Clinical trial NCT06137144: AZD3470 as Monotherapy and in Combination With Anticancer Agents in Participants With Relapsed/Refractory Haematologic Malignancies.
Official title: 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Lymphoma
Non-Hodgkin
Hodgkin Lymphoma
Keywords: Haematologic Malignancies
Hodgkin lymphoma
MTAP deficient
PRMT5
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
First posted: 2023-11-18
Enrollment: 110
Sex: ALL
Minimum age (years): 15
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Incidence and severity of adverse events (AEs) and serious adverse events (SAEs)
timeFrame: From Screening until 28 days after the last dose of study medication.
measure: Incidence of DLTs (Dose Escalation only)
timeFrame: From first dose of AZD3470 to end of Cycle 1 (each cycle is 21 days).
Secondary outcomes:
measure: Part A and Part B: Response endpoints - Objective Response Rate (ORR)/Complete Response Rate (CRR)
timeFrame: 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).
measure: Part A and Part B: Response endpoints - Duration of Response (DoR)
timeFrame: 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).
measure: Part A and Part B: Progression-free Survival (PFS)
timeFrame: 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).
measure: Part A and Part B: Overall Survival (OS)
timeFrame: 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).
measure: Part A and Part B: Maximum observed plasma drug concentration (Cmax)
timeFrame: 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).
measure: Part A: Dose normalised maximum observed plasma drug concentration (Cmax)
timeFrame: 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).
measure: Part A: Accumulation ratio for maximum observed plasma drug concentration (Cmax)
timeFrame: 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).
measure: Part A and Part B: Minimum observed plasma drug concentration (Cmin)
timeFrame: 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).
measure: Part A and Part B: Time to reach peak or maximum observed concentration following drug administration (Tmax)
timeFrame: 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).
measure: Part A and Part B: Area under the plasma concentration-curve over the dosing interval (AUCtau)
timeFrame: 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).
measure: Part A: Dose normalized area under the plasma concentration-curve over the dosing interval (AUCtau)
timeFrame: 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).
measure: Part A: Accumulation ratio for area under the plasma concentration-curve over the dosing interval (AUCtau)
timeFrame: 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).
measure: Part A: Cumulative amount (%) of drug recovered unchanged in urine during dosing interval (Ae,tau)
timeFrame: From Cycle 1 Day 1 to end of Cycle 1 at predefined intervals throughout the cycle (each cycle is 21 days).
measure: Part A: Renal clearance (Clr)
timeFrame: From Cycle 1 Day 1 to end of Cycle 1 at predefined intervals throughout the cycle (each cycle is 21 days).
measure: Part B: Ratio of maximum observed plasma drug concentration (Cmax) under fed/fasted state
timeFrame: From Cycle 1 Day 1 to Cycle 2 Day 1 at predefined intervals (each cycle is 21 days).
measure: Part B: Time to reach peak or maximum observed concentration following drug administration (Tmax) under fed conditions
timeFrame: From Cycle 1 Day 1 to Cycle 2 Day 1 at predefined intervals (each cycle is 21 days).
measure: Part B: Time to reach peak or maximum observed concentration following drug administration (Tmax) under fasted conditions
timeFrame: From Cycle 1 Day 1 to Cycle 2 Day 1 at predefined intervals (each cycle is 21 days).
measure: Part B: Ratio of area under the plasma concentration-curve over the dosing interval (AUCtau) under fed/fasted state
timeFrame: From Cycle 1 Day 1 to Cycle 2 Day 1 at predefined intervals (each cycle is 21 days).
Other outcomes:
Locations:
city: Miami
country: United States
facility: Research Site
state: Florida
city: Atlanta
country: United States
facility: Research Site
state: Georgia
city: Boston
country: United States
facility: Research Site
state: Massachusetts
city: Philadelphia
country: United States
facility: Research Site
state: Pennsylvania
city: Houston
country: United States
facility: Research Site
state: Texas
city: Nedlands
country: Australia
facility: Research Site
city: Creteil
country: France
facility: Research Site
city: Lille
country: France
facility: Research Site
city: Pierre Benite
country: France
facility: Research Site
city: Villejuif Cedex
country: France
facility: Research Site
city: Köln
country: Germany
facility: Research Site
city: Alessandria
country: Italy
facility: Research Site
city: Bologna
country: Italy
facility: Research Site
city: Milan
country: Italy
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: L'Hospitalet de Llobregat
country: Spain
facility: Research Site
city: Madrid
country: Spain
facility: Research Site
city: Manchester
country: United Kingdom
facility: Research Site
city: Oxford
country: United Kingdom
facility: Research Site
Study officials:
References: