Platform Trial Evaluating Safety and Efficacy of Ezabenlimab Anti- PD-1 Based Combination Therapies in PD-(L)1 naïve and PD- (L)1 Pretreated Patient Populations With Advanced/Metastatic Solid Tumours

Boehringer Ingelheim

Status and phase: Completed; Phase 2

Conditions: Advanced Tumors; Neoplasm Metastasis; Metastatic Solid Tumors

Treatments: Drug: Ezabenlimab; Drug: BI 754111; Drug: BI 836880

Study type: Interventional

Funder types: Industry

Identifiers

NCT03697304

2018-002344-81 (EudraCT Number)

1381-0009

Details and patient eligibility

About

This is a study in adults with various types of advanced cancer. The purpose of the study is to test a medicine called BI 754091 in combination with several other cancer medicines. BI 754091 is an immunotherapy. This means it may help the immune system fight cancer. Such therapies are also called immune checkpoint inhibitors.

How long the participants are in the study depends on whether they benefit from treatment and whether they experience unacceptable side effects. The participants are put into different groups. Each group receives BI 754091 in combination with another medicine.

The doctors check whether the tumors shrink or disappear. The doctors also check the general health of the participants.

Enrollment: 211 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

Inclusion Criteria

Master Protocol:

• Provision of signed and dated, written Master informed consent form (ICF) prior to any trial-specific procedures, sampling, or analyses.
• Patient ≥18 years of age at the time of signature of the ICF.
• Eastern Cooperative Oncology Group (ECOG) score: 0 or 1.
• Patient must agree to a pre-treatment biopsy (if archival tissue is not available) and on-treatment tumour biopsy. If archived tumour tissue is available from the last treatment failure, sections may be supplied instead of a pre-treatment biopsy.
• Life expectancy of at least 12 weeks after the start of the treatment according to the Investigator's judgement.
• Male or female patients. Women of childbearing potential (WOCBP) 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:

- Histologically confirmed diagnosis of one of the following cohorts:

• Cohort 1 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.
• Cohort 2 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
• Cohort 3 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:

  • Cohort 1: GEC: Locally advanced, unresectable or metastatic gastric adenocarcinoma or GEC.
  • Cohort 2: Patients with secondary resistance to anti-PD-1 or anti-PD-L1 based therapy: Any advanced or metastatic solid tumour (excluding NSCLC and melanoma) with previously anti-PD-1 or anti-PD-L1 based treatment which progressed after achieving benefit.
  • Cohort 3: 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.
  • Cohort 4: Locally advanced, unresectable or metastatic second line or greater, microsatellite stable (MSS) colorectal cancer.
  • Cohort 5: Advanced Endometrial cancer: Endometrial carcinoma that is pMMR (Mismatch Repair-Proficient)/MSS and is advanced, recurrent, or persistent and has relapsed or is refractory to curative therapy.

• All patients must have at least one measurable lesion according to RECIST v1.1

• Further inclusion criteria apply

Exclusion Criteria

Master Protocol:

• 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.
• More than one anti-PD-(L)1-based treatment regimen prior to entering study study, more specifically defined in the modules. Note: once in a trial Module, patients may crossover to different Module if all other eligibility criteria are met.
• 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.
• Known history of severe hypersensitivity reactions to other mAbs or known hypersensitivity to the trial drugs or their excipients.
• Presence of central nervous system (CNS) metastases, unless treated and asymptomatic and off corticosteroids and/or anticonvulsant therapy for at least 2 weeks prior to start of treatment.
• Immunosuppressive corticosteroid doses (>10 mg prednisone daily or equivalent) within 4 weeks prior to the first dose of study treatment.
• Active autoimmune disease or a documented history of autoimmune disease, except vitiligo or resolved childhood asthma/atopy. Patients who were permanently discontinued from previous anti-PD-1 or anti-PD-L1 therapy because of an immune-related adverse event (irAE).

Module A:

- Previous treatment with an anti-LAG-3 Agent

Module C:

• Unresolved, Grade >1 toxicity before the start of treatment with the study drug except for hair loss (alopecia) and hypothyroidism that requires thyroid hormone supplements but is asymptomatic under therapy.
• 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)
• History of severe haemorrhagic or thromboembolic event in the past 12 months
• Known inherited predisposition to bleeding or to thrombosis, in the opinion of the investigator - Further exclusion criteria apply

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Sequential Assignment

Masking: None (Open label)

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211 participants in 8 patient groups

Module C, Cohort 1: GEC patients

Experimental group

Description:

Patients with locally advanced, unresectable or metastatic gastric adenocarcinoma or gastro-oesophageal adenocarcinoma (GEC) with at least one prior systemic treatment, who failed standard therapy, for whom no further effective options existed, and with no prior PD-1 or PD-L1-based treatment, were administered 240 mg of ezabenlimab (BI 754091), intravenously, on Day 1 of 21-day cycles, along with 720 mg of BI 836880, in the form of i.v. infusion, on Day 1 of 21-day cycles.

Treatment:

Drug: BI 836880

Drug: Ezabenlimab

Module C, Cohort 2: 2ary resistance patients

Experimental group

Description:

Patients with any advanced or metastatic solid tumor (excluding non-squamous lung cancer, non-small-cell lung cancer, and melanoma) who had received prior anti-PD-1- or anti-PD-L1-based treatment and progressed after achieving benefit (at least stable disease with a minimum duration of benefit of 4 months) and minimum treatment duration of 2 months on the previous anti-PD-1- or anti-PD-L1-based treatment without progressive disease, were administered 240 mg of ezabenlimab (BI 754091), intravenously, on Day 1 of 21-day cycles, along 720 mg of BI 836880 on Day 1, intravenously, on Day1 of 21-day cycles.

Treatment:

Drug: BI 836880

Drug: Ezabenlimab

Module C, Cohort 3: 1ary resistance patients

Experimental group

Description:

Patients with select advanced or metastatic solid tumors with prior anti-PD-1- or anti-PD-L1-based treatment without achieving benefit ( stable disease duration of less than 4 months or progressive disease in less than 4 months while on treatment), were administered 240 mg of ezabenlimab (BI 754091), intravenously, on Day 1 of 21-day cycles, along with 720 mg of BI 836880, intravenously, on Day 1 of 21-day cycles.

Treatment:

Drug: BI 836880

Drug: Ezabenlimab

Module C, Cohort 4: CRC patients

Experimental group

Description:

Patients with locally advanced, unresectable or metastatic second-line or greater, microsatellite-stable colorectal cancer (CRC) without prior anti-PD-1- or anti-PD-L1-based treatment, were administered 240 mg of ezabenlimab (BI 754091), intravenously, on Day 1 of 21-day cycles, along with 720 mg of BI 836880, intravenously, on Day 1 of 21-day cycles.

Treatment:

Drug: BI 836880

Drug: Ezabenlimab

Module C, Cohort 5: EC patients

Experimental group

Description:

Patients with advanced endometrial carcinoma (EC), excluding microsatellite instability-high or mismatch repair deficient types, who progressed following one line of chemotherapy, were not eligible for curative surgery or radiation, and had not been previously treated with anti-PD-1- or anti-PD-L1-based therapies, were administered 240 mg of ezabenlimab (BI 754091), intravenously, on Day 1 of 21-day cycles, along with 720 mg of BI 836880, intravenously, on Day 1 of 21-day cycles.

Treatment:

Drug: BI 836880

Drug: Ezabenlimab

Module A, Cohort 1: GEC patients

Experimental group

Description:

Patients with locally advanced, unresectable or metastatic gastric adenocarcinoma or gastro-oesophageal adenocarcinoma, who received prior anti-PD-1 or anti-PD-L1-based treatment, were administered 240 mg of ezabenlimab (BI 754091), intravenously, on Day 1 of 21-day cycles, along with 600 mg of BI 754111, intravenously, on Day 1 of 21-day cycles.

Treatment:

Drug: BI 754111

Drug: Ezabenlimab

Module A, Cohort 2: 2ary resistance patients

Experimental group

Description:

Patients with any advanced or metastatic solid tumors who had been previously treated with anti-PD-1 or anti-PD-L1-based therapies, and who progressed after achieving benefit (at least stable disease with a minimum duration of benefit of 6 months) and minimum treatment duration of 2 months without experiencing disease progression, were administered 240 mg of ezabenlimab (BI 754091), intravenously, on Day 1 of 21-day cycles, along with 600 mg of BI 754111, intravenously, on Day 1 of 21-day cycles.

Treatment:

Drug: BI 754111

Drug: Ezabenlimab

Module A, Cohort 3: 1ary resistance patients

Experimental group

Description:

Patients with select advanced or metastatic solid tumor types, who have been previously treated with previous anti-PD-1 or anti-PD-L1-based therapies without achieving benefit (stable disease for less than 6 months or progressive disease in less than 6 months), were administered 240 mg of ezabenlimab (BI 754091), intravenously, on Day 1 of 21-day cycles, along with 600 mg of BI 754111, intravenously, on Day 1 of 21-day cycles.

Treatment:

Drug: BI 754111

Drug: Ezabenlimab