SHR0302 Combined With PD-1/PD-L1 Inhibition for Treatment naïve or Acquired Resistant to Immunology NSCLC

Official title

A Multi-cohort, Phase II Study of SHR0302 Combined With PD-1/PD-L1 Inhibition for Treatment naïve or Acquired Resistant to Immunology NSCLC

Overview

Recent studies showed that the dysregulated activation of the JAK/STAT pathway, which leads to the prolonged release of IFN-γ, is a significant contributor to the resistance to immune checkpoint inhibitors in cancer immunotherapy. Preclinical and clinical studies have demonstrated that the combination of JAK inhibitors with PD-1 immunotherapy can reverse or delay onset of immunotherapy resistance by modulating the JAK/STAT pathway in Hodgkin's lymphoma and non - small cell lung cancer (NSCLC). SHR0302, being a highly selective JAK1 inhibitor, has shown excellent clinical benefits by effectively inhibiting the JAK/STAT pathway, leading to its approval for the treatment of Ankylosing Spondylitis in China. Preclinical studies also show that the combination of SHR0302 and PD-L1 inhibitor has synergistic potentials for anti-tumor effect in resistant to-immune checkpoint blockade patients. Thus, we conducted a phase 2 clinical trial evaluating SHR0302 combined with PD1/PD-L1 inhibitors as treatment-naïve or acquired resistant to first-line checkpoint inhibitor resistant NSCLC patients.

Interventions

• Drug PD-1 inhbitor+SHR0302
  PD-1 inhbitor+SHR0302 in the maintenance treatment
• Drug PD-L1 inhibitor+SHR0302
  PD-L1 inhibitor+SHR0302 in second line

Primary outcome measures

• Progression-free survival [Time frame: through study completion, an average of 18 months]

Secondary outcome measures (3)

• Objective response rate [Time frame: percentage of evaluable subjects who achieve a complete or partial clinical response at 12 weeks]
• Duration of Response [Time frame: through study completion, an average of 18 months]
• Overall survival [Time frame: through study completion, an average of 18 months]

Eligibility criteria

Inclusion criteria

• Inoperable or non-suitable for radical radiotherapy and chemotherapy IIIB/IIIC and Stage IV or metastatic non-small cell lung cancer (NSCLC)
• Provide written informed consent for the trial.
• Patients ≥ 18 years of age
• Arm 1: treatment naive; Arm 2: acquired resistant to first-line PD-1/PD-L1 inhibition. Acquired resistance is defined as documented initial objective response (partial or complete response by RECIST or WHO) to therapy or significant and durable (> 6 months) clinical benefit (stable disease defined by RECIST or WHO).
• Subject must have adequate tumor burden at a safely accessible site for biopsy.
• At least one measurable lesion according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1
• ECOG performance status 0 or 1
• Adequate organ function:

(1) White Blood Cell ≥3.0×109/L; Absolute neutrophil count (ANC) ≥ 1.5×10\*9 /L; Platelets ≥ 100×10\*9 /L; Hemoglobin ≥ 9g/dl; (2) Serum creatinine ≤1.5 X upper limit of normal or creatinine clearance ≥ 40 mL/min; (3) Serum total bilirubin ≤ 1.5 X ULN; AST and ALT ≤ 2.5 X ULN OR ≤ 5 X ULN for subjects with liver metastases; 9. Subjects of reproductive potential must agree to use acceptable birth control methods

Exclusion criteria

• Non-small cell cancer contains components of small cell lung cancer or neuroendocrine carcinoma.
• Sensitizing mutations in Epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) or ROS1 proto-oncogene receptor tyrosine kinase (ROS1) translocations;
• Arm 1: Currently participating in or has participated in a study of an investigational agent or anticipated use of an investigational device within 4 weeks of the first dose of study treatment.
• Receiving Chinese patent medicines with anti-tumor indications or drugs with immunomodulatory effects within 2 weeks before the first administration.
• Having a history of allergic reaction to any component of the study drug.
• Having active hemoptysis requiring clinical intervention, active diverticulitis, abdominal abscess, gastrointestinal obstruction, and peritoneal metastasis.
• Having clinically uncontrollable pleural effusion/abdominal effusion (patients who do not need to drain the effusion or whose effusion does not increase significantly within 3 days after stopping drainage can be enrolled).
• The tumor compressing surrounding vital organs (such as the esophagus) and accompanied by related symptoms, compressing the superior vena cava or invading the large vessels in the mediastinum, the heart, etc.
• Severe comorbidities such as a history of severe lung or heart diseases, and having experienced any arterial thrombosis, embolism, or ischemia within 6 months before being selected for treatment, such as myocardial infarction, unstable angina pectoris, cerebrovascular accident, or transient ischemic attack, etc.
• Having a history of deep vein thrombosis, pulmonary embolism, or any other serious thromboembolism within 3 months before enrollment.
• Interstitial pneumonia (ILD), drug-induced pneumonia, radiation pneumonia requiring steroid treatment, or symptomatic active pneumonia.
• Receiving systemic corticosteroids (>10 mg/d prednisone equivalent drugs) or other systemic immunosuppressants within 2 weeks before enrollment. Local, ophthalmic, intra-articular, intranasal, and inhaled corticosteroids are allowed.
• A history of autoimmune diseases. Patients with autoimmune-related hypothyroidism who are receiving a stable dose of thyroid hormone replacement therapy are eligible to participate in this study. Patients with type 1 diabetes mellitus who are under control after receiving a stable insulin treatment regimen are eligible to participate in this study.
• Active systemic infection, including tuberculosis (clinical diagnosis includes clinical history, physical examination, and imaging findings, as well as TB examinations according to local medical routines), hepatitis B (known to be positive for HBV surface antigen (HBsAg) and HBV DNA ≥1000 cps/ml or the lower limit of its reference value), hepatitis C, or human immunodeficiency virus (positive for HIV antibody).
• Known presence of mental illness or drug abuse that may affect compliance with the requirements of the trial.
• Recently receiving sufficient oral or non-oral anticoagulants or thrombolytics. Prophylactic use of anticoagulants is allowed.
• Having a medical history, disease, treatment, or laboratory abnormal results that may interfere with the trial results or prevent the subject from participating in the study throughout the whole process, or the investigator deems that participating in the study is not in the best interest of the subject.

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

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

Center list to be confirmed — check the primary protocol.

Identifiers

NCT: NCT06925048 · 2024LY1179

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗