Clinical trial NCT06187740: Thoracic Consolidation Radiotherapy for ES-SCLC Treated With Chemo-immunotherapy
Official title: A Phase I Dose Escalation Study of Thoracic Consolidation Radiotherapy for Extensive-stage Small Cell Lung Cancer Patients Treated With Chemo-immunotherapy
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
Conditions: Small Cell Lung Cancer Extensive Stage
Keywords: small cell lung cancer
chemotherapy
immunotherapy
thoracic radiotherapy
Lead sponsor: Fudan University
Sponsor class: OTHER
First posted: 2024-01-03
Enrollment: 28
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: Initial dose of 30 Gy in 10 fractions (3 patients, Arm 1). Dose escalation will start after acceptable safety was observed, 35 Gy/10Fx (3 patients, Arm 2), 40 Gy/10Fx (22 patients, Arm 3).
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Incidence of treatment-related dose-limiting toxicities (DLTs)
timeFrame: 90 days after the start of thoracic consolidation radiotherapy in enrolled patients
Secondary outcomes:
measure: Incidence of all dose limiting toxicities (DLTs):
timeFrame: 90 days after the start of thoracic consolidation radiotherapy in enrolled patients
Other outcomes:
Locations:
city: Shanghai
country: China
facility: Fudan University Shanghai Cancer Center
state: Shanghai
Study officials:
References: