Safusidenib Phase 2 Study in IDH1 Mutant Glioma

Study Overview
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Brief Summary
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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.

Official Title
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A Phase 2, Multicenter, Open Label, Two Parts Clinical Study to Evaluate the Efficacy and Safety of Safusidenib Erbumine in Patients With Isocitrate Dehydrogenase 1 (IDH1) Mutant Glioma

Conditions
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Glioma

Intervention / Treatment
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* Drug: safusidenib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient must be ≥ 18 years of age at the time of signing the informed consent form (ICF). Type of Patient and Disease Characteristics 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. 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. 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. Patient has received no more than 2 prior therapies for disease recurrence/progression. Patient has disease recurrence or progression or cannot tolerate the most recent therapy. 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. Patient must have life expectancy ≥ 3 months. Patient must have KPS score ≥ 60. 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. 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). 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. 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. Patient should be willing to provide written ICF. Ability to undergo the protocol-specified procedures, including blood tests and urinalysis. Exclusion Criteria: 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. Uncontrolled active systemic fungal, bacterial, or other infection (despite appropriate antibiotics or other treatment). Gastrointestinal diseases that may interfere with oral ingestion of safusidenib or may affect absorption of safusidenib. Psychiatric disease or symptoms that may interfere with the patient's continuous participation in the study. 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. 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 Patient did receive the prior therapy targeted to IDH1 mutation. 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. 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. 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. Evidence of intraspinal dissemination or diffuse leptomeningeal disease by MRI. Positive test results for human immunodeficiency virus (HIV) antibody. 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. Pregnant or breastfeeding female patient. Known hypersensitivity to safusidenib or to any drug with similar chemical structure or to any other excipient present in the pharmaceutical form of safusidenib.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: safusidenib 125mg bid<br>safusidenib 125mg bid administered continuously as a single agent dosed orally on Days 1 to 28 of a 28-day cycle. Subjects may continue treatment with safusidenib until disease progression or development of other unacceptable toxicity. | Drug: safusidenib<br>* safusidenib administered continuously as dosed single agent orally on Days 1 to 28 of a 28-day cycle. Subjects may continue treatment with agent safusidenib until disease progression or development of other unacceptable toxicity.<br>* Other names: AB-218;|
| Experimental: safusidenib 250mg bid<br>safusidenib 250mg bid administered continuously as a single agent dosed orally on Days 1 to 28 of a 28-day cycle. Subjects may continue treatment with safusidenib until disease progression or development of other unacceptable toxicity. | Drug: safusidenib<br>* safusidenib administered continuously as dosed single agent orally on Days 1 to 28 of a 28-day cycle. Subjects may continue treatment with agent safusidenib until disease progression or development of other unacceptable toxicity.<br>* Other names: AB-218;|
| Experimental: safusidenib 500mg qd<br>safusidenib 500mg qd administered continuously as a single agent dosed orally on Days 1 to 28 of a 28-day cycle. Subjects may continue treatment with safusidenib until disease progression or development of other unacceptable toxicity. | Drug: safusidenib<br>* safusidenib administered continuously as dosed single agent orally on Days 1 to 28 of a 28-day cycle. Subjects may continue treatment with agent safusidenib until disease progression or development of other unacceptable toxicity.<br>* Other names: AB-218;|
| Experimental: safusidenib 375mg bid<br>safusidenib 375mg bid administered continuously as a single agent dosed orally on Days 1 to 28 of a 28-day cycle. Subjects may continue treatment with safusidenib until disease progression or development of other unacceptable toxicity. | Drug: safusidenib<br>* safusidenib administered continuously as dosed single agent orally on Days 1 to 28 of a 28-day cycle. Subjects may continue treatment with agent safusidenib until disease progression or development of other unacceptable toxicity.<br>* Other names: AB-218;|
| Experimental: safusidenib 500mg bid<br>safusidenib 500mg bid administered continuously as a single agent dosed orally on Days 1 to 28 of a 28-day cycle. Subjects may continue treatment with safusidenib until disease progression or development of other unacceptable toxicity. | Drug: safusidenib<br>* safusidenib administered continuously as dosed single agent orally on Days 1 to 28 of a 28-day cycle. Subjects may continue treatment with agent safusidenib until disease progression or development of other unacceptable toxicity.<br>* Other names: AB-218;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| part1: Incidence of adverse events (AEs) and serious adverse events (SAEs) | calculate Percentage and numbers of participants with adverse events (AEs) and serious adverse events (SAEs) assessed by CTCAE 5.0 | From participants sign ICF to 30 days after last dose，average 2 years | 
| part2: ORR by the IRC | ORR (defined as the proportion of participants with the best overall confirmed response of CR or PR[for RANO LGG] according to the appropriate tumor response criteria) as assessed by the IRC | from drug treatment to 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1 Stage 1: Cmax of safusidenib | Peak Plasma Concentration (Cmax) | on Cycle 1 Day 1 and Day 8 | 
| Part 1 Stage 1: Tmax of safusidenib | the time for safusidenib to reach Cmax | on Cycle 1 Day 1 and Day 8 | 
| Part 1 Stage 1: AUC8h of safusidenib | Area under the plasma concentration curve (AUC) from time 0 to 8 hours | on Cycle 1 Day 1 and Day 8 | 
| Part 1 Stage 1: AUC12h of safusidenib | Area under the plasma concentration curve (AUC) from time 0 to 12 hours | on Cycle 1 Day 1 and Day 8 | 
| Part 1 Stage 1: AUC24h [QD only] of safusidenib | Area under the plasma concentration curve (AUC) from time 0 to 24h hours for 500mg qd cohort | on Cycle 1 Day 1 and Day 8 | 
| Part 1 Stage 1: Ctrough of safusidenib | Lowest plasma concentration reached after AB-218 administration | on Days 2, 3, 4, 6, 8, 9 of Cycle 1 and Day 1 of Cycles 2, 3, 4, 6 and 8 | 
| Part 1 Stage 2: Cmax of safusidenib | Peak Plasma Concentration (Cmax) | on Cycle 1 Day 1 and Day 8 | 
| Part 1 Stage 2: Tmax of safusidenib | the time for AB-218 to reach Cmax | on Cycle 1 Day 1 and Day 8 | 
| Part 1 Stage 2: AUC6h of safusidenib | Area under the plasma concentration curve (AUC) from time 0 to 6 hours | on Cycle 1 Day 1 and Day 8 | 
| Part 1 Stage 2: Ctrough of safusidenib | Lowest plasma concentration reached after AB-218 administration | on Days 4, 8 of Cycle 1 and Day 1 of Cycles 2, 4, 6, and 8 | 
| Part 1: ORR assessed by the investigator | ORR (defined as the proportion of participants with the best overall confirmed response of CR or PR [for RANO LGG] according to the appropriate tumor response criteria) as assessed by the Investigator | from drug treatment to 2 years | 
| Part 1: DOR assessed by the Investigator | Duration of response (DOR, defined as the time from the first date of objective response [CR or PR, to the first documented date of disease progression per RANO or RANO LGG or the date of death due to any cause, whichever occurs first) as assessed by the Investigator | from drug treatment to 2 years | 
| Part 1: DCR assessed by the Investigator | Disease control rate (DCR, defined as the proportion of patients with a best overall response of CR, PR, stable disease, or MR [for RANO LGG], per RANO or RANO LGG) as assessed by the Investigator | from drug treatment to 2 years | 
| Part 1: PFS assessed by the Investigator | Progression free survival (PFS, defined as the time from first dose of AB 218 until the date of disease progression per RANO or RANO LGG or death [by any cause in the absence of progression]) as assessed by the Investigator | from drug treatment to 2 years | 
| Part2: ORR, per RANO or RANO LGG, as applicable, by the Investigator | ORR (defined as the proportion of participants with the best overall confirmed response of CR or PR[for RANO LGG] according to the appropriate tumor response criteria) as assessed by the Investigator | from drug treatment to 2 years | 
| Part2: DOR assessed by the IRC and by the Investigator | DOR, defined as the time from the first date of objective response [CR or PR, to the first documented date of disease progression per RANO or RANO LGG or the date of death due to any cause, whichever occurs first) as assessed by the Investigator and IRC | from drug treatment to 2 years | 
| Part2: DCR assessed by the IRC and by the Investigator | DCR, defined as the proportion of patients with a best overall response of CR, PR, stable disease, or MR [for RANO LGG], per RANO or RANO LGG) as assessed by the Investigator and IRC | from drug treatment to 2 years | 
| Part2: PFS assessed by the IRC and by the Investigator | PFS, defined as the time from first dose of AB 218 until the date of disease progression per RANO or RANO LGG or death [by any cause in the absence of progression]) as assessed by the Investigator and IRC | from drug treatment to 2 years | 
| Part2: Overall survival (OS) | OS: defined as the time from first dose of safusidenib until the date of death. | from first dose of safusidenib to death | 
| Part2: Incidence of AEs and SAEs | Percentage and numbers of participants with adverse events (AEs) and serious adverse events (SAEs) assessed by CTCAE 5.0 | From participants sign ICF to 30 days after last dose, average 2 years | 
| Part2: Cmax of safusidenib | Peak Plasma Concentration (Cmax) | on Cycle 1 Day 1 and Day 8 | 
| Part2: Tmax of safusidenib | the time for safusidenib to reach Cmax | on Cycle 1 Day 1 and Day 8 | 
| Part2: AUC6h of safusidenib | Area under the plasma concentration curve (AUC) from time 0 to 6 hours | on Cycle 1 Day 1 and Day 8 | 
| Part2: Ctrough of safusidenib | Lowest plasma concentration reached after safusidenib administration | on Days 4, 8 of Cycle 1 and Day 1 of Cycles 2, 4, 6, and 8 |