Safety and Tolerability of LDRT Plus Concurrent Partial SBRT and Tislelizumab in Patients With Bulky Tumors

This is 3+3 escalation phase I study which will be conducted in West China Hospital.

Step A: A dose escalation of low dose radiotherapy (LDRT) and partial SBRT, at least 3 patients per cohort (a total of at least 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 and Tislelizumab at different dose levels (described as below). Tislelizumab will be given at 200mg as recommended in the instruction manual every 3 weeks until disease progression, unacceptable toxicities, the patient withdraws informed consent, or Tislelizumab reaches a maximum of up to 24 months.

Patients in the dose escalation will receive LDRT + partial SBRT at 3 cohorts with increasing dose levels: 6 Gy (2 Gy/f) + 24 Gy (8 Gy/f); 6 Gy (2 Gy/f) + 30 Gy (10 Gy/f); 6 Gy (2 Gy/f) + 45 Gy (15 Gy/f).

Step B: A dose expansion of LDRT + partial SBRT A cohort of 15 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.

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 solid tumours.
• 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.
• 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
• Known allogeneic organ transplantation (except corneal transplantation) or allogeneic hematopoietic stem cell transplantation.