Clinical trial NCT06130553: A Study of AZD3470, a PRMT5 Inhibitor, in Patients With MTAP Deficient Advanced/Metastatic Solid Tumors
Official 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Advanced Solid Tumors That Are MTAP Deficient
Keywords: solid tumor
MTAP deficient
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
First posted: 2023-11-14
Enrollment: 234
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SEQUENTIAL
Intervention 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 tumors. The study consists of individual modules, each evaluating safety and tolerability of AZD3470 dosed as a monotherapy and in combination with specific treatments. Module 1 describes AZD3470 monotherapy, and will have at least two parts. Part A will include the dose escalation cohorts. Part B will include the dose optimization and expansion cohorts.
Primary purpose: TREATMENT

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.

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

Eligibility criteria: 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.

Primary outcomes:
measure: Incidence of adverse events (AEs) and serious adverse events (SAEs)
timeFrame: From time of informed consent to 28 days post last dose of AZD3470
measure: Incidence of dose-limiting toxicities (DLT)
timeFrame: From first dose of study treatment until the end of Cycle 1 (each cycle is 21 days)
Secondary outcomes:
measure: Radiological response assessed by the Investigator evaluated according to RECIST v1.1 - ORR (Objective Response Rate)
timeFrame: From date of first dose of AZD3470 up until progression, or the last evaluable assessment in the absence of progression (approximately 2 years).
measure: Radiological response assessed by the Investigator evaluated according to RECIST v1.1 - DoR (Duration of Response)
timeFrame: From date of first dose of AZD3470 up until progression, or the last evaluable assessment in the absence of progression (approximately 2 years).
measure: Radiological response assessed by the Investigator evaluated according to RECIST v1.1 - Best percentage change in tumor size
timeFrame: From date of first dose of AZD3470 up until progression, or the last evaluable assessment in the absence of progression (approximately 2 years).
measure: Radiological response assessed by the Investigator evaluated according to RECIST v1.1 - PFS (Progression Free Survival)
timeFrame: From date of first dose of AZD3470 up until progression, or the last evaluable assessment in the absence of progression (approximately 2 years).
measure: Radiological response assessed by the Investigator evaluated according to RECIST v1.1 - DCR (Disease Control Rate) at 12 weeks
timeFrame: 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).
measure: Overall Survival (OS)
timeFrame: From date of first dose of AZD3470 up until the date of death due to any cause (approximately 2 years).
measure: Module 1 Endpoints Part A (Dose escalation) Measurement of PK parameters: AUC
timeFrame: At predefined intervals throughout the treatment period (for each patient this is expected to be measured up to approximately 4 weeks)
measure: Module 1 Endpoints Part A (Dose escalation) Measurement of PK parameters: C-max
timeFrame: At predefined intervals throughout the treatment period (for each patient this is expected to be measured up to approximately 4 weeks)
measure: Module 1 Endpoints Part A (Dose escalation) Measurement of PK parameters: half life
timeFrame: At predefined intervals throughout the treatment period (for each patient this is expected to be measured up to approximately 4 weeks)
measure: Module 1 Endpoints Part A (Dose escalation) Measurement of PK parameters: Ae (excreted in urine)
timeFrame: At predefined intervals throughout the treatment period (for each patient this is expected to be measured up to approximately 4 weeks)
measure: Module 1 Endpoints Part A (Dose escalation) Measurement of PK parameters: Clr (renal clearance)
timeFrame: At predefined intervals throughout the treatment period (for each patient this is expected to be measured up to approximately 4 weeks)
measure: Module 1 Endpoints Part A drug-drug interaction (DDI) - Measurement of PK parameters of Midazolam: Cmax
timeFrame: At predefined intervals throughout the treatment period (for each patient this is expected to be measured up to approximately 4 weeks)
measure: Module 1 Endpoints Part A (DDI) - Measurement of PK parameters of Midazolam: AUC
timeFrame: At predefined intervals throughout the treatment period (for each patient this is expected to be measured up to approximately 4 weeks)
measure: Module 1 Endpoints Part A (DDI) - Measurement of PK parameters of Dextromethorphan: Cmax
timeFrame: At predefined intervals throughout the treatment period (for each patient this is expected to be measured up to approximately 4 weeks)
measure: Module 1 Endpoints Part A (DDI) - Measurement of PK parameters of Dextromethorphan: AUC
timeFrame: At predefined intervals throughout the treatment period (for each patient this is expected to be measured up to approximately 4 weeks)
measure: Module 1 Endpoints Part A pharmacodynamic backfill cohorts - Measurement of SDMA in tumor.
timeFrame: From screening baseline timepoint to up to four weeks on treatment timepoint.
Other outcomes:
Locations:
city: San Francisco
country: United States
facility: Research Site
state: California
city: West Hollywood
country: United States
facility: Research Site
state: California
city: New Haven
country: United States
facility: Research Site
state: Connecticut
city: Baltimore
country: United States
facility: Research Site
state: Maryland
city: Portland
country: United States
facility: Research Site
state: Oregon
city: Pittsburgh
country: United States
facility: Research Site
state: Pennsylvania
city: Providence
country: United States
facility: Research Site
state: Rhode Island
city: Fairfax
country: United States
facility: Research Site
state: Virginia
city: Melbourne
country: Australia
facility: Research Site
city: Beijing
country: China
facility: Research Site
city: Chengdu
country: China
facility: Research Site
city: Shanghai
country: China
facility: Research Site
city: Villejuif
country: France
facility: Research Site
city: Chuo-ku
country: Japan
facility: Research Site
city: Kashiwa
country: Japan
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Amsterdam
country: Netherlands
facility: Research Site
city: Barcelona
country: Spain
facility: Research Site
city: Madrid
country: Spain
facility: Research Site
Study officials:
References: