| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Advanced or metastatic squamous cell carcinoma of the esophagus |
|
| E.1.1.1 | Medical condition in easily understood language |
| Squamous cell carcinoma forms in the thin, flat cells lining the inside of the esophagus. It is most often found in the upper and middle part of the esophagus |
|
| 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 | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10015362 |
| E.1.2 | Term | Esophageal cancer |
| E.1.2 | System Organ Class | 100000004864 |
|
| 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 RO7121661 and RO7247669 compared with nivolumab based on overall survival |
|
| E.2.2 | Secondary objectives of the trial |
• To evaluate the safety and tolerability of RO7121661 and RO7247669 compared with nivolumab
• To evaluate the efficacy of RO7121661 and RO7247669 compared with nivolumab based on objective response rate (ORR), disease control rate (DCR), duration of response (DoR), progression-free survival (PFS) and proportion of participants reporting clinically meaningful improvement in global health status/quality of life, emotional functioning, social functioning and dysphagia
• To investigate the pharmacokinetics (PK) of RO7121661, RO7247669, and nivolumab
• To evaluate the immune response after administration of RO7121661, RO7247669, and nivolumab
• To assess treatment-induced pharmacodynamic (PD) changes (PD Biomarkers) in peripheral blood and tumor microenvironment
• To assess baseline characteristics in the tumor microenvironment as predictive biomarkers of response |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
• Age >=18 years
• Participants whose major lesion was histologically confirmed esophageal squamous-cell carcinoma (ESCC)
• Patients who have previously received 1 line of treatment with either a fluoropyrimidine- and platinum- or a taxane- and platinum-based regimen in non-curative intention prior to randomization or patients who received treatment with a fluoropyrimidine-/taxane- and platinum-based regimen in curative intention and had recurrence within 24 weeks after the last dose of the treatment.
• Radiologically measurable disease according to Response evaluation criteria in solid tumors version 1.1 (RECIST v1.1). Previously irradiated lesions should not be counted as target lesions unless clearly progressed after the radiotherapy
• Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1
• A life expectancy of >=12 weeks
• Tissue samples must be provided for analysis of anti–programmed death-1 (PD-L1) tumor positivity.
• Adequate cardiovascular function
• AEs from any prior radiotherapy, chemotherapy, or surgical procedure must have resolved to Grade <=1, except alopecia (any grade), vitiligo, endocrinopathy managed with replacement therapy, and Grade 2 peripheral neuropathy
• Adequate hematological function
• Adequate liver function
• Adequate renal function
• Serum albumin >=25 grams per liter (g/L),
• For participants not receiving therapeutic anticoagulation: prothrombin time (PT) and activated partial thromboplastin time <=1.5*Upper limit of normal (ULN), for participants receiving therapeutic anticoagulation: stable anticoagulant regimen
• Male and/or female participants. A female participant is eligible to participate if she is not pregnant, not breastfeeding, not a woman of childbearing potential (WOCBP) and WOCBP, who agree to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods during the treatment period and for at least 5 months after the final dose of study drug and have a negative pregnancy test (blood) within the 7 days prior to randomization. A male participant must remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures such as a condom plus an additional contraceptive method during the treatment period and for at least 5 months after the final dose of study drug |
|
| E.4 | Principal exclusion criteria |
• Pregnancy, lactation, or breastfeeding
• Known hypersensitivity to any of the components of RO7121661, RO7247669, or nivolumab, including but not limited to, hypersensitivity to Chinese hamster ovary cell products or other recombinant human or humanized antibodies
• Patients with significant malnutrition. Patients whose nutrition has been well controlled for >=28 days prior to randomization may be enrolled
• Evidence of complete esophageal obstruction not amenable to treatment
• Higher risk of bleeding or fistula caused by esophageal lesions invading adjacent organs (aorta or tracheobronchial tree)
• Symptomatic central nervous system (CNS) metastases
• Spinal cord compression not definitively treated with surgery and/or radiation or without evidence that disease has been clinically stable for >=14 days prior to randomization
• Active or history of carcinomatous meningitis/leptomeningeal disease
• Asymptomatic CNS primary tumors or metastases if they have requirement for steroids or enzyme inducing anticonvulsants in the last 28 days prior to randomization
• Uncontrolled tumor-related pain. Participants requiring pain medication must be on a stable regimen at study entry
• Patients with an active second malignancy
• Evidence of significant, uncontrolled concomitant diseases that could affect compliance with the protocol or interpretation of results, including diabetes mellitus, history of relevant pulmonary disorders, known autoimmune diseases or immune deficiency, or other diseases with ongoing fibrosis (such as scleroderma, pulmonary fibrosis, emphysema, neurofibromatosis, palmar/plantar fibromatosis, etc.).
• Encephalitis, meningitis, or uncontrolled seizures in the year prior to informed consent
• Significant cardiovascular/cerebrovascular disease within 6 months prior to randomization
• Known active or uncontrolled bacterial, viral, fungal, mycobacterial (including but not limited to tuberculosis [TB] and typical mycobacterial disease), parasitic, or other infection (excluding fungal infections of nail beds) or any major episode of infection requiring treatment with intravenous (IV) antibiotics or hospitalization (relating to the completion of the course of antibiotics, except if for tumor fever) within 28 days prior to randomization
• Known clinically significant liver disease, including alcoholic hepatitis, cirrhosis, and inherited liver disease.
• Major surgical procedure or significant traumatic injury (excluding biopsies) within 28 days prior to randomization, or anticipation of the need for major surgery during the course of the study
• Any other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or render the participant at high risk from treatment complications
• Dementia or altered mental status that would prohibit informed consent
• Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (expected to occur once monthly or more frequently).
• Active or history of autoimmune disease or immune deficiency
• Positive human immunodeficiency virus (HIV) test at screening
• Positive hepatitis B surface antigen (HBsAg) or positive total hepatitis B core antibody (HBcAb) test at screening
• Positive hepatitis C virus (HCV) antibody test at screening
• Prior cancer therapy with any immunomodulatory agents including checkpoint inhibitor (CPIs) (such as anti-PDL1/PD1, anti-CTLA-4, anti-LAG3, anti-TIM3)
• Vaccination with live vaccines within 28 days prior to randomization, or anticipation that a live attenuated vaccine will be required during the study
• Treatment with therapeutic oral or IV antibiotics within 14 days prior to randomization
• Concurrent therapy with any other investigational drug (defined as treatment for which there is currently no regulatory authority approved indication) 28 days or 5 half-lives of the drug (whichever is shorter) prior to randomization
• Treatment with immune-modulating and immune suppressive agents/medication 5 half-lives or 28 days (whichever is shorter) prior to randomization
• Regular immunosuppressive therapy (i.e., for organ transplantation, chronic rheumatologic disease)
• Radiotherapy within the last 28 days before start of study drug treatment is not allowed, with the exception of limited palliative radiotherapy
• Prior treatment with adoptive cell therapies, such as Chimeric antigen receptor T cells (CAR-T) therapies |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 1. From randomization to death (approximately 27 months) |
|
| E.5.2 | Secondary end point(s) |
1. Frequency, and severity of adverse events (AEs) graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 (NCI-CTCAE v5.0)
2. ORR, defined as the proportion of participants with an objective response (i.e., complete response [CR] or partial response [PR]), according to RECIST v1.1
3. DCR defined as ORR plus stable disease rate (SDR)
4. DoR for participants with ORR, defined as the time from the first occurrence of a documented objective response to disease progression according to RECIST v1.1 or death from any cause, whichever occurs first
5. PFS defined as the time from randomization to the first occurrence of progression as determined according to RECIST v1.1 or death during the treatment period or within 60 days of the last tumor assessment after treatment discontinuation from any cause, whichever occurs first
6. Percentage of participants reporting clinically meaningful improvement in global health status/quality of life, emotional functioning, social functioning and dysphagia as measured by the European Organisation for Research and Treatment of Cancer (EORTC) Quality of life questionnaire (QLQ)-C30, defined as an improvement of at least 10 points
7. Percentage of participants reporting clinically meaningful improvement in global health status/quality of life, emotional functioning, social functioning and dysphagia as measured by the EORTC-QLQ-IL97, defined as an improvement of at least 10 points
8. Percentage of participants reporting clinically meaningful improvement in global health status/quality of life, emotional functioning, social functioning and dysphagia as measured by the EORTC-QLQ-OES-18, defined as an improvement of at least 10 points
9. Serum concentrations of RO7121661
10. Serum concentrations of RO7247669
11. Serum concentrations of nivolumab
12. Incidence and titer of anti-drug antibodies (ADAs) against RO7121661 during the study relative to the prevalence of ADAs at baseline
13. Incidence and titer of ADAs against RO7247669 during the study relative to the prevalence of ADAs at baseline
14. Incidence and titer of ADAs against nivolumab during the study relative to the prevalence of ADAs at baseline
15. Changes from baseline in the phenotype and activation status (CD4/CD8 HLA-DR+Ki67+) of T cell subsets in the peripheral blood
16. Changes from baseline such as CD8 T cell infiltration, proliferation (CD8+Ki67+) in the tumor microenvironment
17. Baseline PDL1, CD8+PD1+, CD8+TIM3+, and CD8+LAG3+ expression in the tumor microenvironment |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1-5. Up to 27 months
6. Day 1 of Cycles 1, 4, 7, and 10 (and then every 3 months until the completion of the first year post discontinuation)
7. Day 1 of Cycles 1, 2, 3, 5, 6, 8 and 9
8. Day 1 of Cycles 1, 2, 3, 4, 5, 6, 7, 8 and 9 (and then every 3 months until the completion of the first year post discontinuation)
9-11. Days 1 and 8 of Cycle 1; Day 1 of Cycles 2, 3, 4; Days 1 and 8 of Cycle 5; and then Day 1 of subsequent cycles
12-14. Day 1 of Cycles 1, 2, 3, 4, 5, 7 and then Day 1 of every 3 cycles
15. Screening (Day -28 to -1) and Day 1 of Cycles 1, 2, 3, 5, 9 and then Day 1 of every 3 cycles
16: Based on an archival sample or at Screening (Day-28 to -1) and Cycle 3 Day 1
17. Based on an archival sample or at Screening (Day-28 to -1) |
|
| 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 | Yes |
| 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 | 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 38 |
| 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 |
| Korea, Republic of |
| Russian Federation |
| Singapore |
| Taiwan |
| Thailand |
| Turkey |
| Ukraine |
| Belgium |
| Denmark |
| France |
| Germany |
| Hungary |
| Italy |
| Netherlands |
| Poland |
| Spain |
| United Kingdom |
| Czechia |
|
| 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 the study will occur when all of the following criteria have been met:
• The required number of deaths for the primary analysis of OS has been observed.
• The last participant, last visit has occurred.
The Sponsor has the right to terminate this study at any time. Further information can be found in Section 4.3 in the protocol. |
|
| 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 | 4 |
| 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 | 4 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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