Phase III Randomized Study of AZD0486 + Rituximab versus Standard Chemoimmunotherapy in Previously Untreated Follicular Lymphoma

The study evaluates the safety, tolerability and optimal Phase III dose of the investigational monoclonal antibody AZD0486 in combination with rituximab in previously untreated Follicular Lymphoma, and seeks to demonstrate superiority of this regimen versus investigator‑selected chemo‑immunotherapy by comparing progression‑free survival and end‑of‑induction objective response rate. Establishing a favorable safety profile and a dose that maximizes efficacy is essential for improving first‑line therapeutic options in this disease.

Secondary objectives include:

• Evaluate preliminary efficacy by ORR, complete response rate, CR at end of induction, duration of response and progression‑free survival using Lugano 2014 criteria.
• Characterise pharmacokinetic parameters and incidence of immunogenicity for AZD0486 with rituximab.
• Demonstrate superiority for overall survival versus standard chemo‑immunotherapy.
• Assess additional efficacy measures, including the impact on minimal residual disease-negative complete response.
• Evaluate long‑term safety, tolerability and cumulative toxicity of the combination.
• Assess patient‑reported overall side‑effect burden and B‑symptom profile.

The trial enrolled 1,000 individuals diagnosed with Follicular Lymphoma, inclusive of both female and male participants aged 18 years and older. Eligibility required histologically confirmed disease per the WHO 2022 classification, disease stage II–IV, an FLIPI score of 2–5, and fulfillment of at least one GELF criterion indicating the need for systemic therapy. Participants demonstrated an ECOG performance status of 0–2, measurable FDG‑avid disease, and adequate hepatic, renal, hematologic, and cardiac function. Selection was based on meeting these clinical and laboratory parameters, with no specific lifestyle restrictions reported. The cohort comprised treatment‑naïve patients who had not received prior therapy for follicular lymphoma.

The study is a randomized, open‑label, controlled Phase III trial evaluating the investigational monoclonal antibody AZD0486 in combination with rituximab versus investigator‑selected chemoimmunotherapy in participants with previously untreated Follicular Lymphoma. Participants are screened for eligibility, then randomized 1:1 to receive either AZD0486 + rituximab or standard chemotherapy (cyclophosphamide, vincristine, doxorubicin, bendamustine, prednisolone) plus rituximab; treatment is administered intravenously according to the assigned regimen. The protocol specifies a screening (inclusion) visit, an induction phase with scheduled treatment cycles, regular follow‑up visits for safety and efficacy assessments (including laboratory tests, imaging for disease response, and adverse‑event monitoring), and a final end‑of‑study visit. Participant involvement is expected to last up to approximately 30 months, encompassing treatment, post‑treatment follow‑up, and final assessment. Early termination may occur if a participant experiences unacceptable toxicity, disease progression, withdrawal of consent, or if the investigator deems continuation medically inappropriate. The primary efficacy endpoints are progression‑free survival (PFS) and end‑of‑induction objective response rate, with secondary endpoints including overall survival, duration of response, and safety outcomes; the trial recruitment period spans from September 2026 to November 2031.

The investigational agent AZD0486 is a human IgG4‑kappa monoclonal antibody directed against CD3 and CD19, supplied as a solution for infusion and administered intravenously. The dose and infusion schedule are defined in the study protocol and are given on the same days as the concomitant rituximab infusions.

Rituximab is provided for intravenous infusion. In the experimental arm it is combined with AZD0486 and administered according to the dosing schedule outlined in the protocol, typically on day 1 of each treatment cycle.

Cyclophosphamide for the comparator arm is an intravenous solution. It is infused at the protocol‑specified dose on day 1 of each chemotherapy cycle.

Vincristine, supplied as an intravenous formulation, is administered on day 1 of each cycle at the dose defined in the protocol.

Doxorubicin hydrochloride, presented as an intravenous preparation, is infused on day 1 of each cycle according to the protocol‑specified dosing.

Bendamustine hydrochloride, provided as an intravenous solution, is given on day 1 of each cycle at the dose stipulated in the study protocol.

Prednisone, an oral tablet, is taken daily at the dose prescribed in the protocol for the duration of each treatment cycle.

All study drugs are administered in a clinical setting under the supervision of qualified personnel. Dosing intervals follow the predefined cycle length, and adherence is monitored by treatment logs, infusion records, and pill counts for oral medication. Compliance assessments are performed at each study visit.

Efficacy will be evaluated by comparing the investigational regimen with investigator‑chosen chemoimmunotherapy using predefined clinical endpoints. The primary efficacy assessment focuses on demonstrating superiority in progression‑free survival and the objective response rate at the end of induction (EoI). Secondary efficacy endpoints include overall response rate, complete response rate, complete response at EoI, duration of response, overall survival, complete response rate at 30 months, time to first subsequent treatment, and PFS2.

Response assessments will be performed at baseline, at the end of induction, and at prespecified follow‑up visits as defined in the protocol. Imaging studies and clinical evaluations will be used to determine response status according to the protocol‑specified criteria. Collected data will be analyzed using appropriate statistical methods to compare the investigational arm with the standard‑of‑care arm, with the primary analysis testing for superiority in the predefined efficacy parameters.