2024-513738-39-00招募中1/2 期
A Phase 1b/2, multicenter study of vorasidenib in combination with temozolomide (TMZ) in participants with IDH1- or IDH2-mutant glioma
试验速览
- 阶段
- 1/2 期
- 状态
- 招募中
- 入组人数
- 13
- 试验地点
- 13
- 主要终点
- DLTs (for Phase 1b only), incidence and severity of AEs, SAEs, and AESIs
研究概览
简要总结
- To evaluate the safety and tolerability of vorasidenib when administered in combination with TMZ and determine (for Phase 1b) the RCD.
- To assess preliminary clinical efficacy of vorasidenib in combination with TMZ based on the PFS rate at 12 months (per RANO 2.0) for participants with IDHm Grade 4 astrocytoma enrolled in Phase 2 and Phase 1b and treated at the RCD.
研究设计
- 分配方式
- Not Applicable
- 主要目的
- Phase 2: Vorasidenib recommended combination dose (RCD) and Temozolomide (TMZ)
- 盲法
- None
入排标准
- 年龄范围
- 18 years 至 65+ years（18-64 Years, 65+ Years）
- 接受健康志愿者
- 否
入选标准
- •Be ≥18 years of age with a weight at screening ≥40 kg.
- •"Phase 1b ONLY: Have histologically confirmed Grade 2, 3 or 4 IDHm (as per WHO 2021) glioma (astrocytoma or oligodendroglioma).
- •For oligodendroglioma: Have local testing at an accredited laboratory demonstrating presence of 1p19q co deletion
- •For astrocytoma: Have local testing by an accredited laboratory demonstrating lack of 1p19q co-deletion and/or documented loss of nuclear ATRX expression or ATRX mutation"
- •Phase 1b ONLY: Are appropriate to receive TMZ as post-radiotherapy (RT) adjuvant therapy or as treatment for first disease recurrence after prior RT and/or chemotherapy, per Investigator judgement. For those receiving TMZ in the post-RT adjuvant setting, study treatment must begin no more than 6 weeks after completion of RT.
- •Have adequate hepatic function as evidenced by:
- •Serum total bilirubin ≤1.5×upper limit of normal (ULN); if ≥1.5×ULN and due to Gilbert syndrome, total bilirubin ≤3×ULN with direct bilirubin ≤ULN,
- •AST and ALT ≤ULN, An elevation ≤1.5×ULN. For phase 2, an elevation ≤1.5×UL considered not clinically significant by the Investigator may be allowed after Sponso) approval, and
- •Alkaline phosphatase ≤2.5×ULN.
- •Phase 2 ONLY: Have histologically confirmed Grade 4 astrocytoma, IDHm (per 2021 WHO criteria). Those who meet the Grade 4 designation via homozygous deletion of CDKN2A/B are eligible.
- •Phase 2 ONLY: Have absence of 1p19q co-deletion (i.e., non-co-deleted, or intact) and/or documented loss of nuclear ATRX expression or ATRX mutation by local testing.
- •Phase 2 ONLY: Have received SOC RT with concurrent TMZ (RT-TMZ) before enrollment. Study treatment must begin no more than 6 weeks after completion of RT-TMZ.
- •Have documented IDH1 or IDH2 mutation based on local testing of tumor tissue by an accredited laboratory.
- •Have adequate renal function, defined as a creatinine clearance ≥40 mL/min based on the Cockcroft-Gault glomerular filtration rate estimation
- •Have adequate bone marrow function as evidenced by: - Absolute neutrophil count ≥1,500/mm3 or 1.5×109/L - Hemoglobin ≥9 g/dL or 90 g/L - Platelets ≥100,000/mm3 or 100×109/L
- •Have recovered from any clinically relevant toxicities associated with previous anticancer therapy unless they are stable and manageable per Investigator’s judgment.
- •Have expected survival of ≥3 months.
- •KPS ≥70 at the start of study treatment.
- •Participants on corticosteroids for reasons related to glioma must be on a stable or decreasing dose (≤4mg/day dexamethasone or equivalent) for ≥5 days before the start of study treatment.
- •Female participants of reproductive potential must have a negative serum pregnancy test before starting study treatment. Female participants of reproductive potential are defined as having had onset of their first menstrual period and have not undergone a hysterectomy or bilateral oophorectomy or are not naturally postmenopausal (i.e., have not menstruated in the preceding 24 consecutive months).
排除标准
- •Unable to swallow oral medication.
- •Have significant active cardiac disease within 6 months before Screening, including New York Heart Association (NYHA) Class III or IV congestive heart failure, myocardial infarction, unstable angina, and/or stroke.
- •Have heart rate corrected QT interval (using Fridericia's formula) (QTcF) ≥450 msec or have other factors that increase risk of QT prolongation or arrhythmic events (e.g., heart failure, hypokalemia, family history of long QT interval syndrome). Right bundle branch block and prolonged QTcF interval may be permitted based on local cardiology assessment.
- •Are taking medications that are substrates of CYP2C19 or CYP3A with a narrow therapeutic index or taking medications that are strong CYP1A2 inhibitors. Participants should be transferred to other medications before receiving the first dose of study treatment"
- •Have known active hepatitis B (HBV) or hepatitis C (HCV) infections, known positive human immunodeficiency virus (HIV) antibody results, or acquired immunodeficiency syndrome (AIDS) related illness. Participants with a sustained viral response to HCV treatment will be permitted. Participants with chronic HIV that is adequately suppressed per institutional practice will be permitted. Participants with evidence of prior HBV infection will be excluded.
- •Phase 1b ONLY: For participants receiving TMZ in the frontline post-RT adjuvant setting: Have progressive disease during RT or after completion of SOC RT and before the start of study treatment.
- •Phase 1b ONLY: For participants receiving TMZ in the recurrent disease setting: Have received prior systemic anti-cancer therapy (other than surgery) within 1 month (or 6 weeks for nitrosoureas and 6 months for TMZ) of the start of study treatment. In addition, the first dose of study treatment should not occur before a period of 28 days or ≥5 half-lives of any prior investigational agent have elapsed, whichever is longer. Have received more than one prior line of therapy for glioma (Note: prior RT + chemotherapy is considered one line of therapy)."
- •Had Grade ≥2 hepatic-related toxicity (AST, ALT, and/or bilirubin elevations) during prior systemic chemotherapy (for phase 1b) or during concurrent RT-TMZ (phase 2)
- •Had Grade 4 hematologic toxicity (excluding lymphopenia) that did not recover within 7 days during a prior course of TMZ
- •Phase 2 ONLY: Have received any other glioma-directed therapy other than surgery and SOC RT-TMZ
- •Phase 2 ONLY: Have progressive disease during RT-TMZ or after completion of SOC RT-TMZ
- •Are pregnant or breastfeeding.
- •"Are participating in another interventional study at the same time; participation in non-interventional registries or epidemiological studies is allowed."
- •Have leptomeningeal disease.
- •Have a known coagulopathy.
- •Received prior therapy with an IDH inhibitor, IDH-directed vaccine, or bevacizumab.
- •Have a history of another concurrent primary cancer, with the exception of:
- •curatively resected non-melanoma skin cancer, or
- •curatively treated carcinoma in situ. Participants with other previously treated malignancies are eligible provided they have been disease-free for 3 years at Screening.
- •Have a known diagnosis of replication repair-deficient glioma (e.g., a known diagnosis of constitutional mismatch repair deficiency or Lynch syndrome).
- •Have a known hypersensitivity to any of the components or metabolites of vorasidenib or TMZ.
结局指标
主要结局
DLTs (for Phase 1b only), incidence and severity of AEs, SAEs, and AESIs
DLTs (for Phase 1b only), incidence and severity of AEs, SAEs, and AESIs
Progression-free Survival (PFS) status at 12 months
Progression-free Survival (PFS) status at 12 months
次要结局
- PFS, OS, OR, and clinical benefit (CR+ PR+SD)
- Plasma concentrations and PK parameters of vorasidenib and its metabolite AGI-69460 and TMZ
研究者
Clinical Studies Department
Scientific
Institut De Recherches Internationales Servier IRIS
研究点 (13)
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