Safusidenib Phase 2 Study in IDH1 Mutant Glioma

This is a Phase 2, multicenter, open label, two parts, clinical study to evaluate the efficacy, safety, and PK of safusidenib. Patients with recurrent or progressive histologically confirmed IDH1 mutant WHO Grade 2/3 glioma10 outside Japan, will be enrolled in this study. It was divided into 2 parts.

Part 1: Up to 25 patients will be randomized 1:1:1:1:1 (5 patients per group) to receive one of the daily oral doses of safusidenib at 125 mg twice a day (BID), 250 mg BID, 500 mg once daily (QD), 375 mg BID, or 500 mg BID. The PK characteristics and safety and initial efficacy data will be assessed in Part 1.

Part 2: It is planned to open 2 glioma subtype cohorts: Grade 2 and Grade 3 glioma cohorts with 30 eligible patients enrolled in each cohort. Total 60 patients will be enrolled.

Part 2 is to evaluate the efficacy of safusidenib in the treatment of recurrent/progressive WHO CNS Grade 2 and grade 3 IDH1 mutant glioma.

Exploratory Surgery Cohort: This cohort will be conducted in parallel with Part 2, for explorative purpose once RP2D is decided. 5 patients with primarily enhancing lesions and other 5 with primarily non-enhancing lesions will be enrolled. Participants will receive oral safusidenib treatment continuously, with 28 days as a cycle, until disease progression, unacceptable toxicity, consent withdrawal, start of new anti-cancer therapy, investigator decision or death, upon whichever earlier.

Besides baseline, the anti-tumor response will be evaluated every 8 weeks following RANO or RANO-LGG criteria as applicable, until disease progression, consent withdrawal or death, upon whichever earlier.


Eligibility Criteria:
Inclusion Criteria:

1. Patient must be ≥ 18 years of age at the time of signing the informed consent form (ICF).

   Type of Patient and Disease Characteristics
2. Patient must have histologically confirmed recurrent or progressive WHO Grade 2 glioma or Grade 3 glioma with IDH1 R132H or R132C mutation confirmed by immunohistochemistry or molecular genetic testing.
3. Patient has available archived primary tumor biopsy or surgical specimens, or biopsies of recurrence of metastasis for retrospective IDH mutation confirmation and other genes testing to support the reconfirmation of Glioma WHO classification and explorative studies.
4. The IDH mutation, and other applicable gene/molecular alterations (see Table 10-2) are determined by a validated assay as performed in Clinical Laboratory Improvement Amendments (CLIA)-certified/College of American Pathologists (CAP)-accredited or locally equivalent clinical laboratories. Prior clinical pathology report fulfilling the diagnosis criteria prior to screening with tumor samples collected is acceptable for patient enrollment in both Part 1 and Part 2.
5. Patient has received no more than 2 prior therapies for disease recurrence/progression.
6. Patient has disease recurrence or progression or cannot tolerate the most recent therapy.
7. Patient must have a measurable lesion(s) as per the RANO-HGG criteria for primarily enhancing lesions or RANO-LGG criteria for primarily non-enhancing lesions. The lesion (s) must be visible on 2 or more axial slices and have perpendicular diameters of at least 10 × 10 mm. The definition of primarily enhancing lesions or primarily non-enhancing lesions is referred to Section 8.3.1.
8. Patient must have life expectancy ≥ 3 months.
9. Patient must have KPS score ≥ 60.
10. Patient who has adequate organ functions as defined below:

    * AST and ALT: ≤ 2.5 × upper limit of normal (ULN)
    * Total bilirubin: ≤ 1.5 × ULN
    * Absolute neutrophil count: ≥ 1,500/μL
    * Platelet count: ≥ 100,000/μL (or ≥ 50,000/μL for prior temozolomide therapy)
    * Hemoglobin: ≥ 9.0 g/dL
    * Creatinine clearance (Cockcroft-Gault Formula) ≥ 60 mL/min An out-of-range laboratory test will be repeated up to 2 times before declaring a screen failure, and after expiration of screening window, patients will be re-screened.
11. Recovery to Grade 1 or baseline from any toxicities due to prior therapies (except conditions such as alopecia, temozolomide-induced lymphopenia and irreversible changes associated with radiation therapy).
12. Female patients who engage in heterosexual intercourse must be of non-childbearing potential, defined as either surgically sterile (e.g., hysterectomy, bilateral salpingectomy, or bilateral oophorectomy), OR be postmenopausal with at least 1 year of amenorrhea, OR must agree to use a highly effective method of contraception from the beginning of Screening until at least 90 days after the last dose of safusidenib.

    Acceptable highly effective methods of contraception include:
    * Combined estrogen-progestin oral hormonal contraception associated with consistent inhibition of ovulation
    * Desogestrel-based progestin-only contraception associated with consistent inhibition of ovulation; this includes oral, injectable, and implantable methods
    * Intravaginal and transdermal hormone delivery methods
    * Intrauterine device (with or without hormone elution)
    * Bilateral tubal occlusion or ligation (must be documented)
    * Vasectomized partner (must be documented) or
    * Sexual abstinence (only when it is the usual and preferred lifestyle of the patient)

    Additional information for contraceptive measurements is provided in Appendix 4:

    Contraceptive and Barrier Guidance.
13. Male patients should agree to use a condom when sexually active with a female partner of childbearing potential from Screening until at least 90 days after the last dose of safusidenib (or be surgically sterile \[e.g., vasectomy with documentation\]; or remain abstinent \[when this is in line with the preferred and usual lifestyle\]). Male patients should also agree to not donate sperm for the duration of the study and until at least 90 days after the last dose of safusidenib.
14. Patient should be willing to provide written ICF.
15. Ability to undergo the protocol-specified procedures, including blood tests and urinalysis.

Exclusion Criteria:

1. Patients with history or complication of any of the following diseases within 6 months prior to the initial dose of safusidenib:

   * Myocardial infarction
   * Severe or unstable angina pectoris
   * Coronary or peripheral endovascular treatment
   * Heart failure
   * Cerebrovascular disorder including transient ischemic attack, stroke, central nervous system (CNS) bleeding.
2. Uncontrolled active systemic fungal, bacterial, or other infection (despite appropriate antibiotics or other treatment).
3. Gastrointestinal diseases that may interfere with oral ingestion of safusidenib or may affect absorption of safusidenib.
4. Psychiatric disease or symptoms that may interfere with the patient's continuous participation in the study.
5. Patients should be tested for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and those with active infection detected using either molecular or antigen tests in accordance with local testing guidelines will be excluded.
6. Prior anti-cancer therapy, within the applicable periods shown below, before the start of the protocol treatment:

   * Systemic drug therapies: within 3 weeks (lomustine within 6 weeks)
   * Surgery: within 3 weeks
   * Radiation therapy: within 12 weeks
   * Investigational agents: within 5 half-lives for other investigational agents
7. Patient did receive the prior therapy targeted to IDH1 mutation.
8. Patients taking substrates of cytochrome CYP2C8, CYP2C9, and CYP3A4 (See Appendix 7) with narrow therapeutic window, should be excluded unless they can be transferred to other medications prior to enrolling. Patients taking sensitive CYP 2C8, 2C9 or 3A4 substrate medications may require dosage adjustment unless they can be transferred to other medications within ≥ 5 half-lives prior to dosing.
9. Patients taking sensitive substrates of P-gp and BCRP transporters (See Appendix 7) should be excluded unless they can be transferred to other medications prior to enrolling.

   Patients taking sensitive substrates of P-gp and BCRP may require dosage adjustment unless they can be transferred to other medications within ≥ 5 half-lives prior to dosing.
10. Advanced arrhythmia of Grade ≥ 2 per NCI-CTCAE v5.0, uncontrolled atrial fibrillation (any grade) and corrected QT interval by Fredericia's formula (QTcF) \> 470 msec.
11. Evidence of intraspinal dissemination or diffuse leptomeningeal disease by MRI.
12. Positive test results for human immunodeficiency virus (HIV) antibody.
13. Positive test results for hepatitis B surface (HBs) antigen and/or hepatitis C virus (HCV) antibody. Patients who have tested positive for hepatitis B core (HBc) antibody and/or HBs antibody, despite negative test results for HBs antigen, may be enrolled only if they have negative finding on quantitative hepatitis B virus (HBV) DNA assays and the Anti-HBV treatment is allowing during study period. Patients who are hepatitis C antibody positive will need to have a negative polymerase chain reaction (PCR) result before enrollment; those who are hepatitis C PCR positive will be excluded.
14. Pregnant or breastfeeding female patient.
15. Known hypersensitivity to safusidenib or to any drug with similar chemical structure or to any other excipient present in the pharmaceutical form of safusidenib.