Integrating Allogeneic NK Cells in High-risk Advanced Stage III-IV Nasopharyngeal Cancer Patients (AlloNK1)

Singapore Health Services (SingHealth)

Status and phase: Not yet enrolling; Phase 2; Phase 1

Conditions: Recurrent Nasopharyngeal Carcinoma; Maximum Tolerated Dose; Nasopharyngeal Carcinoma (NPC); Minimal Residual Disease

Treatments: Biological: Allogenic expanded Natural Killer Cells (AlloNK1)

Study type: Interventional

Funder types: Other

Identifiers

NCT07247201

CTGIIT23jul-0003 (Other Grant/Funding Number)

CSAINV22jul-0014 (Other Grant/Funding Number)

2024-2264

Details and patient eligibility

About

This clinical trial aims to determine whether Natural Killer (NK) cell therapy administered in combination with concurrent chemoradiotherapy (CRT) can reduce recurrence in patients with advanced nasopharyngeal cancer (NPC), and to identify the highest safe and tolerable dose of allogeneic NK cells. Allogeneic NK cells, derived from healthy donors, have demonstrated good tolerability in cancer patients.

The primary research questions are:

1. What is the maximum tolerated dose (MTD) of allogeneic NK cells when administered with CRT in NPC patients?
2. Can the addition of allogeneic NK cells to standard CRT reduce the proportion of NPC patients with detectable plasma EBV-DNA from 30% to 10%?

Phase 1: Participants will receive one of five escalating doses of allogeneic NK cells with CRT to determine the MTD.

Phase 2: Participants will receive the established MTD NK dose together with CRT.

Participants will undergo regular safety monitoring, side-effect assessment, measurement of plasma EBV-DNA levels, and surveillance for disease recurrence.

Full description

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 U/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, they will receive an optional 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.

Enrollment: 31 estimated patients

Sex: All

Ages: 21 to 80 years old

Volunteers: No Healthy Volunteers

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.

Trial design

Primary purpose: Prevention

Allocation: N/A

Interventional model: Sequential Assignment

Masking: None (Open label)

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31 participants in 1 patient group

Concurrent and adjuvant allogeneic NK cell therapy

Experimental group

Description:

Participants will receive standard chemoradiotherapy for locally advanced nasopharyngeal carcinoma along with adjuvant therapy of NK cells. Nk cells would be enriched and expanded using PBMCs from healthy donors. Phase 1 dose escalation study which uses 5 different dosages of 0.5 x 10\^7, 0.8x10\^7, 1.1x10\^7, 1.4 x 10\^7, and 1.8x10\^7 to determine the Maximum tolerated dose (MTD). If the MTD is determined in phase 1, the study will enter phase 2, where the determined dose level will be used for participants. The participants will receive six intravenous NK cell infusions at weeks 3,6,7,8,9, and 10 during and after CRT. If the participant's EBV level is still detectable, they would be suggested for supplementary NK cell treatments for an additional four weeks.

Treatment:

Biological: Allogenic expanded Natural Killer Cells (AlloNK1)