IRB Study Number 24-373
Status Recruiting
Institute Taussig Cancer Institute
Description
Primary Objective
To evaluate the efficacy of brigimadlin by the proportion of patients with objective response (OR).
Secondary Objectives
To evaluate the efficacy of brigimadlin by median estimate of duration of objective response (DOR), progression-free survival (PFS), and overall survival (OS) as well as the assessment of health-related quality of life as assessed by the EORTC QLQ-C30 and the EORTC QLQ-BIL21.
Inclusion Criteria
- Diagnosis of a solid tumour which meets the criteria for an open trial cohort:
o Cohorts 1 and 1-CN (biliary tract adenocarcinoma): Locally advanced or metastatic biliary tract adenocarcinoma (intra- and extrahepatic cholangiocarcinoma, gallbladder cancer, and ampullary cancer). Patients must have unresectable disease and have received all available conventional therapies known to confer clinical benefit for their disease based on local approved standards; or (in the opinion of the investigator) patients are unlikely to tolerate or derive clinically meaningful benefit from appropriate standard of care therapy.
o Cohort 2 (pancreatic ductal adenocarcinoma): Locally advanced or metastatic pancreatic ductal adenocarcinoma. Patients must have unresectable disease and have received all available conventional therapies known to confer clinical benefit for their disease based on local approved standards.
o Cohort 3 (lung adenocarcinoma): Locally advanced or metastatic lung adenocarcinoma. Patients must have unresectable disease and have received all available conventional therapies known to confer clinical benefit for their disease based on local approved standards.
o Cohort 4 (urothelial bladder cancer): Locally advanced or metastatic urothelial bladder cancer. Patients must have unresectable disease and have received all available conventional therapies known to confer clinical benefit for their disease based on local approved standards.
Written pathology report / molecular profiling report indicating MDM2 amplification*, and TP53 wild-type status. This must have been confirmed with a tissue-based test. A test with liquid biopsy is not accepted. * The MDM2 copy number must be ≥8. An exception is when the molecular pathology test has been performed by a laboratory designated by the sponsor for development of the companion diagnostic test (see section 5.4.2.1), in which case the copy number information is not required.
Archival tissue (formalin fixed paraffin embedded [FFPE] tumour blocks or slides) must be provided for retrospective confirmation of MDM2 amplification and TP53 status. See Section 5.4.2.1 for details and an exception.
Presence of at least 1 measurable target lesion according to RECIST version 1.1.
Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1.
Patient must be willing to donate mandatory blood samples for the pharmacokinetics, pharmacodynamics, and biomarker analyses, as specified in the Flowchart.
Adequate organ function, defined as meeting all criteria in Table 1.
All toxicities related to previous anti-cancer therapies have resolved to ≤CTCAE Grade 1 prior to trial treatment administration (except for alopecia and amenorrhea / menstrual disorders which can be of any grade and peripheral neuropathy which must be ≤CTCAE Grade 2).
Life expectancy ≥3 months at the start of treatment in the opinion of the investigator.
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.
Male or female patients ≥18 years old at the time of signature of the ICF. Women of childbearing potential (WOCBP; for a definition see section 4.2.2.3) and men able to father a child must be ready and able to use 2 medically acceptable 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 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.
Exclusion Criteria
Previous administration of brigimadlin or any other MDM2-p53 or MDMX (MDM4)-p53 antagonist.
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).
Major surgery (major according to the investigator’s assessment) performed within 4 weeks prior to start of trial treatment or planned within 6 months after screening (e.g. hip replacement).
Clinically significant previous or concomitant malignancies in the opinion of the investigator affecting the efficacy and/or outcome of the trial.
Patients who must or intend to continue the intake of restricted medications (see Section 4.2.2.1) or any drug considered likely to interfere with the safe conduct of the trial.
Currently enrolled in another investigational device or drug trial.
Any history of, or concomitant condition that, in the opinion of the investigator, would compromise the patient’s ability to comply with the trial or interfere with the evaluation of the safety and efficacy of the trial drug.
Patients not expected to comply with the protocol requirements or not expected to complete the trial as scheduled (e.g. chronic alcohol or drug abuse or any other condition that, in the investigator’s opinion, makes the patient an unreliable trial participant).
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 breastfeeding from the start of trial treatment until 6 months and 12 days after last dose of trial treatment.
Patients with known history of human immunodeficiency virus (HIV) infection who meet 1 or more of the following criteria:
o CD4+ count <350 cells/μL
o Viral load >400 copies/mL (local laboratory assessment)
o Not receiving antiretroviral therapy
o Receiving established antiretroviral therapy for <4 weeks prior to the start of trial treatment
o History of AIDS-defining opportunistic infections within 12 months prior to start of trial 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 a HIV/Infectious Diseases specialist or a HIV/Infectious Diseases specialist must be consulted prior to inclusion.
- Patients with a history of HCV infection who meet 1 or more of the following criteria:
o Currently receiving curative antiviral treatment
o Not yet achieved sustained viral response (SVR)
o HCV viral load is above the limit of quantification (HCV RNA positive)
Patients with chronic HBV infection with active disease who meet the criteria for anti-HBV therapy (according to local / institutional standard) and who have not been treated with suppressive antiviral therapy prior to initiation of trial treatment.
Any history or presence of uncontrolled gastrointestinal disorders that could affect the intake and/or absorption of the trial drug (e.g. nausea, vomiting, Crohn’s disease, ulcerative colitis, chronic diarrhoea, malabsorption) in the opinion of the investigator.
Known hypersensitivity to brigimadlin or any of its excipients.
Active major infection requiring systemic treatment (antibacterial, antiviral, or antifungal therapy) at treatment start in this trial. Cholangitis being treated for at least 1 week with antibiotics and well controlled is allowed.
History or presence of cardiovascular abnormalities such as uncontrolled hypertension, congestive heart failure NYHA classification of ≥III or IV, unstable angina or poorly controlled arrhythmia which are considered as clinically relevant by the investigator. Myocardial infarction, stroke or pulmonary embolism within 6 months prior to the start of trial treatment.
Patients with uncontrolled ascites related to portal hypertension and/or active, uncontrolled cholangitis.
Receiving treatment for brain metastases or leptomeningeal disease (LMD) which may interfere with safety and/or efficacy endpoint assessment.
Any of the following cardiac criteria:
o Mean resting corrected QT interval (QTcF) >470 msec
o 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
o 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.
o Patients with an 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 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 trial drug 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.
- Patients who cannot swallow pills.
