| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Previously Untreated, Locally Advanced, Unresectable Non-Small Cell Lung Cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
| Non-Small Cell Lung Cancer |
|
| 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 | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10061873 |
| E.1.2 | Term | Non-small cell lung cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 PFS as assessed by the Independent Review Committee (IRC) per
Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (v1.1) in the
Intent-to-Treat (ITT) Analysis Set between Arm A (ociperlimab plus tislelizumab
plus cCRT followed by ociperlimab plus tislelizumab) versus Arm C (cCRT followed by durvalumab) in previously untreated, locally advanced, unresectable non-small cell lung cancer (LA NSCLC)
• To compare complete response rate (CRR) by the IRC per RECIST v1.1 in the ITT Analysis Set between Arm A and Arm C in previously untreated, unresectable LA NSCLC
• To compare PFS as assessed by the IRC per RECIST v1.1 in the ITT Analysis Set
between Arm B (tislelizumab plus followed by tislelizumab) versus Arm C in
previously untreated, unresectable LA NSCLC |
|
| E.2.2 | Secondary objectives of the trial |
• To compare overall survival (OS) between Arm A and Arm C
• To compare PFS as assessed by the IRC per RECIST v1.1 in PD-L1-positive
population between Arm A and Arm C
• To compare PFS as assessed by the IRC per RECIST v1.1 between Arm A and
Arm B
• To compare OS between Arm B and Arm C, and between Arm A and Arm B
• To compare CRR as assessed by the investigator per RECIST v1.1 between Arm A and Arm C and to compare CRR as assessed by both the IRC and the investigator per RECIST v1.1 between Arm B and Arm C and between Arm A and Arm B
• To compare overall response rate (ORR) and duration of response (DOR) as assessed by both the IRC and the investigator between Arm A and Arm C, between Arm B and Arm C, and between Arm A and Arm B
• To compare PFS as assessed by the investigator per RECIST v1.1 between Arm A and Arm C, between Arm B and Arm C, and between Arm A and Arm B
[More are listed in the study protocol] |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Age ≥ 18 years on the day of signing the ICF (or the legal age of consent in the jurisdiction in which the study is taking place).
2. Ability to provide written informed consent and to understand and agree to comply with the requirements of the study and the schedule of assessments.
3. Patient has newly diagnosed, histologically confirmed, locally advanced, Stage III unresectable NSCLC (AJCC Cancer Staging Manual 2017).
a. Tumors of mixed non-small cell histology will be categorized by the predominant cell type; if small cell elements are present, the patient is ineligible.
b. Staging will be confirmed at screening by positron emission tomography (PET)/computed tomography (CT) and brain imaging by magnetic resonance imaging (MRI) or computed tomography (CT) with contrast.
c. Fluorodeoxyglucose (FDG)-PET/CT will be performed for the whole body, or sufficient to rule out distant metastases (eg, from skull base to knees), to exclude distant disease and confirm that patients are in Stage III. If the CT scan portion is with contrast and is of sufficiently high quality, a separate CT scan at screening can be skipped.
d. While centers are encouraged to obtain tissue confirmation of lymph node metastases in N2 or N3 disease, the tumor board/multidisciplinary team in individual cases may dispense with this procedure (AJCC Cancer Staging Manual 2017).
4. Measurable disease as assessed by RECIST v1.1.
5. Patients must submit archival tumor tissue (formalin-fixed paraffin-embedded [FFPE] block containing tumor [preferred] or approximately 15 [at least 6] freshly cut unstained FFPE slides) with an associated pathology report, or agree to a tumor biopsy for determination of PD-L1 expression and other biomarker analyses (Fresh tumor biopsies are strongly recommended at baseline in patients with readily accessible tumor lesions and who consent to the biopsies. An additional ≥ 6 slides are required if EGFR mutation status needs to be tested in a central laboratory). PD-L1 expression in TC will be prospectively assessed via VENTANA PD-L1 (SP263) assay at a central laboratory. Only patients who have evaluable PD-L1 expression results are eligible.
6. ECOG Performance Status of 0 or 1.
7. Patients must have adequate organ function as indicated by the following screening laboratory values obtained within 7 days before the first study treatment:
a. Patients must not have required blood transfusion or growth factor support ≤ 14 days before sample collection at screening for the following:
i. Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
ii. Platelets ≥ 100 x 109/L
iii. Hemoglobin ≥ 90 g/L or ≥ 5.6 mmol /L (Note: Criteria must be met without a transfusion within 14 days of obtaining the sample)
b. Calculated creatinine clearance (CrCl) ≥ 60 mL/min (Cockcroft-Gault formula) for patients receiving cisplatin and ≥ 45 mL/min (Cockcroft-Gault formula) for patients receiving carboplatin or pemetrexed.
c. Serum total bilirubin ≤ 1.5 x upper limit of normal (ULN) (total bilirubin must be < 3 x ULN for patients with Gilbert syndrome).
d. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x ULN.
8. Females of childbearing potential must consent to use a highly effective method of birth control for the duration of the study, and for ≥ 120 days after the last dose of ociperlimab and tislelizumab in Arm A or tislelizumab in Arm B, or at least 3 months after the last dose of durvalumab, or at least 180 days after the last dose of chemotherapy or radiotherapy, and have a negative urine or serum pregnancy test ≤ 7 days before the first dose of any of the study treatment.
9. Nonsterile males must consent to use a highly effective method of birth control for the duration of the study and for ≥ 120 days after the last dose of ociperlimab and tislelizumab in Arm A or tislelizumab in Arm B, or at least 3 months after the last dose of durvalumab, or at least 180 days after the last dose of chemotherapy or radiotherapy
a. A sterile male is defined as one for whom azoospermia has been previously demonstrated in a semen sample examination as definitive evidence of infertility.
b. Males with known “low sperm counts” (consistent with “sub-fertility”) are not to be considered sterile for purposes of this study. |
|
| E.4 | Principal exclusion criteria |
1. Any prior therapy for lung cancer, including but not limited to chemotherapy, radiotherapy, targeted therapy, biologic therapy, or immunotherapy.
2. Any prior radiotherapy to the thorax, including radiotherapy to the esophagus, mediastinum, or for breast cancer.
3. Prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, TIGIT, or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways.
4. Diagnosed with NSCLC that harbors an EGFR-sensitizing mutation or ALK gene translocation.
a. For non-squamous and squamous NSCLC, patients with known EGFR mutation status or ALK translocation who are sensitive to available targeted inhibitor therapy are excluded.
b. For non-squamous NSCLC, patients with unknown EGFR mutation status will be required to undergo a tissue-based EGFR test locally or at a central laboratory before enrollment. Patients with sensitive EGFR mutation status will be excluded. Patients with unknown ALK status may be enrolled.
c. Patients with squamous NSCLC and unknown EGFR mutation or ALK status will not be required to be tested at screening.
5. Any patient for whom the clinician plans to perform neoadjuvant therapy (eg chemotherapy, chemoradiotherapy) followed by definite surgery, or induction therapy (eg chemotherapy) followed by definitive chemoradiotherapy will be considered ineligible.
6. Patient’s radiation treatment plans are likely to encompass a volume of whole lung (total lung volume minus PTV) receiving ≥ 20 Gy in total (V20) of more than 35% of lung volume.
7. Active autoimmune diseases or history of autoimmune diseases that may relapse.
8. Any active malignancy ≤ 2 years before the first dose of study treatment except for the specific cancer under investigation in this study and any locally recurring cancer that has been treated curatively.
9. Any condition that required systemic treatment with either corticosteroids (> 10 mg daily of prednisone or equivalent) or other immunosuppressive medication ≤ 14 days before the first dose of study treatment.
10. 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 the first dose of study treatment.
11. Uncontrollable pleural effusion, pericardial effusion, or ascites requiring frequent drainage (recurrence within 2 weeks of intervention).
12. History of interstitial lung disease, non-infectious pneumonitis or uncontrolled lung diseases including pulmonary fibrosis, acute lung diseases, etc.
13. Infection (including tuberculosis infection, etc) requiring systemic antibacterial, antifungal or antiviral therapy within 14 days before the first dose of study treatment.
14. Untreated chronic hepatitis B or chronic HBV carriers with HBV DNA > 500 IU/mL (or > 2500 copies/mL) at screening.
15. Patients with active hepatitis C.
16. Known history of HIV infection.
17. Any major surgical procedure ≤ 28 days before the first dose of study treatment. Patients must have recovered adequately from the toxicity and/or complications from the intervention before the first dose of study treatment.
18. Prior allogeneic stem cell transplantation or organ transplantation.
19. Any of the following cardiovascular risk factors:
a. Cardiac chest pain, defined as moderate pain that limits instrumental activities of daily living, ≤ 28 days before the first dose of study treatment.
b. Pulmonary embolism ≤ 28 days before the first dose of study treatment.
c. Any history of acute myocardial infarction ≤ 6 months before the first dose of study treatment.
d. Any history of heart failure meeting New York Heart Association (NYHA) Classification III or IV ≤ 6 months before the first dose of study treatment.
e. Any event of ventricular arrhythmia ≥ Grade 2 in severity ≤ 6 months before the first dose of study treatment.
f. Any history of cerebrovascular accident ≤ 6 months before the first dose of study drug.
g. Uncontrolled hypertension that cannot be managed by standard anti-hypertension medications ≤ 28 days before the first dose of study treatment.
h. Any episode of syncope or seizure ≤ 28 days before the first dose of study treatment.
20. Known left ventricular ejection fraction < 40%
21. A history of severe hypersensitivity reactions to other monoclonal antibodies.
22. A history of allergic reactions to cisplatin, carboplatin, other platinum-containing compounds, etoposide, paclitaxel, or pemetrexed.
23. Receipt of any immunotherapy (eg, interleukin, interferon, thymosin, etc) or any investigational therapies within 14 days or 5 half-lives (whichever is longer) before the first dose of study treatment.
24. Patients with toxicities (as a result of prior anticancer therapy) that have not recovered to baseline or stabilized, except for AEs not considered a likely safety risk (eg, alopecia and specific laboratory abnormalities).
[More listed in study protocol] |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
• PFS by IRC in the ITT Analysis Set, defined as the time from the date of randomization to the date of first documentation of disease progression assessed by the IRC per RECIST v1.1 or death, whichever occurs first
• CRR by IRC in the ITT Analysis Set, defined as the proportion of patients who achieve a complete response (CR) assessed by the IRC per RECIST v1.1
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
• OS in both the ITT Analysis Set and the PD L1 Positive Analysis Set, defined as the time from the date of randomization until the date of death due to any cause
• PFS by IRC in the PD L1 Positive Analysis Set, defined as the time from the date of randomization to the date of first documentation of disease progression assessed by the IRC per RECIST v1.1 or death, whichever occurs first
• CRR in the ITT Analysis Set, defined as the proportion of patients who achieve a CR assessed by both the IRC and the investigator per RECIST v1.1
• ORR in both the ITT Analysis Set and the PD-L1-Positive Analysis Set, defined as the proportion of patients who achieve a CR or partial response (PR) assessed by both the IRC and the investigator per RECIST v1.1
• DOR in both the ITT Analysis Set and the PD-L1-Positive Analysis Set, defined as the time from the first determination of a confirmed objective response assessed by both the IRC and the investigator per RECIST v1.1 until the first documentation of disease progression or death, whichever occurs first
• PFS by the investigator in both the ITT Analysis Set and the PD-L1-Positive Analysis Set, defined as the time from the date of randomization to the date of first documentation of disease progression assessed by the investigator per RECIST v1.1 or death, whichever occurs first
• Time to death or distant metastasis (TTDM) in both the ITT Analysis Set and the PD-L1-Positive Analysis Set, defined as the time from the date of randomization until the first date of distant metastasis assessed by both the IRC and the investigator or death. Distant metastasis is defined as any new lesion that is outside of the radiation field per RECIST v1.1 or proven by biopsy
• Safety and tolerability, defined as AEs (using NCI CTCAE v5.0), laboratory tests, vital signs, ECOG Performance Status, physical examinations, concomitant medications, and dose modifications
• HRQoL in both the ITT Analysis Set and the PD-L1-Positive Analysis Set, measured via patient-reported outcomes (PROs) using EORTC QLQ-C30, EORTC QLQ-LC13, and EQ-5D-5L
• Serum concentrations of ociperlimab and tislelizumab at specified timepoints
• Immunogenic responses to ociperlimab and tislelizumab evaluated through detection of anti-drug antibodies
• Evaluate PD-L1 and TIGIT expression in archival and/or fresh tumor tissues before study treatment or at disease progression/reoccurrence, and their association with clinical efficacy. |
|
| 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 | 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 | 9 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 59 |
| 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 |
| Japan |
| Korea, Republic of |
| Russian Federation |
| Taiwan |
| United States |
| Belgium |
| France |
| Germany |
| Italy |
| Netherlands |
| Poland |
| Romania |
| Spain |
| Switzerland |
|
| 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 | 11 |
| E.8.9.1 | In the Member State concerned days | 27 |
| 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 | 11 |
| E.8.9.2 | In all countries concerned by the trial days | 27 |
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