Clinical trial NCT05303519: Safusidenib Phase 2 Study in IDH1 Mutant Glioma
Official title: A Phase 2, Multicenter, Clinical Study to Evaluate the Efficacy and Safety of Safusidenib Erbumine in Patients With Isocitrate Dehydrogenase 1 (IDH1) Mutant Glioma
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Glioma
Astrocytoma, Grade IV
IDH1-mutant Glioma
Astrocytoma, IDH-Mutant, Grade 3
Astrocytoma, IDH-Mutant, Grade 4
Keywords: safusidenib
IDH1-mutant glioma
astrocytoma
Lead sponsor: Nuvation Bio Inc.
Sponsor class: INDUSTRY
Collaborators: name: AnHeart Therapeutics Inc.
First posted: 2022-03-31
Enrollment: 125
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is a 2-part study. The purpose of Part 1 of the study is to evaluate the efficacy, safety, and pharmacokinetic (PK) characteristics of safusidenib in participants with recurrent/progressive IDH1-mutant World Health Organization (WHO) Grade 2 or Grade 3 glioma.

The purpose of Part 2 will be to evaluate the efficacy of maintenance safusidenib treatment versus placebo in IDH1-mutant Grade 3 astrocytoma with high-risk features or Grade 4 IDH1-mutant astrocytoma, following standard-of-care radiation or chemoradiation and adjuvant temozolomide. Part 2 will be randomized, double blind, and placebo controlled.

Detailed description: Part 1 of this study will enroll up to 25 patients that 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.was fully enrolled as of 19 Dec 2023 and participants are currently ongoing.

Part 2 will include approximately 100 participants with IDH1-mutant astrocytoma, Grade 3 with high-risk features or IDH1-mutant Grade 4 astrocytoma, following standard-of-care radiation or chemoradiation and adjuvant temozolomide. Participants will be randomized (1:1) after their last dose of adjuvant temozolomide to receive either oral safusidenib 250 mg BID or placebo in 28-day continuous cycles. Patients will continue treatment until progression of disease or until other discontinuation criteria are met. The tumor response evaluation will be conducted on a regular basis until progression of disease per Blinded Independent Central Review (BICR), consent withdrawal, or death, whichever occurs first. Long-term survival follow-up will be conducted as well.

Eligibility criteria: Key Inclusion Criteria for Part 1:

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

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.

Key Inclusion Criteria for Part 2:

1. Must be ≥18 years old at the time of signing the ICF.
2. Diagnosis of histologically confirmed IDH1-mutant Grade 3 with high risk features or Grade 4 astrocytoma, per WHO 2021 classification and Investigator Assessment.
3. Have an IDH1 mutation (R132H/C/G/S/L) based on IHC (R132H only), polymerase chain reaction (PCR), or next-generation sequencing (NGS). CDKN2A/B status and at least 1 of the following must be confirmed: absence of 1p19q co-deletion by fluorescence in situ hybridization, array comparative genomic hybridization, or NGS; presence of an ATRX loss of function mutation by NGS; or loss of normal ATRX expression by IHC. A validated assay performed in a CLIA-certified/CAP-accredited (or local equivalent) clinical laboratory must be used for all of the aforementioned results. Documentation of biomarker status, including redacted molecular pathology and NGS reports, must be provided during Screening.
4. Must not have experienced disease recurrence or disease progression.
5. Participants must have completed radiation therapy with a minimum of 90% of planned treatment completed (with or without concurrent temozolomide) and between 6 and 12 cycles of adjuvant temozolomide and have no evidence of disease progression. Randomization must occur at least 28 days and not more than 75 days after the final dose of temozolomide.
6. Must agree to submit sufficient tumor tissue for retrospective biomarker and histological analyses. This requirement may be waived in rare circumstances with approval by the Sponsor.
7. Has adequate hematologic and organ functions

Key Exclusion Criteria for Part 1:

* 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..
* Known hypersensitivity to safusidenib or to any drug with similar chemical structure or to any other excipient present in the pharmaceutical form of safusidenib.

Key Exclusion Criteria for Part 2:

1. Participants may not have received any anticancer treatments other than surgery, radiation, concurrent/adjuvant temozolomide, and tumor-treating fields. Tumor-treating fields must be discontinued prior to randomization.
2. Participants with prior or anticipated treatment with anti-angiogenic agents such as Avastin (bevacizumab), agents known to target IDH1 or IDH2, or investigational agents for glioma are excluded.
3. Have brainstem or spinal cord involvement either as primary location, site of multifocal involvement, or by significant tumor extension.
4. Significant functional or neurocognitive deficits, including uncontrolled seizures, that would preclude participation in protocol-defined study activities, as assessed by Investigator.
5. Evidence of diffuse leptomeningeal disease by MRI.
6. History of significant cardiac disease within 12 months prior to randomization.
7. If taking corticosteroids, must be on a stable or decreasing dose for the 14 days prior to randomization.
8. Participants with other malignancies must have received curative treatment and been disease-free for at least 3 years. Curatively resected non-melanoma skin cancer or curatively treated carcinoma in situ is allowed.
9. Have a condition that would interfere with, or increase the risk of, study participation.

Primary outcomes:
measure: Part 1: Incidence of adverse events (AEs) and serious adverse events (SAEs)
timeFrame: From participants sign ICF to 30 days after last dose，average 2 years
measure: Part 2: Progression-free survival (PFS) assessed by Blinded Independent Central Review (BICR) per Response Assessment in Neuro-Oncology (RANO) 2.0
timeFrame: From randomization until the date of first documented disease progression, average 2 years
Secondary outcomes:
measure: Part 1: Cmax of safusidenib
timeFrame: on Cycle 1 Day 1 and Day 8 (every cycle is 28 days)
measure: Part 1: Tmax of safusidenib
timeFrame: on Cycle 1 Day 1 and Day 8 (every cycle is 28 days)
measure: Part 1: AUC8h of safusidenib
timeFrame: on Cycle 1 Day 1 and Day 8 (every cycle is 28 days)
measure: Part 1 : AUC12h of safusidenib
timeFrame: on Cycle 1 Day 1 and Day 8 (every cycle is 28 days)
measure: Part 1: AUC24h [QD only] of safusidenib
timeFrame: on Cycle 1 Day 1 and Day 8 (every cycle is 28 days)
measure: Part 1 : Ctrough of safusidenib
timeFrame: on Days 2, 3, 4, 6, 8, 9 of Cycle 1 and Day 1 of Cycles 2, 3, 4, 6 and 8 (every cycle is 28 days)
measure: Part 1: Overall Response Rate (ORR) assessed by the investigator
timeFrame: from the first dose of study drug until the date of first documented disease progression, average 2 years
measure: Part 1: Duration of Response (DOR) assessed by the Investigator
timeFrame: from the first dose of study drug until the date of first documented disease progression, average 2 years
measure: Part 1: Disease control rate (DCR) assessed by the Investigator
timeFrame: from the first dose of study drug until the date of first documented disease progression, average 2 years
measure: Part 1: Progression free survival (PFS) assessed by the Investigator
timeFrame: from the first dose of study drug until the date of first documented disease progression, average 2 years
measure: Part1: Time to Response (TTR) assessed by the Investigator.
timeFrame: From the first dose of study drug until the date of first documented objective response, average 2 years
measure: Part 1: Overall Survival (OS)
timeFrame: from the first dose of study drug to date of death, average 7 years
measure: Part 2: Overall Survival (OS)
timeFrame: from randomization to date of death, average 7 years
measure: Part2: PFS assessed by the Investigator.
timeFrame: from randomization until the date of first documented disease progression, average 2 years
measure: Part2: DCR assessed by BICR and by the Investigator
timeFrame: from randomization until the date of first documented disease progression, average 2 years
measure: Part2: ORR
timeFrame: from randomization until the date of first documented disease progression, average 2 years
measure: Part2: DOR, assessed by BICR and the Investigator
timeFrame: from randomization until the date of first documented disease progression, average 2 years
measure: Part2: Time to Response (TTR) assessed by BICR and by the Investigator
timeFrame: From randomization until the date of first documented objective response, average 2 years
measure: Part2: Time to Next Intervention (TTNI) by Investigator assessment
timeFrame: From randomization until the date of next treatment, average 2 years
measure: Part2: Health-related quality of life
timeFrame: From the first dose of study drug to treatment discontinuation, average 2 years
measure: Part2: Safety and tolerability
timeFrame: from the first dose of study drug until 30 days after treatment discontinuation, average 2 years
measure: Part2: Seizure Activity
timeFrame: from the first dose of study drug until the date of first documented disease progression, average 2 years
measure: Part2: Safusidenib PK Profile
timeFrame: from the first dose of study drug through 20 weeks
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: St. Joseph's Hospital and Medical Center
state: Arizona
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Dana-Farber Cancer Institute
state: Massachusetts
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Durham
country: United States
facility: Duke Cancer Institute
state: North Carolina
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Salt Lake City
country: United States
facility: Huntsman Cancer Insititute, University of Utah
state: Utah
city: Charlottesville
country: United States
facility: UVA Health, Emily Couric Clinical Cancer Cente
state: Virginia
Study officials:
References: