Liposarcoma, Dedifferentiated
Conditions
Brief summary
This study is open to people with a type of cancer called dedifferentiated liposarcoma. People with advanced liposarcoma aged 18 or older who are not receiving any other cancer treatment can participate. The purpose of this study is to compare a medicine called brigimadlin (BI 907828) with doxorubicin in people with liposarcoma. Brigimadlin (BI 907828) is a so-called MDM2 inhibitor that is being developed to treat cancer. Doxorubicin is a medicine already used to treat cancer including liposarcoma. During the study, participants get either brigimadlin (BI 907828) or doxorubicin. Every 3 weeks, participants take brigimadlin (BI 907828) as tablets or doxorubicin as an infusion into a vein. Participants can switch to brigimadlin (BI 907828) treatment if they did not benefit from doxorubicin treatment. Participants can continue treatment in the study as long as they benefit from it and can tolerate it. Doctors regularly check the size of the tumour and check whether it has spread to other parts of the body. The doctors also regularly check participants' health and take note of any unwanted effects.
Interventions
DRUGBrigimadlin
Brigimadlin taken orally on day 1 of each 21-day cycle (q3w).
DRUGDoxorubicin
Intravenous infusion of 75 milligram per square meter (mg/m2) on Day 1 of each 21-day cycle (q3w) until a maximum cumulative dose of 450 mg/m2 (approximately 6 cycles).
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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. * Male or female patients ≥18 years old at the time of signature of the informed consent form (ICF). Women of childbearing potential (WOCBP) 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. * Histologically proven locally advanced or metastatic, unresectable (surgery morbidity would outweigh potential benefits), progressive or recurrent dedifferentiated liposarcoma (DDLPS). Locally performed histopathological diagnosis will be accepted for entry into this trial but will be confirmed by independent pathological review while the patients receive treatment in this trial. * Written pathology report indicating the diagnosis of DDLPS with positive mouse double minute 2 homolog (MDM2) immunohistochemistry or MDM2 amplification as demonstrated by fluorescence in situ hybridization or next generation sequencing (NGS) must be available. * Formalin fixed paraffin embedded tumor blocks or slides must be available for retrospective histopathological central review. * Presence of at least one measurable target lesion according to Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1. In patients who only have one 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 (PS) of 0 or 1. * Patient must be willing to donate blood samples for the pharmacokinetics, pharmacodynamics, and tumor mutation analysis. * Patient willing to undergo a mandatory tumor biopsy at the time point specified in the flowchart unless exempt. * Adequate organ function.
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 randomization or planned within 6 months after screening. * Prior systemic therapy for liposarcoma in any setting (including adjuvant, neoadjuvant, maintenance, palliative). * Previous or concomitant malignancies other than DDLPS or WDLPS, treated within the previous 5 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. * Previous treatment with anthracyclines in any setting (systemic treatment with other anticancer agents is allowed if completed at least 5 years prior to study entry with the exception of hormone therapy). * Patients who must or intend 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 ending another investigational device or drug trial(s) or receiving other investigational treatment(s). * 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). * Further
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS) | Up to 20.6 months. | Progression-free survival (PFS) based on blinded central independent review. For each patient, PFS was defined as the time interval from randomization until tumor progression according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (solely based on blinded central independent review) or death from any cause, whichever occurs first. Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 millimeter. (Note: the appearance of one or more new lesions is also considered progression). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response (OR) | Up to 20.6 months. | Objective response (OR), defined as a best overall response of confirmed complete response (CR) or confirmed partial response (PR) according to RECIST version 1.1 (based on blinded central independent review) from the date of randomization until disease progression, death, or last evaluable tumor assessment before start of subsequent anti-cancer therapy, loss to follow-up, or withdrawal of consent, whichever occurs first. Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. |
| Duration of Objective Response (DOR) | Up to 20.6 months. | Duration of objective response (DOR), defined as the time interval from first documented confirmed OR until disease progression or death among patients with confirmed OR (based on blinded central independent review), whichever occurs first. |
| Disease Control (DC) | Up to 20.6 months. | Disease control (DC), defined as a best overall response of CR, PR, or stable disease (SD) according to RECIST version 1.1 (based on blinded central independent review). Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. |
| Change in Health-Related Quality of Life at Week 6 and 18 | Baseline (cycle 1 day 1), week 6 and week 18. | Mean change from baseline to week 6 and 18 in the following European Organization for Research and Treatment on Cancer (EORTC) Quality of Life Core Questionnaire 30 items (QLQ-C30) scores: * Physical functioning (higher score is better) * Pain (higher score is worse) * Fatigue (higher score is worse) * Global health status / QoL (higher score is better) and the following scores obtained using items from the EORTC QLQ-C30 and EORTC Item Library (higher score is worse): * Fatigue symptoms * Fatigability * Fatigue impact * Pain descriptors * Pain impact All of the scales and single-item measures range in score from 0 to 100. |
Countries
Australia, Belgium, Canada, China, Czechia, Denmark, Finland, France, Germany, Greece, Hong Kong, Italy, Japan, Netherlands, Norway, Portugal, Spain, Sweden, Taiwan, Turkey (Türkiye), United Kingdom, United States
Participant flow
Recruitment details
This was a randomized, active-controlled, open-label, global trial with a seamless Phase II part and Phase III part parallel design.
Pre-assignment details
All subjects were screened for eligibility prior to participation in the trial. Subjects attended a specialist site which ensured that they (the subjects) strictly met all inclusion and none of the exclusion criteria. Subjects were not to be allocated to a treatment group if any of the entry criteria were violated.
Participants by arm
| Arm | Count |
|---|---|
| Brigimadlin 30 mg q3w Patients with advanced or metastatic dedifferentiated liposarcoma (DDLPS) received 30 milligram (mg) brigimadlin taken orally on day 1 of each 21-day cycle (q3w). | 90 |
| Brigimadlin 45 mg q3w Patients with advanced or metastatic dedifferentiated liposarcoma (DDLPS) received 45 milligram (mg) brigimadlin taken orally on day 1 of each 21-day cycle (q3w). | 148 |
| Doxorubicin Patients with advanced or metastatic dedifferentiated liposarcoma (DDLPS) received one intravenous infusion of 75 milligram per square meter (mg/m2) on Day 1 of each 21-day cycle (q3w) until a maximum cumulative dose of 450 mg/m2 (approximately 6 cycles). | 162 |
| Total | 400 |
Baseline characteristics
| Characteristic | Brigimadlin 30 mg q3w | Brigimadlin 45 mg q3w | Doxorubicin | Total |
|---|---|---|---|---|
| Age, Continuous | 62.3 years STANDARD_DEVIATION 11.7 | 64.7 years STANDARD_DEVIATION 9.8 | 63.0 years STANDARD_DEVIATION 11.7 | 63.5 years STANDARD_DEVIATION 11 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 8 Participants | 6 Participants | 9 Participants | 23 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 79 Participants | 138 Participants | 150 Participants | 367 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 3 Participants | 4 Participants | 3 Participants | 10 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Asian | 20 Participants | 39 Participants | 29 Participants | 88 Participants |
| Race/Ethnicity, Customized Black or African American | 1 Participants | 1 Participants | 2 Participants | 4 Participants |
| Race/Ethnicity, Customized Missing | 3 Participants | 5 Participants | 3 Participants | 11 Participants |
| Race/Ethnicity, Customized White | 65 Participants | 103 Participants | 128 Participants | 296 Participants |
| Sex: Female, Male Female | 35 Participants | 52 Participants | 62 Participants | 149 Participants |
| Sex: Female, Male Male | 55 Participants | 96 Participants | 100 Participants | 251 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 31 / 89 | 40 / 147 | 15 / 154 | 5 / 7 | 22 / 70 |
| other Total, other adverse events | 89 / 89 | 144 / 147 | 153 / 154 | 6 / 7 | 67 / 70 |
| serious Total, serious adverse events | 27 / 89 | 57 / 147 | 42 / 154 | 1 / 7 | 22 / 70 |
Outcome results
Primary
Progression-free Survival (PFS)
Progression-free survival (PFS) based on blinded central independent review. For each patient, PFS was defined as the time interval from randomization until tumor progression according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (solely based on blinded central independent review) or death from any cause, whichever occurs first. Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 millimeter. (Note: the appearance of one or more new lesions is also considered progression).
Time frame: Up to 20.6 months.
Population: Randomised Set (RS): All patients randomized, regardless of whether they have received any trial medication or not.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Brigimadlin 30 mg q3w | Progression-free Survival (PFS) | 8.18 Months |
| Brigimadlin 45 mg q3w | Progression-free Survival (PFS) | 8.38 Months |
| Doxorubicin | Progression-free Survival (PFS) | 7.16 Months |
Comparison: The primary estimator for the hazard ratio is the median unbiased estimator. The confidence interval (CI) for the hazard ratio is calculated as a repeated CI. The p-value is obtained using a weighted inverse normal method combining one-sided p-values from two stages.p-value: 0.095695% CI: [0.6, 1.06]Regression, Cox
Secondary
Change in Health-Related Quality of Life at Week 6 and 18
Mean change from baseline to week 6 and 18 in the following European Organization for Research and Treatment on Cancer (EORTC) Quality of Life Core Questionnaire 30 items (QLQ-C30) scores: * Physical functioning (higher score is better) * Pain (higher score is worse) * Fatigue (higher score is worse) * Global health status / QoL (higher score is better) and the following scores obtained using items from the EORTC QLQ-C30 and EORTC Item Library (higher score is worse): * Fatigue symptoms * Fatigability * Fatigue impact * Pain descriptors * Pain impact All of the scales and single-item measures range in score from 0 to 100.
Time frame: Baseline (cycle 1 day 1), week 6 and week 18.
Population: Randomised Set (RS). As per protocol, the endpoint was performed as part of the Phase III of the trial, which only includes the selected investigational arm (brigimadlin 45 mg q3w) and the doxorubicin control arm.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Brigimadlin 30 mg q3w | Change in Health-Related Quality of Life at Week 6 and 18 | Fatigue - Change from baseline at Week 6 | 3.4 Score on a scale | Standard Deviation 21.2 |
| Brigimadlin 30 mg q3w | Change in Health-Related Quality of Life at Week 6 and 18 | Fatigue symptoms - Change from baseline at Week 18 | 7.9 Score on a scale | Standard Deviation 26.7 |
| Brigimadlin 30 mg q3w | Change in Health-Related Quality of Life at Week 6 and 18 | Fatigability - Change from baseline at Week 6 | 3.3 Score on a scale | Standard Deviation 19.8 |
| Brigimadlin 30 mg q3w | Change in Health-Related Quality of Life at Week 6 and 18 | Pain - Change from baseline at Week 6 | -3.7 Score on a scale | Standard Deviation 20.2 |
| Brigimadlin 30 mg q3w | Change in Health-Related Quality of Life at Week 6 and 18 | Fatigability - Change from baseline at Week 18 | 5.1 Score on a scale | Standard Deviation 23.3 |
| Brigimadlin 30 mg q3w | Change in Health-Related Quality of Life at Week 6 and 18 | Fatigue - Change from baseline at Week 18 | 8.1 Score on a scale | Standard Deviation 27.5 |
| Brigimadlin 30 mg q3w | Change in Health-Related Quality of Life at Week 6 and 18 | Fatigue impact - Change from baseline at Week 6 | -1.5 Score on a scale | Standard Deviation 20.5 |
| Brigimadlin 30 mg q3w | Change in Health-Related Quality of Life at Week 6 and 18 | Physical functioning - Change from baseline at Week 18 | -5.9 Score on a scale | Standard Deviation 20.8 |
| Brigimadlin 30 mg q3w | Change in Health-Related Quality of Life at Week 6 and 18 | Fatigue impact - Change from baseline at Week 18 | 1.6 Score on a scale | Standard Deviation 23.5 |
| Brigimadlin 30 mg q3w | Change in Health-Related Quality of Life at Week 6 and 18 | Global health status / quality of life - Change from baseline at Week 6 | -0.6 Score on a scale | Standard Deviation 18.6 |
| Brigimadlin 30 mg q3w | Change in Health-Related Quality of Life at Week 6 and 18 | Pain descriptors - Change from baseline at Week 6 | -2.7 Score on a scale | Standard Deviation 18.5 |
| Brigimadlin 30 mg q3w | Change in Health-Related Quality of Life at Week 6 and 18 | Pain - Change from baseline at Week 18 | 1.4 Score on a scale | Standard Deviation 26 |
| Brigimadlin 30 mg q3w | Change in Health-Related Quality of Life at Week 6 and 18 | Pain descriptors - Change from baseline at Week 18 | 0.4 Score on a scale | Standard Deviation 24.1 |
| Brigimadlin 30 mg q3w | Change in Health-Related Quality of Life at Week 6 and 18 | Global health status / quality of life - Change from baseline at Week 18 | -5.8 Score on a scale | Standard Deviation 24.5 |
| Brigimadlin 30 mg q3w | Change in Health-Related Quality of Life at Week 6 and 18 | Pain impact - Change from baseline at Week 6 | -3.0 Score on a scale | Standard Deviation 14.7 |
| Brigimadlin 30 mg q3w | Change in Health-Related Quality of Life at Week 6 and 18 | Physical functioning - Change from baseline at Week 6 | -2.1 Score on a scale | Standard Deviation 17.4 |
| Brigimadlin 30 mg q3w | Change in Health-Related Quality of Life at Week 6 and 18 | Pain impact - Change from baseline at Week 18 | 0.6 Score on a scale | Standard Deviation 19.6 |
| Brigimadlin 30 mg q3w | Change in Health-Related Quality of Life at Week 6 and 18 | Fatigue symptoms - Change from baseline at Week 6 | 3.4 Score on a scale | Standard Deviation 19.2 |
| Brigimadlin 45 mg q3w | Change in Health-Related Quality of Life at Week 6 and 18 | Pain impact - Change from baseline at Week 18 | 2.4 Score on a scale | Standard Deviation 20.5 |
| Brigimadlin 45 mg q3w | Change in Health-Related Quality of Life at Week 6 and 18 | Physical functioning - Change from baseline at Week 6 | -5.5 Score on a scale | Standard Deviation 17.9 |
| Brigimadlin 45 mg q3w | Change in Health-Related Quality of Life at Week 6 and 18 | Physical functioning - Change from baseline at Week 18 | -7.5 Score on a scale | Standard Deviation 16.3 |
| Brigimadlin 45 mg q3w | Change in Health-Related Quality of Life at Week 6 and 18 | Pain - Change from baseline at Week 6 | 0.8 Score on a scale | Standard Deviation 25.2 |
| Brigimadlin 45 mg q3w | Change in Health-Related Quality of Life at Week 6 and 18 | Pain - Change from baseline at Week 18 | -1.0 Score on a scale | Standard Deviation 26.7 |
| Brigimadlin 45 mg q3w | Change in Health-Related Quality of Life at Week 6 and 18 | Fatigue - Change from baseline at Week 6 | 10.5 Score on a scale | Standard Deviation 23.5 |
| Brigimadlin 45 mg q3w | Change in Health-Related Quality of Life at Week 6 and 18 | Fatigue - Change from baseline at Week 18 | 14.1 Score on a scale | Standard Deviation 27.5 |
| Brigimadlin 45 mg q3w | Change in Health-Related Quality of Life at Week 6 and 18 | Global health status / quality of life - Change from baseline at Week 6 | -8.9 Score on a scale | Standard Deviation 22.4 |
| Brigimadlin 45 mg q3w | Change in Health-Related Quality of Life at Week 6 and 18 | Global health status / quality of life - Change from baseline at Week 18 | -8.0 Score on a scale | Standard Deviation 20.8 |
| Brigimadlin 45 mg q3w | Change in Health-Related Quality of Life at Week 6 and 18 | Fatigue symptoms - Change from baseline at Week 6 | 10.6 Score on a scale | Standard Deviation 25.1 |
| Brigimadlin 45 mg q3w | Change in Health-Related Quality of Life at Week 6 and 18 | Fatigability - Change from baseline at Week 6 | 11.2 Score on a scale | Standard Deviation 21.8 |
| Brigimadlin 45 mg q3w | Change in Health-Related Quality of Life at Week 6 and 18 | Fatigability - Change from baseline at Week 18 | 16.4 Score on a scale | Standard Deviation 24.3 |
| Brigimadlin 45 mg q3w | Change in Health-Related Quality of Life at Week 6 and 18 | Fatigue impact - Change from baseline at Week 6 | 3.5 Score on a scale | Standard Deviation 23.7 |
| Brigimadlin 45 mg q3w | Change in Health-Related Quality of Life at Week 6 and 18 | Fatigue impact - Change from baseline at Week 18 | 6.2 Score on a scale | Standard Deviation 25.9 |
| Brigimadlin 45 mg q3w | Change in Health-Related Quality of Life at Week 6 and 18 | Pain descriptors - Change from baseline at Week 6 | 0.9 Score on a scale | Standard Deviation 16.5 |
| Brigimadlin 45 mg q3w | Change in Health-Related Quality of Life at Week 6 and 18 | Pain descriptors - Change from baseline at Week 18 | 1.8 Score on a scale | Standard Deviation 17.7 |
| Brigimadlin 45 mg q3w | Change in Health-Related Quality of Life at Week 6 and 18 | Pain impact - Change from baseline at Week 6 | 1.9 Score on a scale | Standard Deviation 18.9 |
| Brigimadlin 45 mg q3w | Change in Health-Related Quality of Life at Week 6 and 18 | Fatigue symptoms - Change from baseline at Week 18 | 14.7 Score on a scale | Standard Deviation 26.2 |
Secondary
Disease Control (DC)
Disease control (DC), defined as a best overall response of CR, PR, or stable disease (SD) according to RECIST version 1.1 (based on blinded central independent review). Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.
Time frame: Up to 20.6 months.
Population: Randomised Set (RS): All patients randomized, regardless of whether they have received any trial medication or not.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Brigimadlin 30 mg q3w | Disease Control (DC) | 71 Participants |
| Brigimadlin 45 mg q3w | Disease Control (DC) | 128 Participants |
| Doxorubicin | Disease Control (DC) | 117 Participants |
Comparison: Odds ratios are calculated from a logistic regression model with the stratification factor (locally advanced vs. metastatic) included as a covariate.95% CI: [0.81, 2.82]
Comparison: Odds ratios are calculated from a logistic regression model with the stratification factor (locally advanced vs. metastatic) included as a covariate. Exact 95% confidence interval (CI) by Clopper and Pearson.95% CI: [1.48, 4.84]
Secondary
Duration of Objective Response (DOR)
Duration of objective response (DOR), defined as the time interval from first documented confirmed OR until disease progression or death among patients with confirmed OR (based on blinded central independent review), whichever occurs first.
Time frame: Up to 20.6 months.
Population: All patients randomized who had an objective response.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Brigimadlin 30 mg q3w | Duration of Objective Response (DOR) | NA Months |
| Brigimadlin 45 mg q3w | Duration of Objective Response (DOR) | 9.92 Months |
| Doxorubicin | Duration of Objective Response (DOR) | 9.99 Months |
Secondary
Objective Response (OR)
Objective response (OR), defined as a best overall response of confirmed complete response (CR) or confirmed partial response (PR) according to RECIST version 1.1 (based on blinded central independent review) from the date of randomization until disease progression, death, or last evaluable tumor assessment before start of subsequent anti-cancer therapy, loss to follow-up, or withdrawal of consent, whichever occurs first. Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
Time frame: Up to 20.6 months.
Population: Randomised Set (RS): All patients randomized, regardless of whether they have received any trial medication or not.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Brigimadlin 30 mg q3w | Objective Response (OR) | 13 Participants |
| Brigimadlin 45 mg q3w | Objective Response (OR) | 33 Participants |
| Doxorubicin | Objective Response (OR) | 14 Participants |
Comparison: The primary estimator and CI for the odds ratio is by Cochran-Mantel-Haenszel.95% CI: [1.52, 5.67]