Fraction Dose Escalation of Hypo-fractionated Radiotherapy in LANSCLC

Study Overview
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Brief Summary
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This Phase 1 trial aimed to determine the maximum tolerated fraction dose (MTD) of hypofractionated radiotherapy (hypo-RT) combined with concurrent chemotherapy and subsequent consolidation immune checkpoint inhibitors (cICI) for patients with locally advanced non-small cell lung cancer (LA-NSCLC).

Official Title
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Fraction Dose Escalation of Hypofractionated Radiotherapy With Concurrent Chemotherapy and Subsequent Consolidation Immunotherapy in Locally Advanced Non-small Cell Lung Cancer: a Phase 1 Study

Conditions
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Locally Advanced Lung Carcinoma

Intervention / Treatment
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* Radiation: Hypofractionated radiotherapy
* Drug: Concurrent chemotherapy
* Drug: Consolidation immunotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Non-small cell lung cancer confirmed by histology. Tumor size is measured according to RECIST standard. Unresectable stage IIIA (N2) and IIIB/IIIC, confirmed by PET-CT/or chest and abdomen CT, brain MRI, and whole body bone scan. 18-75 years old, regardless of gender. The ECOG score is 0-1. Newly treated or underwent neoadjuvant chemotherapy and/or immunotherapy. Have not received chest radiotherapy in the past. Serum hemoglobin ≥10 mg/dL, platelets ≥100000/μL, absolute neutrophil count ≥1500/μL. Serum creatinine ≤1.25 times UNL or creatinine clearance ≥60 ml/min. Serum bilirubin ≤1.5 times UNL, AST (SGOT) and ALT (SGPT) ≤2.5 times UNL, alkaline phosphatase≤ 5 times UNL. FEV1>1 L. CB6 normal range. The patient and his family members agree and sign an informed consent form. Exclusion Criteria: Other malignant tumors in the past or during treatment, except for non-melanoma of the skin or carcinoma in situ of the cervix. Any other diseases or conditions are contraindications to chemotherapy (such as active infection, within 6 months after myocardial infarction, symptomatic heart disease, including unstable angina, congestive heart failure or uncontrolled arrhythmia, immunosuppressive therapy). Pregnant or breastfeeding women, women who have not undergone a pregnancy test (within 14 days before the first dose), and pregnant women. Those who are pregnant, breastfeeding or have fertility but have not taken contraceptive measures. People with bleeding tendency. Those who participated in other clinical trials within 30 days before participating in this experiment. Drug addiction, long-term alcoholism, and AIDS patients. People with uncontrollable seizures or loss of self-control due to mental illness. People with a history of severe allergies or specific physique. The researcher believes that the patient is inappropriate to participate in this trial. Exit criteria The treatment cannot be carried out in accordance with the requirements of the research protocol; The patient has an allergic reaction ≥ grade 4 or a serious adverse reaction to the study drug; The patient is pregnant or has not used adequate contraceptive measures; The researcher judges that the patient should not continue to participate the clinical trial; The subject asked to withdraw.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Split-course adaptive HRT-CHT<br>In keeping the same total radiation dose (60Gy), we escalate the fraction dose to find the maximum tolerable fraction dose. Level 1: DT 4500cGy/15 daily fractions/300cGy in the first course，DT 1500cGy/5 daily fractions/300cGy in the second course; Level 2: DT 4000cGy/10 daily fractions/400cGy in the first course， DT 2000cGy/5 daily fractions/400cGy in the second course; Level 3: DT 3000cGy/6 daily fractions/500cGy in the first course， DT 3000cGy/6 daily fractions/500cGy in the second course. RT is delivered using the IMRT technique with daily cone-beam CT image guidance. The dose limitation of organ at risk (OAR) are shown in Table 1. Patients receive a weekly infusion of docetaxel (25mg/m2) and cisplatin (25mg/m2) during RT. Consolidative immunotherapy (PD-1 or PD-L1 inhibitor) up to 1 year is administered for those without disease progression after HRT-CHT. | Radiation: Hypofractionated radiotherapy<br>* Split-course adaptive HRT-CHT is administered at the following three dose levels: Level 1: DT 4500cGy/15 daily fractions/300cGy in the first course，DT 1500cGy/5 daily fractions/300cGy in the second course; Level 2: DT 4000cGy/10 daily fractions/400cGy in the first course， DT 2000cGy/5 daily fractions/400cGy in the second course; Level 3: DT 3000cGy/6 daily fractions/500cGy in the first course， DT 3000cGy/6 daily fractions/500cGy in the second course.<br>Drug: Concurrent chemotherapy<br>* weekly infusion of docetaxel (25mg/m2) and cisplatin (25mg/m2) during RT<br>Drug: Consolidation immunotherapy<br>* Consolidative immunotherapy (PD-1 or PD-L1 inhibitor) up to 1 year is administered for those without disease progression after HRT-CHT.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| the maximally tolerated fraction dose | The maximum tolerated fraction dose was defined as the highest DL in which <=2 patients of the 6 treated patients experienced G3+ toxicity and <=1 patient experienced G4+ toxicity within 12 months after RT. If a patient had multiple types of toxicities, only the highest grade of toxicity was counted. | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective response rate | Proportion of patients with PR and CR at 2 months after radiotherapy | 2 months after radiotherapy | 
| Overall survival |  | 1-year | 
| Progression-free survival |  | 1-year | 
| Distant-metastasis free survival |  | 1-year | 
| Loco-regional recurrence-free survival |  | 1-year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Locally advanced non-small cell lung cancer, Definitive hypofractionated chemoradiotherapy, Fraction dose escalation, Consolidation immunotherapy