Integrating Allogeneic NK Cells in High-risk Advanced Stage III-IV Nasopharyngeal Cancer Patients

The investigator plans to enrol 31 newly diagnosed NPC patients with Stage III-IVA/B (T1-4, N1-3, M0) disease who are scheduled to receive standard-of-care treatment over an estimated 24-36-month period.

The clinical trial consists of a Phase 1 dose-escalation study followed by a single-arm Phase 2 study. In Phase 1, at least six participants will be treated at the MTD of allogeneic NK cells, after which an additional 25 participants are expected to be enrolled in Phase 2.

Phase 1 will use the Bayesian Model Averaging Continual Reassessment Method (BMA-CRM) to determine the MTD, evaluating five NK-cell dose levels of 0.5×10⁷, 0.8×10⁷, 1.1×10⁷, 1.4×10⁷, and 1.8×10⁷ cells/kg, with the starting dose set at 0.8×10⁷ cells/kg. Dose-limiting toxicity (DLT) is defined as Grade 3 to 5 toxicities per CTCAE criteria, and the target toxicity limit (TTL) is set at a maximum allowable DLT probability of 30%. Toxicity probability will be reassessed whenever a DLT occurs to determine whether it exceeds the TTL. If the cohort completes evaluation at a given dose level and the toxicity probability is within the TTL, dose escalation will proceed; however, if the toxicity probability exceeds the TTL, the dose will be rejected, and de-escalation will occur. When toxicity probability is low, accelerated escalation may be implemented.

Phase 1 will conclude once six participants have been treated at the designated MTD without developing Grade 3 to 5 toxicities; at that point, the MTD will be accepted. All participants in Phase 1 will receive standard NPC treatment combined with the NK-cell dose evaluated at the time of their enrollment.

Phase 2 is a single-arm study based on historical findings that approximately 25% to 30% of locally advanced NPC patients continue to exhibit detectable circulating EBV-DNA following standard CRT. The study hypothesizes that the addition of allogeneic NK cells will reduce this proportion to 10%.

All participants in Phase 2 will receive standard CRT along with NK-cell infusions administered once weekly during weeks 3, 6, 7, 8, 9, and 10. Interleukin-2 (200 IU/mL) will be co-administered with NK cells in Plasma-Lyte 148 supplemented with 2% human serum albumin (HSA). The primary endpoint of Phase 2 is the reduction in the proportion of patients with detectable post-treatment circulating EBV-DNA. At week 9, if the participants' circulating EBV-DNA levels have decreased but remain detectable, would be given an option for an additional four NK-cell infusions during weeks 12 to 15.

The secondary endpoint is the improvement in survival and recurrence rates within 24 to 36 months compared with historical cohorts receiving standard treatment alone. NK cells will be generated from healthy-donor PBMCs.

Inclusion criteria

• Diagnosed with NPC Stage III-IVA/B (T1-4, N1-3, M0)
• Able to tolerate convectional CRT
• Detectable EBV level at diagnosis
• Adequate organ function ANC ≥ 1500/µL Platelet count ≥ 100,000/µL Creatinine clearance ≥60ml/minute Total bilirubin ≤ 1.5 x upper limit normal (ULN) AST ≤ 2 x upper limit normal ALT ≤ 2 x upper limit normal
• ECOG performance status of 0-1

Exclusion criteria

• History of Autoimmune Disease or any condition resulting in immunocompromised state (e.g., Drug induced)
• ECOG performance status above or equal to 2
• Poor Organ Function
• Lactating or pregnant
• Serious concomitant disorders that would compromise the safety of the patient or compromise the patient's ability to complete the study.