Phase I Study of Low Dose Radiotherapy and Concurrent SBRT in Combination With PD-1 Inhibitors in Advanced Non-small Cell Lung Cancer (NSCLC) .
Trial Snapshot
- Phase
- Phase 1
- Status
- Active, not recruiting
- Sponsor
- Enrollment
- 9
- Locations
- 1
- Primary Endpoint
- 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.
Study Overview
Brief Summary
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 9 participants will be enrolled in this study. All will take part at West China Hospital, Sichuan University.
Detailed Description
This exploratory phase I study will be conducted in West China Hospital, Sichuan University. 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) and dose-limiting toxicity (DLT).
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.
Study Design
- Study Type
- Interventional
- Allocation
- Na
- Intervention Model
- Single Group
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •1. Be willing and able to provide written informed consent/assent for the trial.
- •2. Be ≥18 years of age on day of signing informed consent.
- •3. Patients with histologically or cytologically confirmed stage IV NSCLC.
- •4. Be willing to undergo repeat biopsy of tumor lesions according to the study protocol.
- •5. Patients who have failed the standard therapy, or who are unsuitable for standard treatment, or refuse chemotherapy.
- •6. 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.
- •7. The target lesions (irradiated lesions) are \> 5cm in in diameter
- •8. ECOG 0-2.
- •9. Life expectancy of \> 3 months.
- •10. Patients must have normal organ and bone marrow function as defined below: Total bilirubin \/= 3500/uL, ANC \>/= 1500/uL \*Platelets \>/= 90K/ul \*Hemoglobin \>/= 9g/dL \*Creatinine \/= 50% and QTcF (Fridericia's formula) ≤ 450ms
- •11. Patients has recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to a previously administered agent.
- •12. 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.
- •13. 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.
- •14. 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.
Arms & Interventions
LDRT+SBRT Combined with PD-1 Inhibitors
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).
Intervention: Low Dose Radiotherapy (Radiation)
LDRT+SBRT Combined with PD-1 Inhibitors
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).
Intervention: stereotactic body radiation therapy (Radiation)
LDRT+SBRT Combined with PD-1 Inhibitors
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).
Intervention: PD-1 Inhibitors (Drug)
Outcomes
Primary Outcomes
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.
Time Frame: 48 months
Secondary Outcomes
- Progression Free Survival (PFS)(up to 48 months after the enrollment)
- Overall Survival (OS)(up to 48 months after the enrollment)
Investigators
You Lu
Chair of Department of Thoracic Cancer
Sichuan University