A Study in Patients With Different Types of Advanced Cancer (Solid Tumors) to Test Different Doses of BI 907828 in Combination With BI 754091 (Ezabenlimab) and 754111 or BI 907828 in Combination With BI 754091 (Ezabenlimab)

  • STATUS
    Recruiting
  • End date
    Jun 30, 2025
  • participants needed
    144
  • sponsor
    Boehringer Ingelheim
Updated on 20 January 2022
carcinoma
warfarin
BRAF
TP53
metastasis
neutrophil count
liver metastasis
EGFR
pd-l1
advanced cancer
primary cancer
targeted therapy
solid neoplasm
sarcoma

Summary

This study has 2 parts. The first part is open to adults with different types of advanced cancer (solid tumours). The second part is open to people with specific types of advanced lung cancer, skin cancer, sarcoma, liposarcoma, and liver cancer. The participants get a combination of 3 medicines called BI 907828, BI 754091, and BI 754111. BI 907828 is a so-called MDM2 inhibitor that is being developed to treat cancer. BI 754091 and BI 754111 are antibodies that may help the immune system fight cancer (immune checkpoint inhibitors).

The purpose of the first part of the study is to find out the highest dose of BI 907828 that the participants can tolerate in combination with BI 754091 and BI 754111. Once the best dose of BI 907828 for the combination with BI 754091 and BI 754111 is found, it will be used in the second part of the study.

The purpose of the second part is to see whether the combination of BI 907828 with BI 754091 and BI 754111 is able to make tumours shrink. Some participants in the second part get combinations of 2 instead of 3 medicines: BI 754091 and BI 754111 or BI 754091 and BI 907828.

The participants are in the study as long as they benefit from and can tolerate treatment. During this time, they get infusions of BI 754091 and BI 754111, and take tablets with BI 907828 every 3 weeks. The doctors check how many participants have health problems during the study. The doctors also monitor the size of the tumour.

Details
Condition Neoplasms
Treatment BI 754091, BI 754111, BI 907828
Clinical Study IdentifierNCT03964233
SponsorBoehringer Ingelheim
Last Modified on20 January 2022

Eligibility

Yes No Not Sure

Inclusion Criteria

All cohorts
Provision of signed and dated, written informed consent form ICF in accordance with International Council on Harmonization-Good Clinical Practice (ICH-GCP)and local legislation prior to any trial-specific procedures, sampling, or analyses
Male or female ≥18 years old at the time of signature of the ICF
ECOG performance status of 0 or 1
Life expectancy of at least 12 weeks after the start of the treatment according to the Investigator's judgement
Patients with radiologically documented disease progression or relapse during or after all standard of care treatments. Patients who are not eligible to receive standard of care treatments, and for whom no proven treatments exist, are eligible
Previous treatment with an anti-PD-1/PD-L1 mAb is allowed as long as the last administration of the anti-PD-1/PD-L1 mAb on the previous treatment occurred a minimum of 28 days prior to the first administration of study treatment
Patient must be willing to submit to the blood sampling for the Pharmacokinetics (PK), Pharmacodynamics (PD), biomarker, and PGx analyses
Adequate organ function defined as all of the following (all screening labs should be performed locally within 10 days of treatment initiation)
Hematological
Absolute neutrophil count - ≥1.5 x 10^9/L
Platelets - ≥125 x 10^9/L
Hemoglobin 0 ≥9.0 g/dL or ≥5.6 mmol/L (red blood cell transfusion allowed to meet eligibility criteria)
Hepatic
Total bilirubin ≤ upper limit of normal (ULN), (patients with Gilbert's syndrome, total bilirubin must be < 2 x ULN)
Aspartate Transaminase (AST) and Alanine Aminotransferase (ALT) ≤2.5 x ULN OR ≤5 x ULN for patients with liver metastases
Renal
\--- Creatinine - ≤1.5 x ULN - Patients may enter if creatinine is >1.5 x ULN
and estimated glomerular filtration rate (eGFR) >30 mL/min/1.73 m^2 (assessed
by Chronic Kidney Disease Epidemiology [CKDEPI] Collaboration equation)
confirmation of eGFR is only required when creatinine is >1.5 X ULN
Coagulation --- International Normalised Ratio (INR) or Prothrombin Time (PT). Activated Partial Thromboplastin Time (aPTT) - ≤1.5 x institutional ULN. Patients taking low dose warfarin must have their INR followed closely and according to institutional guidelines
Women of childbearing potential (WOCBP, defined as female patients who are
premenopausal or who had no cessation of menses within 12 months without an
Phase Ia (dose escalation part)
Patients with a confirmed diagnosis of unresectable, advanced and/or metastatic solid tumors (any type) irrespective of the TP53 mutation status
alternative medical cause, but not including female patients who are
Patient with either evaluable or non-evaluable disease
permanently sterilized) and men able to father a child must be ready and able
Availability and willingness to provide a sample of archival Formalin-fixed paraffin embedded (FFPE) tumor tissue material
to use two medically acceptable methods of birth control per ICH M3 (R2) that
Phase Ib (expansion part)
Phase Ia (Expansion Cohort)
result in a low failure rate of less than 1% per year when used consistently
At least one target lesion that can be accurately measured per RECIST 1.1. In patients who only have one target lesion, the baseline imaging must be performed at least two weeks after any biopsy of the target lesion
Patients with MDM2 amplified tumors and absence of known TP53 mutation
and correctly beginning at screening, during trial participation and until 35
Expansion cohorts
days and 3 months, respectively for women and men, after trial completion
Cohort 1: Patients with unresectable, advanced and/or metastatic TP53 wt NSCLC, who received in the advanced/metastatic setting, at least one line of systemic medical treatment that includes, but is not limited to, a platinum-based combination chemotherapy and immune checkpoint inhibitor(s) except anti-LAG-3. Patients with NSCLC harboring genomic aberrations for which FDA approved targeted therapy is available such as non-resistant EGFR mutations, EGFR T790M mutation, ALK rearrangement, ROS re-arrangement, and BRAF V600E mutation, must have received prior treatment with FDA-approved targeted therapy
(i.e. after the last administration of trial medication). A list of
Cohort 2: Patients with unresectable, advanced and/or metastatic TP53 wt melanoma, who received in the advanced/metastatic setting, at least one line of systemic medical treatment that has included immune checkpoint inhibitor(s), except anti-LAG-3, and for patients with a V600 BRAF mutation, a prior treatment with BRAF and MEK inhibitors
contraception methods meeting these criteria is provided in the patient
At least one target lesion that can be accurately measured per RECIST 1.1. In patients who only have one target lesion, the baseline imaging must be performed at least two weeks after any biopsy of the target lesion
Cohort 3: Patients with unresectable, advanced and/or metastatic TP53 wt well-differentiated or dedifferentiated liposarcoma (n = 10 patients) or TP53 wt undifferentiated pleomorphic sarcoma (n = 10 patients), who received in the advanced/metastatic setting, at least one line of systemic medical treatment that may have included immune checkpoint inhibitor(s), except anti-LAG-3 antibody
information
Cohort 4: Patients with unresectable, advanced and/or metastatic TP53 wt hepatocellular carcinoma (HCC), who received at least one line of systemic medical treatment in the advanced/metastatic setting, with or without prior treatment with anti-PD-1/PD-L1 antibody, and whose Child-Pugh score is 7 or less

Exclusion Criteria

In Phase Ib (expansion phase) only: a documented amino-acid altering mutation in TP53 occurring in the patient's tumor
Active or untreated brain metastases. Note: Patients with previously treated brain metastases may participate provided they are stable, without evidence of progression by imaging (using the identical imaging modality for each assessment, either MRI or computed tomography (CT) scan), for at least four weeks prior to the first dose of trial treatment, and any neurologic symptoms have returned to baseline; have no evidence of new or enlarging brain metastases. Patients on corticosteroids must have a stable dose for at least 5 days prior to baseline MRI
Current use of warfarin, factor Xa inhibitors and direct thrombin inhibitors. Note: Low molecular weight heparin and prophylactic low dose warfarin are permitted; PT/PTT must meet the inclusion criteria; patients taking low dose warfarin must have their INR followed closely and according to institutional guidelines
Previous administration of BI 907828 or any other MDM2-p53 or MDMX (MDM4)-p53 antagonist
Patients with history of bleeding diathesis
Major surgery (major according to the Investigator's assessment) performed within 12 weeks prior to start of study treatment, or planned within 12 months after screening (e.g. hip replacement)
Any other documented active or suspected malignancy or history of malignancy within 3 years prior to screening, except appropriately treated basal cell carcinoma of the skin or in situ carcinoma of uterine cervix, or other local tumors considered cured by local treatment
Patients who must or wish to continue the intake of restricted medications or any drug considered likely to interfere with the safe conduct of the trial
Currently enrolled in another investigational device or drug trial, or less than 4 weeks since receiving other investigational treatments. Patients who are in follow-up/observation for another clinical trial are eligible
Patients who have been treated with any other anticancer drug within 4 weeks or within 5 half-life periods (whichever come earlier) prior to first administration of study treatment
Positive results of hepatitis B surface (HBs) antigen
Presence of HBc antibody together with HBV-DNA
Known history of human immunodeficiency virus (HIV) infection
Any of the following laboratory evidence of hepatitis virus infection
Presence of hepatitis C RNA However, in Phase Ib Cohort 4 (HCC), patients with HBV and/or HCV infection are allowed. Patients in Cohort 4 (HCC), with HBV infection must be receiving effective antiviral therapy (viral load <100 IU/mL)
Known hypersensitivity to the trial drugs or their excipients
Serious concomitant disease or medical condition affecting compliance with trial requirements or which are considered relevant for the evaluation of the efficacy or safety of the trial drug, such as neurologic, psychiatric, infectious disease or active ulcers (gastro-intestinal tract, skin) or laboratory abnormality that may increase the risk associated with trial participation or trial drug administration, and in the judgment of the Investigator, would make the patient inappropriate for entry into the trial
Chronic alcohol or drug abuse or any condition that, in the Investigator's opinion, makes them an unreliable trial patient or unlikely to complete the trial
Women who are pregnant, nursing, or who plan to become pregnant while in the trial; female patients who do not agree to the interruption of breast feeding from the start of study treatment to within 30 days after the last study treatment
History (including current) of interstitial lung disease or pneumonitis within the last 5 years
History of severe hypersensitivity reactions to other monoclonal antibodies
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
Persistent toxicity from previous treatments that has not resolved to ≤ Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 (except for alopecia and CTCAE Grade 2 neuropathy, or asthenia/fatigue)
Active infection requiring systemic treatment (antibacterial, antiviral, or antifungal therapy) at start of treatment in this trial
Any of the following cardiac criteria
Mean resting corrected QT interval (QTc) >470 msec
Any clinically important abnormalities (as assessed by the Investigator) in rhythm, conduction, or morphology of resting ECGs, e.g., complete left bundle branch block, third degree heart block
Any factor that increases the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalaemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years-of-age, or any concomitant medication known to prolong the QT interval
Patients with an ejection fraction (EF) <50% or the lower limit of normal of the institutional standard will be excluded. Only in cases where the Investigator (or the treating physician or both) suspects cardiac disease with negative effect on the EF, will the EF be measured during screening using an appropriate method according to local standards to confirm eligibility (e.g., echocardiogram, multi-gated acquisition scan). A historic measurement of EF no older than 6 months prior to first administration of study drug can be accepted provided that there is clinical evidence that the EF value has not worsened since this measurement in the opinion of the Investigator or of the treating physician or both
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