Abstract P119

Efficacy of Ultra-Low-Dose Nivolumab in Combination with Gemcitabine and Cisplatin as Remission-Induction Therapy in Primary Progressive and Relapsed Hodgkin Lymphoma: A Randomized Phase II study with two ultra-low-dose schedules

Background: Patients with relapsed/refractory (R/R) classical Hodgkin lymphoma (cHL),achieve complete remission (CR) in only 40–50% of cases with first-line salvage chemotherapy. Although nivolumab is highly effective in R/R cHL, the minimum biologically effective dose remains unknown. In a prior phase II study, we demonstrated a 90% overall response rate(ORR) using low-dose nivolumab (40 mg) with standardized flow cytometric analysis showing near-complete PD-1 receptor saturation and persistence of receptor occupancy at trough time-points (https://doi.org/10.1016/j.bict.2025.100011). In-vitro, we have also demonstrated complete PD-1 receptor saturation with lower doses of nivolumab (20mg and 10mg). These findings suggest that efficacy may be retained with further dose and schedule de-escalation, potentially improving affordability and access to PD-1 blockade.

Methods: This investigator-initiated, single-centre, randomized phase II trial evaluates ultra-low-dose nivolumab combined with gemcitabine, cisplatin, and dexamethasone (GCD) in patients aged ≥12 years with R/R cHL. Patients are randomized 1:1 to receive GCD plus nivolumab 20 mg for two cycles (Arm A) or GCD plus a single 20 mg dose during cycle 1 only (Arm B). The primary endpoint is ORR by end-of-treatment FDG-PET. Secondary endpoints include CR rate, toxicity, PD-1 receptor saturation, proportion proceeding to autologous stem cell transplantation, and 2-year PFS. Peripheral blood samples collected before and 2 hours after nivolumab administration, and at response assessment, will be analyzed for PD-1 receptor occupancy and T-cell activation. Patients achieving less than CR after two cycles will discontinue protocol therapy.

Statistical Considerations: Salvage chemotherapy alone yields ORRs of approximately 40–50%, whereas PD-1-based chemo-immunotherapy achieves ORRs approaching 85%. Assuming an ORR of 85% with ultra-low-dose nivolumab plus GCD, a sample size of 30 patients (15 per arm) provides 80% power at a two-sided significance level of 0.05 to demonstrate significant improvement over historical chemotherapy outcomes, while generating preliminary comparative data regarding the adequacy of single versus repeated ultra-low-dose nivolumab administration.

Current Status: Registered, Currently recruiting; Clinical Trials Registry of India,[CTRI/2025/06/089253 [20/06/2025]

Off-Label Disclosure: Nivolumab is being evaluated at a dose of 20 mg (1–2 doses), below the FDA-approved dosing regimen.