A Phase Ib Study on Toripalimab Combined With Anlotinib and SBRT for Patients With Untreated Brain Metastases of Driven Gene-negative Non-small Cell Lung Cancer
Overview
- Phase
- Phase 1
- Intervention
- Anlotinib
- Conditions
- NSCLC
- Sponsor
- Hubei Cancer Hospital
- Enrollment
- 13
- Locations
- 1
- Primary Endpoint
- Intracranial response rate (iORR)
- Status
- Completed
- Last Updated
- last year
Overview
Brief Summary
The purpose of this study is to explore the efficacy and safety of toripalimab combined with anlotinib and SBRT for non-driver gene mutation untreated brain metastases non-small Cell Lung Cancer.
Detailed Description
Brain metastases (BM) develop in 22-54% of NSCLC patients during the disease course. NSCLC patients with BM with a median overall survival (OS) of 2-3 months when treated with systemic corticosteroid alone, and a median OS of 10-12 months when treated with brain radiation therapy. Recently, several studies have reported the benefits of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) for EGFR mutation NSCLC patients with BM. The median OS of EGFR mutation patients with BM significantly improved with TKIs treatment, which ranged from 11.8 to 18.8 months. However, for the EGFR wide-type NSCLC patients with BM, the prognosis remains poor. JS-001 is the first monoclonal antibody (mAb) against programmed cell death protein-1 (PD-1) approved by the China Food and Drug Administration (CFDA) into the clinical trails. Anlotinib hydrochloride is a multi-target receptor tyrosine kinase inhibitor that has significant inhibitory activity against angiogenesis related kinases such as VEGFR1/2/3, FGFR1/2/3, and other tumor related kinases such as PDGFR /, C-Kit, Ret, etc. (e.g., Met, FGFR1/2/3). The previously study (2021 EMSO congress abstract) found that Apatinib, another kind of tyrosine kinase inhibitor that selectively inhibits the VEGFR-2, combined with brain radiation therapy could improve mOS time to 17 months in lung cancer patients with BMs. Therefore, the investigators initiated this study to evaluate the efficacy and safety of toripalimab combined with anlotinib and SBRT for non-driver gene mutation untreated brain metastases non-small Cell Lung Cancer.
Investigators
HAN GUANG
Clinical Professor
Hubei Cancer Hospital
Eligibility Criteria
Inclusion Criteria
- •Age ≥ 18 years, no gender limit；
- •Pathologically or cytologically confirmed NSCLC, stage IV tumor with untreated BMs diagnosed by imaging 2 weeks before enrollment, 1\~5 intracranial metastases (The primary tumor disease has not received systemic treatment, or brain metastasis occurs 6 months after the completion of postoperative adjuvant treatment or radical treatment);
- •Negative driver genes (EGFR, ALK, ROS1, etc.);
- •ECOG PS score: 0～1;
- •The expected survival time ≥ 3 months;
- •Intracranial metastases can be measured and evaluated by MRI;
- •Intracranial lesions are suitable for stereotactic radiotherapy based on the linear accelerator;
- •Able to independently complete neurocognitive tests;
- •Able to complete the QOL questionnaire independently;
- •Female subjects with fertility should undergo a urine or serum pregnancy test within 72 hours before receiving the first study drug administration, and prove to be negative, and are willing to use effectively during the test period to 3 months after the last administration Methods of contraception. For male subjects whose partners are women of childbearing age, effective methods of contraception should be used during the trial and within 3 months after the last administration;
Exclusion Criteria
- •The lesion has received prior radiotherapy and is not suitable for SBRT;
- •Have leptomeningeal metastasis;
- •EGFR, ALK or ROS1 genomic tumour alterations;
- •Patients who cannot undergo MRI examination due to metal implants or claustrophobia;
- •Currently participating in interventional clinical research and treatment, or receiving other research drugs or treatment with research equipment within 4 weeks before the first administration;
- •Accept solid organ or blood system transplantation;
- •Past treatment history of CTLA-4, PD-1 or PD-L1 immune checkpoint inhibitors;
- •Has received VEGF pathway targeted therapy including anlotinib and bevacizumab.
- •Suffer from active autoimmune diseases that require hormone or immunomodulatory treatment, such as rheumatoid arthritis, ankylosing spondylitis, type I diabetes, psoriasis, vitiligo, immune-related thyroid dysfunction, etc. (hormone replacement Can be included after treatment is normal);
- •Suffer from acute or chronic infectious diseases, such as hepatitis B, hepatitis C, tuberculosis, and HIV;
Arms & Interventions
Anlotinib combined with SBRT
Induction therapy (D1-D21): SBRT 7Gy✖️5 QD, D1-D5 + Anlotinib 12mg, QD, PO, D1-D14； Maintenance (D22\~1year): Toripalimab 240mg iv drip D1 Q3W + Anlotinib 12mg, QD, PO, D1-D14, Q3W, until progression (up to approximately 1 year)
Intervention: Anlotinib
Anlotinib combined with SBRT
Induction therapy (D1-D21): SBRT 7Gy✖️5 QD, D1-D5 + Anlotinib 12mg, QD, PO, D1-D14； Maintenance (D22\~1year): Toripalimab 240mg iv drip D1 Q3W + Anlotinib 12mg, QD, PO, D1-D14, Q3W, until progression (up to approximately 1 year)
Intervention: SBRT 7Gy✖️5 QD
Anlotinib combined with SBRT and Toripalimab
Induction therapy (D1-D21): SBRT 7Gy✖️5 QD, D1-D5 + Toripalimab 240mg iv drip D1 + Anlotinib 12mg, QD, PO, D1-D14； Maintenance (D22\~1year): Toripalimab 240mg iv drip D1 Q3W + Anlotinib 12mg, QD, PO, D1-D14, Q3W, until progression (up to approximately 1 year)
Intervention: Toripalimab
Anlotinib combined with SBRT and Toripalimab
Induction therapy (D1-D21): SBRT 7Gy✖️5 QD, D1-D5 + Toripalimab 240mg iv drip D1 + Anlotinib 12mg, QD, PO, D1-D14； Maintenance (D22\~1year): Toripalimab 240mg iv drip D1 Q3W + Anlotinib 12mg, QD, PO, D1-D14, Q3W, until progression (up to approximately 1 year)
Intervention: Anlotinib
Anlotinib combined with SBRT and Toripalimab
Induction therapy (D1-D21): SBRT 7Gy✖️5 QD, D1-D5 + Toripalimab 240mg iv drip D1 + Anlotinib 12mg, QD, PO, D1-D14； Maintenance (D22\~1year): Toripalimab 240mg iv drip D1 Q3W + Anlotinib 12mg, QD, PO, D1-D14, Q3W, until progression (up to approximately 1 year)
Intervention: SBRT 7Gy✖️5 QD
Outcomes
Primary Outcomes
Intracranial response rate (iORR)
Time Frame: 4 weeks after Radiotherapy.
Proportion of patients with a complete or partial response in intracranial metastases as measured using RECIST 1.1 criteria (modified for brain metastases - bm RECIST).
Treatment-related adverse events
Time Frame: up to 24 month
AEs per Common Terminology Criteria for Adverse Events (CTCAE V5.0)
Secondary Outcomes
- Intracranial progression-free survival (iPFS)(Tumor assesment at 4 weeks and 12 weeks after radiotherapy, and then every 12 weeks, up to 24 months)
- Overall survival (OS)(Tumor assesment at 4 weeks and 12 weeks after radiotherapy, and then every 12 weeks, up to 24 months)
- Local Control Rate (LCR)(Tumor assesment at 4 weeks and 12 weeks after radiotherapy, and then every 12 weeks, up to 24 months)