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

Phase 2RecruitingNCT06137144

AstraZeneca110 enrolled

Overview

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.

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.

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

110

Conditions

Lymphoma Non-Hodgkin Hodgkin Lymphoma

Interventions

AZD3470DRUG

AZD3470 is a novel, potent and selective, second-generation, Methylthioadenosine (MTA)-selective, small molecule inhibitor of PRMT5.

Eligibility

Sex: ALLMin age: 15 Years

Medical Language ↔ Plain English

Inclusion criteria * Adequate organ and bone marrow function. * 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 * Must provide FFPE baseline tumour tissue to meet the minimum tissue requirement for central MTAP expression determination. * Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. * Contraceptive use by males or females should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. Module 1 (cHL): * At least 1 radiographically measurable, and/or FDG-avid lymphoma lesion \> 1.5 cm. * Participants must have documented r/r active disease, must have previously received at least 3 prior lines of therapy (including Brentuximab Vedotin and anti-PD-1 therapy) for the treatment of cHL, and must have exhausted all available therapies with demonstrated clinical benefit. 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 toxicities of Grade \> 1 from prior anticancer therapy (excluding peripheral neuropathy, vitiligo, alopecia, and endocrine disorders that are controlled with replacement hormone therapy, and asymptomatic laboratory abnormalities), unless immune-mediated. * 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.

Locations (20)

Research Site

Miami, Florida, United States

RECRUITING

Research Site

Atlanta, Georgia, United States

Outcomes

Primary Outcomes

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.

Time frame: 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.

Time frame: From first dose of AZD3470 to end of Cycle 1 (each cycle is 21 days).

Secondary Outcomes

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.

Time frame: 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.

Time frame: 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.

Central Contacts

AstraZeneca Clinical Study Information Center

CONTACT

1-877-240-9479 information.center@astrazeneca.com

Data from ClinicalTrials.gov

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Research Site

Boston, Massachusetts, United States

RECRUITING

Research Site

Philadelphia, Pennsylvania, United States

RECRUITING

Research Site

Houston, Texas, United States

RECRUITING

Research Site

Nedlands, Australia

RECRUITING

Research Site

Créteil, France

RECRUITING

Research Site

Lille, France

RECRUITING

Research Site

Pierre-Bénite, France

RECRUITING

Research Site

Villejuif, France

RECRUITING

...and 10 more locations

Time frame: 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.

Time frame: 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)