| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Locally Advanced or Metastatic Non-Small Cell Lung Cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
| Advanced Non-Small Cell Lung Cancer |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
- To compare the overall survival (OS) of tislelizumab and sitravatinib combination therapy with that of docetaxel monotherapy
- To compare the progression-free survival (PFS) of tislelizumab and sitravatinib combination therapy with that of docetaxel monotherapy, as assessed by the Independent Review Committee (IRC)
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| E.2.2 | Secondary objectives of the trial |
- To compare the PFS of tislelizumab and sitravatinib combination therapy with that of docetaxel monotherapy, as assessed by the investigator
- To compare the overall response rate (ORR), duration of response (DOR), and disease control rate (DCR) of tislelizumab and sitravatinib combination therapy with that of docetaxel monotherapy, as assessed by the IRC
- To evaluate the safety and tolerability of tislelizumab and sitravatinib combination therapy compared with that of docetaxel monotherapy
- To evaluate and compare health-related quality of life (HRQoL) between the tislelizumab and sitravatinib combination therapy with that of docetaxel monotherapy via patient reported outcomes using EORTC-QLQ-C30 (measuring general cancer) and its lung cancer module, QLQ-LC13, and the European Quality of Life 5-Dimension 5-Level (EQ-5D-5L)
To characterize the pharmacokinetics (PK) of sitravatinib when given in combination with
tislelizumab, if data permit
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Able to provide written informed consent and can understand and agree to comply with the requirements of the study and the schedule of assessments
2. Age ≥ 18 years on the day of signing the informed consent form (or the legal age of consent if > 18 in the jurisdiction in which the study is taking place)
3. Metastatic or unresectable locally advanced histologically or cytologically confirmed NCSLC, not amenable to treatment with curative intent
4. Able to provide archival/fresh tumor tissues for biomarker analysis to assess PD-L1 expression and other biomarkers. Tumor tissues should be of good quality and acceptable sample type (see Section 7.7.1 for details). Written informed consent is required before performance of fresh tumor biopsies.
5. No known EGFR or BRAF sensitizing mutation, or ALK rearrangement or ROS1 rearrangement
6. Radiographic progression per RECIST v1.1 on or after anti-PD-(L)1-containing therapy for locally advanced and unresectable or metastatic NSCLC. If the anti-PD-(L)1-containing therapy is not the most recent systemic treatment, patients should also have radiographic progression per RECIST v1.1 on or after the most recent systemic treatment. Prior line(s) of treatment must include a platinum-based chemotherapy and an anti-PD-(L)1 antibody, with the anti-PD-(L)1 antibody administered in combination with, or sequentially before or after the platinum-based chemotherapy. Patients must have received no more than 2 lines of prior systemic therapy for locally advanced and unresectable or metastatic disease.
7. Criterion deleted
8. At least 1 measurable lesion as defined based on RECIST v1.1 by investigator
9. Eastern Cooperative Oncology Group Performance Status ≤ 1
10. Adequate organ function as indicated by the laboratory values detailed on p.59 of the protocol (obtained ≤ 7 days before randomization)
11. Females of childbearing potential must be willing to use a highly effective method of birth control while on study treatment, and within 180 days after the last dose of study drug(s) and have a negative serum pregnancy test ≤ 7 days before randomization. See Appendix 10.
12. Nonsterile males must be willing to use a highly effective method of birth control for the duration of the study and for ≥ 180 days after the last dose of study drug(s).
More detailed information on each inclusion criteria can be found in the clinical trial protocol. |
|
| E.4 | Principal exclusion criteria |
1. Has received docetaxel as monotherapy or in combination with other therapies.
2. Squamous NSCLC with central cavitation, or NSCLC with hemoptysis (> 50 mL/day)
3. Patients with tumor shown by imaging to be located around important vascular structures or if the investigator determines that the tumor is likely to invade important blood vessels and may cause fatal bleeding.
4. Active leptomeningeal disease for metastatic NSCLC, or uncontrolled or untreated brain metastasis.
5. Active autoimmune diseases or history of autoimmune diseases that may relapse.
6. Any active malignancy ≤ 2 years before randomization except for the specific cancer under investigation in this study and any locally recurring cancer that has been treated curatively
7. Any condition that required systemic treatment with either corticosteroids (> 10 mg daily of prednisone or equivalent) or other immunosuppressive medication ≤ 14 days before randomization
8. History of uncontrolled diabetes, or > Grade 1 laboratory test abnormalities in potassium, sodium, or corrected calcium despite standard medical management, or ≥ Grade 3 hypoalbuminemia ≤ 14 days before randomization
9. History of interstitial lung disease, noninfectious pneumonitis or uncontrolled lung diseases, including pulmonary fibrosis and acute lung diseases.
10. Severe chronic or active infection requiring systemic antibacterial, antifungal, or antiviral therapy (not including antiviral therapy for hepatitis or HIV) within 14 days before randomization
11. Untreated HIV infection, if known. Patients with a known HIV infection are eligible if the following criteria are met:
12. Untreated chronic hepatitis B or chronic hepatitis B virus (HBV) carriers with HBV DNA ≥ 500 IU/mL or 2500 copies/mL, or active hepatitis C virus (HCV) carriers
13. Any major surgical procedure ≤ 28 days before randomization. Patients must have recovered adequately from the toxicity and/or complications from the intervention before randomization.
14. Prior allogeneic stem cell transplantation or organ transplantation
15. Any of the following cardiovascular risk factors:
16. Patients with inadequately controlled hypertension
17. Patients with hypersensitivity to tislelizumab, sitravatinib, docetaxel, to any ingredient in the formulation, or to any component of the container.
18. Patients who use anticoagulants such as warfarin or similar agents requiring therapeutic INR monitoring.
19. Within 4 weeks before randomization, patients with active bleeding disorder or any bleeding events ≥ CTCAE level 3, unhealed wounds, ulcers, or fractures
20. Patients with a history of artery/deep vein thrombosis within 6 months before randomization, such as cerebrovascular incident (including temporary ischemic attack), deep vein thrombosis, and pulmonary embolism
21. Received any Chinese herbal medicine or Chinese patent medicine for the treatment of NSCLC within 14 days before randomization, or received palliative radiation within 28 days before randomization for the lung or within 14 days before randomization for other organs.
22. Unacceptable toxicity on prior anti-PD-(L)1 treatment, defined as on p. 63 of the protocol
23. Patient was administered a live vaccine ≤ 28 days before randomization.
24. Underlying medical conditions (including laboratory abnormalities) or alcohol or drug abuse or dependence that will be unfavorable for the administration of study drug, affect the explanation of drug toxicity or AEs, or result in insufficient or impaired compliance with study conduct according to the investigator’s judgement.
25. Concurrent participation in another therapeutic clinical study.
26. Unable to swallow capsules or with disease significantly affecting gastrointestinal function such as malabsorption syndrome, resection of the stomach or small bowel, bariatric surgery procedures, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction.
27. Patients with spinal cord compression due to metastatic disease not definitively treated with surgery and/or radiation or previously diagnosed and treated spinal cord compression without evidence that the disease has been clinically stable for > 2 weeks before randomization.
28. Criterion deleted
29. Prior randomization in a tislelizumab study regardless of the treatment arm, until the primary and key secondary endpoints of the study have read out.
30. Patients with toxicities which have not recovered to baseline or stabilized, except for AEs not considered a likely safety risk (eg, alopecia, neuropathy and specific laboratory abnormalities).
31. Women who are pregnant or are breastfeeding.
32. Known COVID-19 antigen positive by a licensed test during the screening period.
33. Uncontrollable pleural effusion, pericardial effusion, or ascites requiring frequent drainage (recurrence ≤ 14 days after intervention)
More detailed information on each exclusion criteria can be found in the clinical trial protocol. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
- OS, defined as the time from randomization to death from any cause
- PFS, defined as the time from randomization to the first occurrence of disease progression as determined by the IRC based on Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, or death from any cause, whichever occurs first
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|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
- PFS, defined as the time from randomization to the first occurrence of disease progression as determined by the investigator based on RECIST v1.1, or death from any cause, whichever occurs first
- ORR, defined as the proportion of patients with partial response or complete response as determined by the IRC based on RECIST v1.1
- DOR, defined as the time from the first occurrence of a documented objective response to the time of the first occurrence of disease progression, as determined by the IRC based on RECIST v1.1, or death from any cause, whichever comes first
- DCR, defined as the proportion of patients whose best overall response (BOR) is complete response, partial response or stable disease as determined by the IRC based on RECIST v1.1
- HRQoL, defined as changes in patient-reported outcomes (PRO), according to the European Organisation for Research and Treatment of Cancer (EORTC) core cancer (QLQ-C30) and its lung cancer module, QLQ-LC13, and the European Quality of Life 5-Dimension 5-Level (EQ-5D-5L) from time of randomization to End of Treatment Visit, death or drop out, whichever comes first.
- Incidence and severity of treatment-emergent adverse events (TEAEs) graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) v5.0
- Plasma concentrations and the derived PK parameters of sitravatinib if data permit
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
|
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 25 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| China |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| The end of study is defined as the timepoint when the final data point is collected from the last patient in the study. This is when the last patient dies, withdraws consent, completes all study assessments, or is lost to follow-up. Alternatively, the end of study is when the sponsor decides to terminate the study. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 8 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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