AZD3470 as Monotherapy and in Combination With Anticancer Agents in Participants With Relapsed/Refractory Haematologic Malignancies.

Study Overview
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Brief Summary
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This study is designed to evaluate the safety, tolerability, PK and preliminary efficacy following oral administration of AZD3470 as a monotherapy, and in combination with other anticancer agents in participants with haematologic malignancies.

Detailed Description
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This is a FTiH modular, Phase I/II, open-label, multicentre, dose escalation and expansion study in participants with r/r haematologic malignancies. The study is designed to evaluate the safety, tolerability, PK and preliminary efficacy following oral administration of AZD3470 as a monotherapy, and in combination with other anticancer agents in participants with haematologic malignancies. This study will follow a modular protocol design evaluating AZD3470 as monotherapy and in combination with other anticancer agents. New cohorts (including further monotherapy expansion) and new modules for combination treatments may be added as protocol amendments in the future based on emerging supportive preclinical and/or clinical data. Module 1 Part A includes a dose escalation of AZD3470 monotherapy in participants with r/r haematologic malignancies, initially focused on r/r cHL. Dose escalation cohorts will evaluate the safety, tolerability, PK, and preliminary efficacy in participants with r/r cHL. Module 1 Part B optimization/expansion cohorts may be opened at selected dose levels. These cohorts will further characterise the safety, PK, and preliminary efficacy of AZD3470 to support dose optimization. Both adult and adolescent participants with r/r cHL will be eligible for this part of the study. Adolescent participants will only be enrolled once there is sufficient PK and safety data in adults. A preliminary effect of food on AZD3470 pharmacokinetics will be explored in this part of the study. The protocol may be amended in the future to incorporate further expansion of cHL at the RP2D, additional monotherapy cohorts in other hematologic malignancies, and/or additional modules investigating AZD3470 in combination with other anticancer agents.

Official Title
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A Modular Phase I/II, Open-label, Multicentre Study to Evaluate the Safety, Tolerability, and Efficacy of AZD3470, a PRMT5 Inhibitor, as Monotherapy and in Combination With Anticancer Agent(s) in Participants With Relapsed/Refractory Haematologic Malignancies

Conditions
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Lymphoma, Non-Hodgkin, Hodgkin Lymphoma

Intervention / Treatment
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* Drug: AZD3470


Participation Criteria
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Eligibility Criteria
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Inclusion criteria In Part A (dose escalation), participants must be aged ≥ 18 years at the time of signing the informed consent. In Part B (dose optimization/expansion), participants must be at least 15 years of age. Histologically confirmed documented diagnosis of r/r cHL based on criteria established by the World Health Organization Willing to provide FFPE baseline tumour tissue to meet the minimum tissue requirement for central MTAP expression determination. Participants must have documented r/r active disease, must have previously received at least 3 prior lines of therapy for the treatment of cHL, and must have exhausted all available therapies with demonstrated clinical benefit. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Module 1 (cHL): At least 1 radiographically measurable, and/or FDG-avid lymphoma lesion > 1.5 cm. Adequate organ and bone marrow function Contraceptive use by males or females should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. Exclusion criteria Any significant laboratory finding or any severe and uncontrolled medical condition. Active CNS involvement by lymphoma, leptomeningeal disease, or spinal cord compression. Serologic active HBV or HCV infection. Known to have tested positive for HIV. Active gastrointestinal disease or other condition that will interfere with oral therapy. Any of the following cardiac criteria: Mean resting QTcF > 470 msec or clinically important abnormalities in rhythm (ventricular arrhythmias and uncontrolled atrial fibrillation) Factors that increase the risk of QTc prolongation or risk of arrhythmic events Cardiac procedures or conditions within the last 6 months: Coronary artery bypass graft (CABG), percutaneous coronary intervention (PCI) or heart valve intervention vascular stent implantation, acute coronary syndrome / myocardial infarction, uncontrolled angina pectoris, use of therapeutic anti-coagulation for treatment of active thromboembolic events. Severe valvular heart disease Congestive heart failure Grade II to Grade IV Prior or current cardiomyopathy Uncontrolled hypertension Brain perfusion problems such as haemorrhagic or thrombotic stroke (including transient ischemic attacks) Unresolved non-haematological toxicity from prior anticancer therapy of Grade > 1, except alopecia. History of another primary malignancy. History of significant haemoptysis or haemorrhage within 4 weeks of the first dose of study treatment. Requires ongoing immunosuppressive therapy, including systemic corticosteroids. Prior treatment with a MAT2A inhibitor or a PRMT5 inhibitor.

Ages Eligible for Study
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Minimum Age: 15 Years
Maximum Age: 130 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
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Module 1: Part A (Dose Escalation) and Part B (Dose Expansion/Optimization)<br>In Part A, participants with Relapsed/Refractory classical Hodgkin Lymphoma (cHL) will take AZD3470 tablets orally until PD, unacceptable toxicity, or withdrawal of consent. In Part B, adult and adolescent participants with r/r cHL will take AZD3470 tablets orally until PD, unacceptable toxicity, or withdrawal of consent. | Drug: AZD3470<br>* AZD3470 is a novel, potent and selective, secondgeneration, 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 and severity of adverse events (AEs) and serious adverse events (SAEs) | AEs: Number of patients with adverse events by system organ class and preferred term. SAEs: Number of patients with serious adverse events by system organ class and preferred term. | From Screening until 28 days after the last dose of study medication. | 
| Incidence of DLTs (Dose Escalation only) | In the Dose Escalation cohorts in Part A, the number of participants with at least 1 dose-limiting toxicity (DLT), which is any toxicity defined as a DLT in the Clinical Study Protocol | From first dose of AZD3470 to end of Cycle 1 (each cycle is 21 days). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A and Part B: Response endpoints - Objective Response Rate (ORR)/Complete Response Rate (CRR) | ORR is defined as the proportion of participants who have a CR or PR and CRR is defined as the proportion of participants who have a CR. Assessment of ORR/CRR will be done according to the Lugano Classification for cHL. | From first dose (Cycle 1 Day 1, each cycle is 21 days) until disease progression or the last evaluable assessment in the absence of progression (assessed approximately up to 2 years) | 
| Part A and Part B: Response endpoints - Duration of Response (DoR) | The time from the date of first documented response until the date of documented progression as assessed by the investigator according to the Lugano classification for cHL, or death due to any cause | From first dose (Cycle 1 Day 1, each cycle is 21 days) until disease progression or death, whichever comes first (assessed approximately up to 2 years). | 
| Part A and Part B: Progression-free Survival (PFS) | Time from date of first dose (non- randomised study parts) or date of randomization (randomised study parts) until progression as assessed by the investigator according to the Lugano Classification for cHL, or death due to any cause. | Non-randomized study parts: from first dose (each cycle is 21 days) until disease progression or death, whichever comes first. Randomized parts: from date of randomization until disease progression or death, whichever comes first. (Approx up to 2 years) | 
| Part A and Part B: Overall Survival (OS) | Time from date of first dose (non-randomised study parts) or date of randomization (randomised study parts) until the date of death due to any cause. | Non-randomized study parts: From first dose (Cycle 1 Day 1, each cycle is 21 days) until death. Randomized study parts: from date of randomization until the date of death due to any cause (assessed approximately up to 2 years). | 
| Part A and Part B: Maximum observed plasma drug concentration (Cmax) | Assessed to characterize the plasma PK profile of AZD3470. | From Cycle 1 Day 1 (each cycle is 21 days) to EoT, at predefined intervals throughout the treatment period (for each patient this is expected to be approximately 6 months). | 
| Part A: Dose normalised maximum observed plasma drug concentration (Cmax) | Assessed to characterize the plasma PK profile of AZD3470. | From Cycle 1 Day 1 (each cycle is 21 days) to EoT, at predefined intervals throughout the treatment period (for each patient this is expected to be approximately 6 months). | 
| Part A: Accumulation ratio for maximum observed plasma drug concentration (Cmax) | Assessed to characterize the plasma PK profile of AZD3470. | From Cycle 1 Day 1 (each cycle is 21 days) to EoT, at predefined intervals throughout the treatment period (for each patient this is expected to be approximately 6 months). | 
| Part A and Part B: Minimum observed plasma drug concentration (Cmin) | Assessed to characterize the plasma PK profile of AZD3470. | From Cycle 1 Day 1 (each cycle is 21 days) to EoT, at predefined intervals throughout the treatment period (for each patient this is expected to be approximately 6 months). | 
| Part A and Part B: Time to reach peak or maximum observed concentration following drug administration (Tmax) | Assessed to characterize the plasma PK profile of AZD3470. | From Cycle 1 Day 1 (each cycle is 21 days) to EoT, at predefined intervals throughout the treatment period (for each patient this is expected to be approximately 6 months). | 
| Part A and Part B: Area under the plasma concentration-curve over the dosing interval (AUCtau) | Assessed to characterize the plasma PK profile of AZD3470. | From Cycle 1 Day 1 (each cycle is 21 days) to EoT, at predefined intervals throughout the treatment period (for each patient this is expected to be approximately 6 months). | 
| Part A: Dose normalized area under the plasma concentration-curve over the dosing interval (AUCtau) | Assessed to characterize the plasma PK profile of AZD3470. | From Cycle 1 Day 1 (each cycle is 21 days) to EoT, at predefined intervals throughout the treatment period (for each patient this is expected to be approximately 6 months). | 
| Part A: Accumulation ratio for area under the plasma concentration-curve over the dosing interval (AUCtau) | Assessed to characterize the plasma PK profile of AZD3470. | From Cycle 1 Day 1 (each cycle is 21 days) to EoT, at predefined intervals throughout the treatment period (for each patient this is expected to be approximately 6 months). | 
| Part A: Cumulative amount (%) of drug recovered unchanged in urine during dosing interval (Ae,tau) | Assessed to characterize the urine PK profile of AZD3470. | From Cycle 1 Day 1 to end of Cycle 1 at predefined intervals throughout the cycle (each cycle is 21 days). | 
| Part A: Renal clearance (Clr) | Assessed to characterize the urine PK profile of AZD3470. | From Cycle 1 Day 1 to end of Cycle 1 at predefined intervals throughout the cycle (each cycle is 21 days). | 
| Part B: Ratio of maximum observed plasma drug concentration (Cmax) under fed/fasted state | Preliminary food effect on plasma PK of AZD3470 administered as a monotherapy in participants enrolled in dose expansion. | From Cycle 1 Day 1 to Cycle 2 Day 1 at predefined intervals (each cycle is 21 days). | 
| Part B: Time to reach peak or maximum observed concentration following drug administration (Tmax) under fed conditions | Preliminary food effect on plasma PK of AZD3470 administered as a monotherapy in participants enrolled in dose expansion. | From Cycle 1 Day 1 to Cycle 2 Day 1 at predefined intervals (each cycle is 21 days). | 
| Part B: Time to reach peak or maximum observed concentration following drug administration (Tmax) under fasted conditions | Preliminary food effect on plasma PK of AZD3470 administered as a monotherapy in participants enrolled in dose expansion. | From Cycle 1 Day 1 to Cycle 2 Day 1 at predefined intervals (each cycle is 21 days). | 
| Part B: Ratio of area under the plasma concentration-curve over the dosing interval (AUCtau) under fed/fasted state | Preliminary food effect on plasma PK of AZD3470 administered as a monotherapy in participants enrolled in dose expansion. | From Cycle 1 Day 1 to Cycle 2 Day 1 at predefined intervals (each cycle is 21 days). | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Haematologic Malignancies, Hodgkin lymphoma, MTAP deficient, PRMT5