E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
non-small cell lung cancer (NSCLC) |
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E.1.1.1 | Medical condition in easily understood language |
Cancer of the lung which is not of the small cell carcinoma type |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10029519 |
E.1.2 | Term | Non-small cell lung cancer stage III |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10025052 |
E.1.2 | Term | Lung cancer non-small cell stage III |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10025054 |
E.1.2 | Term | Lung cancer non-small cell stage IIIB |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10025053 |
E.1.2 | Term | Lung cancer non-small cell stage IIIA |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10025061 |
E.1.2 | Term | Lung cancer stage III |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10080083 |
E.1.2 | Term | Advanced lung cancer |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 |
The primary objective is to compare the progression free survival (PFS) of tislelizumab in combination with concurrent chemoradiotherapy (cCRT) followed by tislelizumab monotherapy (Arm 1) versus cCRT alone (Arm 3); in addition, tislelizumab given sequentially after cCRT (Arm 2) will be compared with cCRT alone (Arm 3) in newly diagnosed stage III subjects with locally advanced unresectable non-small cell lung cancer (NSCLC). |
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E.2.2 | Secondary objectives of the trial |
• Compare overall survival (OS)
• Compare OS at 24 months
• Compare centrally assessed objective response rate (ORR)
• Compare centrally assessed duration of response (DOR)
• Compare proportion of subjects alive and progression-free at 12 and 18 months (APF12, APF18)
• Compare time to death or distant metastasis (TTDM)
• Compare safety and tolerability of tislelizumab in combination cCRT followed by tislelizumab monotherapy versus cCRT alone, and tislelizumab given sequentially after cCRT versus cCRT alone
• Compare impact on patient-reported lung cancer symptoms (appetite loss, cough, chest pain, dyspnea, and fatigue) assessed by the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-C30 and its lung cancer module (EORTC QLQ-LC13)
• Compare the proportion of subjects who received at least one dose of tislelizumab or placebo in the monotherapy phase before progression in Arm 1 versus Arm 2 and 3. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Subject is ≥ 18 years of age at the time of signing the informed consent form (ICF).
2. Subject must understand and voluntarily sign an ICF prior to any study-related assessments/procedures being conducted.
3. Subject has newly diagnosed, histologically confirmed, locally advanced, stage III unresectable NSCLC.
4. Subject must have EGFR mutation and ALK gene translocation status available (testing using tumor tissue only) prior to randomization.
5. Subjects must be able to provide fresh or archival tumor tissues (formalin-fixed paraffin embedded [FFPE] blocks or at least 15 to 20 freshly cut unstained FFPE slides) with an associated pathological report (squamous or nonsquamous). In the absence of archival tumor tissues, a fresh biopsy (a minimum of 2 to 3 cores) of a tumor lesion at baseline is mandatory. Subjects may be permitted to be enrolled on a case-by-case basis after discussion with the Sponsor medical monitor if fewer than 15 unstained slides can be provided.
6. Subject has Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1.
7. Subject has adequate hematologic and end-organ function, as defined by the following laboratory results (obtained ≤ 2 weeks prior to randomization):
a. Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L
b. Platelet count ≥ 100 x 10^9/L
c. Hemoglobin ≥ 9 g/dL or ≥ 5.6 mmol/L (≥ 28 days after growth factor support or transfusion)
d. Calculated creatinine clearance (CrCl) ≥ 60 mL/min (Cockcroft-Gault formula) for subjects receiving cisplatin/etoposide, and ≥ 45mL/min (Cockcroft-Gault formula) for subjects receiving carboplatin / paclitaxel.
e. Total serum bilirubin ≤ 1.5 x upper limit of normal (ULN) (≤ 3 x ULN, if Gilbert’s syndrome or if indirect bilirubin concentrations are suggestive of extrahepatic source of the elevation)
f. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 x ULN
8. A female of childbearing potential (FCBP) is a female who: 1) has achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral oophorectomy, or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (ie, has had menses at any time in the preceding 24 consecutive months) and must:
a. Have 2 negative pregnancy tests as verified by the Investigator prior to starting study therapy. She must agree to ongoing pregnancy testing during the course of the study, and after end of study therapy.
b. Agree to use 2 reliable forms of contraception simultaneously or to practice complete abstinence from heterosexual contact during the following time periods related to this study: 1) for at least 28 days before starting study treatment; 2) while taking study treatment; 3) during dose interruptions; and 4) for at least 120 days after the subject’s last dose of tislelizumab or placebo and 180 days after the subject’s last dose of chemotherapy. The 2 methods of reliable contraception must include one highly effective method and one additional effective (barrier) method.
9. Male subjects must:
a. Practice true abstinence (which must be reviewed on a monthly basis) or agree to use a condom during sexual contact with a pregnant female or a female of childbearing potential while participating in the study, during dose interruptions and for at least 120 days after the subject’s last dose of tislelizumab or placebo and 180 days after the subject’s last dose of chemotherapy, or longer if required by local regulations, even if he has undergone a successful vasectomy.
b. Agree to not donate sperm
10. Subject is willing and able to adhere to the study visit schedule and other protocol requirements. |
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E.4 | Principal exclusion criteria |
1. Subject has received prior therapies targeting PD-1 or PD-L1.
2. Subject has received chemotherapy, radiation, targeted therapy, biologic therapy, immunotherapy or investigational agent used to control NSCLC.
3. Subject has a history of severe hypersensitivity reactions to other monoclonal antibodies.
4. Subject has a history of interstitial lung disease or documented ongoing interstitial lung disease or history of pneumonitis that has required oral or intravenous steroids.
5. Subject’s radiation treatment plans are likely to encompass a volume of whole lung receiving ≥ 20 Gy in total (V20) of more than 38% of lung volume.
6. Subject has clinically significant pericardial effusion.
7. Subject has clinically uncontrolled pleural effusion or ascites that requires pleurocentesis or paracentesis for drainage within 2 weeks prior to randomization.
8. Subject has had a major surgical procedure, open biopsy, or significant traumatic injury ≤14 days prior to randomization, or anticipation of need for major surgical procedure during the course of the study.
9. Subject has any active malignancy ≤ 2 years before randomization, with the exception of NSCLC and any locally recurring cancer that has been treated curatively (eg, resected basal or squamous cell skin cancer, superficial bladder cancer, carcinoma in situ of the cervix or breast).
10. Subject has severe chronic or active infections requiring systemic antibacterial, antifungal or antiviral therapy, including tuberculosis infection.
11. Subject has known Human Immunodeficiency Virus (HIV) infection.
12. Subject has untreated chronic hepatitis B or chronic hepatitis B virus (HBV) carriers with HBV deoxyribonucleic acid (DNA) > 500 IU/mL (2500 copies/mL), or active hepatitis C.
13. Subject has active autoimmune diseases or history of autoimmune diseases that may relapse. Subjects with the following diseases are allowed to be enrolled after further screening: type I diabetes, hypothyroidism managed with hormone replacement therapy only, skin diseases not requiring systemic treatment (such as vitiligo, psoriasis, or alopecia), or diseases not expected to recur in the absence of external triggering factors.
14. Subject has medical conditions requiring systemic treatment with either corticosteroids (>10 mg daily prednisone or equivalent) or other immunosuppressive medications within 14 days of randomization.
15. Subject has any of the following cardiovascular criteria:
a. Evidence of acute or ongoing cardiac ischemia
b. Current symptomatic pulmonary embolism
c. Acute myocardial infarction ≤ 6 months prior to randomization
d. Heart failure of New York Heart Association Classification III or IV ≤ 6 months prior to randomization
e. Grade ≥ 2 ventricular arrhythmia ≤ 6 months prior to randomization
f. Cerebral vascular accident or transient ischemic attack ≤ 6 months prior to randomization
16. Subject has had prior allogeneic stem cell transplantation or organ transplantation.
17. Subject has used any live vaccines against infectious diseases (eg, varicella, zoster, etc.) within 4 weeks (28 days) of randomization. Seasonal influenza vaccines that do not contain live virus are permitted.
18. Subject has used any herbal or patent medicines to control cancer or boost immunity within 14 days of the first study treatment administration.
19. Subject has any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study.
20. Subject has any condition including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study.
21. Subject has any condition that confounds the ability to interpret data from the study.
22. Subject has a contraindication to the planned chemotherapy regimen to be administered on the study. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Progression free survival (PFS) defined as the time from the date of randomization to the date of the first objectively documented tumor progression as assessed by blinded independent central review per 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 |
Every 6 weeks post C1D1 for the first 36 weeks and then every 9 weeks until disease progression, new disease therapy, death or withdrawal of consent. |
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E.5.2 | Secondary end point(s) |
1. Overall survival (OS) defined as the time from the date of randomization to the date of death due to any cause.
2. OS at 24 months defined as the proportion of subjects alive at 24 months after randomization.
3. Objective response rate (ORR) defined as the proportion of subjects in the ITT population who had complete response (CR) or partial response (PR) as assessed by blinded independent central review per RECIST v1.1.
4. Duration of response (DoR) defined as the time from the first occurrence of a documented objective response to the time of relapse, as determined by blinded independent central review per RECIST v1.1, or death from any cause, whichever comes first.
5. Proportion of subjects alive and progression-free at 12 months (APF12) defined as the Kaplan-Meier estimate of progression-free survival (PFS) at 12 months.
6. Proportion of subjects alive and progression-free at 18 months (APF18) defined as the Kaplan-Meier estimate of progression-free survival (PFS) at 18 months.
7. Time to distant metastasis (TTDM) defined as the time from the date of randomization until the first date of distant metastasis or death in the absence of distant metastasis. Distant metastasis is defined as any new lesion that is outside of the radiation field according to RECIST v1.1 or proven by biopsy.
8. Safety and tolerability will be assessed from adverse events (using NCI CTCAE v5.0), laboratory tests, vital signs, ECOG performance status, physical
exams, concomitant medications, and dose modifications.
9. Impact on the selected patientreported lung cancer symptoms (appetite loss, cough, chest pain, dyspnea, and fatigue) assessed by the corresponding domains in EORTC QLQ-C30 and its lung cancer module (EORTC QLQLC13).
10. Proportion of subjects who continue to monotherapy phase defined as proportion of subjects who receive at least one dose of tislelizumab or placebo in the monotherapy phase before progression as determined by blinded independent central review per RECIST v1.1 |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Overall survival (OS): Randomization to death.
2. OS at 24 months: Randomization to 24 months.
3-7. ORR; DoR; APF12; APF18; TTDM will be assessed every 6 weeks post C1D1 for the first 36 weeks and then every 9 weeks until disease progression, new disease therapy, death or withdrawal of consent.
8. Safety and tolerability will be assessed from signature of informed consent through 90 days after the last dose of study treatment.
9. Impact on the selected patientreported lung cancer symptoms will be assessed based on tislelizumab/placebo 21-day cycle and at discontinuation of the study treatment and 30 days after the last dose of tislelizumab/placebo.
10. Proportion of subjects who continue to monotherapy phase: Randomization to the first dose in the monotherapy phase. |
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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 | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
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 | Yes |
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 | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
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) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 3 |
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 | 8 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 108 |
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 |
Belgium |
Canada |
Chile |
China |
Finland |
France |
Germany |
Greece |
Hungary |
Ireland |
Israel |
Italy |
Japan |
Korea, Republic of |
Mexico |
Netherlands |
New Zealand |
Poland |
Portugal |
Romania |
Russian Federation |
Singapore |
Spain |
Switzerland |
Taiwan |
United Kingdom |
United States |
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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
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The End of Trial is defined as either the date of the last visit of the last subject to complete the posttreatment follow-up, or the date of receipt of the last data point from the last subject that is required for primary, secondary and/or exploratory analysis, as prespecified in the protocol, whichever is the later date. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 1 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 5 |
E.8.9.2 | In all countries concerned by the trial days | 0 |