Evaluation of Ezabenlimab and BI 907828 in Adult Patients with Locally Advanced or Metastatic Solid Tumors: A Phase II Clinical Trial
- Trial ID
- 2023-506823-28-00
- Protocol
- IB 2023-02
- Sponsor
- Institut Bergonie
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to investigate the **antitumor activity** of the combination of ezabenlimab and BI 907828 in two distinct cohorts of participants. Cohort A includes participants with soft-tissue sarcoma, while Cohort B comprises participants with solid tumors, specifically non-small cell lung cancer (NSCLC), triple-negative breast cancer (TNBC), microsatellite stable colorectal cancer (MSS-CCR), or biliary tract cancer (BTC). The antitumor activity will be assessed in terms of disease control according to RECIST v1.1 criteria. This objective is clinically relevant as it aims to determine the efficacy of the combination therapy in controlling tumor progression in these specific cancer types.
Secondary objectives include: - Evaluating the antitumor activity of the combination therapy in terms of objective response, duration of response (DoR), progression-free survival (PFS), and overall survival (OS) independently for each cohort, as per RECIST v1.1. - For Cohort A, assessing the efficacy in two subgroups of patients with altered/biomarker-positive soft tissue sarcomas based on MDM2 status. - Evaluating the safety and tolerability of the combination therapy using NCI-CTCAE v5. - Assessing predictive and prognostic effects and pharmacodynamics of exploratory biomarkers in tissue and blood, and their association with disease status, mechanisms of resistance, and/or response to the combination therapy.
Participants
The clinical trial involves **adult patients** with locally advanced or metastatic solid tumors, specifically targeting two cohorts: those with soft-tissue sarcoma and those with solid tumors such as non-small cell lung cancer (NSCLC), triple negative breast cancer (TNBC), MMS colorectal cancer (MSS-CCR), or biliary tract cancer (BTC). The study population includes both **male and female** participants aged 18 years and older. Participants are required to have a histologically or cytologically confirmed diagnosis of the specified conditions, with a life expectancy of at least 8 weeks and adequate hematologic and end-organ function. The trial does not include a vulnerable population. Participants must have advanced, unresectable, and/or metastatic disease, and they should have measurable disease as defined by RECIST v1.1 criteria. The selection process ensures that participants have either experienced disease progression on prior treatment or have untreated disease with no available acceptable treatment. The sponsor has not provided information regarding the total number of participants. Lifestyle considerations such as diet and physical activity are not specified, but participants must be able to comply with the study protocol. Key inclusion criteria include a performance status of 0-2 and the ability to provide informed consent. The trial excludes individuals with prior or concurrent malignant disease diagnosed or treated in the last 2 years, except for certain superficial or non-invasive cancers treated with curative intent.
Plans and Procedures
The clinical trial is designed to evaluate the **antitumor activity** of a combination therapy involving **ezabenlimab** and BI 907828 in adult patients with locally advanced or metastatic solid tumors. This trial is structured as a randomized, double-blind, controlled study, with an estimated duration extending until September 2027. Participants will be divided into two cohorts: Cohort A, consisting of individuals with soft-tissue sarcoma, and Cohort B, comprising patients with solid tumors such as non-small cell lung cancer (NSCLC), triple-negative breast cancer (TNBC), microsatellite stable colorectal cancer (MSS-CCR), or biliary tract cancer (BTC). The primary objective is to assess disease control as per RECIST v1.1 criteria, with secondary endpoints including objective response rate, duration of response, progression-free survival, and overall survival.
The trial will commence with an inclusion (screening) visit to confirm eligibility based on criteria such as histologically or cytologically confirmed diagnosis, adequate hematologic and end-organ function, and a life expectancy of at least eight weeks. Participants will undergo regular follow-up visits to monitor treatment response and safety, with assessments conducted through centralized radiological review. The end-of-study visit will conclude the trial for each participant, evaluating the overall treatment outcomes and any adverse events experienced during the study period.
Participant involvement is expected to last up to 156 weeks, with conditions for early termination including disease progression, unacceptable toxicity, or withdrawal of consent. The trial will adhere to rigorous ethical standards, ensuring informed consent is obtained from all participants. The study will not include individuals with prior or concurrent malignant diseases diagnosed or treated in the last two years, except for specific exceptions such as superficial bladder cancer or basal cell carcinoma treated with curative intent. The trial aims to provide valuable insights into the efficacy and safety of the combination therapy in treating advanced solid tumors.
Treatment
The clinical trial involves the administration of **BI 907828**, a highly potent MDM2-p53 antagonist, formulated as a **film-coated tablet**. This experimental medication is administered orally. The trial includes three different dosage regimens of BI 907828: 20 mg, 30 mg, and 45 mg, with a maximum daily dose corresponding to each regimen. The treatment period for each dosage is up to 156 days. The active substance in BI 907828 is a chemical compound identified as (3S,3'S,3A'S,10A'S)-6-chloro-3'-(3-chloro-2-fluorophenyl)-1'-(cyclopropylmethyl)-6'-methyl-2-oxo-1,2,3',3A',10',10A'-hexahydro-1'H-spiro[indole-3,2'-pyrrolo[2',3':4,5]pyrrolo[1,2-b]indazole]-7'-carboxylic acid. Participant compliance with the dosing schedule is monitored throughout the trial.
Additionally, the trial includes the administration of **Ezabenlimab**, a solution for infusion, which is an **anti-PD-1 monoclonal antibody**. Ezabenlimab is administered via intravenous use, with a maximum daily dose of 240 mg. The treatment period for Ezabenlimab is also up to 156 days. The active substance, Ezabenlimab, is a protein-based compound, specifically a humanized IgG4 monoclonal antibody targeting the programmed cell death protein 1 (PD-1). The administration of Ezabenlimab is conducted in conjunction with BI 907828 to evaluate the combined antitumor activity in participants with specific types of cancer, including soft-tissue sarcoma and various solid tumors.
Efficacy
Efficacy in this clinical trial will be assessed primarily through the evaluation of **disease control** as per RECIST v1.1 criteria. The primary endpoint is defined as the disease control rate (DCR), which includes confirmed complete response (CR), unconfirmed complete response (CRu), confirmed partial response (PR), unconfirmed partial response (PRu) of any duration, or stable disease (SD) lasting for at least 24 weeks. The DCR will be reported as the proportion of patients achieving disease control for at least 24 weeks from the onset of treatment.
Secondary endpoints include several measures: the objective response rate (ORR), which is the proportion of patients with a confirmed or unconfirmed CR or PR within 24 weeks of treatment onset; the duration of response (DoR), defined as the time from documentation of tumor response to disease progression; progression-free survival (PFS), which is the time from the first day of treatment to the first documented disease progression or death; and overall survival (OS), defined as the time from the first day of treatment to death from any cause. These assessments will be conducted through centralized radiological review, with additional evaluations based on local radiological assessments performed by investigators.
For cohort A, exploratory analyses will be conducted to assess secondary endpoints in subgroups of patients with altered or biomarker-positive soft tissue sarcomas, specifically those with amplified or non-amplified MDM2 status. The safety and tolerability of the treatment combination will also be monitored, with adverse events (AEs) and serious adverse events (SAEs) graded using the Common Terminology Criteria for Adverse Events (CTCAE) from the NCI v5.0 and coded according to MedDRA.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Histologically or cytologically confirmed diagnosis: - For cohort A: soft-tissue sarcoma. As recommended by the French NCI, diagnosis must be reviewed or confirmed by the RRePS Network (Réseau de référence en pathologie des sarcomes et des viscères) as recommended by the French NCI (Institut National du Cancer, Inca). - For cohort B: non-small cell lung cancer (NSCLC) or triple negative breast cancer (TNBC) or MMS colorectal cancer (MSS-CCR) or biliary tract cancer (BTC)
- Age ≥ 18 years
- Advanced/unresectable and/or metastatic disease
- Mature TLS positive status: tumors will be considered mature TLS-positive when containing either a visible germinal center on HES or a meshwork of CD23+ follicular dendritic cells or isolated CD23+ dendritic cell if the cell harbored a morphology fitting with dendritic differentiation (i.e., cytoplasmic dendritic extensions). Mature TLS displaying germinal centers visible on HES are confirmed with a double CD20/CD23 staining. Note that for TLS status, ensure the availability of archived FFPE (Formalin-Fixed Paraffin-Embedded) tumor tissue sample or tumor material newly obtained by biopsy. Except if TLS analysis have been already performed by Biopathological platform at Bergonié Institute, presence or absence of TLS should be confirmed by central
- TP53-wild type status known (by molecular biology)
- Cohort A: MDM2 status known at the time of inclusion
- Cohort B: are eligible the following populations NSCLC - known PD-L1 tumor proportion score (TPS) < 50% AND naïve from treatment with ICI AND for whom standard treatments are not indicated or have been deemed unsuitable based on their clinical condition and in consultation with their treating physicians - NSCLC exposed to anti-PD1 or PD-L1 based therapy with clinical benefit (clinical benefit is defined as objective response or stable disease for at least 4 months). - Patients with the following targetable genomic alterations must have received the corresponding targeted therapy or be excluded unless contraindications to these therapies exist or treatment is not available/reimbursed in the site country: • EGFR Exon 19 Deletion or Exon 21 L858R • EGFR Exon 20 Insertion Mutation • ALK Rearrangement • KRAS G12C Mutation • ROS1 Rearrangement • BRAF V600E Mutation • MET Exon 14 Skipping Mutation • RET Rearrangement TNBC - exposed to anti-PD1 or PD-L1 based therapy with clinical benefit (clinical benefit is defined as objective response or stable disease for at least 4 months) - For patients with genetically confirmed BRCA1/2 mutations (gBRCAm): patients who previously received treatment with a PARP inhibitor, except if they presented contraindications to such treatment. - For all patients, including those with HER2-low expressed tumors: patients who previously received treatment with sacituzumab govitecan or trastuzumab deruxtecan, except if they were considered ineligible to this treatment due to medical reasons. MSS-CCR naïve from treatment with ICI - Patients must have received the following treatments: fluoropyrimidine, irinotecan, oxaliplatin, anti-VEGF, anti-EGFR if RASwt and anti-BRAF if BRAF mutated, except if they presented contraindications to such treatments. - - For patients with liver metastases only, these metastases have to be unresectable. BTC - exposed to anti-PD1 or PD-L1 based therapy with clinical benefit (clinical benefit is defined as objective response or stable disease for at least 4 months). - For patients diagnosed with intrahepatic cholangiocarcinoma harboring FGFR mutations (FGFRm) or IDH mutations (IDHm): these patients must have received the corresponding targeted therapy, in accordance with current treatment guidelines and best practices, unless contraindications to these therapies exist.
- Patients must have measurable disease (lesion in previously irradiated filed can be considered as measurable if progressive at inclusion according to RECIST v1.1) defined as per RECIST v1.1 with at least one lesion that can be measured in at least one dimension (longest diameter to be recorded) as > 10 mm with spiral CT scan.
- Performance status 0-2
- Life expectancy ≥ 8 weeks
- Adequate hematologic and end-organ function as defined below: a) Abolute neutrophil count (ANC) ≥ 1.5 G/l b) Platelet count ≥ 100 G/l c) Hemoglobin ≥ 8.5 g/dL (if applicable, previous transfusion at least 4 weeks before screening laboratory assessment) d) Total bilirubin ≤ 1.5 x upper limit of normal (ULN), with the following exception: patients with known Gilbert’s syndrome who have a serum bilirubin ≤ 3 x ULN may be enrolled. e) AST and ALT ≤ 2.5 x ULN, with the following exception: patients with liver metastases who have an AST or ALT ≤ 5 x ULN may be enrolled. f) Uncontrolled or symptomatic hypercalcemia (ionized calcium ≤ 1.5 mmol/L, calcium ≤ 12 mg/dL, or corrected calcium ≤ ULN) g) INR or PT and aPTT ≤ 1.5 x ULN
- Disease progression on prior treatment, or previously untreated disease with no available acceptable treatment
- Recovery to grade ≤ 1 from any adverse event (AE) derived from previous treatment (excluding alopecia and vitiligo of any grade and non-painful peripheral neuropathy grade ≤ 2) according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE, version 5.0)
- Ability to comply with the study protocol, in the investigator's judgment
- Female subjects of childbearing potential must have a negative serum pregnancy test within 14 days prior to the first dose of study treatment. Serum or urine pregnancy test must be repeated within 72 hours prior to receiving the first dose of study medication
- Both women of childbearing potential and men must agree to use two medically acceptable methods of contraception throughout the treatment period and for: - Women: 6 months and 12 days after end of BI 907828; 6 months after end of ezabenlimab. - Men: 102 days after end of BI 907828; 11 months after end of ezabenlimab
- No prior or concurrent malignant disease diagnosed or treated in the last 2 years except for: a. superficial/non-invasive bladder cancer, or basal or squamous cell carcinoma in situ treated with curative intent; b. endoscopically resected GI cancers limited to the mucosal layer without recurrence in > 1 year
- Voluntarily signed and dated written informed consent prior to any study specific procedure
- Patients with a social security in compliance with the French law
Exclusion Criteria
- Prior treatment with ezabenlimab and/or BI 907828,
- Significant cardiovascular disease, such as New York Heart Association cardiac disease (Class II or higher), myocardial infarction, or cerebrovascular accident within 3 months prior to enrollment, unstable arrhythmias, or unstable angina
- Uncontrolled tumor-related pain. Patients requiring pain medication must be on a stable regimen at study entry. Symptomatic lesions (e.g., bone metastases or metastases causing nerve impingement) amenable to palliative radiotherapy should be treated prior to enrollment. Patients should be recovered from the effects of radiation. There is no required minimum recovery period. Asymptomatic metastatic lesions that would likely cause functional deficits or intractable pain with further growth (e.g., epidural metastasis that is not currently associated with spinal cord compression) should be considered for loco-regional therapy if appropriate prior to enrollment.
- Women who are pregnant or breast feeding,
- Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (once monthly or more frequently). Patients with indwelling catheters (e.g., PleurX®) are allowed.
- Active or history of autoimmune disease or immune deficiency, including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barré syndrome, or multiple sclerosis, with the following exceptions: - Patients with a history of autoimmune-related hypothyroidism who are on thyroid-replacement hormone are eligible for the study. - Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen are eligible for the study. - Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis are excluded) are eligible for the study provided all of following conditions are met: o rash must cover ≤ 10% of body surface area. o Disease is well controlled at baseline and requires only low-potency topical corticosteroids o No occurrence of acute exacerbations of the underlying condition requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, or high-potency or oral corticosteroids within the previous 12 months
- History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography (CT) scan. History of radiation pneumonitis in the radiation field (fibrosis) is permitted.
- Active tuberculosis
- Severe infection within 4 weeks prior to initiation of ezabenlimab combined with BI 907828, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia
- Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of ezabenlimab combined with BI 907828. Patients receiving prophylactic antibiotics (e.g., to prevent a urinary tract infection or chronic obstructive pulmonary disease exacerbation) are eligible for the study.
- Prior allogeneic stem cell or solid organ transplantation
- History of leptomeningeal disease
- Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of ezabenlimab combined with BI 907828, or anticipation of need for such a vaccine during treatment or within 6 months after the final dose ezabenlimab combined with BI 907828. Seasonal flu vaccines that do not contain a live virus are permitted,
- Current treatment with anti-viral therapy for HBV
- Treatment with systemic immunostimulatory agents (including, but not limited to, interferon and interleukin 2 [IL-2]) within 4 weeks or 5 drug elimination half-lives (whichever is longer) prior to initiation of ezabenlimab combined with BI 907828
- Participation to a study involving a medical or therapeutic intervention in the last 30 days,
- Treatment with systemic immunosuppressive medication (including, but not limited to corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-TNF-α agents) within 2 weeks prior to initiation of ezabenlimab combined with BI 907828, or anticipation of need for systemic immunosuppressive medication during ezabenlimabcombined with BI 907828, with the following exceptions: - Patients who received acute, low-dose systemic immunosuppressant medication or a one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hours of corticosteroids for a contrast allergy, a one-time dose of dexamethasone for nausea or chronic use of ≤10 mg/day of prednisone or dose-equivalent corticosteroid) are eligible for the study. The use of inhaled corticosteroids is allowed. - Patients who received mineralocorticoids (e.g., fludrocortisone), corticosteroids for chronic obstructive pulmonary disease (COPD) or asthma, or low-dose corticosteroids for orthostatic hypotension or adrenal insufficiency are eligible for the study
- Patients with oral anticoagulation based on Vitamin K antagonist.
- Previous enrolment in the present study,
- Patient unable to follow and comply with the study procedures because of any geographical, social or psychological reasons,
- Inability to swallow,
- History of severe allergic anaphylactic reactions to chimeric or humanized antibodies or fusion proteins,
- Primary CNS tumors with any of the following characteristics: - History of intracranial hemorrhage or spinal cord hemorrhage - Neurosurgical resection or brain biopsy to the primary brain tumor within 28 days of Cycle 1 Day 1
- Known hypersensitivity to Chinese hamster ovary cell products or to any component of the ezabenlimabor BI 907828 formulation,
- Symptomatic or actively progressing central nervous system (CNS) metastases. Note that asymptomatic patients with treated or untreated CNS metastases are eligible, provided that all of the following criteria are met: - No ongoing requirement for corticosteroids as therapy for CNS metastases - No evidence of interim progression between completion of CNS-directed therapy and screening radiographic study - No history of intracranial hemorrhage or spinal cord hemorrhage
- Prohibited concomitant medication specified in section 7.5.2 and 7.5.3 within 3 weeks or 5 half-lives (whichever is shorter) prior to initiation of BI 907828 (during the pre-treatment and treatment phase (including retreatment for post-complete response relapse) of this trial) included CYP2C8 substrates, UGT1A1 substrates, CYP2B6 substrates, narrow therapeutic index drugs that are P-gp and BCRP substrates (digoxin), OATP1B1/B3 inhibitors, strong inhibitors or inducers of CYP3A4.
- Any systemic anticancer treatment within 2 weeks or 5 half-lives (whichever is shorter) prior to start of ezabenlimab combined with BI 907828,
- Whole brain radiotherapy within 14 days prior to start of BI 754091 combined with BI 907828
- Sterotactic radiosurgery within 7 days prior to start of ezabenlimabcombined with BI 907828
- Active bleeding, significant risk of haemorrhage (e.g. previous severe gastrointestinal bleeding, previous haemorrhagic stroke at any time), or current bleeding disorder (e.g. haemophilia, von Willebrand disease)
- History of or concurrent serious medical condition or abnormality in clinical laboratory tests that, in the investigator's judgment, precludes the patient's safe participation in and completion of the study or confounds the ability to interpret data from the study
- Incomplete recovery from any surgery prior to the start of ezabenlimab combined with BI 907828 that would interfere with the determination of safety or efficacy of ezabenlimab combined with BI 907828
- Participants with a prior history of myeloid malignancies, including myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML)
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Not Recruiting | 01 Sept 2024 | 120 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
BI 907828 | Test | FILM-COATED TABLET | ORAL | 20 | 156 | PRD10565901 |
Ezabenlimab | Test | SOLUTION FOR INFUSION | INTRAVENOUS USE | 240 | 156 | PRD10081670 |
BI 907828 | Test | FILM-COATED TABLET | ORAL | 30 | 156 | PRD10565907 |
BI 907828 | Test | FILM-COATED TABLET | ORAL | 45 | 156 | PRD10565911 |