Controlled Cold Exposure Combined With PD-1/PD-L1 Immunotherapy in Solid Tumors (NIVALIS)

Official title

NIVALIS Trial: A Single-Center, Prospective, Single-Arm, Open-Label Phase I Exploratory Study Evaluating the Safety, Feasibility, and Preliminary Antitumor Activity of Controlled Cold Exposure Combined With PD-1/PD-L1 Immunotherapy in Patients With Solid Tumors

Overview

This is a single-center, prospective, single-arm, open-label phase I exploratory study that plans to enroll 24 participants with solid malignancies. All participants will receive controlled cold exposure in addition to standard PD-1/PD-L1 inhibitor monotherapy or PD-1/PD-L1 inhibitor-based standard combination therapy. A 2-day cold acclimation phase will precede formal intervention, consisting of approximately 20°C exposure for 8 hours on Day -2 and approximately 18°C exposure for 10 hours on Day -1. The first combination cycle begins on Day 1 concurrently with PD-1/PD-L1-based treatment, with exposure to an 18°C temperature-controlled hospital room for 12 hours per day for 7 consecutive days. If tolerated, cold exposure may be repeated in subsequent PD-1/PD-L1 treatment cycles. The primary objective is to evaluate safety, tolerability, and feasibility. Secondary objectives are to explore preliminary antitumor activity and the effects on brown adipose tissue activation, peripheral immune profiling, circulating cytokines, metabolomics, gut microbiota, patient-reported outcomes, and tumor immune/metabolic biomarkers when paired tumor tissue is available.

Detailed description

This study does not alter the participant's predetermined standard antitumor treatment pathway. It is non-randomized, does not include a parallel thermoneutral control arm, and uses an open-label design. A total of 24 participants are planned to obtain 20 evaluable participants. For early safety protection, staggered enrollment will be used: the first 2 participants will complete the first combination intervention and the dose-limiting toxicity observation window before further enrollment proceeds, provided no predefined unacceptable toxicity is observed. Efficacy and mechanistic endpoints will be explored primarily through longitudinal within-participant comparisons and descriptive analyses.

Interventions

• Other Controlled Cold Exposure
  Controlled environmental cold exposure in a temperature-controlled hospital room. Cold acclimation includes approximately 20°C for 8 hours on Day -2 and approximately 18°C for 10 hours on Day -1; formal intervention consists of 18°C exposure for 12 hours per day for 7 consecutive days and may be repeated in later cycles if tolerated.
• Drug Investigator-Selected Standard PD-1/PD-L1 Inhibitor-Based Therapy
  Standard PD-1/PD-L1 inhibitor monotherapy or PD-1/PD-L1 inhibitor-containing standard combination therapy selected according to tumor type, clinical guidelines, and routine clinical practice.

Primary outcome measures

• Incidence of Adverse Events, Serious Adverse Events, and Safety-Related Treatment Modifications [Time frame: From the start of the first study-related intervention until 30 days after the last protocol-specified treatment or the initiation of a new anticancer therapy, whichever occurs first.]
• Completion Rate and Adherence to Controlled Cold Exposure [Time frame: Primarily assessed during the first combined intervention cycle (Day 1 to Day 7), and continuously recorded until completion of the last protocol-specified cold exposure treatment.]

Secondary outcome measures (12)

• Objective Response Rate [Time frame: The first imaging assessment will be performed 6-8 weeks after treatment initiation, and subsequently every 8-12 weeks until disease progression, withdrawal from the study, or study completion, up to 12 months.]
• Disease Control Rate [Time frame: The first imaging assessment will be performed 6-8 weeks after treatment initiation, and subsequently every 8-12 weeks until disease progression, withdrawal from the study, or study completion, up to 12 months.]
• Progression-Free Survival [Time frame: From the start of the first study-related intervention until study completion, up to 36 months.]
• Overall Survival [Time frame: From the start of the first study-related intervention until study completion, up to 36 months.]
• Degree of brown adipose tissue activation after the cold exposure cycle [Time frame: 7 ± 2 days after completion of the first cold exposure cycle.]
• Change from baseline in the proportion of peripheral blood immune cell subsets [Time frame: From enrollment to the end of treatment, an average of 3 months.]
• Change from baseline in plasma metabolomics [Time frame: From enrollment to the end of treatment, an average of 3 months.]
• Change from baseline in the gut microbiota [Time frame: From enrollment to the end of treatment, an average of 3 months.]
• Incidence of cold exposure-related discomfort [Time frame: At baseline, daily during the cold adaptation period, and daily during the initial combined intervention phase, until the end of cold exposure. From enrollment to the end of treatment, an average of 3 months.]
• Changes in Tumor Immune and Metabolic Biomarkers in Paired Tumor Tissue (If Available) [Time frame: At baseline biopsy and at surgical resection, an average of 3 months.]
• Surgery rate [Time frame: Assessed at the planned time point for surgery, an average of 1 months.]
• R0 resection rate [Time frame: Assessed at the completion of surgery and postoperative pathological evaluation, an average of 1 months.]

Eligibility criteria

Inclusion criteria

• 1\. Age 18-75 years, regardless of sex. 2. Histologically or cytologically confirmed malignant solid tumor. 3. Evaluated by the treating physician or multidisciplinary team (MDT) as currently planned to receive standard PD-1/PD-L1 inhibitor monotherapy or a standard combination regimen containing PD-1/PD-L1 inhibitors.

4\. Applicable settings include neoadjuvant, perioperative, or conversion therapy, as well as unresectable locally advanced, recurrent, or metastatic disease planned for systemic therapy.

5\. At least one evaluable lesion; for patients assessed by RECIST 1.1, at least one measurable lesion is required. Patients planned for surgery may also be included if adequate preoperative imaging and postoperative pathological assessment are available, even if RECIST measurability is not fully met.

6\. ECOG performance status 0-1; selected patients with ECOG 2 may be enrolled at the investigator's discretion if considered able to tolerate the study procedures.

7\. Expected survival ≥3 months. 8. Adequate major organ function, including hematologic, hepatic, renal, and electrolyte parameters acceptable for clinical study participation.

9\. Cardiopulmonary function at rest adequate to tolerate the study procedures, without obvious abnormalities indicating intolerance to cold exposure.

10\. Toxicities from prior antitumor therapy must have recovered to ≤ Grade 1, except for alopecia or clinically insignificant abnormalities judged by the investigator; for patients previously treated with PD-1/PD-L1 inhibitors, at least 4 weeks must have elapsed before enrollment, and prior related adverse events must have recovered or stabilized sufficiently for re-exposure.

11\. No clear contraindication to cold exposure, and deemed able to tolerate cold exposure combined with immunotherapy by the investigator.

12\. Negative pregnancy test for women of childbearing potential; participants of reproductive potential must agree to use effective contraception during the study and for at least 3 months after the last dose.

13\. Able to understand the study objectives, procedures, and potential risks, and willing to provide written informed consent.

14\. For participants planned for neoadjuvant, perioperative, or conversion therapy, the investigator must confirm that study procedures will not delay planned surgery or other critical treatments.

Exclusion criteria

• 1\. Participation in another interventional clinical study or receipt of another investigational treatment within 4 weeks before study treatment initiation.

2\. Uncontrolled active infection, including but not limited to severe bacterial, viral, or fungal infection, or active tuberculosis.

3\. HIV infection; chronic HBV or HCV infection with uncontrolled viral replication or unacceptable liver function.

4\. Known severe hypersensitivity to the intended PD-1/PD-L1 inhibitor or its excipients.

5\. Active autoimmune disease or a requirement for long-term moderate- to high-dose immunosuppressive therapy; physiological replacement-dose steroids may be allowed at the investigator's discretion.

6\. Prior severe or life-threatening immune-related adverse events during PD-1/PD-L1 inhibitor therapy that have not resolved or are considered high-risk for re-exposure.

7\. Significant cardiovascular disease, including but not limited to unstable angina, severe arrhythmia, NYHA class III-IV heart failure, LVEF <50%, or myocardial infarction, stroke, or severe thrombotic events within 6 months.

8\. Severe chronic respiratory disease, especially conditions likely to worsen under cold stimulation, such as severe COPD or severe asthma.

9\. Clear contraindications to cold exposure, including prior severe cold-related injury, cold urticaria, cryoglobulinemia, active Raynaud's syndrome, or other diseases judged by the investigator to preclude tolerance to a cold environment.

10\. Uncontrolled symptomatic central nervous system metastases. 11. Severe psychiatric illness, cognitive impairment, substance abuse, or alcohol dependence that would interfere with compliance.

12\. Pregnancy or breastfeeding. 13. Uncontrolled diabetes, severe malnutrition, marked frailty, or any other condition judged to make the participant unable to tolerate cold exposure or study procedures.

14\. Any situation in which study participation may significantly delay standard therapy, planned surgery, or other critical treatment timing.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

China · 1 center

• West China Hospital of Sichuan University — Chengdu

Publications

• Walker ME, Kodani SD, Mena HA, Tseng YH, Cypess AM, Spite M. Brown Adipose Tissue Activation in Humans Increases Plasma Levels of Lipid Mediators. J Clin Endocrinol Metab. 2024 Jun 17;109(7):1837-1849. doi: 10.1210/clinem/dgae016. PMID 38198796
• Lin B, Lin D, Ou X, Wang J, Yu S, Chen G, Wen J. Brown adipose tissue activation and cardiovascular risk following PD-1 antibody therapy in cancer patients: a retrospective cohort study. Eur J Med Res. 2025 Nov 28;30(1):1195. doi: 10.1186/s40001-025-03463-w. PMID 41316332
• Seki T, Yang Y, Sun X, Lim S, Xie S, Guo Z, Xiong W, Kuroda M, Sakaue H, Hosaka K, Jing X, Yoshihara M, Qu L, Li X, Chen Y, Cao Y. Brown-fat-mediated tumour suppression by cold-altered global metabolism. Nature. 2022 Aug;608(7922):421-428. doi: 10.1038/s41586-022-05030-3. Epub 2022 Aug 3. PMID 35922508

Identifiers

NCT: NCT07538479 · Approval No. 2270 (2025)

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗