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

Official title

Safety and Tolerability of Low Dose Radiotherapy Plus Concurrent Partial Stereotactic Ablative Radiotherapy (Eclipse-RT) and Tislelizumab in Patients With Bulky Tumors

Overview

This is a 3+3 dose escalation phase I study which aims to evaluate the safety and tolerability of low dose radiotherapy (LDRT) plus concurrent partial Stereotactic Ablative Radiotherapy (SBRT) and Tislelizumab in Patients with bulky tumors who have failed standard therapy. At least 9 participants will be enrolled in this study.

Detailed description

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.

Interventions

• Drug Tislelizumab
  Patients will receive treatment with Tislelizumab (200 mg, iv, d1), every 3 weeks for a maximum of 48 months.
• Radiation Low Dose Radiotherapy
  LDRT (d1-d3): 6Gy/3f with conventional external beam radiation.
• Radiation Stereotactic Ablative Radiotherapy
  Partial SBRT at dose escalation levels: 24Gy/3f, 30Gy/3f, 45Gy/3f.

Primary outcome measures

• Dose Limiting Toxicities [Time frame: 24 months]

Secondary outcome measures (3)

• Objective Response Rate (ORR) [Time frame: up to 24 months after the enrollment]
• Progression Free Survival (PFS) [Time frame: up to 24 months after the enrollment]
• Overall Survival (OS) [Time frame: up to 24 months after the enrollment]

Eligibility criteria

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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

China · 1 center

• West China Hospital, Sichuan University — Chengdu

Publications

• Yin L, Xue J, Li R, Zhou L, Deng L, Chen L, Zhang Y, Li Y, Zhang X, Xiu W, Tong R, Gong Y, Huang M, Xu Y, Zhu J, Yu M, Li M, Lan J, Wang J, Mo X, Wei Y, Niedermann G, Lu Y. Effect of Low-Dose Radiation Therapy on Abscopal Responses to Hypofractionated Radiation Therapy and Anti-PD1 in Mice and Patients With Non-Small Cell Lung Cancer. Int J Radiat Oncol Biol Phys. 2020 Sep 1;108(1):212-224. doi: 1 PMID 32417411
• Lan J, Li R, Yin LM, Deng L, Gui J, Chen BQ, Zhou L, Meng MB, Huang QR, Mo XM, Wei YQ, Lu B, Dicker A, Xue JX, Lu Y. Targeting Myeloid-derived Suppressor Cells and Programmed Death Ligand 1 Confers Therapeutic Advantage of Ablative Hypofractionated Radiation Therapy Compared With Conventional Fractionated Radiation Therapy. Int J Radiat Oncol Biol Phys. 2018 May 1;101(1):74-87. doi: 10.1016/j.ijro PMID 29619980
• Zhou X, Zhou L, Yao Z, Huang M, Gong Y, Zou B, Zhu J, Liu Y, Peng F, Zhang Y, Yu M, Li Y, Na F, Wu Y, Kang K, Xiu W, Zhang X, Zhou L, Xu Y, Wang J, Wang Y, Yang X, Wu Y, Li R, Zhang Y, Yang Z, Zhou Z, Bai J, Yi X, Tong R, Yin L, Chen C, Niedermann G, Lu Y, Xue J. Safety and Tolerability of Low-Dose Radiation and Stereotactic Body Radiotherapy + Sintilimab for Treatment-Naive Stage IV PD-L1+ Non-Sm PMID 37581611
• Zhou L, Liu Y, Wu Y, Yang X, Spring Kong FM, Lu Y, Xue J. Low-dose radiation therapy mobilizes antitumor immunity: New findings and future perspectives. Int J Cancer. 2024 Apr 1;154(7):1143-1157. doi: 10.1002/ijc.34801. Epub 2023 Dec 7. PMID 38059788
• Barsoumian HB, Ramapriyan R, Younes AI, Caetano MS, Menon H, Comeaux NI, Cushman TR, Schoenhals JE, Cadena AP, Reilly TP, Chen D, Masrorpour F, Li A, Hong DS, Diab A, Nguyen QN, Glitza I, Ferrarotto R, Chun SG, Cortez MA, Welsh J. Low-dose radiation treatment enhances systemic antitumor immune responses by overcoming the inhibitory stroma. J Immunother Cancer. 2020 Oct;8(2):e000537. doi: 10.1136/j PMID 33106386
• Barsoumian HB, Sezen D, Menon H, Younes AI, Hu Y, He K, Puebla-Osorio N, Wasley M, Hsu E, Patel RR, Yang L, Cortez MA, Welsh JW. High Plus Low Dose Radiation Strategy in Combination with TIGIT and PD1 Blockade to Promote Systemic Antitumor Responses. Cancers (Basel). 2022 Jan 3;14(1):221. doi: 10.3390/cancers14010221. PMID 35008385
• Menon H, Chen D, Ramapriyan R, Verma V, Barsoumian HB, Cushman TR, Younes AI, Cortez MA, Erasmus JJ, de Groot P, Carter BW, Hong DS, Glitza IC, Ferrarotto R, Altan M, Diab A, Chun SG, Heymach JV, Tang C, Nguyen QN, Welsh JW. Influence of low-dose radiation on abscopal responses in patients receiving high-dose radiation and immunotherapy. J Immunother Cancer. 2019 Sep 4;7(1):237. doi: 10.1186/s4042 PMID 31484556
• Welsh JW, Tang C, de Groot P, Naing A, Hess KR, Heymach JV, Papadimitrakopoulou VA, Cushman TR, Subbiah V, Chang JY, Simon GR, Ramapriyan R, Barsoumian HB, Menon H, Cortez MA, Massarelli E, Nguyen Q, Sharma P, Allison JP, Diab A, Verma V, Raju U, Shaaban SG, Dadu R, Cabanillas ME, Wang K, Anderson C, Gomez DR, Hahn S, Komaki R, Hong DS. Phase II Trial of Ipilimumab with Stereotactic Radiation Ther PMID 31658994

Identifiers

NCT: NCT06349837 · ECLIPSE-02

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗