Safety and Tolerability of Low Dose Radiotherapy Concurrent SBRT and PD-1 Inhibitors in Advanced NSCLC.

Study Overview
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Brief Summary
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This pilot phase I trial aims to investigate the safety and tolerability of low dose radiotherapy (LDRT) and concurrent partial stereotactic body radiation therapy (SBRT) in combination with programmed cell death-1 (PD-1) inhibitors in Stage IV non-small cell lung cancer (NSCLC) patients who have failed standard therapy. At least 14 participants will be enrolled in this study. All will take part at West China Hospital, Sichuan University.

Detailed Description
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This exploratory phase I study will be conducted in two steps: Step A: A dose escalation of low dose radiotherapy (LDRT) and partial SBRT, 3 patients per cohort (a total of 9 patients) will be enrolled to determine the maximum tolerated dose (MTD), dose-limiting toxicity (DLT) and recommended dose for expansion (RDE) for lung LDRT and partial SBRT. All eligible patients will receive LDRT + partial SBRT at different dose levels (decried as below), followed by PD-1 inhibitors starting within 7 days after radiation completed. PD-1 inhibitors will be given at doses as recommended in the instruction manual every 3 weeks until disease progression, unacceptable toxicities, the patient withdraws informed consent, or PD-1 inhibitors reaches a maximum of up to 48 months. Patients in the dose escalation will receive LDRT + partial SBRT at 3 cohorts with increasing dose levels: 2 Gy (2 Gy/f) + 10 Gy (10 Gy/f) in 1 fraction in dose level 1; 4 Gy (2 Gy/f) + 20 Gy (10 Gy/f) in 2 fractions in dose level 2; 6 Gy (2 Gy/f) + 30 Gy (10 Gy/f) in 3 fractions in dose level 3. Step B: A dose expansion of LDRT + partial SBRT A cohort of 5 patients will receive lung LDRT and partial SBRT at the RDE determined during the dose escalation phase in combination with PD-1 inhibitors to obtain additional safety and response data.

Official Title
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Phase I Study of Low Dose Radiotherapy and Concurrent SBRT in Combination With PD-1 Inhibitors in Advanced Non-small Cell Lung Cancer (NSCLC) .

Conditions
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NSCLC, Low Dose Radiotherapy, Stereotactic Body Radiotherapy, PD-1 Inhibitor

Intervention / Treatment
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* Radiation: Low Dose Radiotherapy
* Radiation: stereotactic body radiation therapy
* Drug: PD-1 Inhibitors


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Be willing and able to provide written informed consent/assent for the trial. Be ≥18 years of age on day of signing informed consent. Patients with histologically or cytologically confirmed stage IV NSCLC. Be willing to undergo repeat biopsy of tumor lesions according to the study protocol. Patients who have failed the standard therapy, or who are unsuitable for standard treatment, or refuse chemotherapy. At least one measurable lesion according to RECIST 1.1. A lesion that has previously received radiotherapy can be considered a target lesion only if this lesion is clearly progressed after radiotherapy. The target lesions (irradiated lesions) are > 5cm in in diameter ECOG 0-2. Life expectancy of > 3 months. Patients must have normal organ and bone marrow function as defined below: Total bilirubin </= 1.5 x upper limit of normal (ULN). Aminotransferase (AST) Serum Glutamic Oxaloacetic Transaminase (SGOT)/ Alanine Aminotransferase (ALT) Serum Glutamic-Pyruvic Transaminase (SGPT) <2.5 X institutional upper limit of normal (</= 5 X institutional ULN for subjects with liver metastases) *WBC >/= 3500/uL, ANC >/= 1500/uL *Platelets >/= 90K/ul *Hemoglobin >/= 9g/dL *Creatinine </= 1.5 x ULN, or creatinine clearance ≥ 50 ml/min（Cockcroft-Gault equation）. Coagulation: International Normalized Ratio (INR)≤ 1.5 × ULN, Partial thromboplastin time (PTT) ≤1.5 × ULN; left ventricular ejection fraction (LVEF) >/= 50% and QTcF (Fridericia's formula) ≤ 450ms Patients has recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to a previously administered agent. Wash out period for chemotherapy is more than ≥ 4 weeks, for targeted small molecule therapy ≥ 5 half-lives; palliative radiotherapy must have been completed for at least ≥ 2 weeks, chest radiotherapy must have been completed for at least ≥ 4 weeks, and major surgery must have been completed for ≥ 4 weeks. Subjects with no severe pulmonary ventilation dysfunction, no acute heart failure, and no contraindication to radiotherapy as judged by the radiotherapist. Subjects who agree to receive immunotherapy and radiotherapy treatment. Subjects should agree to use an adequate method of contraception. Exclusion Criteria: Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis and/or spinal cord compression, etc. With oncologic emergencies that require immediate treatment EGFR/ALK/ROS-1 mutation or mutation status unknown. Has evidence of interstitial lung disease or active and/or non-infectious pneumonitis (drug-induced pneumonia, radiation-induced pneumonia, etc.) requiring steroid therapy. History of pulmonary fibrosis, pulmonary hypertension, severe irreversible airway obstruction disease Patients with peripheral neuropathy. Significant heart disease or impairment of cardiac function Fluid accumulating in the third space, such as pericardial effusion, pleural effusion and peritoneal effusion that remains uncontrolled by aspiration or other treatment Known allergy to drugs or excipients, known severe allergic reaction to any of the PD-1 monoclonal antibodies Severe infection within 4 weeks prior to the start of study treatment, including but not limited to hospitalization for infection, bacteremia, or severe pneumonia; treatment with oral or intravenous antibiotics within 2 weeks prior to the start of study treatment; patients receiving prophylactic antibiotic therapy (e.g., to prevent urinary tract infection or exacerbation of COPD) are eligible for this study. Known or suspected active autoimmune disease (congenital or acquired) such as uveitis, enterocolitis, hepatitis, pituitary inflammation, vasculitis, nephritis, thyroiditis, etc. (patients with vitiligo, or resolved childhood asthma may be enrolled; patients with type I diabetes with good insulin control may also be enrolled) Known allogeneic organ transplantation (except corneal transplantation) or allogeneic hematopoietic stem cell transplantation.

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: LDRT+SBRT Combined with PD-1 Inhibitors<br>Part A-Dose escalation cohort. DOSE LEVEL: Low Dose Radiotherapy (LDRT) dose from 2 Gy to 6Gy (2 Gy/f) + partial stereotactic body radiation therapy (SBRT) dose at 10 Gy to 30 Gy (10 Gy/f) + PD-1 inhibitor (dose as recommended in the instruction manual). Part-B - Expansion cohort. LDRT and partial SBRT doses at MTD determined in Part A + PD-1 inhibitor (dose as recommended in the instruction manual). | Radiation: Low Dose Radiotherapy<br>* LDRT at dose escalation levels: 2 Gy/1f, 4 Gy/2f, 6 Gy/3f with conventional external beam radiation.<br>* Other names: LDRT;Radiation: stereotactic body radiation therapy<br>* Partial SBRT at dose escalation levels: 10 Gy/1f, 20 Gy/2f, 30 Gy/3f.<br>* Other names: SBRT;Drug: PD-1 Inhibitors<br>* Patients will receive treatment with PD-1 inhibitor (dose as recommended in the instruction manual) every 3 weeks for a maximum of 48 months.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with Adverse Events and/or Dose Limiting Toxicities as a Measurement of Safety and Tolerability of Low Dose Radiotherapy, Concurrent SBRT and PD-1 Inhibitors in Advanced NSCLC. |  | 48 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) | Investigator assessed PFS according to RECIST v1.1. Progression free survival is defined as time of enrollment to first evidence of progressive disease. | up to 48 months after the enrollment | 
| Overall Survival (OS) | OS is defined as the difference (in months) between the date of study enrollment to the date death due to any cause | up to 48 months after the enrollment |