Recruiting
Phase 1
Controlled Cold Exposure Combined With PD-1/PD-L1 Immunotherapy in Solid Tumors (NIVALIS)
Condition(s) studied
Solid TumorsSolid MalignanciesCold ExposureImmunotherapy
Investigational drug(s) / intervention(s)
Controlled Cold ExposureInvestigator-Selected Standard PD-1/PD-L1 Inhibitor-Based Therapy
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.
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.
Study summary
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.
Eligibility
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.
Primary outcome measure(s)
- Incidence of Adverse Events, Serious Adverse Events, and Safety-Related Treatment Modifications — 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.
The safety of the study treatment will be evaluated by recording adverse events (AEs), serious adverse events (SAEs), treatment-emergent adverse events (TEAEs), immune-related adverse events (irAEs), grade 3-4 TEAEs, and interruptions, delays, or discontinuations of controlled cold exposure or immunotherapy due to adverse events. Results will be reported as the proportion of participants experiencing the corresponding events (%) and the number of events.
- Completion Rate and Adherence to Controlled Cold Exposure — 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.
The feasibility of the controlled cold exposure intervention will be evaluated by assessing the completion rate of planned cold exposure, intervention adherence, early withdrawal rate, and interruptions or discontinuations of cold exposure due to intolerance. Results will be reported separately as proportions (%).
Trial sites (1)
| Facility | City | Region | Status |
|---|
| West China Hospital of Sichuan University |
Chengdu |
Sichuan |
Recruiting |
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