| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Dedifferentiated liposarcoma |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10024631 |
| E.1.2 | Term | Liposarcoma NOS |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10024633 |
| E.1.2 | Term | Liposarcoma stage unspecified |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The primary objective is to compare progression-free survival (PFS) between the milademetan treatment arm and trabectedin control arm, as determined by blinded independent central review (BICR), in patients with unresectable or metastatic dedifferentiated (DD) liposarcoma, with or without a well-differentiated (WD) component, who progressed on 1 or more prior systemic therapies including at least 1 anthracycline-based therapy. |
|
| E.2.2 | Secondary objectives of the trial |
To compare the milademetan treatment arm versus the trabectedin control arm
for the following efficacy measures:
o Overall survival (OS)
o Disease control rate (DCR) by BICR and Investigator assessment
o Objective response rate (ORR) by BICR and Investigator assessment
o Duration of response (DOR) by BICR and Investigator assessment
o PFS by Investigator assessment
To assess the safety profile of milademetan
To evaluate patient-reported outcomes of quality of life from health economics and outcomes research. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Each patient must meet all the following criteria:
1. Is a male or female patient ≥ 18 years old
2. Has a signed and dated informed consent form prior to the start of any study-specific qualification procedures
3. Has histologically confirmed WD/DD liposarcoma, by local pathologic review; central pathologic review will also be performed but is not required for inclusion.
Note: Patient must be willing to provide either an archival tumor tissue sample that is ≤ 3 years old and of adequate quality or a fresh pretreatment biopsy sample. If a fresh pretreatment biopsy sample is clinically not recommended and the patient is subsequently documented as exempt by the Sponsor, archival material > 3 years may be acceptable after discussion with the Sponsor
4. Has documented advanced unresectable (i.e., where resection is deemed to cause unacceptable morbidity or mortality) and/or metastatic WD/DD
liposarcoma
5. Has measurable tumor lesion(s) in accordance with RECIST version 1.1
6. Has 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
7. Has resolution of any clinically relevant toxic effects of prior chemotherapy, surgery, radiotherapy, or hormonal therapy.
Note: AEs from prior therapy must resolve to Grade ≤ 1 per the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events
(CTCAE) version 5.0, with the exception of peripheral neuropathy, which must resolve to Grade ≤ 2, and alopecia
8. Has an ECOG performance status of 0 or 1
9. Has adequate bone marrow function, defined as:
o Platelet count ≥ 100 × 109/L
o Hemoglobin ≥ 9.0 g/dL
o Absolute neutrophil count ≥ 1.5 × 109/L
10. Has adequate renal function, defined as creatinine clearance ≥ 30 mL/min, as calculated using the modified Cockcroft-Gault equation (or
equivalent glomerular filtration rate calculated using the Chronic Kidney Disease Epidemiology Collaboration formula)
11. Has adequate hepatic function, defined as: Alanine aminotransferase and aspartate aminotransferase ≤ 3 × upper limit of normal (ULN) if no liver metastases are present; ≤ 5 × ULN if liver metastases are present
o Total bilirubin ≤ 1.5 × ULN. Patients with Gilbert’s disease who have serum bilirubin level ≤ 3 x ULN, may be enrolled
12. Is willing and able to comply with the protocol requirements.
13. Patients requiring anticoagulation medication should be on a stable regimen, defined as at least 4 weeks on the same dose
14.Patients requiring antihypertensive medication should be on a stable regimen, defined as at least 4 weeks on the same dose
15. If a woman of childbearing potential (WOCBP), must have a negative serum pregnancy test at screening and a negative urine pregnancy test on Cycle 1 Day 1 before receiving her first dose of study drug or within 72 hours of the first dose of study drug
Note: A female patient must be willing to use a highly effective contraceptive method as discussed with the Investigator upon randomization through the Treatment Period and until 3 months after the final dose of study drug. A female is considered to be of childbearing potential following menarche and until becoming postmenopausal (no menstrual period for a minimum of 12 months without an alternative medical cause) unless permanently sterile (undergone a hysterectomy, bilateral salpingectomy, or bilateral oophorectomy) with surgery at least 1 month before randomization or confirmed by testing follicle stimulating hormone (FSH) levels. A high FSH level in the postmenopausal range may be used to confirm a postmenopausal state in women not using hormonal contraception or hormonal replacement therapy; however, in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient.
16.If a male patient is surgically sterile, willing to use a condom, or remain abstinent upon randomization through the Treatment Period and for 5 months after the final dose of study drug
Note: For this study, male abstinence is defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatment. Periodic abstinence, withdrawal (coitus interruptus), or the use of spermicides only are not acceptable methods of contraception.
|
|
| E.4 | Principal exclusion criteria |
A patient who meets any of the following criteria will not be eligible to participate in the study:
1-Has received prior treatment with any mouse double minute 2 (MDM2) inhibitor or trabectedin
2. Has other primary malignancies that have required systemic cancers that have apparently been cured (e.g., nonmelanoma skin cancer, superficial bladder cancer, or carcinoma in situ of the prostate, cervix, or breast) and will not interfere with the study outcomes
3. Has gastrointestinal conditions that could affect the absorption of milademetan, in the opinion of the Investigator
4. Has an uncontrolled infection within the last 7 days requiring IV antibiotics, antivirals, or antifungals
5. Has known HIV infection or active hepatitis B or C infection
6. Has 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.
7. Has not met the minimum washout period before randomization, defined as:
a. Cytochrome P450 3A4 isozyme strong inhibitor: 5 elimination half lives of the inhibitor
b. CYP3A strong or moderate inducers (e.g., St. John's wort and modafinil): 4 weeks
c. Systemic anticancer therapy (chemotherapy; small molecules, including antibody drug therapy; retinoid therapy; or hormonal therapy) or investigational therapy: 3 weeks or 5 half-lives, whichever is shorter.
d. Immunotherapy with checkpoint inhibitor: 4 weeks
8. Has had major surgery ≤ 3 weeks from randomization
9. Has had curative-intent radiation therapy ≤ 4 weeks or palliative radiation therapy, defined as ≤ 30 Gy in ≤ 10 fractions (e.g., 20 Gy in 5 fractions or 8 Gy in 1 fraction) ≤ 2 weeks from randomization
10. Has uncontrolled or significant cardiovascular disease, including:
a. QTcF at rest, where the mean QTcF interval is > 480 milliseconds (average of triplicate electrocardiograms [ECGs])
b. Myocardial infarction within 6 months prior to screening
c. Uncontrolled angina pectoris within 6 months prior to screening
d. New York Heart Association Class 3 or 4 congestive heart failure
e. Uncontrolled hypertension (resting systolic blood pressure > 180
mmHg or diastolic blood pressure > 110 mmHg)
11. Is a female who is pregnant or breastfeeding or intends to become pregnant during the study
12. Has a concomitant medical condition that would interfere with the assessment of efficacy or increase the risk of toxicity, in the opinion of the Investigator or Sponsor |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy endpoint is Progression Free Survival defined as the time from randomization to the earliest date of the first objective documentation of radiographic disease progression as determined by BICR or death due to any cause. Tumor response will be assessed in accordance with RECIST version 1.1. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Tumor response evaluations will be performed at screening; at the end of Week 8, Week 16, Week 24, and Week 32; and then every 12 weeks (± 1 week [7 days]) while the patient remains on study drug and any other time during the study as clinically indicated. |
|
| E.5.2 | Secondary end point(s) |
Secondary efficacy endpoints include:
- Overall Survival (OS)
- Disease Control Rate (DSR) by BICR and Investigator assessment
- Objective Response Rate (ORR) by BICR and Investigator assessment
- Duration Of Response (DOR) by BICR and Investigator assessment
- Progression Free Survival (PFS)
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
- Overall Survival is measured from the date of randomization to the date of death by any cause.
- Disease Control Rate is measured as percentage of patients who have achieved Complete Response, Partial Response, or Stable Disease for ≥ 8 weeks
- Objective Response Rate is measured as the percentage of patients who achieve a confirmed Complete Response or Partial Response
-Duration Of Response is measured as the time from date of first response to date of disease progression or death
- Progression Free Survival is measured as the time from randomization to the earliest date of the first objective documentation of radiographic disease progression, based on Investigator assessments or death due to any cause |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 43 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Canada |
| Hong Kong |
| Korea, Republic of |
| Taiwan |
| United States |
| Austria |
| France |
| Poland |
| Spain |
| Germany |
| Italy |
| Belgium |
| Georgia |
| Ireland |
| United Kingdom |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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