A Phase I, Open Label, Multicenter, Dose-escalation Study of BI 907828 in Adult Patients With Wild-type TP53 Enriched Advanced Solid Tumors and Expansion in Patients With MDM2 Amplified Advanced Solid Tumors

Primary Outcome Measures :

1. Phase Ia- MTD based on number of patients with DLTs during first treatment cycle [ Time Frame: up to 24 Months ]
   
2. Ph Ib - Objective response per RECIST, RANO criteria, or RANO-BM, and assessed by Investigator, measured separately for each cohort, from treatment start until earliest of progression, death, or last tumor assessment and before subsequent therapy [ Time Frame: up to 24 Months ]
   
3. Phase Ia - Number of patients with DLTs during first treatment cycle (21 days, Arm A; 28 days, Arm B) [ Time Frame: up to 28 days ]
   

Secondary Outcome Measures :

1. Phase Ia- Cmax: maximum measured concentration of BI 907828 in plasma [ Time Frame: up to 24 Months ]
   
2. Phase Ia - AUC0-∞: area under the concentration-time curve in plasma over the time interval from 0 extrapolated to infinity. [ Time Frame: up to 24 Months ]
   
3. Phase Ib - Disease control (DC) with tumor assessment until disease progression (according to RECIST v.1.1 for non-brain lesions, or RANO/RANO-BM- criteria for brain lesions) as assessed by the Investigator, or start of subsequent anti-cancer treatment [ Time Frame: up to 24 Months ]
   
4. Phase Ib - Progression-free Survival defined from date of start of BI 907828 to earliest of date of disease progression or death (according to RECIST 1.1, RANO/RANO-BM as applicable), as assessed by the Investigator, measured separately for each cohort. [ Time Frame: up to 24 Months ]
   
5. Phase Ib - Number of patients with Grade ≥3 treatment-related adverse events observed during the entire treatment period. [ Time Frame: up to 24 Months ]
   
6. Phase Ib - Cmax: maximum measured concentration of BI 907828 in plasma [ Time Frame: up to 24 Months ]
   
7. Phase Ib - AUC0-∞: area under the concentration-time curve in plasma over the time interval from 0 extrapolated to infinity [ Time Frame: up to 24 Months ]
   

Inclusion Criteria:

• 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 analyses.
• 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 urothelial carcinoma.
  • 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 PGx analyses.
• 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 the ICF
• 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 Investigator's judgement.
• 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 patient information.

Exclusion Criteria:

• Previous administration of BI 907828 or any other TP53-MDM2 or TP53-MDMX (MDM4) antagonist.
• 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 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 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 907828.
• 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 standard.