Efficacy and Safety of PRaG Therapy in Elderly Patients with Advanced Malignant Tumors: A Prospective,Multicenter Clinical Study Protocol (PRaG 9.0 Study)

Abstract

Background: Current evidence from evidence-based medicine is limited regarding the efficacy and safety of immunotherapy in elderly patients aged 75 years and older with malignant solid tumors. PRaG therapy, which combines PD-1/PD-L1 inhibitors, radiotherapy, and granulocyte-macrophage colony-stimulating factor (GM-CSF), aims to treat patients with advanced, refractory tumors. Preliminary findings indicate that patients aged 75 years and older can benefit from this treatment and can tolerate it well. Objective: This study aims to evaluate the efficacy and safety of the PRaG regimen in elderly patients with advanced malignant solid tumors to provide evidence-based support for immunotherapy in this population. Methods and Analysis: This study involves a multicenter, prospective, single-arm phase II clinical trial designed to enroll 29 patients aged 75 years and older with either newly diagnosed or recurrent metastatic advanced solid tumors that are histologically confirmed. All of the eligible patients will have had to receive at least two cycles of PRaG therapy until disease progression or intolerable adverse effects occurred. The study protocol was approved on September 12, 2023, by the Ethics Committee of the Second Affiliated Hospital of Soochow University (JD-LK-2023-082-I01) and by the ethics committees of all of the participating centers (Trial Registration Number: NCT06112041).

Keywords

the PRaG therapy elderly cancer patients GM-CSF thymopentin radiation therapy immunotherapy

Introduction

In current evidence-based medical practices for solid tumors, the primary evidence is derived from randomized controlled trials (RCTs), which often exclude individuals aged 75 years and older. However, PD-1/PD-L1 inhibitors and other immunotherapy drugs are already being used in clinical practice for patients in this age group, despite the lack of robust scientific evidence to support these treatment strategies. To supplement evidence-based data on the treatment of solid tumors in elderly patients, our center plans to conduct a prospective clinical study to evaluate the efficacy and safety of the PRaG therapy regimen in patients aged 75 years and older with advanced solid tumors.

PRaG treatment involves a series of clinical studies that were conducted at our center (ChiCTR1900026175, NCT04892498, NCT05115500, NCT05435768, NCT06047860, NCT05501340, NCT05790447, NCT05603013, and NCT05530200), and they demonstrated preliminary efficacy in the salvage treatment of advanced refractory tumors.¹ Our center has obtained preliminary results using the PRaG regimen in the treatment of various refractory advanced tumors, including esophageal cancer,² gastric cancer,³ colorectal cancer,⁴ pancreatic cancer,⁵ lung cancer,⁶ and breast cancer.⁷ In addition, published studies have shown that the PRaG regimen has demonstrated efficacy in treating difficult-to-treat malignancies such as refractory gastric cancer,⁸ ovarian cancer,⁹ uterine leiomyosarcoma,¹⁰ malignant perivascular epithelioid cell tumors,¹¹ and thyroid cancer.¹² Thousands of patients have received the PRaG therapy and has been implemented in more than 100 hospitals in China. This technology has been selected as a health promotion technology by the National Health Commission of China (RKJS-20240234), providing an optional treatment for patients with advanced refractory tumors.

Data from the PRaG 1.0 study indicate that, among patients with advanced refractory tumors receiving later-line treatment, the objective response rate (ORR) was 16.7% (9/54), with 5.6% (3/54) of patients achieving complete response (CR).¹ Among the three patients who achieved CR, one died 32 months after PRaG treatment, whereas the remaining two patients were still in complete remission, with overall survival (OS) exceeding 4 years posttreatment.

We conducted a retrospective analysis of elderly patients aged ≥75 years who received PRaG treatment, including 25 males and 11 females, with ages ranging from 75–85 years and a median age of 76 years. Among these patients, 34 completed at least one efficacy assessment, thus resulting in an objective response rate (ORR) of 22.3% and a disease control rate (DCR) of 66.7%. The median follow-up time was 46.3 months, with a median progression-free survival (PFS) of 7.0 months (95% CI: 2.4-11.6 months) and a median overall survival (OS) of 11.1 months (95% CI: 5.3-16.9 months). Among the 36 patients, 34 (94.4%) experienced treatment-related adverse events (TRAEs) of any grade. This retrospective analysis indicated that PRaG therapy was well-tolerated in elderly patients with advanced metastatic solid tumors, with manageable toxicity, thus suggesting that PRaG therapy is a viable treatment option for elderly patients.

The PRaG therapy 3.0 study (NCT05115500) conducted by our center, which targets HER2-positive advanced solid tumor patients, uses disitamab vedotin (RC48) combined with radiotherapy, immunotherapy, and GM-CSF. RC48 is an anti-HER-2 antibody-drug conjugate that can exert specific cytotoxic effects on HER-2-positive tumor cells. At the 2025 ASTRO Annual Meeting, preliminary results of the study were reported. Among 52 patients with HER-2-positive advanced tumors who were effectively enrolled, the ORR was 36.5%, and the mPFS was 5.9 months (95% CI: 4.1-6.7 months). The mOS was 14.3 months (95% CI: 8.6-15.7 months). These findings suggest that the combination of disitamab vedotin may further increase the efficacy of PRaG treatment in HER-2-positive patients.¹³ Therefore, RC48 is also added to the treatment regimen for HER2-positive elderly patients in this study, expecting to further improve the treatment effect of elderly tumor patients.

The primary mechanism of PRaG therapy involves activation of the body's antitumor immune response through radiation therapy. However, in elderly patients, immune function decreases with age, thus leading to lower numbers and proportions of naïve T cells in the peripheral blood than in younger individuals.¹⁴ This reduction may be attributed to the conversion of naïve T cells into memory cells following exposure to pathogens, including self-antigens and tumor antigens. Thymopentin (TP5) is a pentapeptide that is synthesized from a 49-amino acid thymic hormone active fragment consisting of arginine, lysine, aspartic acid, valine, and tyrosine.¹⁵ TP5 can modulate excessively strong or suppressed immune responses toward a normal range. It also has beneficial regulatory effects on impaired immune function and autoimmune diseases, thereby achieving bidirectional regulation of the entire immune system.¹⁶ As a promising immunoadjuvant, thymopentin can be utilized in the treatment of malignant tumors to enhance overall immune function.¹⁷

In summary, we will implement a precision PRaG therapy regimen for patients aged ≥75 years with advanced solid tumors by incorporating or excluding disitamab vedotin in combination with PRaG therapy (radiotherapy, PD-L1 inhibitors, and GM-CSF) and thymopentin. The aim of this study is to assess the efficacy and safety of this approach, thereby offering a new treatment option for this older patient population.

Methods and Analysis

Objective

The primary objective of this study is to explore the efficacy of PRaG therapy in elderly patients with advanced malignant solid tumors. The secondary objectives are to evaluate the safety of the treatment, the changes in patients’ quality of life during the treatment period, and to conduct exploratory research on the correlation between the absolute counts of lymphocyte subsets and cytokines and treatment efficacy. In addition, this study will explore the regulatory effect of thymopentin on the immune function of elderly patients by detecting the absolute counts and fine typing indices of peripheral blood lymphocyte subsets before and after thymopentin use.

Study Design

This is a multicenter, prospective, single-arm clinical study that began on October 1, 2023 and is expected to conclude on September 31, 2025. The study design is illustrated in Figures 1 and 2. The study has been registered on ClinicalTrials.gov with the registration number NCT06112041. Detailed information can be found on the ClinicalTrials.gov website. And the reporting of this study conforms to SPIRIT guidelines (SPIRIT2013).¹⁸ All patients who received treatment signed written informed consent forms.

Figure 1.

PRaG 9.0 Therapy Protocol for HER2-Negative Patients.

Figure 2.

PRaG 9.0 Therapy Protocol for HER2-Positive Patients (IHC1+, 2+, or 3+).

HER2 assessment was performed using the immunohistochemistry (IHC) assay. Scoring strictly adhered to the 0/1+/2+/3 + scale defined in the guidelines. For IHC 2 + cases, reflex in situ hybridization (ISH) was performed to confirm HER2 amplification status.

For patients with HER2-negative immunohistochemistry, at one week prior to the first treatment, a loading dose of thymopentin (50 mg/day) is administered via subcutaneous injection for 7 consecutive days, followed by radiotherapy. During the two weeks following the start of radiotherapy, thymopentin is administered at a maintenance dose of 20 mg/day three times a week. During the third week of treatment, thymopentin is administered again at a loading dose of 50 mg/day for 7 consecutive days. This treatment cycle is repeated every 21 days.

For patients with HER2-positive immunohistochemistry (IHC 1+, 2+, or 3+), the first treatment begins with a loading dose of thymopentin (50 mg/day) for 7 consecutive days, followed by treatment with disitamab vedotin (2 mg/kg). Radiotherapy is initiated the day after disitamab vedotin administration. During the two weeks following the start of radiotherapy, thymopentin is administered at a maintenance dose of 20 mg/day three times a week. During the third week of treatment, thymopentin is again administered at a loading dose of 50 mg/day for 7 consecutive days. This treatment cycle is also repeated every 21 days.

The selection of radiation therapy sites is based on the location of primary or metastatic lesions that have not been previously irradiated and that have minimal impact on surrounding normal tissues. The radiation therapy (RT) dosage ranges from 5–8 Gy per session (2-3 fractions), with one session being conducted per day. GM-CSF (200 μg/day) is subcutaneously administered starting on the day of radiation therapy for 5 consecutive days. Within one week after radiation therapy, a PD-L1 inhibitor is administered.

Patients will have received at least two cycles of PRaG therapy until no suitable lesion was available for irradiation or until the tolerance limit of normal tissue to radiation was reached. Afterward, patients will continue maintenance treatment with PD-L1 inhibitors (adebrelimab), GM-CSF, and thymopentin until disease progression or the occurrence of intolerable adverse reactions.

Gross Tumor Volume (GTV): The visible tumor identified through imaging and clinical examinations, including physical examination, fiberoptic colonoscopy, ultrasound, computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography (PET). Internal Target Volume (ITV): The tumor lesion with consideration of respiratory motion or organ displacement. Planning Target Volume (PTV): Gross Tumor Volume/Internal Target Volume plus setup errors. Dose limits were set per AAPM Task Group 101. Re-irradiation rules: Patients with prior radiotherapy were included only if the cumulative dose to OARs did not exceed lifetime limits.

Inclusion Criteria

Age ≥ 75 years.

Patients with newly diagnosed or recurrent metastatic advanced solid malignant tumors with a confirmed pathological diagnosis or medical history. Patients with no standard treatment recommendations according to guidelines, those intolerant to standard treatment, or those who refuse standard treatment due to personal preference. Patients must have measurable metastatic lesions (>1 cm).

No history of congestive heart failure, unstable angina, or unstable arrhythmia in the past 6 months.

An Eastern Cooperative Oncology Group (ECOG) performance status score ranging from 0–3, with an expected survival of ≥3 months.

No previous history of severe hematologic disorders; no previous history of cardiac, pulmonary, hepatic, or renal dysfunction; or no previous history of immune deficiency.

Within one week prior to enrollment, AST and ALT levels of ≤3.0 times the upper limit of normal (ULN) or ≤5.0 times the ULN for liver cancer/metastatic liver cancer; creatinine level of ≤3.0 times the ULN.

Patients able to understand and voluntarily sign the informed consent form.

Exclusion Criteria

History of other malignancies within the past 5 years, except for cured skin cancer or cervical carcinoma in situ.

Uncontrolled epilepsy, central nervous system diseases, or mental disorders that (in the investigator's judgment) could impede the ability to sign informed consent or affect adherence to drug therapy.

Severe (ie, active) heart disease, such as symptomatic coronary artery disease, New York Heart Association (NYHA) class II or higher congestive heart failure, severe arrhythmia requiring medication intervention, or a history of myocardial infarction within the past 12 months.

Patients who require immunosuppressive therapy due to organ transplantation.

Known active infections or significant hematologic, renal, metabolic, gastrointestinal, endocrine, or other severe uncontrolled comorbidities that the investigator believes would impede the study.

Known allergies to any component of the study drugs.

A history of immune deficiency, including positive HIV status; other acquired or congenital immunodeficiency disorders; or a history of organ transplantation. Patients with other immune-related diseases requiring long-term oral corticosteroids were also excluded.

Currently experiencing acute or chronic tuberculosis infection (positive T-spot test or suspicious tuberculosis lesion on chest x-ray).

Any other condition deemed unsuitable for participation by the investigator.

Withdrawal Criteria

Patients showing disease progression on medical imaging who (according to the investigator's judgment) would no longer benefit from continued treatment.

Patients who are unable to tolerate the toxicity of the drugs despite dose adjustments or treatment interruptions.

Patients who withdraw their informed consent and request to leave the study.

Other situations deemed to be necessary for withdrawal by the investigator.

Study Endpoints

Primary Endpoint

The primary endpoint of this study is the objective response rate (ORR). Clinical tumor imaging assessments will be conducted according to the RECIST 1.1 criteria during treatment.

Secondary Endpoints

The secondary endpoints include the disease control rate (DCR), progression-free survival (PFS), overall survival (OS), incidence of treatment-related adverse events (TRAEs), and quality of life scores during treatment. Quality of life assessments were conducted for all patients before each treatment cycle (EORTCQLQ-C30). To comprehensively assess geriatric-specific factors beyond ECOG performance status, the Geriatric Nutritional Risk Index (GNRI) was incorporated to evaluate nutritional frailty—a key determinant of treatment tolerance and outcomes in the elderly. Imaging assessments will be performed every six weeks from the first administration, and peripheral blood samples will be collected before each treatment cycle for subsequent translational research.

Sample Size Calculation

This is a phase II single-arm clinical study using Simon's two-stage optimal design. The primary endpoint is the ORR, and the secondary endpoints are the DCR, PFS, OS, and toxicity. The null hypothesis (H0) assumes that the treatment ORR is ≤0.05, whereas the alternative hypothesis (H1) assumes that the ORR is ≥0.2. With a one-sided α = 0.05 and β = 0.2, the calculated total sample size was 29 patients. Ten patients were enrolled in stage 1, at least 1 patient in stage 1 was enrolled in stage 2 if the treatment was effective, and 19 patients were enrolled in stage 2. If the total number of effective cases is greater than or equal to 4 after the completion of the second stage, the experimental group is considered to be effective. If no patient is assessed as responding to treatment in Phase 1, the study will be terminated.

Statistical Analysis

The data will be analyzed via SPSS 26.0 statistical software. The Shapiro-Wilk test will be used to assess the normal distribution of the residuals, with a significance level of α > 0.05 indicating normality. Data that follow a normal distribution will be analyzed via randomized block variance analysis. For nonnormally distributed data, the randomized block design rank-sum test will be employed, with a significance level of α < 0.05.

Kaplan-Meier analysis will be used to assess patient survival times. In addition, Cox regression analysis will be performed to identify factors influencing survival rates based on survival time.

Planned Timeline

The study was initiated in October 2023. Patient enrollment is projected to continue for two years, followed by an additional six-month period for data collection and follow-up completion. Data processing, analysis, and manuscript preparation are estimated to take another six months.

Discussion

With the deepening of population aging, the number of elderly patients with malignant tumors continues to rise. Although significant progress has been made in cancer treatment over the past decade, age remains the main obstacle hindering elderly patients from participating in clinical trials.¹⁹ Therefore, the optimal treatment regimen for elderly patients with tumors remains unclear. Moreover, elderly tumor patients generally have weaker tolerance to chemotherapy,²⁰ a phenomenon that may directly lead to a decrease in the proportion of this population receiving guideline-recommended treatment regimens.

In recent years, tumor immune checkpoint inhibitors (ICIs) have been proven to be effective drugs for the treatment of various types of malignant tumors.²¹ In clinical practice, patients with solid tumors over 75 years old are also using ICIs, but this treatment strategy lacks sufficient scientific basis. The preliminary results of the series of clinical studies on PRaG therapy conducted by our center show that favorable efficacy has been achieved in advanced refractory tumors and has been implemented in more than 100 hospitals in China. Thousands of patients have received the PRaG therapy, and this technology has been selected as a health promotion technology by the National Health Commission of China (RKJS-20240234), providing an optional treatment for patients with advanced refractory tumors.

The World Health Organization (WHO) defines individuals aged 60 and above as elderly. In subgroup analyses of clinical trials including immunotherapy, 65 years old is typically set as the age threshold. Currently, the upper age limit for participants in the vast majority of clinical trials is 75 years old. Previous research findings indicate that relying solely on chronological age and performance status scores cannot fully reflect the physical condition of elderly tumor patients. Comprehensive assessments incorporating physical function, comorbidities, cognition, medication use, nutrition, psychological status, and social support may be more effective in screening potential populations that benefit from antitumor therapy.²²

The elderly have the characteristic of immunosenescence, which is the dysfunction and decline of the immune system associated with age. With increasing age, the differentiation ability of hematopoietic stem cells (HSCs) in the bone marrow weakens, leading to the differentiation into dysfunctional immune cells. The thymus gradually atrophies, resulting in reduced ability to generate T cells.^23,24 Secondly, changes also occur in immune cell subsets. Innate immune cells such as dendritic cells (DCs) show downregulated expression of MHC-II molecules, weakened co-stimulatory molecule (such as CD80/CD86) signals, reduced antigen uptake, and decreased ability to process and present antigens.²⁵ Macrophages tend to transform into the M2 phenotype, secreting immunosuppressive factors. The number of natural killer (NK) cells increases, but the proportion of CD56bright NK cells decreases, leading to a decline in their immune surveillance function.²⁶

T lymphocytes play a central role in cellular immunity. With increasing age, the number of naïve T cells continues to decrease, and they are continuously transformed into memory T cells following the body's immune response. Due to the gradual reduction of co-stimulatory factors CD28 and CD27 in CD8 + memory T cells accumulated in the elderly, the diversity of T cell receptors (TCRs) is lost.²⁷ A remarkable feature of the elderly is that the number and proportion of naïve CD8+ T cells in their peripheral blood are significantly lower than those in young people, while the proportion of naïve CD4+ T cells is slightly lower than that in young people.¹⁴ Furthermore, immunosenescence leads to the accumulation of inflammation and pro-inflammatory factors. Senescent cells can produce senescence-associated secretory phenotype (SASP) such as angiogenic factors, chemokines, and cytokines, thereby forming inflammaging and reducing the efficiency of immune responses.²⁷

Thymopentin, an immunomodulator, is added to the study protocol. Thymopentin is a synthetic thymic hormone derivative that has shown good clinical efficacy and safety in various diseases, including malignant tumors such as lung cancer, colon cancer, and melanoma, infectious diseases, and tuberculosis.¹⁵ It retains the biological activity of thymopoietin II, which can normalize excessive or suppressed immune responses. Meanwhile, it has a good regulatory effect on immune dysfunction and autoimmune diseases, achieving bidirectional regulation of the entire body's immune system.¹⁶ It reduces the adverse reactions of chemotherapy and radiotherapy by improving the immune status of the tumor microenvironment.²⁸ The use of thymopentin in adjuvant therapy for lung cancer significantly increases the levels of CD3 + cells and the CD4+/CD8 + ratio in peripheral blood, promoting the body's anti-tumor immune response.²⁹ This study will explore the regulatory effect of thymopentin on the immune function of elderly patients by detecting the absolute counts and fine typing indices of peripheral blood lymphocyte subsets before and after thymopentin use, including naïve T cells, activated effector memory T cells, and activated central memory T cells.

Disitamab vedotin (RC48) is a novel HER2-targeted antibody-drug conjugate (ADC) composed of hertuzumab conjugated to monomethyl auristatin E (MMAE) via a cleavable linker. This drug can specifically be phagocytosed by HER2-expressing tumor cells after entering the body, followed by intracellular cleavage to produce tumor-killing effects, and can further generate bystander effects, causing more tumor cell necrosis and antigen exposure.³⁰ RC48 has now shown good clinical effects in patients with GC, UC, and HER2-low expressing BC.^31,32 It has extremely strong cytotoxicity at extremely low concentrations and has lower toxic reactions compared to traditional chemotherapy drugs. The PRaG therapy 3.0 study (NCT05115500) conducted by our center, which targets HER2-positive advanced solid tumor patients, uses RC48 combined with radiotherapy, immunotherapy, and GM-CSF. Preliminary results show that it can significantly improve the clinical efficacy of such patients.¹³ Therefore, RC48 is also added to the treatment regimen for HER2-positive elderly patients in this study, expecting to further improve the treatment effect of elderly tumor patients.

Conclusion

This study will enroll patients with advanced solid tumors aged ≥75 years to observe the efficacy and safety of PRaG therapy in this population, aiming to provide new treatment options for elderly patients and conduct an exploratory analysis of the correlation between lymphocytes, cytokines, and therapeutic efficacy.

Author Note

Mengmeng Yang are now affiliated with People's Hospital of Ningxia Hui Autonomous Region, Ningxia Medical University, Ningxia, China.

Footnotes

Acknowledgements

The authors thank the patients and their families as well as the investigators, co-investigators, and the study teams at each of the participating.

ORCID iD

Liyuan Zhang

Ethics Approval and Consent to Participate

This study received approval from the Research Ethics Committee of the Second Affiliated Hospital of Soochow University (Approval Number: JD-LK2023082-I01; Approval time: November 21, 2023), Jiangxi Provincial People's Hospital (Approval Number: 2024-041 IIT FS, Approval time: April 2, 2024), Suzhou Ninth People's Hospital (Approval Number: KY2024-003-01; Approval time: March 7, 2024) and Zhangjiagang First People's Hospital (Approval Number: ZJGYYLL-2024-01-002; Approval time: February 21, 2024). We will conduct this study in accordance with the principles outlined in the Declaration of Helsinki. Informed consent will be obtained from all of the participants and/or their legal guardian(s).

Author Contribution Statement

Xiangrong Zhao, Junjun Zhang and Mengmeng Yang contributed to the conception of the study and played a major role in writing the manuscript. Rongzheng Chen and Sumeng Wang designed the statistical analyses. Yuehong Kong, Meiling Xu and Qian Yin designed the framework of assessment. Guangqiang Chen was responsible for imaging diagnosis and efficacy evaluation. Pengfei Xing and Liyuan Zhang were responsible for the project design and guidance of the thesis write and revise. All authors have read and approved the final manuscript.

Funding

This work was supported by the National Natural Science Foundation of China (82171828, 82573449), Suzhou Major Disease Multicenter Clinical Research Project (DZXYJ202304), Suzhou Health Talents Program (GSWS2022028), and the Project of State Key Laboratory of Radiation Medicine and Protection (GZN1202302).

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

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