Ensayos clínicos

Inclusion Criteria:

• Provision of signed and dated, written informed consent form (ICF) in accordance with International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) – Good Clinical Practice (GCP) and local legislation prior to any study-specific procedures, sampling, or analyses.
• Male or female patients ≥ 18 years old at the time of signature of the ICF.
• Women of childbearing potential (WOCBP) 1 and men able to father a child must be ready and able to use two medically acceptable methods of birth control per ICH M3 (R2) that result in a low failure rate of < 1% per year when used consistently and correctly beginning at screening, during study participation, and until 6 months and 12 days after last dose for women and 102 days after last dose for men. A list of contraception methods meeting these criteria is provided in the patient information.
• Histologically documented locally advanced or metastatic, unresectable (i.e. surgery morbidity would outweigh potential benefits), progressive or recurrent DDLPS, meeting the criteria for an open study cohort:
  • Cohort A: patient has not received prior systemic therapy for DDLPS in any setting (including adjuvant, neoadjuvant, maintenance, palliative);
  • Cohort B: patient has received any prior systemic therapy for DDLPS in any setting (including adjuvant, neoadjuvant, maintenance, palliative).
• Written pathology report indicating the diagnosis of DDLPS with positive MDM2 immunohistochemistry or MDM2 amplification as demonstrated by fluorescence in situ hybridisation (FISH) or next-generation sequencing (NGS).
• Presence of at least 1 measurable target lesion according to RECIST version 1.1. In patients who only have 1 target lesion, the baseline imaging must be performed at least 2 weeks after any biopsy of the target lesion.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• Life expectancy ≥ 3 months at the start of treatment in the opinion of the investigator.
• All toxicities related to previous anticancer therapies have resolved to CTCAE Grade ≤ 1 prior to study treatment administration (except for alopecia and amenorrhoea or menstrual disorders which can be any grade, and peripheral neuropathy which must be of CTCAE Grade ≤ 2).
• Adequate organ function as defined in Table 3.3.2: 1.

Exclusion Criteria:

• Known mutation in the TP53 gene (screening for TP53 status is not required).
• Major surgery (major according to the investigator’s assessment) performed within 4 weeks prior to start of study treatment or planned within 6 months after screening.
• Previous administration of brigimadlin or any other MDM2-p53 or MDM4 regulator of p53 (MDM4/MDMX)-p53 antagonist.
• Previous treatment in study 1403-0008 (Brightline-1).
• Having to receive, or intending to receive, restricted medications (see Section 4.2.2.1) or any drug considered likely to interfere with the safe conduct of the study.
• Receiving treatment for brain metastases or leptomeningeal disease (LMD) which may interfere with safety and/or endpoint assessment.
• Unable to swallow the study treatment.
• Previous or concomitant malignancies other than the one treated in this study within the previous 2 years, except effectively treated non-melanoma skin cancers, carcinoma in situ of the cervix, ductal carcinoma in situ, or other malignancy that is considered cured by local treatment.
• Any history or presence of uncontrolled GI disorders that could affect the intake and/or absorption of the study treatment (e.g. nausea, vomiting, Crohn’s disease, ulcerative colitis, chronic diarrhoea, malabsorption) in the opinion of the investigator.
• History or presence of clinically relevant cardiovascular abnormalities such as:
  • Mean resting corrected QT interval by Fridericia (QTcF) > 470 msec;
  • Any clinically important abnormalities (as assessed by the investigator) in rhythm, conduction, or morphology of resting electrocardiogram (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;
  • Ejection fraction (EF) < 50% or the lower limit of normal of the institutional standard. 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 by using an appropriate method according to local standards to confirm eligibility (e.g. echocardiogram, multigated acquisition scan). A historic measurement of EF no older than 6 months prior to first administration of study treatment can be accepted provided that there is clinical evidence that the patient’s cardiac disease has not significantly worsened since this measurement in the opinion of the investigator or of the treating physician or both 11.
• Active bleeding, significant risk of haemorrhage (e.g. previous severe GI bleeding, previous haemorrhagic stroke at any time), or current bleeding disorder (e.g. haemophilia, von Willebrand disease).
• Any history of or concomitant condition that, in the opinion of the investigator, would compromise the patient’s ability to comply with the study or interfere with the evaluation of the safety and efficacy of the study treatment.
• Patients not expected to comply with the protocol requirements or not expected to complete the study as scheduled (e.g. chronic alcohol or drug abuse or any other condition that, in the investigator’s opinion, makes the patient an unreliable study patient).
• Women who are pregnant, nursing, or who plan to become pregnant while in the study. Female patients who do not agree to the interruption of breastfeeding from the start of study treatment until 6 months and 12 days after last dose of study treatment.
• Patients with history of human immunodeficiency virus (HIV) infection who meet ≥1 of the following criteria:
  • Cluster of differentiation 4 (CD4) + count < 350 cells/µL;
  • Viral load  > 400 copies/mL (local laboratory assessment);
  • Not receiving antiretroviral therapy
  • Receiving established antiretroviral therapy for < 4 weeks prior to the start of study treatment;
  • History of acquired immunodeficiency syndrome (AIDS)-defining opportunistic infections within 12 months prior to start of study treatment;
  • Patients with a history of HIV who do not meet any of the criteria above are eligible to participate but the patient must be under the care of an HIV or Infectious Diseases specialist or an HIV or Infectious Diseases specialist must be consulted prior to inclusion.
• Patients with a history of hepatitis C virus (HCV) infection who meet ≥ 1 of the following criteria:
  • Currently receiving curative antiviral treatment;
  • Not yet achieved sustained viral response;
  • HCV viral load is above the limit of quantification (HCV ribonucleic acid [RNA] positive).
• Patients with chronic hepatitis B virus (HBV) infection with active disease who meet the criteria for anti-HBV therapy (according to local or institutional standard) and who have not been treated with suppressive antiviral therapy prior to initiation of study treatment.
• Known hypersensitivity or history of allergy to brigimadlin, or its excipients, or similar class drugs.
• Active major infection requiring systemic treatment (antibacterial, antiviral, or antifungal therapy) at treatment start in this study.

Note: Other protocol defined Inclusion/Exclusion Criteria may apply.

Eligibility last updated 8/17/23. Questions regarding updates should be directed to the study team contact.