Dedifferentiated Liposarcoma
Conditions
Keywords
sarcoma, MDM2, pleomorphic liposarcoma
Brief summary
Randomized, multicenter, open-label, Phase 3 registration study designed to evaluate the safety and efficacy of milademetan compared to trabectedin in patients with unresectable (i.e., where resection is deemed to cause unacceptable morbidity or mortality) or metastatic DD liposarcoma that progressed on 1 or more prior systemic therapies, including at least 1 anthracycline-based therapy.
Detailed description
Approximately 160 patients will be randomly assigned in a 1:1 ratio to receive milademetan or trabectedin. Randomization will be stratified by the ECOG performance status (0 or 1) and number of prior treatments (≤ 2 or \> 2) for the patient's liposarcoma. Patients will receive study drug (i.e., milademetan or trabectedin) until reaching unequivocal disease progression (RECIST v.1.1) as determined by the Investigator, experiencing unmanageable toxicity, or until other treatment discontinuation criteria are met. Patients may be treated beyond tumor progression if they are experiencing clinical benefit based on the assessment of the Investigator in discussion with the Medical Monitor. All patients will be followed for documentation of disease progression and survival information (i.e., date and cause of death) and subsequent treatment information (i.e., date/duration of treatment, response, and subsequent disease progression). Long-term follow-up will continue every 12 weeks (± 7 days) until the endpoint of death, the patient is lost to follow-up, or for 24 months following the final dose of study drug, whichever comes first.
Interventions
DRUGRAIN-32
260 mg once daily orally on Days 1 to 3 and Days 15 to 17 of each 28-day cycle
DRUGTrabectedin
1.5 mg/m2 body surface area as a 24-hour IV infusion, every 3 weeks
Sponsors
Rain Oncology Inc
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
* Histologically confirmed DD liposarcoma, with or without a WD component (WD/DD liposarcoma). Note: Patient must be willing to provide an archival tumor tissue sample that is ≤ 3 years old and of adequate quality or willing to provide a fresh pretreatment biopsy sample * Advanced unresectable (i.e., where resection is deemed to cause unacceptable morbidity or mortality) and/or metastatic WD/DD liposarcoma * Measurable tumor lesion(s) in accordance with RECIST version 1.1 * Received 1 or more systemic cancer therapy regimens, including at least 1 anthracycline-based regimen, and had radiographic progressive disease (per RECIST version 1.1) within 6 months before the Screening Visit * Resolution of any clinically relevant toxic effects of prior chemotherapy, surgery, radiotherapy, or hormonal therapy * ECOG performance status of 0 or 1 * Adequate bone marrow function: * Platelet count ≥ 100 × 10\^9/L * Hemoglobin ≥ 9.0 g/dL * Absolute neutrophil count ≥ 1.5 × 10\^9/L * Adequate hepatic function: * Alanine aminotransferase and aspartate aminotransferase ≤ 3 × upper limit of normal (ULN) if no liver metastases are present; ≤ 5 × ULN if liver metastases are present * Total bilirubin ≤ 1.5 × ULN, or ≤ 3 x ULN in the setting of Gilbert's disease
Exclusion criteria
* Prior treatment with any mouse double minute 2 (MDM2) inhibitor or trabectedin * Other primary malignancies that have required systemic antineoplastic treatment within the previous 2 years, except for localized cancers that have apparently been cured * Gastrointestinal conditions that could affect the absorption of milademetan, in the opinion of the Investigator * Uncontrolled infection within the last 7 days requiring IV antibiotics, antivirals, or antifungals * Known HIV infection or active Hepatitis B or C * Untreated brain metastases. Note: Patients who require steroids for brain metastases must be on a stable or tapering dose of corticosteroids for at least 2 weeks before randomization. If applicable, patients must complete stereotactic radiosurgery 7 days before and whole brain radiotherapy 21 days before their first dose of study drug. * Investigational therapy administered within the 28 days or 5 half lives: 1. Cytochrome P450 3A4 isozyme strong inhibitor: 5 elimination half-lives 2. CYP3A strong or moderate inducers: 4 weeks 3. Systemic anticancer therapy or investigational therapy 3 weeks or 5 half-lives, 4. Immunotherapy with checkpoint inhibitor: 4 weeks * Curative-intent radiation therapy ≤ 4 weeks or palliative radiation therapy, * Uncontrolled or significant cardiovascular disease: 1. QTcF at rest, where the mean QTcF interval is \> 480 milliseconds 2. Myocardial infarction within 6 months 3. Uncontrolled angina pectoris within 6 months 4. New York Heart Association Class 3 or 4 congestive heart failure 5. Uncontrolled hypertension
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Compare Progression-free Survival (PFS) as Determined by Blinded Independent Central Review (BICR) Between the Milademetan Treatment Arm and Trabectedin Control Arm | from the randomization date to date of documented progression or death, up to 13 months | PFS is defined as the time from randomization to the earliest date of the first objective documentation of radiographic disease progression, or death due to any cause. Disease progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | From randomization date to death. The result is based on primary analysis data cut. | OS as measured from the date of randomization to date of death by any cause |
| Disease Control Rate (DCR) | From the randomization date to first CR, PR or SD >= 16 weeks or the primary study completion date; up to 26.6 months. | DCR defined as the percentage of patients who have achieved CR, PR, or SD for \>= 16 weeks. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Stable Disease (SD), neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. |
| Objective Response Rate (ORR) | From randomization date to the first confirmed complete or partial response, or study completion date; up to 26.6 months. | ORR defined as the percentage of patients who have achieved a confirmed CR, PR. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions. |
| PFS by Investigator Assessments | disease progression or death | PFS defined as the time from randomization to the earliest date of the first objective documentation of radiographic disease progression or death due to any cause, based on Investigator assessments |
| Number of Participants With Treatment-emergent Adverse Events Until Approximately 30 Days After the Last Study Drug | From first dose date to 30 days after the last dose date or the primary study completion date whichever came first; up to 26.6 months. | All AEs were collected from the initiation of study treatment until 30 days after the last administration study drug or until initiation of another anticancer therapy, whichever came first; up to 26.6 months. |
Countries
Austria, Belgium, Canada, France, Georgia, Germany, Hong Kong, Ireland, Italy, Poland, South Korea, Spain, Taiwan, United Kingdom, United States
Participant flow
Pre-assignment details
A total of 86 subjects were enrolled to the Milademetan arm and a total of 89 subjects were enrolled to the Trabectedin arm. Of the 89 subjects in the trabectedin arm, 79 subjects were treated.
Participants by arm
| Arm | Count |
|---|---|
| Milademetan milademetan 260 mg once daily orally on Days 1 to 3 and Days 15 to 17 of each 28-day cycle | 86 |
| Trabectedin trabectedin 1.5 mg/m2 body surface area as a 24-hour IV infusion, every 3 weeks | 89 |
| Total | 175 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 43 | 30 |
| Overall Study | do not want to continue | 0 | 1 |
| Overall Study | Lost to Follow-up | 0 | 2 |
| Overall Study | Physician Decision | 1 | 1 |
| Overall Study | Withdrawal by Subject | 8 | 13 |
Baseline characteristics
| Characteristic | Milademetan | Trabectedin | Total |
|---|---|---|---|
| Age, Continuous | 59.3 years STANDARD_DEVIATION 13.08 | 61.8 years STANDARD_DEVIATION 11.92 | 60.6 years STANDARD_DEVIATION 12.53 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 6 Participants | 9 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 71 Participants | 72 Participants | 143 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 12 Participants | 11 Participants | 23 Participants |
| Race/Ethnicity, Customized Race American Indian or Alaska Native | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Race Asian | 15 Participants | 12 Participants | 27 Participants |
| Race/Ethnicity, Customized Race Black or African American | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Race Native Hawaiian or Other Pacific Islander | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Race Other | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Race Unknown | 11 Participants | 12 Participants | 23 Participants |
| Race/Ethnicity, Customized Race White | 59 Participants | 63 Participants | 122 Participants |
| Region Europe | 47 Participants | 42 Participants | 89 Participants |
| Region North America | 27 Participants | 37 Participants | 64 Participants |
| Region Rest of World | 12 Participants | 10 Participants | 22 Participants |
| Sex: Female, Male Female | 40 Participants | 36 Participants | 76 Participants |
| Sex: Female, Male Male | 46 Participants | 53 Participants | 99 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 43 / 86 | 30 / 89 |
| other Total, other adverse events | 86 / 86 | 78 / 79 |
| serious Total, serious adverse events | 31 / 86 | 38 / 79 |
Outcome results
Primary
Compare Progression-free Survival (PFS) as Determined by Blinded Independent Central Review (BICR) Between the Milademetan Treatment Arm and Trabectedin Control Arm
PFS is defined as the time from randomization to the earliest date of the first objective documentation of radiographic disease progression, or death due to any cause. Disease progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.
Time frame: from the randomization date to date of documented progression or death, up to 13 months
Population: Analysis population included all the randomized participants up to up to final analysis cut-off date (01 March 2023).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Milademetan | Compare Progression-free Survival (PFS) as Determined by Blinded Independent Central Review (BICR) Between the Milademetan Treatment Arm and Trabectedin Control Arm | 3.6 months |
| Trabectedin | Compare Progression-free Survival (PFS) as Determined by Blinded Independent Central Review (BICR) Between the Milademetan Treatment Arm and Trabectedin Control Arm | 2.2 months |
Secondary
Disease Control Rate (DCR)
DCR defined as the percentage of patients who have achieved CR, PR, or SD for \>= 16 weeks. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Stable Disease (SD), neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD.
Time frame: From the randomization date to first CR, PR or SD >= 16 weeks or the primary study completion date; up to 26.6 months.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Milademetan | Disease Control Rate (DCR) | 33.7 percentage of participants |
| Trabectedin | Disease Control Rate (DCR) | 27.0 percentage of participants |
Secondary
Number of Participants With Treatment-emergent Adverse Events Until Approximately 30 Days After the Last Study Drug
All AEs were collected from the initiation of study treatment until 30 days after the last administration study drug or until initiation of another anticancer therapy, whichever came first; up to 26.6 months.
Time frame: From first dose date to 30 days after the last dose date or the primary study completion date whichever came first; up to 26.6 months.
Population: All AEs were collected from the initiation of study treatment until 30 days after the last administration study drug or until initiation of another anticancer therapy, whichever came first.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Milademetan | Number of Participants With Treatment-emergent Adverse Events Until Approximately 30 Days After the Last Study Drug | 86 Participants |
| Trabectedin | Number of Participants With Treatment-emergent Adverse Events Until Approximately 30 Days After the Last Study Drug | 78 Participants |
Secondary
Objective Response Rate (ORR)
ORR defined as the percentage of patients who have achieved a confirmed CR, PR. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions.
Time frame: From randomization date to the first confirmed complete or partial response, or study completion date; up to 26.6 months.
Population: This analysis is conducted in all participants within the Intent to treat (IIT) population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Milademetan | Objective Response Rate (ORR) | 4.7 percentage of participants |
| Trabectedin | Objective Response Rate (ORR) | 3.4 percentage of participants |
Secondary
Overall Survival (OS)
OS as measured from the date of randomization to date of death by any cause
Time frame: From randomization date to death. The result is based on primary analysis data cut.
Population: Analysis population included all the randomized participants up to up to final analysis cut-off date (01 March 2023).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Milademetan | Overall Survival (OS) | 9.5 months |
| Trabectedin | Overall Survival (OS) | 10.2 months |
Secondary
PFS by Investigator Assessments
PFS defined as the time from randomization to the earliest date of the first objective documentation of radiographic disease progression or death due to any cause, based on Investigator assessments
Time frame: disease progression or death
Population: PFS defined as the time from randomization to the earliest date of the first objective documentation of radiographic disease progression or death due to any cause, based on Investigator assessments
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Milademetan | PFS by Investigator Assessments | 3.7 months |
| Trabectedin | PFS by Investigator Assessments | 2.1 months |