This study has been transitioned to CTIS with ID 2024-511361-11-00 check the CTIS register for the current data. The trial will assess the efficacy and safety of brigimadlin compared to doxorubicin as first line systemic therapy for advanced or…
ID
Source
Brief title
Condition
- Soft tissue neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary endpoint of the trial is progression-free survival (PFS). PFS based
on central independent review will be assessed at the interim futility analysis
at the end of the Phase II part, and the primary PFS analysis will take place
during the Phase III part. For each patient, PFS is 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.
Secondary outcome
• 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.
• Duration of objective response (DOR), defined as the time interval from first
documented confirmed OR until disease progression or death among patients with
confirmed objective response (based on blinded central independent review),
whichever occurs first.
• Overall survival (OS) will be assessed at the end of the Phase III part of
the trial. OS is defined as the time interval from randomization until death
from any cause.
• 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).
• Health-Related Quality of Life (HRQoL), based on data collected through
specific questionnaires (Patient Reported Outcome Measures, PROMs), from
baseline to week 6 and to week 18.
• Time to OR based on blinded central independent review, defined as the time
interval from randomization until the first occurrence of an overall response
of CR or PR based on blinded central independent review among patients with
confirmed OR based on blinded central independent review.
• Time to OR based on investigator assessment, defined as the time interval
from randomization until the first occurrence of an overall response of CR or
PR based on investigator assessment among patients with confirmed OR based on
investigator assessment.
• Progression-free survival 2 (PFS2), defined as the time interval from
randomization until second tumor progression on next-line therapy (including
cross-over) or death from any cause. As both the initiation of subsequent
anti-cancer therapy and determination of second tumor progression on next-line
therapy are dependent upon the investigator assessment data, PFS2 derivations
will only use investigator data and
will not be calculated based on central independent review.
Background summary
Dedifferentiated liposarcoma (DDLPS) represents 15-20% of liposarcoma and
represents a high-grade MDM2-amplified tumor with low responsiveness to
doxorubicin, the standard of care approved in first line treatment (that showed
a median PFS between 2 and 4 months, and a median OS between 8 and 12 months.
In addition, doxorubicin yields many side effects which include irreversible
cardiac toxicity. Therefore, a treatment with a manageable safety profile that
is superior to doxorubicin as first line systemic therapy for advanced or
metastatic DDLPS is needed.
Brigimadlin is an orally available MDM2-p53 antagonist that showed a manageable
safety profile and preliminary signs of efficacy in Phase I studies (1403-0001
and 1403-0002) especially in patients with DDLPS; an MDM2-driven malignancy
fitting BI 907828*s mechanism of action.
The MDM2-p53 antagonist brigimadlin is a new small molecule that inhibits the
interaction between the tumor suppressor TP53 and its negative regulator MDM2.
Inhibition of this protein-protein interaction leads to stabilization of TP53
followed by target gene induction, which may result in cell cycle arrest or
apoptosis in tumors with TP53 wild type status. Pharmacology data support that
the compound can also modulate the immune response. Overall,
brigimadlin-induced p53 activation may trigger an adaptive immunity in TP53
wild type tumors.
To bring new treatments faster to a patient population with a high unmet
medical need, a seamless Phase II/III study design is proposed. In accordance
with the latest regulatory authority guidance, dose optimization of brigimadlin
will be performed in the Phase II part and the chosen dose will be taken
forward for comparison with the control arm in the Phase III part of the study.
Study objective
This study has been transitioned to CTIS with ID 2024-511361-11-00 check the CTIS register for the current data.
The trial will assess the efficacy and safety of brigimadlin compared to
doxorubicin as first line systemic therapy for advanced or metastatic DDLPS.
The primary objective of the trial is to evaluate whether brigimadlin is
superior to doxorubicin as first line systemic therapy for advanced or
metastatic DDLPS.
Study design
The overall trial design is an active-controlled, randomized, open-label,
seamless Phase II/III parallel design. The trial will start with 3 arms in the
Phase II part that will compare 2 different doses of brigimadlin (30 mg and 45
mg) versus doxorubicin. An interim analysis for dose selection will be
performed in the Phase II part, where one of the 2 investigational arms may be
selected to continue enrollment until the end of Phase II. Enrollment of
patients to all 3 arms will continue while this interim analysis is conducted.
The overall sample size is approximately 390 patients. Up to 270 patients will
be randomized 1:1:1 in the Phase II part of the trial. In Phase III, at least
approximately 120 additional patients will be randomized 1:1 to the selected
investigational arm or the control arm. Randomization will be stratified by
*extent of disease* (locally advanced vs. metastatic disease).
An interim futility analysis of PFS will be performed after approximately 56
PFS events, which is expected to align with the end of Phase II. Sample size
re-estimation will be considered at the end of Phase II to support sufficient
conditional power. Enrollment of patients will continue whilst this analysis is
performed. If the selected investigational arm passes the futility boundary,
then the Phase III part will continue to full enrolment.
Patients randomized to the doxorubicin arm will be eligible to cross-over to
receive brigimadlin following confirmed PD by central independent review and if
eligibility criteria are met.
See protocol section 3.1
Intervention
Treatment will be administered until documented disease progression,
unacceptable adverse events, withdrawal of consent, or other reasons requiring
treatment discontinuation, or for the doxorubicin arm for up to the maximum
cumulative dose of 450 mg/m2.
Phase II:
Brigimadlin at 30 mg: Up to 90 patients. Single tablet on Day 1 every 21 days
Brigimadlin at 45 mg: Up to 90 patients. Single tablet on Day 1 every 21 days
Doxorubicin: Approximately 90 patients. Doxorubicin will be administered
intravenously at a dose of 75 mg/m2 on Day 1 every 21 days, for up to the
maximum cumulative dose of 450 mg/m2
Phase III:
Brigimadlin (at the selected dose level): Approximately 60 additional patients
Doxorubicin: Approximately 60 additional patients
Patients randomized to doxorubicin will after confirmed disease progression by
blinded central independent review be allowed to cross-over to treatment with
BI 907828.
See protocol section 4.1
Study burden and risks
Burden:
During the treatment period the patient visits the hospital every week during
cycles 1 and 2, After that, it's once or twice a cycle. Depending on how long
subjects remain in the study and in which treatment group they are randomized,
the following actions assessments will be performed (see also the flowchart in
the protocol):
• Physical examination
• Blood pressure and heart rate measurement
• ECG
• Echocardiogram/ MUGA scan
• CT/MRI (tumor response evaluation, every 6 weeks and from week 36 every 12
weeks)
• Blood and urine analyses (safety)
• Pregnancy test (if applicable) and use contraceptive methods as described in
the patient information form
• Patient Reported Outcomes (EQ-5D-5L, EORTC QLQ-C30, EORTC pain, EORTC
fatigue, FACT-G item GP5, PGIC, PGIS and PRO-CTCAE)
• Blood analyses (PK, PG, and biomarkers)
• Intake CI 907828 on day 1 of each 21-day cycle (without eating at least 2
hours before intake and after taking the tablet, wait at least 1 hour before
eating)
• Administration of doxorubixin on day 1 of each 21-day cycle
• Tumor biopsy (archive material is also allowed during screening if this is
available (otherwise a fresh biopsy is needed) and a fresh biopsy during the
2nd cycle of treatment (unless this is unsafe).
• Women should not become pregnant or breast-feed during the Study
Risks:
Patients may experience side effects. Since the trail drug is still
experimental, it is possible that the drug has side effects that are not yet
known. The patient may also experience problems with the trial assessments,
such as taking biopsies, taking blood samples and imaging (see protocol section
1.4.2).
Basisweg 10
Amsterdam 1043 AP
NL
Basisweg 10
Amsterdam 1043 AP
NL
Listed location countries
Age
Inclusion criteria
1. 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.
2. Male or female patients >=18 years old at the time of signature of the ICF.
Women of childbearing potential 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.
3. Histologically proven locally advanced or metastatic, unresectable (surgery
morbidity would outweigh potential benefits), progressive or recurrent 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.
4. Written pathology report indicating the diagnosis of DDLPS with positive
MDM2 immunohistochemistry or MDM2 amplification as demonstrated by fluorescence
in situ hybridization or NGS must be available.
5. Formalin fixed paraffin embedded tumor blocks or slides must be available
for retrospective histopathological central review.
6. Presence of at least one measurable target lesion according to 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.
7. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1.
8. Patient must be willing to donate blood samples for the pharmacokinetics,
pharmacodynamics, and tumor mutation analysis.
9. Patient willing to undergo a mandatory tumor biopsy at the time point
specified in the flowchart unless exempt.
10. Adequate organ function.
Exclusion criteria
1. Known mutation in the TP53 gene (screening for TP53 status is not required).
2. Major surgery (major according to the investigator*s assessment) performed
within 4 weeks prior to randomization or planned within 6 months after
screening.
3. Prior systemic therapy for liposarcoma in any setting (including adjuvant,
neoadjuvant, maintenance, palliative).
4. 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.
5. Previous treatment with anthracyclines in any setting (systemic treatment
with other anti-cancer agents is allowed if completed at least 5 years prior to
study entry with the exception of hormone therapy).
6. 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.
7. 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).
8. 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).
9. 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 until six months and 12 days after last dose
of study treatment.
10. Patients with known history of human immunodeficiency virus (HIV) infection
(see protocol for more details).
11. Patients with a history of HCV infection (see protocol for more details).
12. Patients with chronic HBV infection (see protocol for more details).
13. 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.
14. Known hypersensitivity or contraindication to the trial drugs or their
excipients.
15. Active major infection requiring systemic treatment (antibacterial,
antiviral, or antifungal therapy) at treatment start in this trial.
16. 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 of stroke within
6 months prior to randomization.
17. Any cardiac criteria (see protocol for more details).
18. Patients with brain metastasis (see protocol for more details).
19. 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).
20. 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.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EU-CTR | CTIS2024-511361-11-00 |
| EudraCT | EUCTR2021-002392-20-NL |
| CCMO | NL79994.100.21 |