| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Dedifferentiated Liposarcoma (DDLS) |
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| E.1.1.1 | Medical condition in easily understood language |
| Dedifferentiated Liposarcoma (DDLS) |
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| 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 | PT |
| E.1.2 | Classification code | 10073135 |
| E.1.2 | Term | Dedifferentiated liposarcoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| 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 |
Phase 2 (now complete):
Assess and compare PFS of patients with advanced unresectable DDLS treated with selinexor (60 mg) or placebo twice weekly. Progression will be defined by disease progression according to RECIST v. 1.1 (Eisenhauer 2009), or by death due to any cause
Phase 3:
Assess and compare PFS of patients with advanced unresectable DDLS treated with selinexor (60 mg) or placebo twice weekly. PFS is defined as time from date of randomization until the first date of progression per RECIST v. 1.1, or death due to any cause. Evaluation of the radiographic data for the PFS primary endpoint will be based on data from a scan review by the independent central reader. |
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| E.2.2 | Secondary objectives of the trial |
Phase 2 (now complete, refer to protocol for Phase 2 secondary objectives).
Phase 3:
• Assess Overall Survival (OS), measured from date of randomization until death due to any cause.
• Compare TTP on study treatment, per RECIST v. 1.1, with TTP on the patient’s last prior systemic therapy.
• Assess Quality of Life (QoL) and patient-reported outcomes as measured by the European Organization for Research and Treatment of Cancer (EORTC) Quality of-Life Questionnaire (QLQ-C30) and the EuroQoL Group Health Questionnaire (EQ-5D-5L).
• Determine the ORR, supported by DOR. Responses will be defined by RECIST v. 1.1.
• Assess PFS according to the Investigator based on clinical and/or radiologic criteria.
• Assess safety of each treatment arm |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Patients eligible for inclusion in this study must meet all of the following criteria:
1. Written informed consent in accordance with national, local, and institutional guidelines obtained prior to any screening procedures
2. Must be willing and able to comply with the protocol
3. Patients ≥ 12 years of age
4. Patients with a BSA ≥ 1.2 m2 as calculated per Dubois 1916 or Mosteller 1987
5. Histologic evidence of DDLS at any time prior to randomization AND current evidence of DDLS requiring treatment:
• This information will be provided based on prior diagnostic testing and is required for randomization.
• Tissue (fresh or archival) will be provided for confirmatory histology at a central laboratory but confirmatory results are not required prior to randomization.
• If archival tissue > 12 months old, the quality of the sample for confirmatory histology must be confirmed by the site histopathologist prior to randomization.
6. Must have measurable disease according to:
• The bidimensional WHO Response Criteria (Miller 1981) (Phase 2 patients only)
• RECIST v. 1.1 (Eisenhauer 2009)(Phase 3 patients only)
7. Radiologic evidence of progressive disease (PD) within 6 months prior to randomization. If the patient received other intervening therapy after PD is documented, further PD must be documented after the completion of the intervening therapy.
8. Must have received at least 2 but no more than 5 prior systemic therapies for the treatment of liposarcoma.
9. Patients should have recovered from all major surgery, radiation or other interventions ≥ 21 days prior to randomization. Patients must have recovered from any clinically significant therapy-related toxicity to ≤ Grade 1 per CTCAE v. 4.03. Minor procedures, such as biopsies, dental work, or placement of a port or intravenous line for infusion, are permitted.
10. If patients received any previous systemic therapy, the last dose must have been ≥ 21 days prior to randomization (or ≥ 5 half-lives of that drug [whichever is shorter]), with all clinically significant therapy-related toxicities having resolved to ≤ Grade 1 CTCAE v. 4.03.
11. ECOG performance status ≤ 1 (Oken 1982)
12. Adequate laboratory functional values:
• Adequate hematopoietic function:
o Absolute neutrophil count (ANC) ≥ 1500/mm3
o Platelets ≥ 100,000/mm3
o Hemoglobin (Hb) ≥ 9 g/dL at baseline
o Transfusions, hematopoietic growth factors, and hematinics are NOT permitted during screening
• Adequate hepatic function:
o Bilirubin ≤ 1.5 x upper limit of normal (ULN) (except patients with Gilbert’s syndrome [hereditary indirect hyperbilirubinemia] who must have a total bilirubin of ≤ 3 x ULN)
o Alkaline phosphatase (ALP), aspartate aminotransferase (AST), and alanine aminotransferase (ALT) < 3.0 x ULN (except patients with liver involvement of their liposarcoma who must have an AST and ALT ≤ 5 x ULN).
• Adequate renal function: estimated creatinine clearance of ≥ 50 mL/min, calculated using the Cockcroft and Gault formula (140 – Age) • Mass (kg)/ (72 • creatinine mg/dL); multiply by 0.85 if female (Cockcroft 1976).
13. Female patients of childbearing potential must agree to use two methods of contraception (including one highly effective and one effective method of contraception [as defined in Section 12.2.5.3]) and have a negative serum pregnancy test at Screening. Male patients must use an effective barrier method of contraception if sexually active with a female of childbearing potential. For both male and female patients, effective methods of contraception must be used throughout the study and for 3 months following the last dose of study treatment.
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| E.4 | Principal exclusion criteria |
Patients meeting any of the following exclusion criteria are not eligible to enroll in this study:
1. Patients with liposarcoma of pure WDLS, myxoid/round cell or pleomorphic tumor histologic subtypes.
2. Significant cardiovascular impairment, defined as:
a. Cardiac failure, New York Heart Association (NYHA) Class ≥ 3 according to the NYHA Functional Classification
b. Unstable angina or myocardial infarction within 3 months of enrollment
c. Serious and potentially life-threatening arrhythmia.
3. Patients with known central nervous system metastases.
4. Female patients who are pregnant or nursing.
5. Prior malignancy that required treatment, or has shown evidence of recurrence (except for non melanoma skin cancer or adequately treated cervical carcinoma in situ) during the 5 years prior to randomization. Cancer treated with curative intent > 5 years prior to randomization and without evidence of recurrence is allowed.
6. Known active Hepatitis B (HepB), Hepatitis C (HepC) or human immunodeficiency virus (HIV) infection. Note: (HepB, HepC, or HIV testing is not required as part of this study).
7. Any medical condition, such as an uncontrolled infection or uncontrolled diabetes mellitus (Type 2), which in the opinion of the Investigator would make study involvement unreasonably hazardous
8. Psychiatric illness that would prevent the patient from giving informed consent or being compliant with the study procedures
9. Patients unable to swallow tablets, patients with malabsorption syndrome, or any other GI disease or GI dysfunction that could interfere with absorption of study treatment
10. Inability or unwillingness to take supportive medications such as anti-nausea and anti-anorexia agents as recommended by the NCCN CPGO for antiemesis and anorexia/cachexia (palliative care).
11. Patients who had involuntary weight loss of ≥ 10% in the 3 months prior to randomization.
12. Participation in an investigational anticancer study ≤ 21 days prior to randomization. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Phase 2:
The primary endpoint PFS for Phase 2 is defined as time from date of randomization until the first date of PD per RECIST v. 1.1, or death due to any cause.
A preplanned preliminary analysis of PFS after 40 PFS events was conducted with an 11 August 2017 data cut with 49 eligible patients whose treatment assignments were available. Patients were analyzed in the treatment arm to which they were randomized. The preliminary PFS analysis was conducted by both WHO and RECIST v. 1.1 Criteria and served as a guideline to inform the final design of the Phase 3 portion of the study.
At the time of the preliminary PFS analysis, there were 48 events by WHO (22 selinexor, 26 placebo) and 28 events by RECIST v.1.1. (10 selinexor, 18 placebo). Both analyses showed trends favoring selinexor over placebo, while RECIST v. 1.1 results show a more significant effect size (hazard ration [HR] of 0.84, 95% CI [0.47, 1.49] by WHO as compared with HR of 0.60, 95% CI [0.28, 1.31] by RECIST v. 1.1). A Landmark analysis based on RECIST v. 1.1 for patients continuing on study after 45 days showed a more significant HR of 0.24 (95% CI [0.05, 1.15]) in favor of selinexor.
Of the 57 patients in Phase 2, only 56 met the eligibility criteria for the study. The formal primary Phase 2 PFS analysis will be performed on all 56 eligible patients randomized to study treatment in Phase 2 when their treatment assignments are unblinded. Phase 2 patients will be analyzed in the treatment arm to which they are randomized.
Phase 3:
The primary PFS analysis will be performed on the intent-to-treat (ITT) population for Phase 3 patients and on the per-protocol (PP) population as a supportive analysis. The stratified log-rank test will be used to test the null hypothesis that the PFS distributions are the same for both treatment groups versus the alternative hypothesis that the duration of PFS for the selinexor arm is longer than the placebo arm using a 1-sided test and alpha=0.025 level of significance, adjusted using the Cui, Hung, and Wang (CHW) method (Cui 1999).
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Phase 2: The primary endpoint analysis has been completed.
Phase 3: The primary endpoint analysis will be performed approximately 12 months after enrollment of the last patient, once 209 PFS events have occurred, at which time all Phase 3 patients will be evaluable for assessment of the primary endpoint. |
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| E.5.2 | Secondary end point(s) |
• OS for non-inferiority, measured from date of randomization until death due to any cause, for all randomized patients. Patients who are alive at the time of the analysis will be censored for survival at the date of the last contact.
• OS for superiority, measured from date of randomization until death due to any cause, for all randomized patients. Patients who are alive at the time of the analysis will be censored for survival at the date of the last contact.
• TTP, defined as duration of time from date of first dose of study treatment to date of PD or death due to disease progression, per RECIST v. 1.1. Patients who remain progression free (whether they withdrew from the study or reached their maximum follow-up) will be censored at the date of their last disease assessment.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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| 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 | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| 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) | Yes |
| 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 | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| Refer to protocol regarding different phases (Phase 2 is now complete). |
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| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 24 |
| 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 |
| Belgium |
| Canada |
| France |
| Germany |
| Israel |
| Italy |
| Poland |
| Spain |
| United Kingdom |
| United States |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| 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
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| 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 | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 8 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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