| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Advanced/metastatic solid tumours |
|
| E.1.1.1 | Medical condition in easily understood language |
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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 | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10049280 |
| E.1.2 | Term | Solid tumour |
| E.1.2 | System Organ Class | 100000004864 |
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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 aim of this study is to assess the efficacy of BI 754091 in combination with other checkpoint inhibitors or anticancer medications in diverse tumour type cohorts. |
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| E.2.2 | Secondary objectives of the trial |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Master Protocol:
1.Provision of signed and dated, written Master informed consent form (ICF) prior to any trial-specific procedures, sampling, or analyses.
2. Several cohorts of patients with various solid tumours have been defined. Details are given in the respective treatment-specific Modules.
3. Patient moving from one module to another must have prior irAEs resolved to a degree that would allow for restart of checkpoint inhibitor therapy according to the irAE management guidelines in the protocol.
4. Patient ≥18 years of age at the time of signature of the ICF.
5. Eastern Cooperative Oncology Group (ECOG) score: 0 to 1.
6. Patient must agree to a pre-treatment biopsy (if archival tissue is not available) and on-treatment tumour biopsy.
7. Life expectancy of at least 12 weeks after the start of the treatment according to the Investigator’s judgement.
8. Male or female patients. Women of childbearing potential (WOCBP)1 and men able to father a child must be willing and able to use highly effective methods of birth control (that result in a low failure rate of less than 1% per year when used consistently and correctly) during trial participation and for at least 6 months after the last administration of trial medication. Acceptable highly effective methods of contraception include total sexual abstinence when this is in line with the preferred and usual lifestyle of the study participant (periodic abstinence such as calendar, ovulation, symptothermal, post-ovulation methods and withdrawal are not acceptable methods of contraception), an intrauterine device or intrauterine hormone-releasing system, bilateral tubal ligation, and vasectomised partner (with post-vasectomy proof of absence of sperm). Male patients with partners of childbearing potential must agree to use condoms and ensure their partners are using an additional highly-effective method of birth control, during the trial and until at least 6 months after the end of the trial treatment.
Module A:
1.Histologically confirmed diagnosis of one of the following cohorts:
· GEC - Locally advanced, unresectable or metastatic gastric adenocarcinoma or gastro oesophageal adenocarcinoma (GEC) (defined as primary tumour localisation below the gastro- oesophageal junction (GEJ) with prior anti-PD-1 or anti-PD-L1 based treated tumour.
Module A and Module C:
· Patients with secondary resistance to anti-PD-1 or anti-PD-L1 based therapy: Any advanced or metastatic solid tumour with previously anti-PD-1 or anti-PD-L1 based treatment who progressed after achieving benefit
· Patients with primary resistance to anti-PD-1 or anti-PD-L1 based therapy: Select advanced or metastatic solid tumour types with previous anti-PD- 1/PD-L1 based treated tumour without achieving benefit.
· All patients must have measurable lesions according to RECIST v1.1
· Patient must agree to pre- and on-treatment tumour biopsies. If archived tumour tissue is available from the last treatment failure, sections may be supplied instead of a pre-treatment biopsy.
Module C:
Histologically confirmed diagnosis of one of the following cohorts:
· GEC: Patients with locally advanced, unresectable or metastatic gastric adenocarcinoma or gastro-oesophageal adenocarcinoma with ≥1 prior systemic treatment, excluding prior anti-PD-1 or anti-PD-L1 based treatment.
· CRC: Locally advanced, unresectable or metastatic second line or greater, microsatellite stable (MSS) colorectal cancer with no prior anti-PD-1 or anti-PD-L1 based treatment.
· Advanced Endometrial cancer: Patients with advanced endometrial carcinoma that is not microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) and who have documented disease progression following one line of chemotherapy and are not candidates for curative surgery or radiation and have not been treated previously with anti-PD1 or anti-PDL1. Patients may have received up to one additional line of chemotherapy if given in the neoadjuvant or adjuvant treatment setting. Patients who have just received one line of chemotherapy in the neoadjuvant or adjuvant treatment setting and progressed without subsequent treatment are also eligible. |
|
| E.4 | Principal exclusion criteria |
Master Protocol:
1.Any investigational treatment anti-tumour treatment within 4 weeks or within 5 half-life periods (whichever is shorter) prior to the initiation of trial treatment.
2.More than one anti-PD-(L)1-based treatment regimen prior to entering study
3.Major surgery (‘major’ according to the Investigator’s assessment) performed within 12 weeks prior to first trial treatment or planned within 12 months after screening, e.g., hip replacement.
4.Known history of severe hypersensitivity reactions to other mAbs or known hypersensitivity to the trial drugs or their excipients.
5.Known presence of symptomatic central nervous system (CNS) metastases, unless asymptomatic and off corticosteroids and/or anti-convulsant therapy for at least 2 weeks prior to start of treatment.
6.Immunosuppressive corticosteroid doses (>10 mg prednisone daily or equivalent) within 4 weeks prior to the first dose of study treatment.
7.Active autoimmune disease or a documented history of autoimmune disease, except
vitiligo or resolved childhood asthma/atopy, or a patient who was permanently discontinued from previous anti-PD-1 or anti-PD-L1 therapy because of an immunerelated
adverse event (irAE).
Module A:
1. Previous treatment with an anti-LAG-3 agent
Module C:
1. Persistent toxicity from previous treatments that has not resolved to ≤Grade 1 with the exception of alopecia
2. Significant cardiovascular/cerebrovascular diseases (i.e. uncontrolled hypertension, unstable angina, history of infarction within past 6 months, congestive heart failure > New York Heart Association [NYHA] II):
•Uncontrolled hypertension is defined as: blood pressure in rested and relaxed condition ≥ 140 mmHg, systolic or ≥ 90 mmHg diastolic (with or without medication), measured according to Appendix 10.5
•Patients with personal or family history of QT prolongation and/or long QT syndrome, or prolonged QTcF at baseline (> 480 ms).
•LVEF < 50%
3. History of severe haemorrhagic or thromboembolic event in the past 12 months (excluding central venous catheter thrombosis and peripheral deep vein thrombosis).
4. Known inherited predisposition to bleeding or to thrombosis, in the opinion of the investigator.
5.Patients who require full-dose anticoagulation (according to local guidelines). No Vitamin K antagonist and other anticoagulation allowed; LMWH allowed only for prevention not for curative treatment.
6. Prior anti-angiogenic therapy (with the exception of CRC Cohort).
7. Known hypersensitivity to the trial drugs or their excipients or risk of allergic of anaphylactic reaction to drug product according to Investigator judgement (e.g. patient with history of anaphylactic reaction or autoimmune disease that is not controlled by nonsteroidal anti-inflammatory drugs (NSAIDs), inhaled corticosteroids, or the equivalent of ≤ 10 mg/day prednisone).
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| 1 - The primary endpoint of the trial is objective response (OR), defined as best overall response of complete response (CR) or partial response (PR) according to RECIST v1.1 as assessed by the Investigator. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
1- Duration of response (DoR), defined as the time from first documented CR or PR (RECIST v1.1) until the earlier of disease progression or death among patients with OR.
2- Disease control (DC), defined as best overall response of CR, PR, or stable disease (SD) according to RECIST v1.1 as assessed by the Investigator.
3- Progression-free survival (PFS), defined as the time from first treatment until PD or death from any cause, whichever occurs earlier. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1- Up to 32 months
2- Up to 32 months
3- Until PD or death from any cause, whichever occurs earlier |
|
| 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) | 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 | No |
| 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) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| Anti PD1, BI 754091 is being used as thebackbone investigational agent in each chort |
|
| 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 | 5 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.5.1 | Number of sites anticipated in the EEA | 5 |
| 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 |
| Canada |
| United Kingdom |
| United States |
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| 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
| |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 42 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 20 |
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