PRIMAVERA: A Modular Phase I/II Study to Evaluate the Safety, Tolerability, and Efficacy of AZD3470, a Protein Arginine Methyltransferase 5 (PRMT5) Inhibitor, in Participants with Relapsed/Refractory Hematologic Malignancies

Background and significance: PRMT5 is an enzyme that methylates arginine residues on many histone/non-histone proteins. It promotes oncogenesis through epigenetic control of gene expression, RNA splicing, and DNA repair. Methylthioadenosine phosphorylase (MTAP)-deficient tumor cells show accumulation of methylthioadenosine (MTA), an endogenous partial inhibitor of PRMT5. AZD3470 is an MTA-cooperative PRMT5 inhibitor that preferentially targets the MTA-bound state of PRMT5, sparing its inhibition in normal cells. While MTAP homozygous deletion is found in ≈15% of advanced solid cancers, >80% of classical Hodgkin lymphoma (cHL) samples have MTAP protein loss, potentially due to epigenetic silencing (ASH 2023, Abstract 4185). Here, we describe a phase I/II trial designed to assess AZD3470 as monotherapy and in combination with anticancer agents in participants with relapsed/refractory (R/R) hematologic malignancies.

Study design and methods: PRIMAVERA (NCT06137144) is a modular, first-in-human phase I/II dose escalation and expansion study. Participants ≥18 years of age with histologically confirmed, measurable R/R cHL who have received ≥3 prior lines of therapy (including brentuximab vedotin and anti-PD-1 unless not indicated due to toxicity or not accessible) and meet hematologic criteria (Hb ≥10 g/dL, ANC ≥1.5x10⁹/L, platelets ≥100x10⁹/L) will be enrolled. In Module 1 Part A (dose escalation), participants will receive daily oral AZD3470 monotherapy to evaluate its safety, tolerability, pharmacokinetics/pharmacodynamics (PK/PD), and preliminary efficacy in a dose-escalation design. In Module 1 Part B, dose optimization/expansion cohorts will open at selected AZD3470 dose level(s) to further characterize safety, PK/PD, and efficacy. An interim safety and futility analysis will be conducted in Module 1 Part B and may trigger expansion at the recommended phase 2 dose (RP2D) of AZD3470 as monotherapy in participants with cHL (Module 1 Part C), as well as testing of AZD3470 in combination with anticancer agents in Module 2. Participants will be treated until progressive disease, unacceptable toxicity, or withdrawal of consent.

The primary objective is to assess the safety/tolerability of AZD3470 to determine the RP2D. The secondary objective is to assess preliminary efficacy (Lugano 2014 criteria). Exploratory objectives will evaluate the effect of AZD3470 on tumor biomarkers and correlation with response.

Recruitment for dose escalation (Module 1 Part A) began in January 2024 and is ongoing. The study is planning to enrol across ≈20 sites and is currently enrolling in the following countries: South Korea, Australia, France, Italy, Spain, Germany, UK, and USA.