Human stem cell derived neuron
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A Phase 1 Study of DSP-0390 in Patients with Recurrent High-Grade Glioma

Summary

This is a Phase 1 study to evaluate the safety, pharmacokinetic, pharmacodynamic, and preliminary antitumor activity of orally administered DSP-0390 in patients with recurrent high-grade glioma. Patients in this study will receive DSP-0390 orally once daily. The study will be divided into 28-day cycles for safety and response assessments. Patients will continue treatment until unacceptable toxicity, withdrawal of consent, loss to follow-up, or discontinuation of the patient by the investigator or sponsor. The study is anticipated to take up to 24 months to complete.

The study will be comprised of 2 parts: dose escalation (Part 1, approximately 21 to 30 patients) and dose expansion (Part 2, approximately 20 to 40 patients). The dose-escalation part will evaluate increasing dose levels of DSP-0390 to determine the maximum tolerated dose or a suitable lower dose for expansion in patients with recurrent World Health Organization (WHO) Grade 3 or 4 malignant glioma.

Cholesterol is an essential component of the mammalian cell membrane, playing an important role in cell proliferation and cell survival. Several oncogenic cell signaling pathways induce cholesterol biosynthesis to drive tumor growth. DSP-0390 is a small molecule inhibitor of emopamil binding protein (also known as 3β-hydroxysterol-Δ8,7-isomerase), which catalyzes one of the last steps of cholesterol biosynthesis in the body. This drug has shown cytotoxic activity against GBM, colorectal cancer, and triple-negative breast cancer preclinical cell culture models.

Inclusion Criteria
  1. Dose-escalation Part: Histologically confirmed diagnosis of WHO Grade 3 or 4 malignant glioma (eg astrocytoma, oligodendroglioma, mixed glioma, glioblastoma, or other), with radiographic evidence of disease progression by RANO (2010) criteria, treatment with at least one prior therapy, and no further established treatment option beyond standard of care.
  2. Dose-expansion Part: Histologically confirmed diagnosis of WHO Grade 4 glioblastoma (IDH-wildtype) with radiographic evidence of first recurrence or progression of GBM following primary therapy, consisting of surgery and radiation with or without chemotherapy, and with measurable disease as defined by RANO (2010) criteria
  3. ≥18 years of age.
  4. Estimated life expectancy ≥3 months
  5. Patients must have recovered from the toxic effects of prior therapy ( chemotherapy, surgery, or radiotherapy) to NCI CTCAE v5.0 Grade 1 (except for laboratory parameters outlined below or toxicities from prior therapy that are considered irreversible and stable for greater than 1 month)
  6. Karnofsky Performance Status (KPS) score ≥70%
  7. Adequate organ function as determined by:
    1. Absolute neutrophil count (ANC) ≥1500/μL (patient may not use G-CSF or GM-CSF to achieve this ANC level)
    2. Platelet count ≥100 × 103/μL
    3. Hemoglobin (Hgb) ≥9.0 g/dL (may not transfuse or use erythropoietin to obtain this Hgb level)
    4. Creatinine clearance ≥40 mL/min (as determined using the Cockcroft-Gault formula)
    5. Total bilirubin ≤1.5 times upper limit of normal (ULN) (or ≤3.0 times ULN for patients with known Gilbert’s syndrome)
    6. Aspartate transaminase (AST) ≤3.0 times ULN
    7. International normalized ratio (INR), prothrombin time (PT), partial thromboplastin time (PTT), or activated partial thromboplastin time (aPTT) ≤1.5 x ULN. The use of anticoagulants is permitted as long as the PT/(a)PTT is within therapeutic limits (according to the local institution standard) and the patient has been on a stable anticoagulant regimen for at least 2 weeks prior to study Day 1
  8. Patients on an antiepileptic drug must be on a stable dose and without seizures for 14 days prior to study Day 1
  9. If the patient is receiving corticosteroids at baseline, the dose administered must be stable or decreasing for at least 5 days prior to study Day 1. For the dose-expansion part of the study, the dose must be ≤4 mg dexamethasone per day (or equivalent dose if other corticosteroids are used). A higher stable dose of corticosteroids, if used as hormone replacement therapy, may be allowed upon discussion with the Medical Monitor.
  10. Females of childbearing potential must have a negative serum or urine pregnancy test
  11. Male or female patients of child-producing potential must agree to use contraception or use prevention of pregnancy measures (oral contraceptives, implantable hormonal contraceptives, or a double-barrier method) or agreement to refrain completely from heterosexual intercourse during the study and for 6 months (for females and males alike) after the last dose of study drug.
Exclusion Criteria
  1. Prior therapy with bevacizumab or other anti-vascular endothelial growth factor (VEGF) treatments within 3 months prior to study Day 1
  2. Multifocal disease, leptomeningeal metastasis, or extracranial metastasis
  3. Abnormal electrocardiograms (ECGs) that are clinically significant, including those where QT prolongation (QT corrected using Fridericia’s formula; QTcF) >450 msec for males and >470 msec for females; and/or a history of Torsade de Pointes
  4. Left ventricular ejection fraction less than 40% as determined by echocardiogram (ECHO) or multiple-gated acquisition (MUGA)
  5. Known dysphagia, short-gut syndrome, gastroparesis, or other conditions that limit the ingestion or gastrointestinal absorption of drugs administered orally
  6. Known active Crohn’s or other inflammatory bowel disease
  7. History of another primary cancer within the 2 years prior to study Day 1, except for the following: nonmelanoma skin cancer, cervical carcinoma in situ, superficial bladder cancer that has been removed and/or curatively treated
  8. A known active, acute,or chronic infection including, but not limited to, human immunodeficiency virus (HIV), hepatitis B* virus (HBV), and hepatitis C virus (HCV). Patients who have completed a course of anti- viral treatment for HCV are eligible provided that an HCV polymerase chain reaction shows no detectable virus. *In cases of negative results for HBV surface antigen with positive HBV core antibody, HBV DNA testing is required.
  9. Pregnant or breastfeeding. Female breastfeeding patients may be enrolled if they interrupt breastfeeding. Breastfeeding should not be resumed for at least 6 months after the last dose of study drug.
  10. The presence of any active retinal abnormality determined by screening tests using visual acuity, visual field, fundoscopy, and Optical Coherence Tomography (OCT).
  11. Significant cardiovascular disease, including New York Heart Association (NYHA) Class III or IV congestive heart failure, myocardial infarction, unstable angina, poorly controlled cardiac arrhythmias, or stroke in the preceding 6 months prior to study Day 1.
  12. Uncontrolled intercurrent illness including, but not limited to, psychiatric illness/social situations that would limit compliance with study requirements, or disorders associated with significant immunocompromised state.
  13. Major surgical procedure, surgical resection, open biopsy, or significant traumatic injury within 4 weeks prior to study Day 1 or anticipation of need for major surgical procedure during the course of the study.
  14. Minor surgical procedures, fine needle aspirations, or core biopsies within 7 days prior to study Day 1
  15. Evidence of central nervous system (CNS) hemorrhage on baseline magnetic resonance imaging (MRI) or computed tomography (CT) scan (except for postsurgical, asymptomatic, Grade 1 hemorrhage that has been stable for at least 4 weeks for enrolled patients)
  16. Chemotherapy or investigational anticancer therapy administered within 4 weeks (except 6 weeks for nitrosoureas and immunotherapy, or 8 weeks for an implanted nitrosoureas wafer) prior to study Day 1
  17. Radiotherapy within 12 weeks prior to study Day 1, unless relapse is confirmed by tumor biopsy or new lesion outside of radiation field, or if there are 2 MRIs (performed 8 weeks apart) confirming progressive disease
  18. Concurrent use of prohibited medications: methylprednisolone, prednisone, carbamazepine, phenytoin, phenobarbital, and other strong or moderate CYP3A4 inhibitors or inducers, and strong CYP2D6 inhibitors. These should be discontinued 1 week or 5 half-lives (whichever is greater) prior to study Day 1.
  19. Concurrent treatment with Tumor Treatment Field (Optune) is not allowed. Patients must stop Optune 1 day prior to the first dose of study drug. Any wounds from Optune must be healed adequately prior to study Day 1.
  20. History of, within 6 months of study Day 1:
    1. Pneumonitis or interstitial lung disease.
    2. Any other lung condition that in the investigators’ judgement may put the patient at an increased risk for lung toxicity (including, but not limited to, suspected interstitial lung disease or radiation-induced lung injury)
Investigator(s)

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