AZD3470 as Monotherapy and in Combination With Anticancer Agents in Participants With Relapsed/Refractory Haematologic Malignancies.
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.
Study details:
This is a modular, Phase I/II, open-label, multicentre study of AZD3470 in participants with haematologic malignancies. The study consists of several study modules, each evaluating the safety, tolerability, PK, pharmacodynamics, and preliminary efficacy of orally administered AZD3470 as a monotherapy and in combination with other anticancer agent(s). Module 1 Cohort 1 will evaluate AZD3470 monotherapy in adults and adolescents with r/r cHL who have received at least 2 prior lines of anticancer therapy.
Part A (dose escalation) will assess AZD3470 at increasing doses to determine Maximum Tolerated Dose and Recommended Dose for Expansion in participants aged 18 years or older. Part B (dose optimization/expansion) will include participants to selected dose levels that were evaluated in Part A to support the recommended phase II dose (RP2D). Safety, tolerability, PK, preliminary efficacy, and food effect will be assessed.
Adolescent participants (aged 12 years and older) will only be enrolled in Part B once sufficient supportive adult safety/PK data is reviewed and agreed upon with Safety Review Committee. Module 1 Cohort 2 will evaluate AZD3470 monotherapy as a consolidation therapy in advanced stage (Stage III/IV) cHL participants aged 50 years or older, who have achieved a response (CR or PR) after at least 4 cycles of frontline standard of care therapy. Safety and tolerability, PK, Pharmacodynamics and preliminary efficacy will be evaluated.
Module 1 Cohort 3 will evaluate AZD3470 monotherapy in participants with r/r PTCL (PTCL NOS, ALCL, AITL) aged 18 years or older, who have received at least one prior anticancer therapy. Safety and tolerability, PK, Pharmacodynamics, and preliminary efficacy will be evaluated. Module 2 Cohort 1 will evaluate AZD3470 in combination with pembrolizumab in r/r cHL participants aged 18 years or older, who have received at least one prior anticancer therapy.
Part A (dose escalation) will include participants at select dose levels below or at the highest tolerable monotherapy dose in Module 1 Cohort 1. Part B (dose optimization/expansion) will include participants to selected dose levels that were evaluated in Part A to support the recommended combination phase II dose (RP2D). Safety, tolerability, PK, Pharmacodynamics and preliminary efficacy, will be evaluated.
The protocol may be amended in the future to incorporate additional cohorts in combination with pembrolizumab or new modules evaluating AZD3470 in combination with other anticancer agents in haematologic malignancies.
Eligibility criteria
Researchers look for people who fit a certain description, called eligibility criteria. See if you qualify.
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.
- 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.
Eligibility
Age eligible for study : NA
Healthy volunteers accepted : No
Gender eligible for study: ALL
Things to know
Study dates
Study start:
Primary completion:
Study completion finish:
Study type
TREATMENT
Phase
- PHASE1PHASE2
Study ID
NCT06137144
Intervention or treatment
DRUG: AZD3470
Conditions
- Lymphoma
- Non-Hodgkin Lymphoma
- Hodgkin Lymphoma
- Peripheral T-cell Lymphoma (PTCL)
- PTCL-NOS
- ALCL
- AITL
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Research sites nearby
Closest Location:
Research Site
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Research Site
Nedlands, Australia
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Who is running the clinical trial?
AstraZeneca
Study Plan
This section provides details of the study plan, including how the study is designed and what the study is measuring.
How is the study designed?
| Participant Group/Arm | Intervention/Treatment |
|---|---|
EXPERIMENTAL: AZD3470 Monotherapy
| Drug: AZD3470 |
EXPERIMENTAL: AZD3470 in combination with Pembrolizumab
| Drug: AZD3470, Drug: Pembrolizumab |
What is the study measuring?
Primary Outcome
| 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
| 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). |
References
Clinical Trials Gov: AZD3470 as Monotherapy and in Combination With Anticancer Agents in Participants With Relapsed/Refractory Haematologic Malignancies.Other trials to consider
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