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

Официальное название

Phase 1/2 Trial Integrating Allogeneic NK Cells in High-risk Advanced Stage III-IV Nasopharyngeal Cancer Patients

Обзор

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.

Подробное описание

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.

Вмешательства

• Биопрепарат Allogenic expanded Natural Killer Cells (AlloNK1)
  The NK cells would be enriched and expanded ex vivo in a GMP facility from healthy donor PBMCs. Prior to administration, the NK cells would be formulated in an infusion medium based on the corresponding dose level that is required for each participant. Participants will receive an intravenous infusion of NK cells during and after the standard CRT. Six doses are administered at weeks 3,6,7,8,9, and 10. In Phase 1, NK cell doses range from 0.5x10\^7 to 1.8x10\^7 cells/kg for the determination of

Первичные конечные точки

• Determine the MTD of allogenic NK cells [Срок оценки: From enrollment to the end of treatment at week 10]
• The percentage of patients with detectable plasma EBV-DNA decreased to 10% post treatment [Срок оценки: From day of enrollment to the end of treatment at week 10]

Вторичные конечные точки (1)

• Determine the patient survival and recurrence rate post-treatment [Срок оценки: 24 to 36 months after the last treatment done at week 10]

Критерии участия

Критерии включения

• 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

Критерии исключения

• 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.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Не применимо

Модель

Последовательный дизайн

Маскирование

Открытое

Основная цель

Профилактика

Центры проведения

Сингапур · 1 центр

• Singapore General Hospital — Singapore

Публикации

• Goodman SN, Zahurak ML, Piantadosi S. Some practical improvements in the continual reassessment method for phase I studies. Stat Med. 1995 Jun 15;14(11):1149-61. doi: 10.1002/sim.4780141102. PMID 7667557
• Cheung, Y.K., Dose FInding by the Continual Reassessment Method. 2011: Chapman & Hall/CRC press.
• cheung, Y.K., Coherence principles in dose-finding studies. Biometrika, 2005. 92: p. 10.
• Yin, G. and Y. Yuan, Bayesian model averaging continual reassessment method in phase I clinical trials. Journal of the American Statistical Association, 2009. 104(487): p. 954-968.
• O'Quigley J, Pepe M, Fisher L. Continual reassessment method: a practical design for phase 1 clinical trials in cancer. Biometrics. 1990 Mar;46(1):33-48. PMID 2350571
• Jin YY, Yang WZ, Zou S, Sun ZY, Wu CT, Yang ZY. Chemoradiotherapy combined with NK cell transfer in a patient with recurrent and metastatic nasopharyngeal carcinoma inducing long-term tumor control: A case report. Medicine (Baltimore). 2020 Oct 23;99(43):e22785. doi: 10.1097/MD.0000000000022785. PMID 33120792
• Lin M, Luo H, Liang S, Chen J, Liu A, Niu L, Jiang Y. Pembrolizumab plus allogeneic NK cells in advanced non-small cell lung cancer patients. J Clin Invest. 2020 May 1;130(5):2560-2569. doi: 10.1172/JCI132712. PMID 32027620
• Ishikawa T, Okayama T, Sakamoto N, Ideno M, Oka K, Enoki T, Mineno J, Yoshida N, Katada K, Kamada K, Uchiyama K, Handa O, Takagi T, Konishi H, Kokura S, Uno K, Naito Y, Itoh Y. Phase I clinical trial of adoptive transfer of expanded natural killer cells in combination with IgG1 antibody in patients with gastric or colorectal cancer. Int J Cancer. 2018 Jun 15;142(12):2599-2609. doi: 10.1002/ijc.312 PMID 29388200

Идентификаторы

NCT: NCT07247201 · 2024-2264 · CSAINV22jul-0014 · CTGIIT23jul-0003

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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