Clinical trial NCT03449381: This Study Aims to Find the Best Dose of BI 907828 (Brigimadlin) in Patients With Different Types of Advanced Cancer (Solid Tumors)
Official title: A Phase Ia/Ib, Open Label, Multicenter, Dose-escalation Study of BI 907828 (Brigimadlin) in Patients With Advanced or Metastatic Solid Tumors
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
Conditions: Neoplasms
Lead sponsor: Boehringer Ingelheim
Sponsor class: INDUSTRY
First posted: 2018-02-28
Enrollment: 267
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: This study is open to adults with different types of advanced cancer (solid tumors). The purpose of this study is to find out the most suitable dose of BI 907828 (brigimadlin) the participants can tolerate. The most suitable dose is used in the second part to find out whether brigimadlin makes tumors shrink.

In this study, brigimadlin is given to humans for the first time. Brigimadlin is a so-called MDM2 inhibitor that is being developed to treat cancer. Brigimadlin is taken as a tablet. Participants either take a dose of brigimadlin on one day every 3 weeks or on two days every 4 weeks.

The participants are in the study for as long as they benefit from and can tolerate treatment. The doctors regularly check the participants' general health during the study.


Eligibility criteria: 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.
* Patients fulfilling one or more of the following criteria:

  * Radiologically documented disease progression or relapse
  * Patients who are not eligible to receive standard of care treatments, and for whom no proven treatments exist.
  * Patients with MDM2 amplified sarcomas who require first line treatment (for Ph Ib/dose expansion - Cohort 1 only).
* Patients with MDM2 amplified sarcomas may fulfil any one of the above three criteria to be considered 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 sarcoma with advanced/metastatic disease at any line of therapy. If TP53 status is not available during screening, the patient may be included with unknown TP53 status if a tissue sample is submitted for central laboratory assessment. If TP53 status cannot be evaluated, the patient may be included if agreed between the Investigator and Sponsor.
* Cohort 2: TP53 wt and MDM2- amplified NSCLC, urothelial, gastric, biliary tract (including cholangiocarcinoma, intra- and extrahepatic biliary tree, gall blander and ampulla of vater) or pancreatic solidPDAC tumors who have had at least one previous line of therapy for advanced/metastatic disease. If TP53 status cannot be evaluated the patient may be included if agreed between the Investigator and Sponsor
* 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.
* Phase Ia:
* Patient must be willing to undergo blood sampling for PK, pharmacodynamic, biomarker, and PGx analyses.
* Phase Ib:
* Patient must be willing to undergo tumor biopsy sampling for pharmacodynamic analyses and blood sampling for PK, pharmacodynamics, and biomarker analyses.
* Willingness to provide a fresh tumor tissue sample obtained after relapse/ 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 within 12 months of enrollment, may be submitted. If these requirements cannot be met, then the patient may be allowed to enter the study at Sponsor discretion, after agreement between the Investigator and Sponsor.
* Further inclusion criteria apply

Exclusion Criteria:

* Previous administration of BI 907828 (brigimadlin) or any other MDM2-p53 or MDMX (MDM4)-p53 antagonist.
* Known TP53 mutant tumor.
* Symptomatic metastases from non-brain tumors. 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.
* 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.
* Further exclusion criteria apply.

Primary outcomes:
measure: Phase Ia- Maximum tolerated dose (MTD) based on number of patients with dose limiting toxicities (DLTs) during first treatment cycle
timeFrame: Up to 28 days
measure: Phase Ib - Progression-free survival
timeFrame: Up to 24 months
measure: Phase Ia - Number of patients with DLTs during first treatment cycle (21 days, Arm A; 28 days, Arm B)
timeFrame: Up to 28 days
measure: Phase Ib - Number of patients with DLTs during the first treatment cycle
timeFrame: Up to 28 days
Secondary outcomes:
measure: Phase Ia - Cmax: Maximum measured concentration of BI 907828 in plasma
timeFrame: Up to 24 months
measure: Phase Ia - AUC0-∞: Area under the concentration-time curve in plasma over the time interval from 0 extrapolated to infinity
timeFrame: Up to 24 months
measure: Phase Ib - Objective response
timeFrame: Up to 24 months
measure: Phase Ib - Overall survival
timeFrame: Up to 24 months
measure: Phase Ib - Number of patients with Grade ≥3 treatment-related adverse events observed during the entire treatment period
timeFrame: Up to 24 months
measure: Phase Ib - Cmax: Maximum measured concentration of BI 907828 in plasma
timeFrame: Up to 24 months
measure: Phase Ib - AUC0-∞: Area under the concentration-time curve in plasma over the time interval from 0 extrapolated to infinity
timeFrame: Up to 24 months
Other outcomes:
Locations:
city: Santa Monica
country: United States
facility: Sarcoma Oncology Center
state: California
city: New Haven
country: United States
facility: Yale University School of Medicine
state: Connecticut
city: Sarasota
country: United States
facility: Florida Cancer Specialists-Sarasota-61670
state: Florida
city: Louisville
country: United States
facility: Norton Cancer Institute, Downtown
state: Kentucky
city: Grand Rapids
country: United States
facility: START Midwest
state: Michigan
city: New York
country: United States
facility: Memorial Sloan-Kettering Cancer Center
state: New York
city: Nashville
country: United States
facility: SCRI Oncology Partners
state: Tennessee
city: Houston
country: United States
facility: The University of Texas MD Anderson Cancer Center
state: Texas
city: Madison
country: United States
facility: University of Wisconsin
state: Wisconsin
city: Bruxelles
country: Belgium
facility: Brussels - UNIV Saint-Luc
city: Leuven
country: Belgium
facility: UZ Leuven
city: Ottawa
country: Canada
facility: The Ottawa Hospital
state: Ontario
city: København Ø
country: Denmark
facility: Rigshospitalet, København
city: Berlin
country: Germany
facility: Helios Klinikum Berlin-Buch
city: Göttingen
country: Germany
facility: Universitätsmedizin Göttingen, Georg-August-Universität
city: Köln
country: Germany
facility: Universitätsklinikum Köln (AöR)
city: Tübingen
country: Germany
facility: Universitätsklinikum Tübingen
city: Tel Aviv
country: Israel
facility: Sourasky Medical Center
city: Tokyo, Chuo-ku
country: Japan
facility: National Cancer Center Hospital
city: Seoul
country: Korea, Republic of
facility: Severance Hospital
city: Poznan
country: Poland
facility: MED POLONIA SP Z O O, Clinical Trials Department,Poznan
city: Warsaw
country: Poland
facility: Oncology Center-Maria Sklodowska-Curie Institute
city: Barcelona
country: Spain
facility: Hospital Vall d'Hebron
city: Barcelona
country: Spain
facility: Hospital Clínic de Barcelona
city: Madrid
country: Spain
facility: Fundación Jiménez Díaz
city: Santiago de Compostela
country: Spain
facility: Hospital Clínico de Santiago
city: Stockholm
country: Sweden
facility: Karolinska Comprehensive Cancer Center
Study officials:
References: