AZD3470 as Monotherapy or in Combination With Anticancer Agent(s) in Participants With Haematologic Malignancies. (PRIMAVERA)

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

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

Study Overview

• Status: Recruiting
• Conditions: Lymphoma; Hodgkin Lymphoma; Non-Hodgkin Lymphoma; PTCL-NOS; AITL; ALCL; Peripheral T-cell Lymphoma (PTCL)
• Intervention / Treatment: Drug: AZD3470; Drug: Pembrolizumab

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 161
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: AstraZeneca Clinical Study Information Center; Phone Number: 1-877-240-9479; Email: information.center@astrazeneca.com

Study Locations

• Australia
  • Adelaide, Australia, 5000
    • Withdrawn
    • Research Site
  • Birtinya, Australia, 4575
    • Withdrawn
    • Research Site
  • Fitzroy, Australia, 3065
    • Not yet recruiting
    • Research Site
  • Nedlands, Australia, 6009
    • Recruiting
    • Research Site
  • South Brisbane, Australia, 4101
    • Withdrawn
    • Research Site
  • Waratah, Australia, 2298
    • Withdrawn
    • Research Site
• China
  • Beijing, China, 100191
    • Not yet recruiting
    • Research Site
  • Guangzhou, China, 510060
    • Not yet recruiting
    • Research Site
  • Shanghai, China, 20032
    • Not yet recruiting
    • Research Site
• France
  • Créteil, France, 94010
    • Terminated
    • Research Site
  • Lille, France, 59000
    • Recruiting
    • Research Site
  • Pierre-Bénite, France, 69310
    • Recruiting
    • Research Site
  • Villejuif, France, 94805
    • Recruiting
    • Research Site
• Germany
  • Berlin, Germany, 12203
    • Not yet recruiting
    • Research Site
  • Cologne, Germany, 50937
    • Recruiting
    • Research Site
  • Erlangen, Germany, 91054
    • Not yet recruiting
    • Research Site
  • Würzburg, Germany, 97080
    • Not yet recruiting
    • Research Site
• Italy
  • Alessandria, Italy, 15100
    • Recruiting
    • Research Site
  • Bologna, Italy, 40138
    • Recruiting
    • Research Site
  • Milan, Italy, 20141
    • Recruiting
    • Research Site
• Japan
  • Bunkyō City, Japan, 113-8677
    • Not yet recruiting
    • Research Site
  • Kōtoku, Japan, 135-8550
    • Not yet recruiting
    • Research Site
• South Korea
  • Seoul, South Korea, 03080
    • Recruiting
    • Research Site
  • Seoul, South Korea, 06351
    • Recruiting
    • Research Site
• Spain
  • L'Hospitalet de Llobregat, Spain, 08908
    • Recruiting
    • Research Site
  • Madrid, Spain, 28041
    • Recruiting
    • Research Site
• United Kingdom
  • Manchester, United Kingdom, M20 4BX
    • Recruiting
    • Research Site
  • Oxford, United Kingdom, OX3 7LE
    • Recruiting
    • Research Site
• United States
  • California
    • Duarte, California, United States, 91010
      • Not yet recruiting
      • Research Site
  • Florida
    • Miami, Florida, United States, 33136
      • Recruiting
      • Research Site
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Withdrawn
      • Research Site
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Recruiting
      • Research Site
  • New York
    • New York, New York, United States, 10016
      • Not yet recruiting
      • Research Site
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Recruiting
      • Research Site
  • Texas
    • Houston, Texas, United States, 77030
      • Recruiting
      • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

Core Inclusion criteria:

1. Adequate adult (ECOG) or adolescent (Karnofsy or Lanksy) Performance Score assessments
2. Adequate organ and bone marrow function.

Module 1 Cohort 1:

1. Age:

   1. Part A (dose escalation): aged ≥ 18 years at the time of signing the informed consent.
   2. Part B (optimization): aged ≥ 12 years of age. Adolescent participants must weigh ≥ 40 kg.
2. Histologically confirmed diagnosis of cHL based on WHO criteria
3. Previous treatment with at least 2 prior lines of therapy for the treatment of cHL (including at least 2 cycles of BV and anti-PD1) and have documented r/r active disease requiring treatment.
4. Participants must provide FFPE baseline tumour tissue.
5. At least 1 radiographically measurable, and/or FDG-avid lymphoma lesion ( >1.5 cm for nodal lesion and >1 cm for extranodal lesion).

Module 1 Cohort 2:

1. Participants must be at least 50 years of age or older at study entry.
2. Histologically confirmed diagnosis of cHL based on WHO criteria
3. Ann Arbor stages III or IV.
4. Participant must have previously received at least 4 cycles of SoC combination therapy with A-AVD, N-AVD, AVD, or ABVD (based on regional SOC, per investigator) as finite first-line induction therapy, and achieved at least a PR post-induction therapy.
5. Participants must provide FFPE baseline tumour tissue.

Module 1 Cohort 3:

1. Participants must be aged ≥ 18 years at the time of signing the informed consent.
2. Histologically confirmed diagnosis of PTCL NOS, systemic ALCL, or AITL based on WHO criteria.
3. Participants must have received at least 1 prior line of therapy for the treatment of PTCL and have exhausted all available therapies with demonstrated clinical benefit. Participants with ALCL must have received prior BV treatment.

4. Participants must provide FFPE baseline tumour tissue

   a. Ability to provide an on-treatment biopsy (if the tumour is suitable for biopsy).

5. At least 1 radiographically measurable, and/or FDG-avid lymphoma lesions (> 1.5 cm for nodal lesion and >1 cm for extranodal lesion).

Module 2 Cohort 1:

1. Participants must be aged ≥ 18 years at the time of signing the informed consent.
2. Histologically confirmed diagnosis of cHL based on WHO criteria
3. At least 1 radiographically measurable, and/or FDG-avid lymphoma lesions (> 1.5 cm for nodal lesion and >1 cm for extranodal lesion).
4. Participant must have received at least 1 prior line of therapy for the treatment of cHL and have documented r/r active disease requiring treatment.
5. Participants must provide FFPE baseline tumour tissue.

Exclusion Criteria:

Core Exclusion criteria:

1. Any significant laboratory finding or any severe and uncontrolled medical condition.
2. Active CNS involvement by lymphoma, leptomeningeal disease, or spinal cord compression.
3. Serologic active HBV or HCV infection.
4. Known to have tested positive for HIV.
5. Active gastrointestinal disease or other condition that will interfere with oral therapy.
6. Any of the following ECG cardiac criteria: Mean resting QTcF > 470 msec, clinically important abnormalities in rhythm, conduction or morphology, and/or any factors that increase the risk of QTc prolongation or risk of arrhythmic events.

7. Undergone any of the following procedures within 6 months prior to first dose:

   1. Coronary artery bypass graft,
   2. Percutaneous coronary intervention or heart valve replacement or repairment,
   3. Vascular stent implantation (venous stent is eligible),
   4. Acute coronary syndrome / myocardial infarction,
   5. Unstable or poorly controlled angina pectoris,
   6. Ventricular arrhythmias requiring continuous therapy,
   7. Uncontrolled atrial fibrillation,
   8. Haemorrhagic or thrombotic stroke (including transient ischaemic attacks) or any other CNS bleeding.
   9. Acute venous or atrial thromboembolic event (unless considered stable or adequately treated with at least 3months of therapeutic anticoagulation).
8. Severe valvular heart disease.
9. Congestive heart failure Grade II to Grade IV.
10. Prior or current cardiomyopathy.
11. Uncontrolled hypertension.
12. History of significant haemoptysis or haemorrhage within4 weeks of the first dose of study treatment.
13. Unresolved toxicities of Grade > 1 from prior anti cancer therapy (excluding peripheral neuropathy, vitiligo, alopecia and endocrine disorders that are controlled with replacement hormone therapy, and asymptomatic laboratory abnormalities), unless immune-mediated.
14. History of another primary malignancy.
15. Received the following anticancer therapies: anti-lymphoma therapy (within 21 days), radiation therapy(within 28 days), allo-HSCT (within 180 days), auto-HSCT/cellular therapy (within 60 days), or MAT2A or PRMT5 inhibitor
16. Requires ongoing immunosuppressive therapy, including systemic corticosteroids.

Module 2 Cohort 1:

1. History of confirmed ILD, drug-induced ILD, radiation pneumonitis requiring steroid treatment or any evidence of clinically active ILD or pneumonitis.
2. ≥Grade 3 immune-mediated AE while receiving prior checkpoint inhibitor immunotherapy, or any unresolved ≥Grade 2 immune-mediated AE.
3. History of immune-mediated myocarditis or pericarditis.
4. Experienced a toxicity that led to permanent discontinuation of prior immunotherapy.
5. Active or prior documented pathologically confirmed autoimmune or inflammatory disorders
6. Refractory to prior checkpoint inhibitor therapy (within 12 weeks of last dose)
7. Eligible for allogeneic or autologous stem cell transplant.
8. Received an allogeneic HSCT within 5 years of the first dose of study treatment; must not have active Graft-versus-host disease.
9. Participants with a known hypersensitivity to pembrolizumab or any of the excipients of the product.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: AZD3470 Monotherapy; Module 1 Cohort 1 evaluates safety, tolerability, efficacy of AZD3470 in r/r cHL participants with 2 prior lines of systemic anticancer therapy (including BV and anti-PD1). Participants will be treated according to protocol-defined windows. Part A (dose escalation) assesses AZD3470 at increasing doses in participants aged ≥18 years, r/r cHL. Part B (dose optimization/ expansion) includes participants at certain dose levels evaluated as tolerable in Part A and may include adolescent patients aged ≥12 years, upon SRC agreement. Module 1 Cohort 2 evaluates the safety, tolerability, efficacy of AZD3470 as consolidation for Stage III/IV cHL participants aged ≥50 years after CR or PR to frontline SOC therapy (either N-AVD, A-AVD, AVD, ABVD) Module 1 Cohort 3 evaluates the safety, tolerability, preliminary efficacy of AZD3470 in participants aged ≥18 years with r/r PTCL (PTCL NOS, ALCL, AITL subtypes) with at least 1 prior line of systemic anticancer therapy.	Drug: AZD3470; AZD3470 is a novel, potent and selective, second-generation, Methylthioadenosine (MTA)-selective, small molecule inhibitor of PRMT5.
Experimental: AZD3470 in combination with Pembrolizumab; Module 2 Cohort 1 will assess participants aged ≥18 years with r/r cHL who have received at least one prior line of anticancer therapy. Participants will receive treatment according to the protocol-defined limit, or until disease progression, unacceptable toxicity as judged by the investigator or until meeting any other discontinuation criteria, as defined in the clinical study protocol, whichever occurs first. Part A (dose escalation) will evaluate the safety and tolerability of AZD3470 in combination with Pembrolizumab. Part B (dose optimization/expansion) will evaluate dose optimization/expansion in certain dose levels of AZD3470 in combination with Pembrolizumab, based on cumulative data from dose escalation part (Part A).	Drug: AZD3470; AZD3470 is a novel, potent and selective, second-generation, Methylthioadenosine (MTA)-selective, small molecule inhibitor of PRMT5.; Drug: Pembrolizumab; Pembrolizumab (CAS nr: 1374853-91-4 ); Other Names: Keytruda

What is the study measuring?

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 continuously until 28 days after the last dose of study medication.
Incidence of DLTs (Dose Escalation Cohorts 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
Response endpoints as assessed by the investigator according to the Lugano Classification: Objective Response Rate (ORR)/Complete Response Rate (CRR)	Applicable to Module 1 Cohort 1 and 3, and Module 2 Cohort 1: 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 and PTCL	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.
Response Endpoints as assessed by investigator according to the Lugano Classification: Conversation rate of Partial Response (PR) to Complete Response (CR)	Applicable to Module 1 Cohort 2: PR to CR conversion rate is defined as the proportion of participants who have a PR at baseline after induction therapy, who subsequently achieve a CR. PR and CR are assessed by investigators according to Lugano classification for lymphoma.	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.
Response endpoints as assessed by the investigator according to the Lugano Classification: Duration of Response (DoR)	Applicable to Module 1 Cohort 1 and Cohort 3 and Module 2 Cohort 1: For the patients who have achieved an objective response (CR or PR), 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 and PTCL, or death due to any cause (in absence of disease progression).	From date of first objective response until documented progression or death due to any cause or censoring (if progression or death have not occurred)
Response endpoints as assessed by the investigator according to the Lugano Classification for CHL: The rate of durable CR	Applicable to Module 2 Cohort 1: Rate of durable complete response is defined as the proportion of participants who have a CR with a duration according to CSP-defined timelines.	From date of first complete response until documented progression or death due to any cause or censoring (if progression or death have not occurred)
Response Endpoints as assessed by the investigator according to the Lugano Classification: Progression-free Survival (PFS)	Applicable to all cohorts: 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 and PTCL, or death, due to any cause.	From first dose (each cycle is 21 days)/from randomisation (for non-randomized & randomized study parts respectively) until disease progression or death, or censoring (if progression or death have not occurred) whichever is first
Response Endpoints as assessed by the investigator according to the Lugano Classification: Overall Survival (OS)	Applicable to all cohorts: 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.	From first dose (each cycle is 21 days)/from randomisation (for non-randomized & randomized study parts respectively) until disease progression or death, or censoring (if progression or death have not occurred) whichever is first
Measurement of Plasma PK parameters: AUC, Cmax, tmax, Ctrough, t1/2 λz, CL/F, and Vz/F	Applicable to all cohorts: 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.
Measurement of Plasma PK parameters under fed or fasted conditions: Ratio of Cmax, Tmax, and AUCtau	Applicable to Module 1 Cohort 1 Part B: 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).
Urine PK parameters including Cumulative percentage of unchanged drug in urine (Ae,tau) during dosing interval and renal clearance	Applicable to Module 1 Cohort 1 Part A: 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).
Percentage change from baseline tumour SDMA mesaured by IHC.	Applicable to Module 1 Cohort 3: To asses the inhibition of PRMT5 in tumour	From Screening to EoT, at predefined intervals throughout the treatment period.

Collaborators and Investigators

• Sponsor: AstraZeneca

Study record dates

Study Major Dates

• Study Start (Actual): January 23, 2024
• Primary Completion (Estimated): April 30, 2029
• Study Completion (Estimated): April 30, 2029

Study Registration Dates

• First Submitted: November 2, 2023
• First Submitted That Met QC Criteria: November 13, 2023
• First Posted (Actual): November 18, 2023

Study Record Updates

• Last Update Posted (Actual): May 19, 2026
• Last Update Submitted That Met QC Criteria: May 18, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: Hodgkin lymphoma; Peripheral T-cell lymphoma (PTCL); Haematologic Malignancies; Methylthioadenosine Phosphorylase (MTAP) deficient; Protein Arginine Methyltransferase 5 (PRMT5)
• Additional Relevant MeSH Terms: Neoplasms; Immune System Diseases; Neoplasms by Histologic Type; Lymphatic Diseases; Lymphoproliferative Disorders; Immunoproliferative Disorders; Lymphoma, T-Cell; Hemic and Lymphatic Diseases; Lymphoma; Lymphoma, Non-Hodgkin; Hodgkin Disease; Lymphoma, T-Cell, Peripheral; pembrolizumab
• Other Study ID Numbers: D9971C00001; 2023-506747-42-00 (Registry Identifier: CTIS (EU))

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All requests will be evaluated as per the AZ disclosure commitment:

https://astrazenecagrouptrials.pharmacm.com /ST/Submission/Disclosure. Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared.

IPD Sharing Time Frame

AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please refer to our disclosure commitment at:

https://astrazenecagrouptrials.pharmacm.com /ST/Submission/Disclosure.

IPD Sharing Access Criteria

When a request has been approved AstraZeneca will provide access to the de-identified individual patientlevel data in an approved sponsored tool. Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at:

https://astrazenecagrouptrials.pharmacm.com /ST/Submission/Disclosure.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No