Non‑inferiority of nivolumab‑based N‑AVD versus brentuximab‑vedotin‑based BrECADD combination therapy as first‑line treatment in advanced Hodgkin lymphoma

The primary objective is to demonstrate the non‑inferiority of the N‑AVD regimen versus the BrECADD regimen in achieving complete metabolic response (CMR) by PET/CT as first‑line treatment for advanced Hodgkin lymphoma, an endpoint that predicts long‑term disease control; secondary objectives include comparison of progression‑free survival, event‑free survival, and overall survival between the two arms, evaluation of treatment‑related morbidity and overall safety profiles, assessment of health‑related quality of life, measurement of minimal residual disease depth using circulating tumor DNA and thymus‑and‑activation‑regulated chemokine, and assessment of gonadal function recovery after therapy.

The sponsor did not provide the total number of participants. Eligible individuals were adults aged 18 years or older of both sexes, including populations considered vulnerable. Participants required a diagnosis of Hodgkin lymphoma that was histologically confirmed as CD30‑positive, classical disease in stage IIB with bulky disease or extranodal involvement, or stage III–IV according to the Ann Arbor classification. General health criteria required an ECOG performance status of 0–2. Selection followed the inclusion criteria of the National Health Fund Drug Program B.77, points 1.1 and 1.2.2, and required written informed consent. Women of childbearing potential needed a negative serum β‑hCG test and agreement to use effective contraception, while male participants of reproductive potential were required to use condoms or practice abstinence during treatment and for six months thereafter.

The study is a randomized, controlled phase III trial (Category 2) evaluating the non‑inferiority of the N‑AVD regimen (nivolumab 240 mg IV infusion, vinblastine 6 mg/m² IV, dacarbazine 375 mg/m² IV, and doxorubicin 25 mg/m² IV) versus the BrECADD regimen (brentuximab vedotin 180 mg IV, etoposide 150 mg/m² IV, dexamethasone 40 mg oral, dacarbazine 250 mg/m² IV, doxorubicin 40 mg/m² IV, and dexaven 40 mg IV) in adult patients with newly diagnosed, CD30‑positive, advanced Hodgkin lymphoma. After obtaining informed consent, participants undergo a screening visit to confirm eligibility criteria, including ECOG 0–2, disease stage, and required laboratory and pregnancy testing. Eligible subjects are then randomized at the baseline visit and begin the assigned chemotherapy cycles; safety, adverse events (CTCAE), and biomarker assessments (ctDNA, TARC) are performed after each cycle. A PET/CT scan is scheduled 6–8 weeks after the completion of chemotherapy to determine the primary endpoint of complete metabolic response. Secondary assessments—including progression‑free survival, event‑free survival, overall survival, quality of life (EORTC QLQ‑HL27), treatment‑related morbidity, and gonadal recovery (FSH at 1 year)—are conducted at predefined intervals throughout the study period. Follow‑up visits continue until the end‑of‑study visit, which occurs after the final efficacy and safety evaluations. The overall participant involvement extends from the screening visit through the end‑of‑study visit, with the trial recruitment planned from 31 July 2026 to 31 July 2032.

NIVOLUMAB is administered as an intravenous infusion at a dose of 240 mg per administration. The pharmaceutical form is not specified. Dosing follows the trial schedule, with each infusion given on the designated treatment day of the cycle.

Doxorubicin hydrochloride (Doxorubicin‑Ebewe) is supplied as a solution for infusion and is given by intravenous injection at a dose of 25 mg/m². The drug is administered according to the protocol‑defined treatment days.

Vinblastine sulfate is provided for intravenous administration at a dose of 6 mg/m². Each dose is delivered on the scheduled day of the treatment cycle.

Dacarbazine (test arm) is administered intravenously at a dose of 375 mg/m². The infusion is performed on the protocol‑specified treatment day.

Brentuximab vedotin is given as an intravenous infusion at a dose of 180 mg per administration. Dosing follows the trial‑defined schedule.

Doxorubicin hydrochloride (comparator) is delivered intravenously at a dose of 40 mg/m² on the assigned treatment days.

Etoposide is administered intravenously at a dose of 150 mg/m² per administration, according to the study schedule.

Dexamethasone is taken orally at a dose of 40 mg per administration. Oral dosing is recorded in the study diary and compliance is verified by pill count.

Dexamethasone phosphate (Dexaven) is supplied as a solution for injection and is given intravenously at a dose of 40 mg per administration on the scheduled day.

Dacarbazine (comparator) is administered intravenously at a dose of 250 mg/m² per infusion, following the protocol‑defined timing.

All intravenous administrations are documented in infusion logs, and adherence to the dosing schedule is monitored through source documentation and, where applicable, patient diaries for oral agents.

The primary efficacy assessment is the Complete metabolic response (CMR) rate, evaluated by PET/CT imaging performed 6–8 weeks after the completion of chemotherapy. The imaging is interpreted according to standardized response criteria to determine metabolic remission.

Secondary efficacy evaluations include:

• Progression-Free Survival (PFS) and Event-Free Survival (EFS), measured from randomization until documented disease progression, relapse, or death, with assessments throughout the study period.
• Quality of life (QoL), captured using the EORTC QLQ‑HL27 questionnaire at baseline (before treatment), after two chemotherapy cycles, at the end of chemotherapy, and at each follow‑up visit.
• Treatment‑related morbidity (TRMB), recorded as the frequency and severity of adverse events graded according to the Common Terminology Criteria for Adverse Events (CTCAE) after each chemotherapy cycle.
• Gonadal recovery, assessed by measuring follicle‑stimulating hormone (FSH) concentrations 1 year after chemotherapy completion.
• Negative residual disease status, determined by quantifying circulating tumor DNA (ctDNA) and thymus and activation‑regulated chemokine (TARC) levels after two chemotherapy cycles and at the end of treatment (concurrent with the PET/CT assessment).
• Overall survival (OS), tracked from randomization until death from any cause, with continuous monitoring over the entire study duration.

All laboratory measurements (FSH, ctDNA, TARC) are performed using validated assay platforms in central laboratories. Imaging and questionnaire data are collected centrally, and statistical analyses will compare the N‑AVD regimen to the BrECADD regimen using appropriate non‑inferiority margins for the primary endpoint and standard survival analysis techniques for secondary time‑to‑event outcomes.