| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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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 | HLT |
| E.1.2 | Classification code | 10024190 |
| E.1.2 | Term | Leiomyosarcomas |
| E.1.2 | System Organ Class | 100000004864 |
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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 |
| The primary objective is to assess PFS of unesbulin plus DTIC versus placebo plus DTIC. |
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| E.2.2 | Secondary objectives of the trial |
• Evaluate OS of subjects treated with unesbulin plus DTIC versus placebo plus DTIC
• Evaluate the antitumor activity of unesbulin plus DTIC versus placebo plus DTIC
• Evaluate safety and tolerability of unesbulin plus DTIC versus placebo plus DTIC
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Inclusion Criteria:
1. Subject is willing and able to provide informed consent
2. Willingness and ability to comply with scheduled visits, drug administration plan, laboratory tests, other study procedures, and study restrictions
3. Disease status including:
a. Histological or cytological confirmation of LMS arising at any anatomic site except bone sarcoma
b. Unresectable or metastatic, relapsed or refractory disease
c. Measurable disease per RECIST 1.1 criteria
d. Disease progression on previous treatment before screening or intolerability to other oncology treatments
Demographics:
4. Age ≥18 years
5. Male or female
Performance status:
6. ECOG PS score of 0 or 1
Hematopoietic:
7. Absolute neutrophil count ≥1500/mm3 without the use of growth factors in the past 7 days
8. Platelet count ≥100000/mm3 without platelet transfusion in the past 14 days
9. Hemoglobin ≥9 g/dL (packed red blood cell transfusion is not allowed within 7 days)
Hepatic:
10. Bilirubin ≤ upper limit of normal (ULN) except for those patients with Gilbert's syndrome
11. Aspartate aminotransferase or alanine aminotransferase <3 times the ULN
12. Subjects with liver metastases may be enrolled
Pulmonary:
13. Subjects with well-controlled asthma (eg, use of rescue medications <2 times per week over the last 12 months) or chronic obstructive pulmonary disease (eg, no exacerbations over the prior 3 months) may be enrolled.
Renal:
14. Creatinine <1.5 times normal OR creatinine clearance ≥ 60 mL/min
Prior therapeutics:
15. Toxicity from prior therapies recovered to Grade ≤1 or subject’s baseline, except for alopecia. In addition, endocrinopathies associated with prior immunotherapy-based treatments that are well controlled on replacement medication are not exclusionary.
Chemotherapy and targeted therapy:
16. At least 1 prior systemic cytotoxic or targeted therapy regimen for LMS LMS, which may include but is not limited to single-agent doxorubicin or other anthracycline, doxorubicin plus ifosfamide, trabectedin,pazopanib, or gemcitabine with or without docetaxel
Surgery:
17. At least 4 weeks since prior surgery and recovered in the opinion of investigator
Other:
18. Capable of swallowing oral medication
19. Women of childbearing potential (WOCBP; as defined by the Clinical Trials Facilitation and Coordination Group [CTFG]) must have a negative serum pregnancy test at screening and agree to abstinence or the use at least one of the following highly effective forms of contraception (with a failure rate of <1% per year when used consistently and correctly) (Clinical Trials Facilitation and Coordination Group 2020). Contraception or abstinence must be continued for the duration of the study and for up to at least 6 months after the last dose of study drug:
• Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation:
-Oral
-Intravaginal
-Transdermal
• Progestogen-only hormonal contraception associated with inhibition of ovulation:
-Oral
-Injectable
-Implantable
• Intrauterine device
• Intrauterine hormone-releasing system
• Bilateral tubal occlusion
• Vasectomized partner with confirmed azoospermia
All females will be considered of childbearing potential unless they are postmenopausal (at least 12 months consecutive amenorrhea in the appropriate age group without other known or suspected cause) or have been sterilized surgically (eg, bilateral salpingectomy, hysterectomy, bilateral oophorectomy).
20. Lactating females are not eligible unless they have agreed not to breastfeed their infants during treatment and for a period of 1 month following completion of treatment.
21. Males who are sexually active with WOCBP who have not had a vasectomy must agree to use a barrier method of birth control from the start of study drug administration through at least 6 months after the last dose of study drug. Males should not donate sperm from the start of study treatment through at least 6 months after the last dose of study drug.
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| E.4 | Principal exclusion criteria |
1. Received temozolomide or DTIC at any time
2. Any other systemic anticancer therapy including investigational agents ≤3 weeks before initiation of study treatment. Additionally, subjects may not have received radiation ≤3 weeks before initiation of study treatment.
3. Known intolerance to DTIC or one or more of the excipients in unesbulin.
4. Co-existing active infection or any co-existing medical condition likely to interfere with study procedures, including:
a. Significant cardiovascular disease (New York Heart Association Class III or IV cardiac disease), myocardial infarction within the past 6 months, unstable angina, congestive heart failure requiring therapy, unstable arrhythmia or a need for anti-arrhythmic therapy, or evidence of ischemia on ECG, marked baseline prolongation of QT/QTc (corrected QT) interval, eg, repeated demonstration of a QTc interval >500 msec (Long QT Syndrome [congenital])
5. Human immunodeficiency virus, hepatitis B virus, or hepatitis C virus positivity
6. History of solid organ transplantation
Therapeutics:
7. Known or suspected allergy or immediate or delayed hypersensitivity to unesbulin or DTIC, their excipients, or any agent given in this study
Gastrointestinal:
8. Bowel obstruction, malabsorption, or other contraindication to oral medication
9. Gastrointestinal disease or other conditions that could affect absorption. Active peptic ulcer disease, active gastritis or previous history of gastric perforation within the last 2 years
10. Inflammatory bowel disease (including ulcerative colitis and Crohn’s disease), diverticulitis, cholecystitis, symptomatic cholangitis, or appendicitis
Wounds/surgery:
11. Serious non-healing wound, ulcer, or bone fractures
12. Major surgery, open biopsy, or significant traumatic injury that has not recovered, in the opinion of the investigator, within 28 days of baseline
13. Mucosal or internal bleeding
Concomitant medications:
14. Concomitant strong CYP1A2 inhibitors (such as fluoroquinolones [broad spectrum quinolone antibiotics, including enoxacin and ciprofloxacin] and selective serotonin reuptake inhibitor [SSRI] agents fluvoxamine and fluoxetine) should be avoided on the same day that DTIC or unesbulin/placebo is administered. CYP1A2 inhibitors may inhibit the conversion of DTIC to its active metabolite and may increase the exposure of unesbulin.
15. Concomitant use of moderate CYP1A2 inducers (such as phenytoin, rifampin, ritonavir, teriflunomide, and barbiturates). Chronic use of
marijuana should be avoided, but irregular recreational use may be permitted at the discretion of the treating investigator. CYP1A2 inducers may increase the conversion of DTIC to its active metabolites.
16. Coadministration of acid-reducing agents should be avoided approximately 4 hours before and after unesbulin/placebo administration.
17. Immunization with a live vaccine within 30 days before starting study drug due to the risk of serious and life-threatening infections.
Other:
18. Prior malignancies, other than LMS, that required treatment or have shown evidence of recurrence (except for non-melanoma skin cancer, adequately treated cervical carcinoma in situ, prostate cancer in situ or any other low risk malignancy that is approved by the medical monitor) during the 5 years before initiation. Cancer treated with curative intent more than 5 years previously and without evidence of recurrence is not an exclusion.
19.Known coagulopathy or bleeding diathesis. Subjects on anticoagulation should be monitored closely and International Normalized Ratio and/or activated partial thromboplastin time (APTT)/prothrombin time (PT) should be within the required range where applicable.
20. Prior or ongoing clinically significant illness, medical or psychiatric condition, medical history, physical findings, ECG findings, or laboratory abnormality that, in the investigator’s opinion, could affect the safety of the subject, or alter the absorption, distribution, metabolism, or excretion of the study drugs, or could impair the assessment of study results.
21. History of brain metastases or leptomeningeal disease at any time in subject’s history, including treated central nervous system (CNS) disease
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| E.5 End points |
| E.5.1 | Primary end point(s) |
• PFS per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 assessed by an independent central imaging laboratory
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| At time of interim analysis and following last subject last visit. |
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| E.5.2 | Secondary end point(s) |
Efficacy:
• Key secondary endpoint is Overall Survival.
• Objective response rate (ORR; proportion of subjects with best overall response [BOR] of either complete response [CR] or partial response [PR])
• Disease control rate (DCR) or clinical benefit rate (CBR), defined as the proportion of subjects with BOR of CR, PR, or at least 3 months of stable disease (SD)
• Duration of response (DoR)
Safety:
• Vital signs, physical examination, electrocardiograms (ECG), laboratory abnormalities, Eastern Cooperative Oncology Group (ECOG) performance status (PS) scores, and AEs
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Following last subject last visit |
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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 | No |
| 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 | No |
| 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 | No |
| 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.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 34 |
| 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 |
| Australia |
| Brazil |
| Canada |
| United Kingdom |
| United States |
| France |
| Germany |
| Hungary |
| Italy |
| Netherlands |
| Poland |
| Spain |
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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 | 4 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
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