Thoracic Consolidation Radiotherapy for ES-SCLC Treated With Chemo-immunotherapy

A Phase I Dose Escalation Study of Thoracic Consolidation Radiotherapy for Extensive-stage Small Cell Lung Cancer Patients Treated With Chemo-immunotherapy

This study intends to recruit ES-SCLC patients with response to standard first-line chemo-immunotherapy to assess the safety of receiving different doses of consolidative thoracic radiotherapy.

Study Overview

• Status: Recruiting
• Conditions: Small Cell Lung Cancer Extensive Stage
• Intervention / Treatment: Radiation: thoracic radiotherapy

Detailed Description

Approximately two-thirds of Small-cell lung cancer (SCLC) patients are in the extensive stage (Extensive-Stage SCLC, ES-SCLC) at the time of diagnosis, and the 5-year survival rate of these patients is less than 5%. Before the immunotherapy era, the standard first-line treatment for ES-SCLC had been platinum-based chemotherapy regimens combined with etoposide.

Since treatment failure patterns revealed high probability of residual thoracic disease and high risk of progression of thoracic lesions after ES-SCLC chemotherapy, previous studies suggest that thoracic consolidation radiotherapy in ES-SCLC patients who are sensitive to first-line chemotherapy can reduce the risk of thoracic recurrence and improve overall survival time. Slotman et al. further conducted a phase III randomized controlled clinical study to explore the application of thoracic consolidation radiotherapy in ES-SCLC (CREST study). The CREST study results showed that in ES-SCLC patients who responded to chemotherapy and had residual thoracic lesions, thoracic residual lesion radiotherapy (30 Gy/1 0Fx) combined with prophylactic brain radiotherapy could reduce the risk of thoracic recurrence by 50% and increase the 2-year survival rate from 3% to 13%.

With the advent of the era of immunotherapy, the IMpower133 trial showed that the combination of atezolizumab and chemotherapy prolonged the median overall survival time of ES-SCLC patients compared with the chemotherapy alone group. In the CASPIAN study, the combination of dulvumab and chemotherapy also resulted in a survival benefit. The ASTRUM-005 study using PD-1 monoclonal antibody Serplulimab in combination with chemotherapy also achieved prolonged overall survival.

Although the overall median survival of ES-SCLC is prolonged after immunotherapy in combination with chemotherapy, patients who truly achieve long-term survival are still limited, with a 3-year OS rate of about 15% - 20%. Accordingly, it is necessary to explore effective methods to combine radiotherapy and maximize the benefit population of immunotherapy in ES-SCLC.

Failure pattern analysis revealed that, consistent with the era of non-immunotherapy, the main progression phenotype in patients receiving first-line chemotherapy + immunotherapy remained thoracic progression, suggesting that sequential thoracic consolidation radiotherapy is still likely to achieve clinical benefit in ES-SCLC patients receiving chemo-immunotherapy.

Immunotherapy combined with concurrent chemoradiotherapy has shown good safety and survival benefit in limited-stage SCLC. In non-small cell lung cancer (NSCLC), the safety of sequential immunotherapy after thoracic chemoradiotherapy has also been verified. However, there is a lack of prospective studies to investigate the safety of sequential thoracic consolidation radiotherapy after first-line immunochemotherapy in ES-SCLC patients.

At present, the widely used ES-SCLC thoracic consolidation radiotherapy regimen is based on the 30 Gy/1 0Fx dose fractionation of CREST study. At the same time, it has been shown that increasing the dose of single radiotherapy within a certain range helps to increase the production of immunogenic death by tumor cells, that is, more tumor-specific antigens that can be recognized by the immune system are produced during the induction of tumor cell death. Therefore, this study intends to perform a dose escalation study based on 30 Gy/10Fx dose fractionation and assess the safety of this treatment mode.

• Study Type: Interventional
• Enrollment (Estimated): 28
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Xiao Chu; Phone Number: 15821383376; Email: chuxiao@sibs.ac.cn
• Study Contact Backup: Name: Huang Chen

Study Locations

• China
  • Shanghai
    • Shanghai, Shanghai, China, 200030
      • Recruiting
      • Fudan University Shanghai Cancer Center
      • Contact: Zhengfei Zhu, MD; Phone Number: +8618017312901; Email: fuscczzf@163.com
      • Contact: Xiao Chu, MD; Email: chuxiao@sibs.ac.cn

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

Inclusion criteria:

1. age ≥ 18 years;
2. ECOG performance status score 0-2 points;
3. pathologically confirmed small cell lung cancer;
4. complete baseline imaging data (including brain enhanced MRI/CT, PET-CT or chest enhanced CT + bone scan + neck and abdominal B ultrasound/CT) before first-line treatment;
5. stage extensive-stage SCLC at initial diagnosis, and first-line treatment received standard platinum-based doublet chemotherapy combined with immunotherapy (PD-1 or PD-L1) for at least 4 cycles after the efficacy assessment of SD or PR (residual lesions assessed by chest CT);
6. no history of other malignancies;
7. reproductive age male/female agreed to contraception during the trial (surgical ligation or oral contraceptives/intrauterine devices + condom contraception);
8. life expectancy ≥ 3 months
9. 1 week before enrollment, the investigator judged that the patient could continue immune maintenance therapy at the same time, And the organ function level meets the following criteria:

1) bone marrow function: hemoglobin ≥ 80 g/L, white blood cell count ≥ 4.0 * 10 ^ 9/L or neutrophil count ≥ 1.5 * 10 ^ 9/L, platelet count ≥ 100 * 10 ^ 9/L; 2) liver: serum total bilirubin level ≤ 1.5 times the upper limit of normal, when serum total bilirubin level > 1.5 times the upper limit of normal direct bilirubin level must be ≤ the upper limit of normal,Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 times of the upper limit of normal; serum albumin ≥ 27 g/L; 3) Kidney: serum creatinine level < 1.5 times of the upper limit of normal or creatinine clearance ≥ 50 ml/min, urea nitrogen ≤ 200 mg/L; 10.Patients must have the ability to understand and voluntarily sign an informed consent form.

Exclusion Criteria:

1. baseline pathological examination found mixed with non-small cell lung cancer components;
2. patients who had used any anti-tumor therapy before the diagnosis of ES-SCLC;
3. patients who had received anti-tumor therapy other than standard chemotherapy + immunotherapy regimen;
4. patients who had PD assessed by chemotherapy combined with immunotherapy efficacy;
5. patients who had no residual thoracic lesions (lung, mediastinal and supraclavicular metastatic lymph nodes, thoracic efficacy CR) on chest enhanced CT during efficacy assessment;
6. patients with severe immune-related toxicities after treatment;
7. symptomatic interstitial lung disease or active infection/non-infectious pneumonia;
8. patients who required long-term use of cortisol or immunosuppressive agents;
9. allergic to PD-1 or PD-L1 monoclonal antibody immunotherapy or other causes of inability to perform immune maintenance therapy;
10. lactating or pregnant women;
11. patients with severe autoimmune diseases: active inflammatory bowel disease (including Crohn 's disease, ulcerative colitis), rheumatoid arthritis, scleroderma, systemic lupus erythematosus, autoimmune vasculitis (such as Wegener' s granulomatosis), etc.;
12. researchers believe that physical examination or clinical trials may interfere with the results or increase the risk of treatment complications, or other uncontrollable diseases;
13. patients with mental illness, substance abuse, social problems affecting compliance are not enrolled after the doctor 's review.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Starting Dose, Arm 1; For ES-SCLC patients who completed first-line four-cycle chemo-immunotherapy, and was evaluated to have any response to treatment. Thoracic radiotherapy is administered to treat residual thoracic lesions during immunotherapy maintenance phase. Thoracic radiotherapy should begin within 42 days after the end of the last chemotherapy at an initial dose of 30 Gy in 10 fractions (3 patients).	Radiation: thoracic radiotherapy; Thoracic radiotherapy should begin within 42 days after the end of the last chemotherapy at an initial dose of 30 Gy in 10 fractions (3 patients). Dose escalation will start after acceptable safety was observed, first at: 35 Gy/10 Fx(3 patients), then to the next dose group: 40 Gy/10 Fx(22 patients). Radiotherapy was administered between two immunotherapy doses (3 weeks interval) to avoid thoracic radiotherapy on the same day with immunotherapy.
Experimental: Dose escalation 1, Arm 2; Dose escalation will start after acceptable safety was observed, first at: 35 Gy/10 Fx (3 patients). Radiotherapy was administered between two immunotherapy doses (3 weeks interval) to avoid thoracic radiotherapy on the same day with immunotherapy. Immunotherapy was maintained until disease progression or the investigator 's judgment there was no further benefit from immunotherapy, patient died, intolerable toxicity developed. Toxicities were assessed periodically during the study. Local radiotherapy is permitted for symptomatic brain/bone metastases.	Radiation: thoracic radiotherapy; Thoracic radiotherapy should begin within 42 days after the end of the last chemotherapy at an initial dose of 30 Gy in 10 fractions (3 patients). Dose escalation will start after acceptable safety was observed, first at: 35 Gy/10 Fx(3 patients), then to the next dose group: 40 Gy/10 Fx(22 patients). Radiotherapy was administered between two immunotherapy doses (3 weeks interval) to avoid thoracic radiotherapy on the same day with immunotherapy.
Experimental: Dose escalation 2, Arm 3; Dose escalation will continue after acceptable safety was observed in the previous dose gourp, at: 40 Gy/10 Fx (22 patients). Radiotherapy was administered between two immunotherapy doses (3 weeks interval) to avoid thoracic radiotherapy on the same day with immunotherapy. Immunotherapy was maintained until disease progression or the investigator 's judgment there was no further benefit from immunotherapy, patient died, intolerable toxicity developed. Toxicities were assessed periodically during the study. Local radiotherapy is permitted for symptomatic brain/bone metastases.	Radiation: thoracic radiotherapy; Thoracic radiotherapy should begin within 42 days after the end of the last chemotherapy at an initial dose of 30 Gy in 10 fractions (3 patients). Dose escalation will start after acceptable safety was observed, first at: 35 Gy/10 Fx(3 patients), then to the next dose group: 40 Gy/10 Fx(22 patients). Radiotherapy was administered between two immunotherapy doses (3 weeks interval) to avoid thoracic radiotherapy on the same day with immunotherapy.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of treatment-related dose-limiting toxicities (DLTs)	The proportion of the number of cases with DLTs associated with the study design treatment to the total evaluable number of cases was assessed according to CTCAE 5.0 criteria. Definition of dose-limiting toxicities (DLTs): Grade 3 or higher non-hematological/laboratory abnormalities reported events that may or definitely be associated with the combination of immunotherapy and thoracic consolidation radiotherapy as judged by the investigator, or Grade 4 or higher hematological/laboratory abnormalities reported.	90 days after the start of thoracic consolidation radiotherapy in enrolled patients

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of all dose limiting toxicities (DLTs):	Incidence of all dose limiting toxicities (DLTs): The proportion of cases with DLTs (whether judged treatment-related or not) as assessed by CTCAE 5.0 criteria compared with the total evaluable cases	90 days after the start of thoracic consolidation radiotherapy in enrolled patients

Collaborators and Investigators

• Sponsor: Fudan University

Study record dates

Study Major Dates

• Study Start (Actual): December 1, 2023
• Primary Completion (Estimated): June 30, 2025
• Study Completion (Estimated): December 31, 2025

Study Registration Dates

• First Submitted: December 17, 2023
• First Submitted That Met QC Criteria: December 17, 2023
• First Posted (Actual): January 3, 2024

Study Record Updates

• Last Update Posted (Actual): January 9, 2024
• Last Update Submitted That Met QC Criteria: January 6, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: chemotherapy; immunotherapy; small cell lung cancer; thoracic radiotherapy
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms; Lung Diseases; Neoplasms by Site; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Small Cell Lung Carcinoma
• Other Study ID Numbers: ES-SCLC-TRT

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No