| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Previously untreated locally advanced or metastatic non-small cell lung cancer (NSCLC) |
|
| E.1.1.1 | Medical condition in easily understood language |
| NSCLC that has spread to areas near the lungs or other organs and has not yet been treated by chemotherapy; it is the most common kind of 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 evaluate the efficacy of RO7247669 in combination with platinum-based chemotherapy (Arm A) compared with pembrolizumab plus platinum-based chemotherapy (Arm B) on the basis of progression-free survival (PFS) after randomization
• To evaluate the efficacy of RO7247669 in combination with platinum-based chemotherapy (Arm A) compared with pembrolizumab plus platinum-based chemotherapy (Arm B) on the basis of objective response rate (ORR)
|
|
| E.2.2 | Secondary objectives of the trial |
• To evaluate the efficacy of Arm A compared with Arm B on the basis of overall survival (OS) after randomization, duration of response for participants with confirmed objective response, PFS and OS in participants by programmed death-ligand 1 (PD-L1) expression groups and the change from baseline to Week 12 in patient-reported outcomes of lung cancer symptoms, physical functioning, role functioning, and global health status/quality of life
• To evaluate the safety of Arm A compared with Arm B
• To investigate the pharmacokinetics of RO7247669, pemetrexed, carboplatin, and paclitaxel
• To evaluate the immune response to RO7247669 on the basis of prevalence of anti-drug antibodies (ADAs) to RO7247669 at baseline and incidence of ADAs to RO7247669 during the study |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
• Age ≥ 18 years
• Eastern Cooperative Oncology Group Performance Status of 0 or 1
• Histologically or cytologically documented locally advanced, unresectable (Stage IIIB/IIIC) or metastatic (Stage IV) NSCLC who are not eligible for curative surgery and/or definitive chemoradiotherapy (8th edition of the UICC/AJCC- staging system)
• No prior systemic treatment for metastatic NSCLC
• Known tumor PD-L1 status through a documented local assessment using a health authority-approved PD L1 immunohistochemistry assay
• Confirmed availability of representative tumor specimens in formalin-fixed, paraffin-embedded blocks or 15 unstained serial slides, along with an associated pathology report
• Measurable disease, as defined by Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1)
• Life expectancy ≥ 12 weeks
• Adequate hematologic and end-organ function
• Negative human immunodeficiency viruses (HIV) test at screening
• Negative hepatitis B surface antigen test at screening
• Positive hepatitis B surface antibody (HBsAb) test at screening, or negative HBsAb at screening accompanied by additional select criteria
• Negative hepatitis C virus (HCV) antibody test at screening or positive HCV antibody test by a negative HCV RNA test at screening
• Adequate cardiovascular function
• For female participants of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraception methods with a failure rate of < 1% per year during the treatment period and for 4 months after the final dose of RO7247669, 4 months after the final dose of pembrolizumab, and 6 months after the final dose of platinum-based chemotherapy. Women must refrain from donating eggs during this same period
• For male participants: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods that together result in a failure rate of < 1% per year during the treatment period and for 4 months after the final dose of RO7247669 and 6 months after the final dose of pemetrexed, paclitaxel, and carboplatin. Men must refrain from donating sperm during this same period |
|
| E.4 | Principal exclusion criteria |
• NSCLC known to have a mutation in the epidermal growth factor receptor gene or an anaplastic lymphoma kinase fusion oncogene
• Symptomatic, untreated, or actively progressing central nervous system metastases
• Spinal cord compression not definitively treated with surgery and/or radiation
• History of leptomeningeal disease
• Uncontrolled tumor-related pain
• Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures
• Uncontrolled or symptomatic hypercalcemia
• Active or history of autoimmune disease or immune deficiency
• History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on the screening chest computed tomography scan
• Active tuberculosis (TB)
• Untreated latent TB
• Current treatment with anti-viral therapy for hepatitis B virus (HBV) or HCV
• Significant cardiovascular disease within 3 months prior to randomization
• Major surgical procedure, other than for diagnosis, within 4 weeks prior to initiation of study treatment, or anticipation of need for a major surgical procedure during the study
• History of malignancy other than NSCLC within 5 years prior to randomization
• Severe infection within 4 weeks prior to initiation of study treatment
• Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of study treatment
• Prior allogeneic stem cell or solid organ transplantation
• Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that contraindicates the use of an investigational drug, may affect the interpretation of the results, or may render the patient at high risk from treatment complications
• Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study treatment, or anticipation of need for such a vaccine during study treatment or within 5 months after the final dose of study treatment
• Treatment with investigational therapy within 28 days prior to initiation of study treatment
• Any anti-cancer therapy, including hormonal therapy, within 21 days prior to initiation of study treatment
• Prior treatment with CD137 agonists or immune checkpoint blockade therapies
• Treatment with systemic immunostimulatory agents within 4 weeks or 5 drug-elimination half-lives prior to initiation of study treatment
• Treatment with systemic immunosuppressive medication within 2 weeks prior to initiation of study treatment, or anticipation of need for systemic immunosuppressive medication during study treatment
• History of severe allergic anaphylactic reactions to chimeric or humanized antibodies, fusion proteins, or platinum-containing compounds
• Known hypersensitivity to Chinese hamster ovary cell products or to any component of the RO7247669 or pembrolizumab formulation
• Known allergy or hypersensitivity or other contraindication to any component of the chemotherapy regimen the patient may receive during the study
• Pregnancy or breastfeeding, or intention of becoming pregnant during the study, within 4 months after the final dose of RO7247669 and pembrolizumab, or 6 months after the final dose of paclitaxel, pemetrexed or carboplatin
• • Known targetable c-ROS oncogene 1 (ROS1), BRAFV600E or rearranged during transfection (RET) proto-oncogene genomic aberrations |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1. PFS after randomization, defined as the time from randomization to the first occurrence of disease progression or death from any cause (whichever occurs first), as determined by the investigator according to RECIST v1.1
2. ORR, defined as the proportion of participants with a complete response or a partial response on two consecutive occasions ≥ 4 weeks apart, as determined by the investigator according to RECIST v1.1
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 1-2. Up to approximately 58 months |
|
| E.5.2 | Secondary end point(s) |
1. OS after randomization, defined as the time from randomization to death from any cause
2. Duration of response for participants with confirmed objective response, defined as the time from the first occurrence of a confirmed objective response to disease progression or death from any cause (whichever occurs first), as determined by the investigator according to RECIST v1.1
3. PFS and OS in participants with PD-L1 expression, defined as tumor cells < 1%, 1%-49%, and ≥ 50%, as assessed by retrospective central PD-L1 testing
4. Change from baseline to Week 12 in patient-reported outcomes of lung cancer symptoms, physical functioning, role functioning, and global health status/quality of life, as assessed through the use of the European Organisation for Research and Treatment of Cancer Item Libraries
5. Incidence and severity of adverse events, with severity determined according to the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0
The severity of cytokine release syndrome will also be determined according to the American Society for Transplantation and Cellular Therapy Consensus Grading Scale.
6. Maximum concentration of RO7247669
7. Time of maximum concentration of RO7247669
8. Clearance of RO7247669
9. Volume of distribution at steady state of RO7247669
10. Area under the concentration-time curve RO7247669
11. Half-life of RO7247669
12. Concentrations of RO7247669 in serum at specified timepoints
13. Concentrations of carboplatin (measured as total platin), pemetrexed, and paclitaxel in plasma at specified timepoints
14. Prevalence of ADAs to RO7247669 at baseline and incidence of ADAs to RO7247669 during the study |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1-3. Up to approximately 58 months
4. From baseline to Week 12
5. Up to approximately 58 months
6-12. On Days 1, 8, and 15 of Cycle 1 and on Day 1 of Cycles 2 and beyond (until disease progression)
13. On Day 1 of Cycles 1 and 5
14. From baseline up to approximately 58 months |
|
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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 | Yes |
| 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 | 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.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 33 |
| 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 |
| Brazil |
| Canada |
| Korea, Republic of |
| United States |
| France |
| Spain |
| Germany |
| Italy |
| Belgium |
| Turkey |
| United Kingdom |
|
| E.8.7 | Trial has a data monitoring committee | No |
| 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 this study is defined as the date of the last visit of the last participant in the study/last scheduled procedure shown in the schedule of activities in this study globally or the date at which the last data point required for statistical analysis (i.e., survival) or safety follow up is received from the last participant, whichever occurs later. The end of the study is expected to occur approximately 36 months after the last participant is enrolled. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| 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 | 4 |
| 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 |
Print
