Chemo-immunotherapy Plus Thoracic Radiotherapy in Extensive Stage Small-cell Lung Cancer

Study Overview
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Brief Summary
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Studies have shown that combining chemotherapy and immune checkpoint inhibitors (ICI) prolongs survival compared with chemotherapy alone in extensive stage small-cell lung cancer (ES SCLC), but the survival benefit is modest. The main aim of this trial is to investigate whether there is a synergistic/additive effect of concurrent thoracic radiotherapy in ES SCLC patients receiving carboplatin/etoposide/durvalumab.

Detailed Description
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Studies show that adding ICI therapy to standard chemotherapy prolongs survival in ES SCLC. The survival benefit, however, is modest, and there is a need for more effective therapy. It has been hypothesized that there is a synergistic effect of combining ICI with radiotherapy. In this randomized phase III study, the main aim is to investigate whether concurrent thoracic radiotherapy of 30 Gy/10 fractions improves survival in ES SCLC patients receiving carboplatin/etoposide/durvalumab. It is currently not possible to classify the patients who benefit from ICIs in SCLC. In this study, biological material (tissue, blood, feces) which will be analyzed for potential predictive and prognostic biomarkers. Prophylactic cranial irradiation in ES SCLC is debated, mainly due to the potentially detrimental effect on cognition. Thus, frequency and timing of brain metastases and cognitive function will be assessed before, during and after study treatment.

Official Title
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Randomized Phase III Trial Investigating the Survival Benefit of Adding Thoracic Radiotherapy to Durvalumab (MEDI4736) Immunotherapy Plus Chemotherapy in Extensive Stage Small-cell Lung Cancer

Conditions
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Small-cell Lung Cancer

Intervention / Treatment
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* Procedure: Thoracic radiotherapy
* Drug: Chemo-immunotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age > 18 years at time of study entry ECOG performance status of 0 or 1 Body weight >30 kg Adequate bone marrow, liver and kidney function Life expectancy of at least 3 months At least one measurable (RECIST 1.1), thoracic lesion that can be irradiated with 30 Gy/10 fractions Histologically or cytologically confirmed SCLC Stage III-IV disease (TNM v8) FEV1 >1 L or >30 % of predicted value and DLCO >30 % of predicted value Patients with brain metastases are eligible provided they are asymptomatic or treated and stable on steroids and/or anticonvulsants prior to the start of treatment Exclusion Criteria: Previous chemo-, immuno- or radiotherapy for SCLC Major surgical procedure last 28 days History of allogenic organ transplantation, autoimmune disease, immunodeficiency, hepatitis or HIV Uncontrolled intercurrent illness Other active malignancy Leptomeningeal carcinomatosis Immunosuppressive medication Pregnant or breastfeeding women

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Chemo-immunotherapy plus thoracic radiotherapy<br>Four courses of carboplatin/etoposide/durvalumab every 3 weeks followed by durvalumab every 4 weeks until intolerable toxicity, progressive disease leading to a need for other treatment, or until the patient no longer wishes to continue treatment. Thoracic radiotherapy of 30 Gy/10 fractions between 2nd and 3rd carboplatin/etoposide/durvalumab course. | Procedure: Thoracic radiotherapy<br>* 30Gy/10 fractions thoracic radiotherapy given between 2nd and 3rd course of chemo-immunotherapy.<br>Drug: Chemo-immunotherapy<br>* Four courses of carboplatin/etoposide/durvalumab every 3 weeks followed by durvalumab every 4 weeks until intolerable toxicity, progressive disease leading to a need for other treatment, or until the patient no longer wishes to continue treatment.<br>* Other names: carboplatin/etoposide/durvalumab;|
| Active Comparator: Chemo-immunotherapy<br>Four courses of carboplatin/etoposide/durvalumab every 3 weeks followed by durvalumab every 4 weeks until intolerable toxicity, progressive disease leading to a need for other treatment, or until the patient no longer wishes to continue treatment. | Drug: Chemo-immunotherapy<br>* Four courses of carboplatin/etoposide/durvalumab every 3 weeks followed by durvalumab every 4 weeks until intolerable toxicity, progressive disease leading to a need for other treatment, or until the patient no longer wishes to continue treatment.<br>* Other names: carboplatin/etoposide/durvalumab;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in 1-year overall survival | The Cox proportional hazards method will be used to compare survival between the treatment groups. | 14 months after last patient entry | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in 2-, 3-, 4- and 5-year survival rate | The Cox proportional hazards method will be used to compare survival between the treatment groups. | 2, 3, 4 and 5 years after last patient entry | 
| Frequency and severity of adverse events | Adverse events will be compared between the treatment arms using the Pearson's Chi-square and Fisher's exact test. | Through study completion, an average of 1 year after last patient entry | 
| Change in progression free survival (PFS) | PFS will be estimated using the Kaplan-Meier method and compared using the log-rank test. A Cox-model adjusting for baseline characteristics will be used for multivariable analyses. | Through study completion, an average of 1 year after last patient entry | 
| Change in overall response rates | Response rates are compared using Pearson's Chi-square test. | Through study completion, an average of 1 year after last patient entry | 
| Change in response rates in non-irradiated lesions | Response rates are compared using Pearson's Chi-square test. | Through study completion, an average of 1 year after last patient entry | 
| Local control rates in the thorax | Local control rates are compared using Pearson's Chi-square test. | Through study completion, an average of 1 year after last patient entry | 
| Health-related quality of life (HRQoL) | All HRQoL scores will be transformed to a scale of 0-100 according to the EORTC QLQ scoring manual. Mean scores will be compared at each assessment timepoint, and a difference of 10 points is considered clinically relevant. | Through study completion, an average of 1 year after last patient entry | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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cancer, chemotherapy, radiotherapy, immunotherapy