| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Locally Advanced, Unresectable, PD L1 Selected Non- Small Cell Lung Cancer Where Disease Has Not Progressed After Concurrent Chemoradiotherapy |
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| E.1.1.1 | Medical condition in easily understood language |
| Non-Small Cell Lung Cancer |
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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 | 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) |
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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 |
• Compare progression-free survival (PFS) as assessed by the Independent Review Committee (IRC) per Response Evaluation Criteria in Solid Tumors (RECIST) Version (v) 1.1 in ociperlimab plus tislelizumab (Arm A) versus Durvalumab (Arm C) among patients with locally advanced non-small cell lung cancer (LA NSCLC) whose disease has not progressed after concurrent chemoradiotherapy (cCRT) and with PD-L1 ≥50%
• Compare PFS as assessed by the IRC per RECIST v1.1 in ociperlimab plus tislelizumab (Arm A) versus Durvalumab (Arm C) among patients with LA NSCLC whose disease has not progressed after cCRT and with PD-L1≥1%
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| E.2.2 | Secondary objectives of the trial |
• Compare overall survival (OS) in Arm A versus Arm C among patients (pts) with PD-L1 ≥ 50%
• Compare OS in Arm A versus Arm C among pts with PD-L1 ≥ 1%
• Evaluate overall response rate (ORR) and duration of response (DOR) in Arm A versus Arm C among pts with PD-L1 ≥ 50% and ≥ 1%
• Evaluate time to death or distant metastasis (TTDM) in Arm A versus Arm C among pts with PD-L1 ≥ 50% and ≥ 1%
• Compare PFS2 in Arm A versus Arm C among pts with PD-L1 ≥ 50% and ≥ 1%
• Evaluate safety and tolerability in 3 treatment arms among pts with PD-L1 ≥ 50% and ≥ 1%
• Compare impact of treatments on pt health related quality of life (HRQoL) in Arm A versus Arm C among pts with PD-L1 ≥50% and ≥ 1%
• Characterize the pharmacokinetics (PK) of ociperlimab and tislelizumab
• Assess host immunogenicity to ociperlimab and tislelizumab
• Evaluate association of PD-L1 and TIGIT expression with clinical efficacy to ociperlimab plus tislelizumab or tislelizumab or durvalumab only
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| 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 histologically or cytologically confirmed, locally advanced, unresectable Stage III NSCLC (AJCC Cancer Staging Manual 2017, derived from IASLC) prior to initiation of cCRT.
4. Patients must have completed at least 2 cycles of platinum-based chemotherapy concurrent with radiotherapy. For patients who are recovering from toxicities associated with prior treatment, the first dose of study treatment may be delayed up to 42 days from the end of the cCRT. It is recommended to screen the patients within 14 days after the completion of cCRT.
a. The platinum-based chemotherapy regimen must contain cisplatin or carboplatin, and may contain one of the following agents: etoposide, vinblastine, vinorelbine, taxane (paclitaxel or docetaxel), or pemetrexed, according to the local standard of care regimens. If a patient was receiving a weekly chemotherapy regimen, platinum-based chemotherapy of at least 4 weeks should be completed.
b. The last dose of chemotherapy must be administered no later than the last dose of radiotherapy. Consolidation chemotherapy is not allowed after radiotherapy; but induction chemotherapy no more than 2 cycles before cCRT is allowed.
c. Where possible, chemotherapy regimens should be given according to National Comprehensive Cancer Network (NCCN) Guidelines, European Society for Medical Oncology (ESMO) Guidelines, Chinese Society of Clinical Oncology (CSCO) Guidelines, Japan Lung Cancer Society (JLCS) Guidelines, or other local guidelines if applicable.
d. Patients must have received a total dose of radiation of 60 ± 10% Gy (54 to 66 Gy), as part of the CRT.
e. The minimum technical standard for radiotherapy is 3D conformal radiotherapy (3D CRT) with CT planning. Intensity modulated radiotherapy (IMRT) is recommended.
f. RT dose received by organs is recommended to be (the medical monitor needs to be consulted to confirm eligibility for the patients who received higher RT dose for the organs below):
• Spinal cord: max dose ≤ 48 Gy
• Lung: V20 ≤ 35%, mean dose ≤ 20 Gy
• Esophagus: mean dose ≤ 34Gy
• Heart: V50 ≤ 25%, mean dose ≤ 20 Gy
5. Patients must have not experienced PD following definitive, platinum based cCRT.
6. Agree to provide archival tissue (formalin-fixed paraffin-embedded block containing tumor [preferred] or approximately 6 to 15 freshly cut unstained slides) or fresh biopsy obtained prior to cCRT (if archival tissue is not available) for prospective central evaluation of PD-L1 levels and retrospective analysis of other biomarkers. PD-L1 status will be assessed centrally in either a previously obtained archival tumor tissue or fresh tissue obtained from a biopsy collected prior to the first dose of cCRT via VENTANA PD L1 (SP263) assay. Only patients with PD L1 ≥ 1% of TC are eligible.
7. ECOG Performance Status of 0 or 1.
8. Patients must have adequate organ function as indicated by the following screening laboratory values obtained within 7 days before randomization:
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 ≥ 75 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. Serum creatinine ≤ 1.5 x upper limit of normal (ULN), or for patients whose serum creatinine > 1.5×ULN, estimated Glomerular Filtration Rate (GFR) by Chronic Kidney Disease Epidemiology Collaboration (CKD EPI) equation or Calculated creatinine clearance (CrCl) by Cockcroft Gault
(CG) equation ≥ 30 mL/min.
c. Serum total bilirubin ≤ 1.5 x 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.
e. INR and aPPT ≤ 1.5 x ULN. This applies only to patients who are not receiving therapeutic anticoagulation; patients receiving therapeutic anticoagulation should be on a stable dose.
[Further inclusion criteria, relating to contraception, can be found in the protocol.]
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| E.4 | Principal exclusion criteria |
1. Prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, TIGIT, or any other antibody or drugs specifically targeting T-cell co-stimulation or checkpoint pathways.
2. Diagnosed with NSCLC that harbors an EGFR-sensitizing mutation, ALK gene translocation, ROS1 gene translocation or RET gene rearrangement.
a. For nonsquamous and squamous NSCLC, patients with known EGFR mutation status, ALK translocation, ROS1 translocation, or RET rearrangement who are sensitive to available targeted inhibitor therapy are excluded.
b. For nonsquamous NSCLC, patients with unknown EGFR mutation status will be required to undergo a tissue-based EGFR test locally or at a central laboratory before randomization. An additional ≥ 6 slides are required if EGFR mutation status needs to be tested in a central laboratory. Patients with sensitive EGFR mutation status will be excluded. Patients with unknown ALK, ROS1, or RET status may be enrolled.
c. Patients with squamous NSCLC and unknown EGFR, ALK, ROS1, or RET status will not be required to be tested before randomization.
3. Distant metastasis identified by imaging assessment and/or other examinations after definitive, platinum-based cCRT.
4. Patients who received chemotherapy and radiotherapy with ≤ 1 cycle overlap for LA NSCLC.
5. Patients who received systemic anticancer treatment besides the specified cCRT.
6. Any unresolved toxicity CTCAE > Grade 2 from the prior cCRT. Patients with irreversible toxicity that is not reasonably expected to be exacerbated by study treatment may be included (eg, hearing loss).
7. Patients with any grade pneumonitis from prior cCRT.
8. Active autoimmune diseases or history of autoimmune diseases that may relapse. Note: Patients with the following diseases are not excluded and may proceed to further screening:
a. Controlled Type I diabetes.
b. Hypothyroidism (provided it is managed with hormone replacement therapy only).
c. Controlled celiac disease.
d. Skin diseases not requiring systemic treatment (eg, vitiligo, psoriasis, alopecia).
e. Any other disease that is not expected to recur in the absence of external triggering factors.
9. 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 (eg, resected basal or squamous cell skin cancer, superficial bladder cancer, carcinoma in situ of the cervix or breast).
10. Any condition that required systemic treatment with either corticosteroids (> 10 mg daily of prednisone [in Japan, prednisolone] or equivalent) or other immunosuppressive medication ≤ 14 days before the first dose of study treatment.
Note: Patients who are currently or have previously been on any of the following steroid regimens are not excluded:
a. Adrenal replacement steroid (dose ≤ 10 mg daily of prednisone [in Japan, prednisolone] or equivalent).
b. Topical, ocular, intra-articular, intranasal, or inhaled corticosteroid with minimal systemic absorption.
c. Short course (≤ 7 days) of corticosteroid prescribed prophylactically (eg, for contrast dye allergy) or for the treatment of a non-autoimmune condition (eg, delayed-type hypersensitivity reaction caused by contact allergen.
11. 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.
12. Uncontrollable pleural effusion, pericardial effusion, or ascites requiring frequent drainage (recurrence within 2 weeks of intervention). Note for sites in Germany: patients with malignant pleural or pericardial effusion or ascites are excluded regardless of whether it is uncontrollable or not.
13. History of interstitial lung disease, non-infectious pneumonitis or uncontrolled lung diseases including pulmonary fibrosis, acute lung diseases, etc.
14. Infection (including tuberculosis infection, etc) requiring systemic antibacterial, antifungal, or antiviral therapy within 14 days before the first dose of study treatment.
15. Untreated chronic hepatitis B or chronic HBV carriers with HBV DNA > 500 IU/mL (or > 2500 copies/mL) at screening.
16. Patients with active hepatitis C.
17. Known history of HIV infection. Note for sites in Germany and where required by Health Authority or local guidance: An HIV serology test (including antigen and/or antibodies) will be conducted at baseline for the patients with unknown HIV status and patients with positive HIV test will be excluded.
18. 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.
19. Prior allogeneic stem cell transplantation or organ transplantation.
[More listed in study protocol]
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Progression-free survival (PFS) by the Independent Review Committee (IRC), 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 |
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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) |
1 Overall Survival (OS) defined as the time from the date of randomization until the date of death due to any cause
2 Overall response rate (ORR), defined as the proportion of patients who achieve a complete response (CR) or partial response (PR) assessed by both the IRC and investigators per RECIST v1.1
3 Duration of response (DOR), defined as the time from the first determination of a confirmed objective response assessed by both the IRC and investigators per RECIST v1.1 until the first documentation of disease progression or death, whichever occurs first
4 Time to death or distant metastasis (TTDM), defined as the time from the date of randomization until the first date of distant metastasis assessed by both the IRC and investigators, 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.
5 PFS2, defined as the time from randomization to the disease progression after next line of treatment, or death from any cause, whichever occurs first
6 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
7 HRQoL, measured via patient-reported outcomes (PROs) using EORTC QLQ-C30, EORTC QLQ-LC13, and EQ 5D 5L questionnaires
8 Serum concentrations of ociperlimab and tislelizumab at specified Timepoints
9 Immunogenic responses to ociperlimab and tislelizumab evaluated through detection of antidrug antibodies
10 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 |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | No |
| 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 | 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 86 |
| 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 |
| Israel |
| Japan |
| United States |
| Switzerland |
| Russian Federation |
| Belgium |
| France |
| Germany |
| Italy |
| Netherlands |
| Poland |
| Romania |
| Spain |
| Korea, Republic of |
| Taiwan |
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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 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.
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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 | 5 |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | 30 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 10 |
| E.8.9.2 | In all countries concerned by the trial days | 30 |
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