Phase Ia - The main objective of the dose-escalation part of the trial is to determine the
maximum tolerated dose (MTD), based on the frequency of patients experiencing dose limiting
toxicities (DLT) during the first treatment cycle, and the recommended dose for expansion
(RDE) of BI 907828 monotherapy, and to evaluate its safety and tolerability, by monitoring
the occurrence and severity of adverse events (AEs), in two different schedules (Arm A with
one single dose every 21 days, Arm B with one single dose on Days 1 and 8, every 28 days).
The secondary objectives are the determination of the pharmacokinetic (PK) profile of BI
907828 monotherapy, and the preliminary assessment of anti-tumor activity in patients with
advanced or metastatic solid tumors.
Phase Ib - In the expansion cohorts of the trial, the main objectives are to assess efficacy,
and to further assess the safety, and PK profiles at the RDE, and determine the recommended
Phase 2 dose (RP2D).
- Provision of signed and dated, written informed consent form ICF in accordance with
ICH-GCP and local legislation prior to any trial-specific procedures, sampling, or
- Pathologically documented, advanced solid tumors.
- 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.
- Phase Ia (dose escalation) only:
- Patient has a tumor with either a known TP53 wild type status, or unknown TP53
status, and regardless of MDM2 amplification status, at the time of study entry.
-- Phase Ib (expansion phase) only:
- Cohort 1: TP53 wt and MDM2-amplified non-squamous NSCLC
- Cohort 2: TP53 wt and MDM2-non-amplified non-squamous NSCLC.
- Cohort 3: TP53 wt and MDM2-amplified soft tissue sarcoma, glioblastoma, and
- Cohort 4: TP53 wt and MDM2-amplified solid tumors with brain metastases. Patients
may have received any systemic and/or local treatment for their brain lesions but
there needs to be unequivocal evidence of progression of at least one brain
lesion. Patients on corticosteroids must have a stable dose for at least 5 days
prior to baseline magnetic resonance imaging (MRI).
- Phase Ia (dose escalation) only:
- Patient with either measurable or non-measurable disease.
- Non-evaluable disease allowed.
-- Phase Ib (expansion phase) only:
- At least one target lesion that can be accurately measured per RECIST v.1.1.
- For glioblastoma: measurable disease by RANO criteria (bidimensional
contrast-enhancing lesions with clearly defined margins by MRI, with 2
perpendicular diameters of at least 10 mm, visible on two or more 2 axial
slices). Patients on corticosteroids must have a stable dose for at least 5 days
prior to baseline MRI.
- Patient must be willing to submit the blood sampling for the PK, PD, biomarker, and
- Availability and willingness to provide a fresh tumor tissue sample obtained after
relapse or progression during or after prior therapy. In case a fresh biopsy cannot be
obtained (e.g. inaccessible lesions or patient safety concern), an archived specimen,
collected before screening, may be submitted.
- Male or female ≥18 years old (for Japan, ≥20 years old) at the time of signature of
- ECOG performance status of 0 or 1 (an ECOG of 2 is acceptable, if it is due to
noncancer- related disability, and after agreement with Sponsor).
- Life expectancy of at least 12 weeks after the start of the treatment according to the
- Adequate organ function
- Male or female patients. Women of childbearing potential (WOCBP, defined as female
patients who are premenopausal or who had no cessation of menses within 12 months
without an alternative medical cause, but not including female patients who are
permanently sterilized) and men able to father a child must be ready and able to use
two highly effective methods of birth control per ICH M3 (R2) that result in a low
failure rate of less than 1% per year when used consistently and correctly beginning
at screening, during trial participation and until 35 days and 3 months, respectively
for women and men, after trial completion (i.e. after the last administration of trial
medication). A list of contraception methods meeting these criteria is provided in the
- Previous administration of BI 907828 or any other TP53-MDM2 or TP53-MDMX (MDM4)
- Patient has a tumor with a documented mutation in the TP53 gene determined previously
or at screening irrespective of MDM2 amplification status. For dose escalation part
only, patients who have tumors with unknown TP53 and/or MDM2 status at the time of
screening are eligible at investigator's discretion.
- Active or untreated brain metastases from non-brain tumors, except for expansion
cohort 4 (solid tumors with 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 according to institutional guidelines.
- 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
- 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 30
days since receiving other investigational treatments. Patients who are in followup/
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 BI
- Persistent toxicity from previous treatments that has not resolved to ≤ CTCAE Grade 1
(except for alopecia and CTCAE Grade 2 neuropathy, or asthenia/fatigue).
- Known human immunodeficiency virus (HIV) infection, acute or chronic viral hepatitis.
Patients with a history of hepatitis B virus infection, irrespective of their
reactivation risk status, should also be excluded. The testing at screening is not
mandatory and left at the discretion of investigator.
- Known hypersensitivity to the trial drug or its 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.
- Any of the following cardiac criteria:
- Mean resting corrected QT interval (QTcF) >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 factors that increase 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
- Ejection fraction <50% or the lower limit of normal of the institutional