Clinical Trials

Key Inclusion Criteria:

• Subject is willing and able to provide informed consent.
• Willingness and ability to comply with scheduled visits, drug administration plan, laboratory tests, other study procedures, and study restrictions.
• Disease status including:
  • Histological or cytological confirmation of LMS arising at any anatomic site except bone sarcoma;
  • Unresectable or metastatic, relapsed or refractory disease;
  • Measurable disease per RECIST 1.1 criteria;
  • Disease progression on previous treatment before screening or intolerability to other oncology treatments.
• Age ≥ 18 years.
• Male or female.
• ECOG PS score of 0 or 1.
• Absolute neutrophil count ≥ 1500/mm^3 without the use of growth factors in the past 7 days.
• Platelet count ≥ 100000/mm^3 without platelet transfusion in the past 14 days.
• Hemoglobin ≥ 9 g/dL (packed red blood cell transfusion is not allowed within 7 days).
• Bilirubin ≤ upper limit of normal (ULN) except for those patients with Gilbert’s syndrome.
• Aspartate aminotransferase or alanine aminotransferase < 3 times the ULN 12.
• Subjects with liver metastases may be enrolled.
• Subjects with well-controlled asthma (e.g., use of rescue medications < 2 times per week over the last 12 months) or chronic obstructive pulmonary disease (e.g., no exacerbations over the prior 3 months) may be enrolled.
• Creatinine < 1.5 times normal OR creatinine clearance ≥ 60 mL/min.
• 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.
• At least 1 prior systemic cytotoxic or targeted therapy regimen for 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.
• At least 4 weeks since prior surgery and recovered in the opinion of investigator.
• Capable of swallowing oral medication.
• 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 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).
• 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.
• 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).

Exclusion Criteria:

• Received temozolomide or DTIC at any time.
• 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.
• Known intolerance to DTIC or one or more of the excipients in unesbulin.
• Co-existing active infection or any co-existing medical condition likely to interfere with study procedures, including:
  • 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 antiarrhythmic 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]).
• Human immunodeficiency virus, hepatitis B virus, or hepatitis C virus positivity.
• History of solid organ transplantation
• Known or suspected allergy or immediate or delayed hypersensitivity to unesbulin or DTIC, their excipients, or any agent given in this study Gastrointestinal:
• Bowel obstruction, malabsorption, or other contraindication to oral medication.
• 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.
• Inflammatory bowel disease (including ulcerative colitis and Crohn’s disease), diverticulitis, cholecystitis, symptomatic cholangitis, or appendicitis.
• Serious non-healing wound, ulcer, or bone fractures.
• Major surgery, open biopsy, or significant traumatic injury that has not recovered, in the opinion of the investigator, within 28 days of baseline.
• Mucosal or internal bleeding Concomitant medications:
  • 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.
• 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.
• Coadministration of acid-reducing agents should be avoided approximately 4 hours before and after unesbulin/placebo administration.
• Immunization with a live vaccine within 30 days before starting study drug due to the risk of serious and life-threatening infections.
• 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.
• 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.
• 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.
• History of brain metastases or leptomeningeal disease at any time in subject’s history, including treated central nervous system (CNS) disease.

Note: Other protocol defined Inclusion/Exclusion Criteria may apply.

Eligibility last updated 10/2/23. Questions regarding updates should be directed to the study team contact.

Eligibility last updated 4/12/22. Questions regarding updates should be directed to the study team contact.