Trial Title:
Vorasidenib in Combination With Temozolomide (TMZ) in IDH-mutant Glioma
NCT ID:
NCT06478212
Condition:
IDH1-mutant Glioma
IDH2-mutant Glioma
Conditions: Official terms:
Glioma
Temozolomide
Conditions: Keywords:
IDH-mutant glioma
IDH mutation
vorasidenib
S95032
Phase 1/2
pediatric
Study type:
Interventional
Study phase:
Phase 1/Phase 2
Overall status:
Not yet recruiting
Study design:
Allocation:
Non-Randomized
Intervention model:
Sequential Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
Vorasidenib
Description:
To be taken by mouth once daily in 28-day cycles with no break between cycles
Arm group label:
Phase 1b: Vorasidenib and Temozolomide (TMZ)
Arm group label:
Phase 2: Vorasidenib recommended combination dose (RCD) and Temozolomide (TMZ)
Intervention type:
Drug
Intervention name:
Temozolomide (TMZ)
Description:
To be taken by mouth once daily for the first 5 days of each 28-day cycle, for a maximum
of 12 cycles
Arm group label:
Phase 1b: Vorasidenib and Temozolomide (TMZ)
Arm group label:
Phase 2: Vorasidenib recommended combination dose (RCD) and Temozolomide (TMZ)
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.
Criteria for 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
Gender:
All
Minimum age:
12 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
University of California Los Angeles
Address:
City:
Los Angeles
Zip:
90095
Country:
United States
Facility:
Name:
University of California, San Francisco (UCSF) School of Medicine
Address:
City:
San Francisco
Zip:
94143
Country:
United States
Facility:
Name:
University of Miami
Address:
City:
Miami
Zip:
33136
Country:
United States
Facility:
Name:
Massachusetts General Hospital
Address:
City:
Boston
Zip:
02114
Country:
United States
Facility:
Name:
Dana Farber Cancer Institute
Address:
City:
Boston
Zip:
02215
Country:
United States
Facility:
Name:
Memorial Sloan Kettering Cancer Center
Address:
City:
New York
Zip:
10065
Country:
United States
Facility:
Name:
Duke University Medical Center
Address:
City:
Durham
Zip:
27710
Country:
United States
Facility:
Name:
MD Anderson Cancer Center
Address:
City:
Houston
Zip:
77030
Country:
United States
Facility:
Name:
Medical University of Vienna - AKH
Address:
City:
Vienna
Zip:
01090
Country:
Austria
Facility:
Name:
West China Hospital of Sichuan University
Address:
City:
Chengdu
Zip:
610041
Country:
China
Facility:
Name:
Beijing Tiantan Hospital, Capital Medical University
Address:
City:
Beijing
Zip:
100050
Country:
China
Facility:
Name:
Huashan Hospital, Fudan University
Address:
City:
Shanghai
Zip:
200040
Country:
China
Facility:
Name:
Hôpital Pierre Wertheimer
Address:
City:
Lyon
Zip:
69003
Country:
France
Facility:
Name:
Hôpital Pitié-Salpêtrière
Address:
City:
Paris
Zip:
75013
Country:
France
Facility:
Name:
IUCT-Oncopole Institut Universitaire du Cancer
Address:
City:
Toulouse
Zip:
31059
Country:
France
Facility:
Name:
Universitätsklinikum Heidelberg
Address:
City:
Heidelberg
Zip:
69120
Country:
Germany
Facility:
Name:
Medizinische Fakultät Mannheim, Universität Heidelberg
Address:
City:
Mannheim
Zip:
68167
Country:
Germany
Facility:
Name:
Universitätsklinikum Regensburg
Address:
City:
Regensburg
Zip:
93053
Country:
Germany
Facility:
Name:
Rabin Medical Center - Davidoff Cancer Center
Address:
City:
Petah tikva
Zip:
4941492
Country:
Israel
Facility:
Name:
The Tel Aviv Sourasky Medical Center (TASMC) (Ichilov Hospital)
Address:
City:
Tel Aviv
Zip:
64239
Country:
Israel
Facility:
Name:
Instituto Clinico Humanitas IRCCS
Address:
City:
Rozzano
Zip:
20089
Country:
Italy
Facility:
Name:
IOV - Ospedale Busonera
Address:
City:
Padua
Zip:
35128
Country:
Italy
Facility:
Name:
Ospedale Molinette - Centro Oncologico Ematologico
Address:
City:
Turin
Zip:
10126
Country:
Italy
Facility:
Name:
Kumamoto University Hospital
Address:
City:
Kumamoto
Zip:
860-8556
Country:
Japan
Facility:
Name:
Kyoto University Hospital
Address:
City:
Kyoto
Zip:
606-8507
Country:
Japan
Facility:
Name:
Nagoya University Hospital
Address:
City:
Nagoya
Zip:
466-8550
Country:
Japan
Facility:
Name:
National Cancer Center Hospital
Address:
City:
Tokyo
Zip:
104-0045
Country:
Japan
Facility:
Name:
Erasmus MC
Address:
City:
Rotterdam
Zip:
503015
Country:
Netherlands
Facility:
Name:
H. Valle de Hebron
Address:
City:
Barcelona
Zip:
08035
Country:
Spain
Facility:
Name:
Hospital 12 de Octubre
Address:
City:
Madrid
Zip:
28041
Country:
Spain
Facility:
Name:
Christie Hospital
Address:
City:
Manchester
Zip:
M20 4BX
Country:
United Kingdom
Facility:
Name:
The Royal Marsden in Sutton
Address:
City:
Sutton
Zip:
SM2 5PT
Country:
United Kingdom
Start date:
December 2, 2024
Completion date:
January 2028
Lead sponsor:
Agency:
Institut de Recherches Internationales Servier
Agency class:
Other
Source:
Servier
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT06478212
