Clinical trial NCT06478212: Vorasidenib in Combination With Temozolomide (TMZ) in IDH-mutant Glioma
Official title: A Phase 1b/2, Multicenter Study of Vorasidenib in Combination With Temozolomide (TMZ) in Participants With IDH1- or IDH2-mutant Glioma
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: IDH1-mutant Glioma
IDH2-mutant Glioma
Keywords: IDH-mutant glioma
IDH mutation
vorasidenib
S95032
Phase 1/2
pediatric
Lead sponsor: Servier
Sponsor class: INDUSTRY
First posted: 2024-06-27
Enrollment: 42
Sex: ALL
Minimum age (years): 12
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: The objective of this study is to determine the safety and tolerability of vorasidenib in combination with temozolomide (TMZ) and to establish the recommended combination dose (RCD) of vorasidenib. The study will begin as a Phase Ib study to determine the RCD and then will transition to a Phase II study to assess the clinical efficacy of vorasidenib at the RCD in combination with TMZ. During the treatment period participants will have study visits on day 1 and 22 of each cycle, with additional visits occurring during the first cycle of the Phase 1b study. Approximately 30 days after treatment has ended, a safety follow-up visit will occur and then participants will be followed for survival every 3 months. Study visits may include questionnaires, blood tests, ECG, vital signs, and a physical examination.


Eligibility criteria: Inclusion Criteria:

* Be ≥12 years of age with a weight at screening ≥40 kg.
* 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: (140 - Age) × (Weight in kg) × (0.85 if female) / 72 × serum creatinine (mg/dL).
* Have adequate bone marrow function as evidenced by:

  1. Absolute neutrophil count ≥1,500/mm3 or 1.5×109/L
  2. Hemoglobin ≥9 g/dL or 90 g/L
  3. Platelets ≥100,000/mm3 or 100×109/L
* Have expected survival of ≥3 months.
* KPS or LPPS ≥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.

Phase 1b ONLY:

* Have histologically confirmed Grade 2, 3 or 4 IDHm (as per WHO 2021) glioma (astrocytoma or oligodendroglioma).

  1. For oligodendroglioma: Have local testing at an accredited laboratory demonstrating presence of 1p19q co deletion
  2. 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
* 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:

  1. 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,
  2. AST and ALT ≤ULN, and
  3. 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.
* 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.
* 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 adequate hepatic function as evidenced by:

  1. Serum total bilirubin ≤1.5×ULN; if ≥1.5×ULN and due to Gilbert syndrome, total bilirubin ≤3×ULN with direct bilirubin ≤ULN,
  2. AST and ALT at or below the upper limit of normal. An elevation ≤1.5×ULN and considered not clinically significant by the Investigator may be allowed after Medical Monitor (Sponsor) approval, and
  3. Alkaline phosphatase ≤2.5×ULN.

Exclusion Criteria:

* Unable to swallow oral medication.
* 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:

  1. curatively resected non-melanoma skin cancer, or
  2. 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.
* 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.
* 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 or immunity to prior HBV infection will be permitted. Participants with chronic HBV or HIV that is adequately suppressed per institutional practice will be permitted.

Phase 1b ONLY:

* For those 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.
* For those receiving TMZ in the recurrent disease setting:

  1. 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.
  2. 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
* 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
* Have progressive disease during RT-TMZ or after completion of SOC RT-TMZ and before the start of study treatment.
* Had Grade 4 hematologic toxicity (excluding lymphopenia) that did not recover within 7 days during concurrent RT-TMZ
* Had Grade ≥2 hepatic-related toxicity (AST, ALT, and/or bilirubin elevations) during concurrent RT-TMZ

Primary outcomes:
measure: Phase 1b ONLY: Dose-limiting toxicities (DLTs)
timeFrame: Through cycle 1 (each cycle is 28 days)
measure: Number and severity of adverse events (AEs), serious adverse events (SAEs), and AEs of special interest (AESIs)
timeFrame: Through 30 days after the end of treatment (Approximately 3 years)
measure: Progression-free Survival (PFS) status at 12 months
timeFrame: 12 months after treatment initiation
Secondary outcomes:
measure: PFS
timeFrame: Through study completion (Approximately 3 years)
measure: Overall survival (OS)
timeFrame: Through study completion (Approximately 3 years)
measure: Objective response rate (ORR)
timeFrame: Through study completion (Approximately 3 years)
measure: Clinical benefit rate (CBR) (CR+partial response [PR]+stable disease [SD])
timeFrame: Through study completion (Approximately 3 years)
measure: Plasma concentration of vorasidenib and its metabolite AGI-69460
timeFrame: Through cycle 13 (each cycle is 28 days)
measure: Phase 1b ONLY: Plasma concentration of TMZ
timeFrame: Through cycle 2 (each cycle is 28 days)
measure: Area under the curve (AUC) of vorasidenib and its metabolite AGI-69460
timeFrame: Through cycle 13 (each cycle is 28 days)
measure: Time to maximum concentration (Tmax) of vorasidenib and its metabolite AGI-69460
timeFrame: Through cycle 13 (each cycle is 28 days)
measure: Maximum concentration (Cmax) of vorasidenib and its metabolite AGI-69460
timeFrame: Through cycle 13 (each cycle is 28 days)
measure: Trough concentration (Ctrough) of vorasidenib and its metabolite AGI-69460
timeFrame: Through cycle 13 (each cycle is 28 days)
measure: Phase 1b ONLY: Area under the curve (AUC) of TMZ
timeFrame: Through cycle 2 (each cycle is 28 days)
measure: Phase 1b ONLY: Time to maximum concentration (Tmax) of TMZ
timeFrame: Through cycle 2 (each cycle is 28 days)
measure: Phase 1b ONLY: Maximum concentration (Cmax) of TMZ
timeFrame: Through cycle 2 (each cycle is 28 days)
measure: Phase 1b ONLY: Trough concentration (Ctrough) of TMZ
timeFrame: Through cycle 2 (each cycle is 28 days)
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: University of California Los Angeles
state: California
city: San Francisco
country: United States
facility: University of California, San Francisco (UCSF) School of Medicine
state: California
city: Miami
country: United States
facility: University of Miami
state: Florida
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: Memorial Sloan Kettering Cancer Center
state: New York
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
city: Vienna
country: Austria
facility: Medical University of Vienna - AKH
city: Chengdu
country: China
facility: West China Hospital of Sichuan University
state: Sichuan
city: Beijing
country: China
facility: Beijing Tiantan Hospital, Capital Medical University
city: Shanghai
country: China
facility: Huashan Hospital, Fudan University
city: Lyon
country: France
facility: Hôpital Pierre Wertheimer
city: Paris
country: France
facility: Hôpital Pitié-Salpêtrière
city: Toulouse
country: France
facility: IUCT-Oncopole Institut Universitaire du Cancer
city: Heidelberg
country: Germany
facility: Universitätsklinikum Heidelberg
city: Mannheim
country: Germany
facility: Medizinische Fakultät Mannheim, Universität Heidelberg
city: Regensburg
country: Germany
facility: Universitätsklinikum Regensburg
city: Petah tikva
country: Israel
facility: Rabin Medical Center - Davidoff Cancer Center
city: Tel Aviv
country: Israel
facility: The Tel Aviv Sourasky Medical Center (TASMC) (Ichilov Hospital)
city: Rozzano
country: Italy
facility: Instituto Clinico Humanitas IRCCS
state: Milan
city: Padua
country: Italy
facility: IOV - Ospedale Busonera
city: Turin
country: Italy
facility: Ospedale Molinette - Centro Oncologico Ematologico
city: Kumamoto
country: Japan
facility: Kumamoto University Hospital
city: Kyoto
country: Japan
facility: Kyoto University Hospital
city: Nagoya
country: Japan
facility: Nagoya University Hospital
city: Tokyo
country: Japan
facility: National Cancer Center Hospital
city: Rotterdam
country: Netherlands
facility: Erasmus MC
city: Barcelona
country: Spain
facility: H. Valle de Hebron
city: Madrid
country: Spain
facility: Hospital 12 de Octubre
city: Manchester
country: United Kingdom
facility: Christie Hospital
city: Sutton
country: United Kingdom
facility: The Royal Marsden in Sutton
Study officials:
References: