Advanced Solid Tumors That Are MTAP Deficient
Conditions
Keywords
solid tumor, MTAP deficient
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. The purpose of the Phase 2 Module 2 is to evaluate the efficacy and safety of AZD3470 in combination with Dato-DXd versus Dato-DXd alone - dose optimization and expansion. New modules for combination treatments may be added in the future based on emerging data.
Interventions
DRUGAZD3470
AZD3470 is a novel, potent and selective, second-generation, MTAP-selective, inhibitor of PRMT5.
DRUGDatopotamab deruxtecan
AZD3470 in combination with Dato-DXd + Dato-Dxd monotherapy
Sponsors
AstraZeneca
Study design
Allocation
NA
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
This is a FTiH (first time in human), modular Phase I/IIa, open-label, multi-centre study of AZD3470 as Monotherapy and in Combination with Anti-cancer agents, 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 or in combination with specific treatments. Module 1 describes AZD3470 monotherapy, and will have at least two parts. Part A consisting of dose escalation cohorts and Part B consisting of optimization and expansion cohorts. Module 2 describes AZD3470 in combination with Dato-DXd and will consist of cohorts of AZD3470 in combination with Dato-DXd and a cohort of Dato-DXd as monotherapy
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 | From time of informed consent to 28 days post last dose of study treatment | Number of participants with AEs and SAEs. |
| Module 1: Incidence of dose-limiting toxicities (DLT) | 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) |
| Module 2: Progression Free Survival assessed by the Investigator according to RECIST v1.1 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| All modules: Radiological response assessed by the Investigator evaluated according to RECIST v1.1 - ORR (Objective Response Rate) | 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 |
| All modules: Radiological response assessed by the Investigator evaluated according to RECIST v1.1 - DoR (Duration of Response) | 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. |
| All modules: Radiological response assessed by the Investigator evaluated according to RECIST v1.1 - Best percentage change in tumor size | 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. |
| Module 1: Progression Free Survival assessed by the Investigator evaluated according to RECIST v1.1 | 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. |
| All modules: Radiological response assessed by the Investigator evaluated according to RECIST v1.1 - DCR (Disease Control Rate) at 12 weeks | 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. |
| All modules: Overall Survival (OS) | 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. |
| Module 1 Endpoints Part A (Dose escalation) Measurement of PK parameters: AUC | 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). |
| Module 1 Endpoints Part A (Dose escalation) Measurement of PK parameters: C-max | 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). |
| Module 1 Endpoints Part A (Dose escalation) Measurement of PK parameters: half life | 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) |
| Module 1 Endpoints Part A (Dose escalation) Measurement of PK parameters: Ae (excreted in urine) | 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). |
| Module 1 Endpoints Part A (Dose escalation) Measurement of PK parameters: Clr (renal clearance) | 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). |
| Module 1 Endpoints Part A drug-drug interaction (DDI) - Measurement of PK parameters of Midazolam: Cmax | 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 |
| Module 1 Endpoints Part A (DDI) - Measurement of PK parameters of Midazolam: AUC | 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 |
| Module 1 Endpoints Part A (DDI) - Measurement of PK parameters of Dextromethorphan: Cmax | 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 |
| Module 1 Endpoints Part A (DDI) - Measurement of PK parameters of Dextromethorphan: AUC | 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 |
| Module 1 Endpoints Part A pharmacodynamic backfill cohorts - Measurement of SDMA in tumor. | 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. |
| Module 2: Time to response (TTR) | 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 |
| Module 2: PK parameters of AZD3470 and Dato-DXd | 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 |
| Module 2: Presence of ADAs (anti-drug antibody) for Dato-DXd | From C1D1 until EOT/28 Day Follow Up | To evaluate the immunogenicity of Dato-DXd Presence of ADAs (anti-drug antibody) for Dato-DXd |
Countries
Australia, China, France, Japan, Netherlands, South Korea, Spain, United States
Contacts
CONTACTAstraZeneca Clinical Study Information Center
Outcome results
None listed