EMPIRE : Targeting MDM2 and PD1 in tumors with tertiary lymphoid structures

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Institut Bergonie, Institut Bergonie

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

14 Jun 2024 → 1 Jul 2024

Decision date (initial)

2024-05-14

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

External identifiers

EU CT number

2023-506823-28-00

ClinicalTrials.gov

NCT06084689

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Pharmacogenomic, Safety, Pharmacodynamic, Therapy

To investigate the antitumor activity of ezabenlimab combined with BI 907828 independently for 2 cohorts of participants :
- [Cohort A] Participants with soft-tissue sarcoma,
- [Cohort B] Participants with solid tumors [non-small cell lung cancer (NSCLC) or triple negative breast cancer (TNBC) or MMS colorectal cancer (MSS-CCR) or biliary tract cancer (BTC)]
In both cohorts, antitumor activity will be assessed in terms of disease control, as per RECIST v1.1.

Secondary objectives 7

1. Independently for each cohort, to evaluate the antitumor activity of ezabenlimab combined with BI 907828 in terms of objective response as per RECIST v1.1
2. Independently for each cohort, to evaluate the antitumor activity of ezabenlimab combined with BI 907828 in terms of Duration of response (DoR), as per RECIST V1.1
3. Independently for each cohort, to evaluate the antitumor activity of ezabenlimab combined with BI 907828 in terms of Progression free survival (PFS), as per RECIST v1.1
4. Independently for each cohort, to evaluate the antitumor activity of ezabenlimab combined with BI 907828 in terms of Overall survival (OS)
5. For cohort A: to evaluate the efficacy of ezabenlimab combined with BI 907828 in two subgroups of patients with altered/biomarker positive soft tissue sarcomas (MDM2 status amplified or not).
6. Independently for each cohort, to evaluate the safety and tolerability of ezabenlimabcombined with BI 907828 (NCI-CTCAE v5).
7. To assess 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 ezabenlimab combined with BI 907828

Conditions and MedDRA coding

Adult patients with locally advanced/metastatic solid tumors

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 19

1. 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)
2. Age ≥ 18 years
3. Advanced/unresectable and/or metastatic disease
4. 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
5. TP53-wild type status known (by molecular biology)
6. Cohort A: MDM2 status known at the time of inclusion
7. 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.
8. 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.
9. Performance status 0-2
10. Life expectancy ≥ 8 weeks
11. 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
12. Disease progression on prior treatment, or previously untreated disease with no available acceptable treatment
13. 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)
14. Ability to comply with the study protocol, in the investigator's judgment
15. 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
16. 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
17. 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
18. Voluntarily signed and dated written informed consent prior to any study specific procedure
19. Patients with a social security in compliance with the French law

Exclusion criteria 33

1. Prior treatment with ezabenlimab and/or BI 907828,
2. 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
3. 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.
4. Women who are pregnant or breast feeding,
5. 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.
6. 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
7. 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.
8. Active tuberculosis
9. 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
10. 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.
11. Prior allogeneic stem cell or solid organ transplantation
12. History of leptomeningeal disease
13. 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,
14. Current treatment with anti-viral therapy for HBV
15. 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
16. Participation to a study involving a medical or therapeutic intervention in the last 30 days,
17. 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
18. Patients with oral anticoagulation based on Vitamin K antagonist.
19. Previous enrolment in the present study,
20. Patient unable to follow and comply with the study procedures because of any geographical, social or psychological reasons,
21. Inability to swallow,
22. History of severe allergic anaphylactic reactions to chimeric or humanized antibodies or fusion proteins,
23. 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
24. Known hypersensitivity to Chinese hamster ovary cell products or to any component of the ezabenlimabor BI 907828 formulation,
25. 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
26. 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.
27. Any systemic anticancer treatment within 2 weeks or 5 half-lives (whichever is shorter) prior to start of ezabenlimab combined with BI 907828,
28. Whole brain radiotherapy within 14 days prior to start of BI 754091 combined with BI 907828
29. Sterotactic radiosurgery within 7 days prior to start of ezabenlimabcombined with BI 907828
30. 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)
31. 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
32. 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
33. 33. Participants with a prior history of myeloid malignancies, including myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML)

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Disease control is defined as 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, as per RECIST v1.1. Disease control rate (DCR), defined as the proportion of patients with disease control lasting for at least 24 weeks since treatment onset, will be reported.

Secondary endpoints 7

1. 1) a) Objective response defined as confirmed complete response (CR), unconfirmed complete response (Cru), confirmed partial response (PR) or unconfirmed partial response (PRu) as per RECIST v1.1. Objective response rate (ORR), defined as the proportion of patients with objective response will be assessed, based on centralized radiological review, within 24 weeks of treatment onset. Note that confirmation of claimed responses at least 4 weeks later is not required.
2. 1) b) Duration of reponse (DoR) defined as the time from documentation of tumor response (CR, Cru, PR, PRu) to disease progression (as per RECIST V1.1). Response assessement will be performed according to centralized radiological review. Note that confirmation of claimed responses at least 4 weeks later is not required.
3. 1) c) Progression-free survival (PFS) defined as the time from the first day of treatment to the first documented disease progression (as per RECIST v1.1) or death (due to any cause), whichever occurs first. Median PFS, 1- year PFS rate will be reported for each cohort. Response assessement will be performed according to centralized radiological review.
4. 1) d) ORR, DoR and PFS defined above, will also be evaluated according to the local radiological assessment (performed by the investigator).
5. 1) e) Overall survival defined as the time from the first day of treatment to death (due to any cause). Median OS, 1- year OS rate will be reported for each cohort.
6. 2) For cohort A: as an exploratory way, secondary endpoints defined above will be assessed in two subgroups of patients with altered/biomarker positive soft tissue sarcomas (MDM2 status amplified or not).
7. 3)The safety and tolerability of the combination: Occurence of adverse events (AEs) and Serious adverse events (SAEs). Events will be graded using the Common Terminology Criteria for Adverse Events (CTCAE) from the NCI v5.0. Both AEs and SAEs will be coded according to the standardized medical terminology MedDRA.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 4

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Institut Bergonie

Sponsor organisation

Institut Bergonie

Address

229 Cours De L Argonne

City

Bordeaux

Postcode

33000

Country

France

Scientific contact point

Organisation

Institut Bergonie

Contact name

Pr Antoine ITALIANO

Public contact point

Organisation

Institut Bergonie

Contact name

Aurore Barthod Malat

Institut Bergonie

Sponsor organisation

Institut Bergonie

Address

180 R De Saint Genes, 229 Cours De L Argonne 229 Cours De L Argonne

City

Bordeaux

Postcode

33000

Country

France

Locations

1 EU/EEA country · 6 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 2 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications