT06130553




Registration number
NCT06130553
Ethics application status
Date submitted
19/10/2023
Date registered
14/11/2023
Date last updated
5/11/2024

Titles & IDs
Public title
A Study of AZD3470, a PRMT5 Inhibitor, in Patients With MTAP Deficient Advanced/Metastatic Solid Tumors
Scientific title
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 Tumors That Are MTAP Deficient
Secondary ID [1] 0 0
165618
Secondary ID [2] 0 0
D9970C00001
Universal Trial Number (UTN)
Trial acronym
PRIMROSE
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Advanced Solid Tumors That Are MTAP Deficient 0 0
Condition category
Condition code

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - AZD3470

Experimental: AZD3470 Monotherapy - Part A dose escalation and back-fill cohorts and Part B dose optimization and expansion cohorts of varying doses of AZD3470


Treatment: Drugs: AZD3470
AZD3470 is a novel, potent and selective, second-generation, MTAP-selective, inhibitor of PRMT5.
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Incidence of adverse events (AEs) and serious adverse events (SAEs)
Timepoint [1] 0 0
From time of informed consent to 28 days post last dose of AZD3470
Primary outcome [2] 0 0
Incidence of dose-limiting toxicities (DLT)
Timepoint [2] 0 0
From first dose of study treatment until the end of Cycle 1 (each cycle is 21 days)
Secondary outcome [1] 0 0
Radiological response assessed by the Investigator evaluated according to RECIST v1.1 - ORR (Objective Response Rate)
Timepoint [1] 0 0
From date of first dose of AZD3470 up until progression, or the last evaluable assessment in the absence of progression (approximately 2 years).
Secondary outcome [2] 0 0
Radiological response assessed by the Investigator evaluated according to RECIST v1.1 - DoR (Duration of Response)
Timepoint [2] 0 0
From date of first dose of AZD3470 up until progression, or the last evaluable assessment in the absence of progression (approximately 2 years).
Secondary outcome [3] 0 0
Radiological response assessed by the Investigator evaluated according to RECIST v1.1 - Best percentage change in tumor size
Timepoint [3] 0 0
From date of first dose of AZD3470 up until progression, or the last evaluable assessment in the absence of progression (approximately 2 years).
Secondary outcome [4] 0 0
Radiological response assessed by the Investigator evaluated according to RECIST v1.1 - PFS (Progression Free Survival)
Timepoint [4] 0 0
From date of first dose of AZD3470 up until progression, or the last evaluable assessment in the absence of progression (approximately 2 years).
Secondary outcome [5] 0 0
Radiological response assessed by the Investigator evaluated according to RECIST v1.1 - DCR (Disease Control Rate) at 12 weeks
Timepoint [5] 0 0
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).
Secondary outcome [6] 0 0
Overall Survival (OS)
Timepoint [6] 0 0
From date of first dose of AZD3470 up until the date of death due to any cause (approximately 2 years).
Secondary outcome [7] 0 0
Module 1 Endpoints Part A (Dose escalation) Measurement of PK parameters: AUC
Timepoint [7] 0 0
At predefined intervals throughout the treatment period (for each patient this is expected to be measured up to approximately 4 weeks)
Secondary outcome [8] 0 0
Module 1 Endpoints Part A (Dose escalation) Measurement of PK parameters: C-max
Timepoint [8] 0 0
At predefined intervals throughout the treatment period (for each patient this is expected to be measured up to approximately 4 weeks)
Secondary outcome [9] 0 0
Module 1 Endpoints Part A (Dose escalation) Measurement of PK parameters: half life
Timepoint [9] 0 0
At predefined intervals throughout the treatment period (for each patient this is expected to be measured up to approximately 4 weeks)
Secondary outcome [10] 0 0
Module 1 Endpoints Part A (Dose escalation) Measurement of PK parameters: Ae (excreted in urine)
Timepoint [10] 0 0
At predefined intervals throughout the treatment period (for each patient this is expected to be measured up to approximately 4 weeks)
Secondary outcome [11] 0 0
Module 1 Endpoints Part A (Dose escalation) Measurement of PK parameters: Clr (renal clearance)
Timepoint [11] 0 0
At predefined intervals throughout the treatment period (for each patient this is expected to be measured up to approximately 4 weeks)
Secondary outcome [12] 0 0
Module 1 Endpoints Part A drug-drug interaction (DDI) - Measurement of PK parameters of Midazolam: Cmax
Timepoint [12] 0 0
At predefined intervals throughout the treatment period (for each patient this is expected to be measured up to approximately 4 weeks)
Secondary outcome [13] 0 0
Module 1 Endpoints Part A (DDI) - Measurement of PK parameters of Midazolam: AUC
Timepoint [13] 0 0
At predefined intervals throughout the treatment period (for each patient this is expected to be measured up to approximately 4 weeks)
Secondary outcome [14] 0 0
Module 1 Endpoints Part A (DDI) - Measurement of PK parameters of Dextromethorphan: Cmax
Timepoint [14] 0 0
At predefined intervals throughout the treatment period (for each patient this is expected to be measured up to approximately 4 weeks)
Secondary outcome [15] 0 0
Module 1 Endpoints Part A (DDI) - Measurement of PK parameters of Dextromethorphan: AUC
Timepoint [15] 0 0
At predefined intervals throughout the treatment period (for each patient this is expected to be measured up to approximately 4 weeks)
Secondary outcome [16] 0 0
Module 1 Endpoints Part A pharmacodynamic backfill cohorts - Measurement of SDMA in tumor.
Timepoint [16] 0 0
From screening baseline timepoint to four weeks on treatment timepoint.

Eligibility
Key inclusion criteria
Principle

* 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
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key 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.

Study design
Purpose of the study
Treatment
Allocation to intervention
Not applicable
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other
Other design features
Phase
Phase 1
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
18/01/2024
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
26/02/2026
Actual
Sample size
Target
210
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
Recruitment hospital [1] 0 0
Research Site - Melbourne
Recruitment postcode(s) [1] 0 0
3000 - Melbourne
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
California
Country [2] 0 0
United States of America
State/province [2] 0 0
Connecticut
Country [3] 0 0
United States of America
State/province [3] 0 0
Maryland
Country [4] 0 0
United States of America
State/province [4] 0 0
Oregon
Country [5] 0 0
United States of America
State/province [5] 0 0
Pennsylvania
Country [6] 0 0
United States of America
State/province [6] 0 0
Rhode Island
Country [7] 0 0
United States of America
State/province [7] 0 0
Virginia
Country [8] 0 0
China
State/province [8] 0 0
Beijing
Country [9] 0 0
China
State/province [9] 0 0
Shanghai
Country [10] 0 0
France
State/province [10] 0 0
Villejuif
Country [11] 0 0
Japan
State/province [11] 0 0
Chuo-ku
Country [12] 0 0
Japan
State/province [12] 0 0
Kashiwa
Country [13] 0 0
Korea, Republic of
State/province [13] 0 0
Seoul
Country [14] 0 0
Netherlands
State/province [14] 0 0
Amsterdam
Country [15] 0 0
Spain
State/province [15] 0 0
Barcelona
Country [16] 0 0
Spain
State/province [16] 0 0
Madrid

Funding & Sponsors
Primary sponsor type
Commercial sector/industry
Name
AstraZeneca
Address
Country

Ethics approval
Ethics application status

Summary
Brief summary
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.
Trial website
https://clinicaltrials.gov/study/NCT06130553
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
AstraZeneca Clinical Study Information Center
Address 0 0
Country 0 0
Phone 0 0
1-877-240-9479
Fax 0 0
Email 0 0
[email protected]
Contact person for scientific queries



Summary Results

For IPD and results data, please see https://clinicaltrials.gov/study/NCT06130553