A Study of AZD3470, a PRMT5 Inhibitor, Given as Monotherapy and in Combination in Patients With MTAP Deficient Advanced/Metastatic Solid Tumors

NCT06130553
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Phase
Phase 1/Phase 2
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Recruitment status
Recruiting
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Participants
334
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Lead sponsor
AstraZeneca
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Start date
2024-01-18
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Number of sites
21
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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.
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Acronym
PRIMROSE
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Short title
A Study of AZD3470, a PRMT5 Inhibitor, Given as Monotherapy and in Combination in Patients With MTAP Deficient Advanced/Metastatic Solid Tumors
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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 Participants With Advanced/Metastatic Solid Tumors That Are MTAP Deficient
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Control arm
Open label
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Registry reports results
No
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Listing at source
Listed
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Recruitment status
Recruiting
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Phase
Phase 1/Phase 2
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Study type
Interventional
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Completion date
2028-12-04
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First posted
2023-11-14
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Registry last updated
2026-08-27
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Primary completion date
2028-12-04
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Start date
2024-01-18
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Participants
334
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Participant count basis
Estimated
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Planned participants
334
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Protocol amendments
4
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Number of sites
21
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Registry sponsor category
Industry
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Lead sponsor
AstraZeneca
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Source registry
ClinicalTrials.gov
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Registry ID
NCT06130553
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ClinicalTrials.gov ID
NCT06130553
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Registry record
Open registry record
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Allocation
Not applicable
Model
Sequential
Purpose
Treatment
Masking
No masking
Sources for study design
clinicaltrials.gov

  1. All Modules: Incidence of adverse events (AEs) and serious adverse events (SAEs). To determine the RP2D of AZD3470 as monotherapy and in combination with anticancer agents

    Timeframe: From time of informed consent to 28 days post last dose of study treatment

    Number of participants with AEs and SAEs.

  2. Module 1: Incidence of dose-limiting toxicities (DLT)

    Timeframe: From first dose of study treatment until the end of Cycle 1 (each cycle is 21 days)

    Incidence of dose-limiting toxicities (DLT) as determined by number of patients with at least 1 dose-limiting toxicity (DLT)

  3. Module 2: Progression Free Survival assessed by the Investigator according to RECIST v1.1

    Timeframe: From date of randomization up until progression, or the last evaluable assessment in the absence of progression (approximately 2 years).

    PFS - defined as time from date of randomization until progression per RECIST v1.1 as assessed by the Investigator at local site, or death due to any cause.

  1. All modules: 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).

    Proportion of participants who have a complete or partial radiological response as determined by the Investigator according to RECIST v1.1

  2. All modules: 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).

    DoR - the time from date of first documented objective response 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.

  3. All modules: 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).

    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.

  4. Module 1: Progression Free Survival assessed by the Investigator evaluated according to RECIST v1.1

    Timeframe: From date of first dose/randomization up until progression, or the last evaluable assessment in the absence of progression (approximately 2 years).

    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.

  5. All modules: 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).

    DCR at 12 weeks defined as the percentage of participants who have a 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.

  6. All modules: Overall Survival (OS)

    Timeframe: From date of first dose of AZD3470 up until the date of death due to any cause (approximately 2 years).

    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.

  7. 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)

    Part A (Dose escalation) Measurement of PK parameters: Area under the concentration time curve (AUC).

  8. 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)

    Part A (Dose escalation) Measurement of PK parameters: Maximum observed plasma concentration of the study drug (C-max).

  9. 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)

    Part A (Dose escalation) Measurement of PK parameters: Terminal elimination half-life (t 1/2)

  10. 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)

    Part A (Dose escalation) Measurement of PK parameters: amount of AZD3470 excreted in urine (Ae).

  11. 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)

    Part A (Dose escalation) Measurement of PK parameters: renal clearance (Clr).

  12. 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)

    Part A (DDI)- Plasma geometric mean ratio (Maximum observed plasma concentration of the study drug (C-max)) of Midazolam evaluated with and without AZD3470

  13. 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)

    Part A (DDI) - Plasma geometric mean ratio (Area under the concentration time curve (AUC)) of Midazolam evaluated with and without AZD3470

  14. 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)

    Part A (DDI)- Plasma geometric mean ratio (Maximum observed plasma concentration of the study drug (C-max)) of Dextromethorphan evaluated with and without AZD3470

  15. 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)

    Part A (DDI) - Plasma geometric mean ratio (Area under the concentration time curve (AUC)) of Dextromethorphan evaluated with and without AZD3470

  16. 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.

    Part A pharmacodynamic backfill- Percentage change from baseline tumor SDMA as measured by immunohistochemistry.

  17. Module 2: Time to response (TTR)

    Timeframe: From randomization until the date of first documented objective response, per RECIST v1.1 as assessed by the investigator

    The time from date of randomization until the date of first documented objective response, per RECIST 1.1. as assessed by the investigator

  18. Module 2: PK parameters of AZD3470 and Dato-DXd

    Timeframe: From C1D1 until EOT/28 Day Follow Up

    Measurement of PK parameters: * Maximum total plasma concentration Cmax * Time to maximum concentration Tmax * Area under total plasma concentration curve AUC

  19. Module 2: Presence of ADAs (anti-drug antibody) for Dato-DXd

    Timeframe: From C1D1 until EOT/28 Day Follow Up

    To evaluate the immunogenicity of Dato-DXd Presence of ADAs (anti-drug antibody) for Dato-DXd

Sources for outcomes
clinicaltrials.gov

Sex
All
Age groups
Adults, Older adults
Minimum age
18 Years
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.

Sources for eligibility
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  • Research SiteSan Francisco, United StatesRecruiting
  • Research SiteWest Hollywood, United StatesWithdrawn
  • Research SiteNew Haven, United StatesRecruiting
  • Research SiteBaltimore, United StatesRecruiting
  • Research SitePortland, United StatesRecruiting
  • Research SitePittsburgh, United StatesRecruiting
  • Research SiteProvidence, United StatesRecruiting
  • Research SiteFairfax, United StatesRecruiting
  • Research SiteMelbourne, AustraliaRecruiting
  • Research SiteBeijing, ChinaRecruiting
  • Research SiteChengdu, ChinaRecruiting
  • Research SiteShanghai, ChinaRecruiting
  • Research SiteWuhan, ChinaNot yet recruiting
  • Research SiteVillejuif, FranceNot yet recruiting
  • Research SiteChūōku, JapanRecruiting
  • Research SiteKashiwa, JapanRecruiting
  • Research SiteAmsterdam, NetherlandsRecruiting
  • Research SiteSeoul, South KoreaRecruiting
  • Research SiteSeoul, South KoreaRecruiting
  • Research SiteBarcelona, SpainRecruiting
  • Research SiteMadrid, SpainRecruiting
Sources for sites
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Other registry identifiers

  • 165618
Sources for references
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Related records

Drugs (1)

Lead sponsors (1)

Targets (2)