This study has been transitioned to CTIS with ID 2024-512961-15-00 check the CTIS register for the current data. Primary:• The primary objective of the study is to demonstrate the efficacy of vorasidenib based on radiographic progression-free…
ID
Source
Brief title
Condition
- Nervous system neoplasms malignant and unspecified NEC
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary endpoint is PFS, defined as the time from date of randomization to
date of the first occurrence of radiographic PD by modified RANO-LGG assessed
by the BIRC or death from any cause, whichever occurs earlier. Progression-free
survival for subjects without centrally confirmed
radiographic PD by RANO-LGG by the BIRC or death will be censored at the date
of the last disease assessment. Censoring reasons also include start of a
subsequent anticancer therapy, withdrawal of consent from overall study
participation, and loss to follow-up.
The primary efficacy analysis will compare the PFS time between the 2 treatment
arms using a 1-sided stratified log-rank test. The test will be stratified by
1p19q status and baseline tumor size. A Cox proportional hazards (PH) model
stratified by randomization stratification factors will be used to estimate the
hazard ratio of PFS, along with its 95% CI.
Assuming a median PFS of 18 months for the placebo arm and a median PFS of 30
months for the vorasidenib arm, a total of 164 PFS events are required to
provide at least 90% power to detect a hazard ratio of 0.6 at a 1-sided alpha
of 0.025 level of significance using a log-rank test stratified by the
randomization stratification factors, and a 3-look group sequential design with
a Gamma family (-24) α-spending function to determine the efficacy boundaries
and a Gamma family (-5) β-spending function to determine the nonbinding
futility boundaries. Assuming a recruitment period of approximately 42 months,
and a 10% dropout rate in PFS at 12 months, approximately 340 subjects will
need to be randomized to the 2 treatment arms in a 1:1 ratio.
There are 3 planned analyses for PFS: an interim analysis for futility, an
interim analysis for superiority, and a final analysis. A small alpha will be
allocated to the PFS futility analysis based on the selected α-spending
function. The interim analyses for PFS will be performed based on FAS and will
take place after the target number of events has occurred as described below.
• Interim analysis 1 (IA1, futility only): will be conducted when approximately
55 PFS events (33.5% of the expected 164 events) have occurred
• Interim analysis 2 (IA2, superiority and futility): will be conducted when
all subjects are randomized and approximately 123 PFS events (75% of the
expected 164 events) have occurred.
• Final analysis (FA): will be conducted when all subjects are randomized and
164 PFS events have occurred.
Secondary outcome
Key secondary endpoint:
The key secondary endpoint is TTNI, defined as the time from randomization to
the initiation of the first subsequent anticancer therapy (including
vorasidenib, for subjects randomized to placebo who subsequently cross over) or
death due to any cause.
The secondary efficacy analysis will compare the TTNI between the 2 treatment
arms using a 1-sided stratified log-rank test. The test will be stratified by
1p19q status and baseline tumor size. A Cox PH model stratified by
randomization stratification factors will be used to estimate the hazard ratio
of TTNI, along with its 95% CI.
The sample size of 340 subjects will also allow an assessment for TTNI assuming
a 10% dropout rate for TTNI at 12 months. With an assumed median TTNI of 21
months for the placebo arm, a total of 152 TTNI events are required to provide
approximately 80% power to detect a hazard ratio of 0.636 at a 1-sided alpha of
0.025 level of significance using a log-rank test stratified by the
randomization stratification factors, and a 2-look group sequential design with
a Gamma family (-22) α-spending function to determine the efficacy boundaries.
To control the overall type I error rate at the 1-sided 2.5% level, the fixed
sequence testing procedure will be used to adjust for multiple statistical
testing of the primary endpoint and key secondary efficacy endpoint TTNI. These
endpoints will be tested in the following order:
• PFS per BIRC
• TTNI.
Other secondary endpoints:
Other secondary efficacy endpoints are TGR, objective response, CR+PR, time to
response, time to CR+PR, duration of response, duration of CR+PR, OS, FACT-Br
scores, and PFS by investigator.
Safety:
Safety will be evaluated by the incidence, severity, and type of adverse
events, and by evaluation of vital signs, KPS/LPPS, clinical laboratory
results, electrocardiograms, and LVEF data (as clinically indicated). All data
will be provided in by-subject listings. All safety data will be listed by
subject and summarized by treatment arm based on the Safety Analysis Set.
Pharmacokinetics:
Descriptive statistics of plasma concentrations (arithmetic and geometric
means, standard deviation, coefficient of variation [CV%], CV% geometric mean,
minimum, median and maximum) of vorasidenib and its metabolite AGI-69460 will
be summarized.
Background summary
There is a protein inside the cells called IDH (isocitrate dehydrogenase).
There are two main types of IDH in the body, called IDH1 and IDH2. Abnormal
changes in the protein (mutations) can be found in certain types of cancer
including glioma.
When IDH1 and/or IDH2 is mutated, it produces an excess amount of a substance
(2-HG). When 2-HG is present in excessive amounts, it results in changes within
the cells, which may result in glioma. As part of pre-screening, the tumor
tissue was tested to see if it was positive for IDH1 or IDH2 mutations. The
subject will only be enrolled in this study and given AG-881 or placebo if the
tumor tissue is positive for mutation in IDH1 or IDH2 and the subject meets the
other inclusion criteria required.
AG-881 is a new investigational drug in development by the Sponsor to
potentially treat patients with glioma. AG-881 is a drug that is designed to
block the abnormal IDH1 and IDH2 protein in cancer cells. Investigational means
that AG-881 has not been approved for use either alone or in combination with
any drug by any health authority. AG-881 may stop the abnormal IDH1 and/or IDH2
protein and lower the level of 2-HG.
Study objective
This study has been transitioned to CTIS with ID 2024-512961-15-00 check the CTIS register for the current data.
Primary:
• The primary objective of the study is to demonstrate the efficacy of
vorasidenib based on radiographic progression-free survival (PFS) per blinded
independent review committee (BIRC) compared with placebo in subjects with
residual or recurrent Grade 2 oligodendroglioma and astrocytoma with an IDH1 or
IDH2 mutation who have undergone surgery as their only treatment.
Key Secondary:
• To demonstrate the efficacy of vorasidenib based on time to next intervention
(TTNI) compared with placebo.
Other Secondary:
• To evaluate the safety and tolerability of vorasidenib
• To evaluate vorasidenib and placebo with respect to tumor growth rate (TGR)
as assessed by volume per the BIRC.
• To evaluate the efficacy of vorasidenib and placebo based on objective
response, complete response (CR) + partial response (PR), time to response,
time to CR+PR, duration of response, and duration of CR+PR with response
assessed per the BIRC and the Investigator.
• To evaluate vorasidenib and placebo with respect to overall survival (OS).
• To evaluate vorasidenib and placebo with respect to health-related quality of
life (HRQoL) as assessed by the Functional Assessment of Cancer Therapy - Brain
(FACT-Br) questionnaire.
• To evaluate vorasidenib and placebo with respect to PFS per the Investigator
assessment.
• To evaluate the pharmacokinetics (PK) of vorasidenib and its circulating
metabolite AGI-69460 in plasma.
Exploratory:
• To evaluate, for subjects who cross over from placebo to vorasidenib, the
time from first dose of vorasidenib to documented progression on vorasidenib,
as assessed by the Investigator or death due to any cause, whichever occurs
first.
• To evaluate TGR before and after treatment with vorasidenib among subjects
who cross over from placebo to vorasidenib.
• To evaluate HRQoL with vorasidenib and placebo as assessed by the EuroQol 5
Dimensions 5 Level (EQ-5D-5L) questionnaire and Patient Global Impression (PGI)
questions.
• To evaluate neurocognitive function in subjects receiving vorasidenib and
placebo as assessed by a validated battery of cognitive performance instruments.
• To evaluate seizure activity in subjects receiving vorasidenib and placebo.
• To evaluate the molecular and cellular markers that may be predictive of
response and/or resistance, where feasible, in blood and archival tumor tissue.
• To evaluate TGR before and after treatment with vorasidenib and placebo.
• To evaluate time to malignant transformation and radiographic changes
associated with histopathology-proven malignant transformation in subjects who
have surgery or biopsy as an intervention.
Study design
Subjects who meet all study eligibility criteria will be randomly assigned in a
1:1 ratio to receive AG 881 orally at a dose of 40 mg once daily (QD) or AG-881-
matched oral placebo QD. Randomization will be stratified by local 1p19q status
(co-deleted or not co-deleted) and baseline tumor size per local assessment
(longest diameter of >=2 cm or <2 cm). Starting with Cycle 1 Day 1 (C1D1),
dosing is continuous; there are no planned intercycle rest periods.
A BIRC will assess radiographic eligibility for study entry, the primary
efficacy endpoint of radiographic PFS per modified Response Assessment for
Neuro-Oncology for Low-Grade Gliomas (RANO-LGG) criteria, and the secondary
efficacy endpoint of TGR as assessed by tumor volume. The BIRC will also be
used to confirm radiographic disease progression (PD) by the Investigator to
permit unblinding and crossover. Radiographic disease assessment (by magnetic
resonance imaging [MRI]) for evaluation of disease response will be conducted
at specified time points throughout the study or at any time PD is suspected.
Target lesion selection and tumor response per RANO LGG criteria will be
performed by the institutional radiologist/Investigator. Scan acquisition
parameters required per protocol will be detailed in a separate site-specific
imaging core manual. All MRI scans will be sent to the BIRC as detailed in the
site-specific Imaging Core Manual.
Subjects who discontinue study treatment for reasons other than centrally
confirmed radiographic PD by the BIRC or withdrawal of consent from treatment
and overall study participation (and not just study treatment) will be followed
in PFS Follow-up until documented radiographic PD by BIRC or the initiation of
new anticancer therapy. Overall Survival Follow-up assessments will occur
approximately 6 months (±4 weeks) after End of Treatment (EOT). For subjects in
PFS Follow-up, OS Follow-up will begin once PFS Follow-up has ended. Overall
Survival Follow-up will continue for up to 5 years after the last subject is
randomized or until all subjects have died, withdrawn consent from overall
study participation, or are lost to follow-up or the Sponsor ends the study,
whichever occurs first.
Intervention
Investigational Product, Dosage, and Mode of Administration:
AG-881 40 mg QD will be taken orally by the subject on Days 1 to 28 in 28-day
cycles. Dosing is continuous; there are no planned intercycle rest periods.
Reference Therapy, Dosage, and Mode of Administration:
AG-881-matched placebo 40 mg QD will be taken orally by the subject on Days 1
to 28 in 28-day cycles. Dosing is continuous; there are no planned intercycle
rest periods.
Approximately 340 subjects are planned to be randomized 1:1 to receive AG-881
or AG-881-matched placebo.
Study burden and risks
What side effects or risks can I expect from being in the study?
You may have side effects while taking part in the study. Everyone taking part
in the study will be carefully monitored for any side effects. Since the study
drug is investigational, there may be other risks that are unknown. You should
talk to your study doctor if you have any side effects during the study or if
you want more information about the side effects.
Certain side effects are known to be caused by the use of vorasidenib
Abnormal liver tests (very common, occurred in 10% or greater)
Vorasidenib may affect your liver function. Your study doctor will check your
liver function with blood tests before you start taking vorasidenib and during
study treatment. It is important to tell your study doctor or site staff if you
have any liver disease.
Certain risks that may be caused by vorasidenib
Abnormal Heartbeat (an abnormal electrical condition of the heart (QT
Prolongation)) (common, occurred in 1% to less than 10%):
Vorasidenib alone or in combination with other certain drugs may cause changes
in the electrical activity of your heart. This change can cause irregular
heartbeats that can be life threatening. Your study doctor will do tests before
you start taking vorasidenib and during your study treatment with vorasidenib
to check the electrical activity of your heart. Other medications taken with
vorasidenib may increase your risk of an abnormal heartbeat, so be sure your
study doctor is aware of all medications, including over-the-counter
medications and dietary supplements, that you are taking at all times. Tell
your study doctor right away if you feel new chest pain or discomfort,
dizziness, or light headedness or if you feel faint.
Gastrointestinal disorders
Some animals given very high doses of vorasidenib developed ulcers of the
stomach and intestine. Similar events have not been seen in human subjects
taking vorasidenib. Inform your study doctor if you develop abdominal pain,
heartburn, nausea, or vomiting as these could be symptoms of a gastrointestinal
ulcer.
Nerve disorders
Animals given high doses of vorasidenib developed neurological disturbances
including, shaking (similar to tremors),impaired balance or coordination and
head tilt (holding head or neck in a twisted or otherwise abnormal position).
Inform your study doctor if you develop any similar neurological disturbance
symptoms.
Skin disorders
Animals receiving high doses of vorasidenibdeveloped skin peeling. Skin peeling
events have not been seen in human subjects taking vorasidenib. Inform your
study doctor if you develop any changes in your skin.
IDH Differentiation Syndrome
IDH Differentiation Syndrome is a condition that may include one or more of the
following symptoms: unexplained fever, shortness of breath, high white blood
cell counts (blood cells that fight infection), high platelet counts (blood
cells that help with clotting), and/or fluid in or around the lungs or heart.
You may require further medical intervention. Until now, this side effect was
only seen in patients with advanced blood cancer. The occurrence of IDH
differentiation syndrome side effect is very common in advanced blood cancer
subjects (occurred in 10% or greater) but has not occurred in any solid tumor
subjects.
Vorasidenib with other medications
You will be provided with a diary so that you can record details around taking
your study drug at home. It is important to fill out the diary and bring it
with you to every visit.
As the study goes on, if new risks are identified with vorasidenib, you will be
made aware of these risks by the study doctor or site staff and may be asked to
sign a new informed consent form.
The effects of vorasidenib when combined with medications, food, or alcohol are
not all known. Vorasidenib may change the amount of other drugs in your body or
the drugs you are taking may change the amount of vorasidenib in your body.
Please discuss with your study doctor the use of alcohol or any drugs (over the
counter, prescription, illegal) you are taking prior to taking vorasidenib.
Other Potential Risks Not Related to the Study Drug
Genetic testing
This research includes genetic testing. To protect your privacy, your genetic
samples are coded. But even without your name or other identifiers, your
genetic information is unique to you. The researchers believe the chance that
someone will identify you is very small, but the risk may change in the future
as people come up with new ways of tracking information.
There can be a risk in knowing genetic information. New health information
about inherited traits that might affect you or your blood relatives could be
found during a research study. Even though your genes are unique, you share
some of the same genes with your blood relatives. Health or genetic information
could be misused by employers, insurance companies, and others. For example, it
could make it harder for you to get or keep a job or insurance, or life
insurance companies may charge a higher rate based on this information.
Blood Drawing
During this study, small amounts of blood will be drawn from a vein to perform
tests that allow your study doctors to check how you are doing and to measure
the amounts of certain substances in your blood. Drawing blood may cause pain
where the needle is inserted, and there is a small risk of bruising and/or
infection at the place where the needle is inserted. Some people experience
dizziness, upset stomach, or fainting when their blood is drawn.
MRI
If you have metal or electronic devices in your body such as heart pacemakers,
implantable defibrillators, artificial limbs, or metal implants, you must
notify your study doctor prior to the MRI scans. The magnet of the MRI can
cause damage to the devices and the devices/ implants will distort the images.
You may be bothered by the MRI machine noise and by feelings of being closed in
(claustrophobia).
At some point during the MRI scan, the scanning procedure will be interrupted
so that you can be given a contrast agent through a needle in your arm. There
is a very minimal risk of discomfort, tingling or warmth in the lips, a
metallic taste in the mouth, tingling in the arm, nausea, and/or headache. If
these symptoms occur, these symptoms go away quickly. There is also a slight
risk of allergic reaction, vomiting, itching, and/or rash. The contrast agents
may also cause problems in subjects with kidney disease.
Biopsy Collection
A biopsy collection will require that you be hospitalized, and the procedure is
performed while you are under anesthesia. Risks associated with tumor biopsy
include pain, swelling, bleeding or blood clot formation, epileptic seizure,
bruising, infection, or reaction to anesthesia. Your study doctor, or site
staff, will complete a detailed review of the risks related to a tumor biopsy
with anesthesia and may ask you to sign a separate consent form related to this
procedure.
ECG
You may have mild irritation, slight redness, or itching at the sites on your
skin where the recording patches are placed.
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Age
Inclusion criteria
1. Be at least 12 years of age and weigh at least 40 kg.
3. Have Grade 2 oligodendroglioma or astrocytoma per WHO 2016 criteria.
4. Have had at least 1 prior surgery for glioma (biopsy, sub-total resection,
gross-total resection), with the most recent surgery having occurred at least 1
year (-1 month) and not more than 5 years (+3 months) before the date of
randomization, and no other prior anticancer therapy, including chemotherapy
and radiotherapy and not be in need of immediate chemotherapy or radiotherapy
in the opinion of the Investigator.
5. Have confirmed IDH1 (IDH1 R132H/C/G/S/L mutation variants tested) or IDH2
(IDH2 R172K/M/W/S/G mutation variants tested) gene mutation status disease by
central laboratory testing during the Prescreening period and available 1p19q
status by local testing (eg, fluorescence in situ hybridization [FISH],
comparative genomic hybridization [CGH] array, sequencing) using an accredited
laboratory.
6. Have MRI-evaluable, measurable, non-enhancing disease, as confirmed by the
BIRC, assessed at Screening on 2D T2-weighted or 2D T2-weighted
fluid-attenuated inversion recovery (FLAIR) MRI with <=4 mm slice thickness and
no interslice gap. Measurable non-enhancing disease is defined as at least 1
target lesion measuring >=1 cm × >=1 cm (bidimensional). Centrally confirmed,
minimal, non-nodular, and non-measurable enhancement that has not changed
between the 2 most recent scans (including screening scan) will be permitted.
7. Have a KPS (Appendix 11.7) score (for subjects >=16 years of age) or LPPS
(Appendix 11.6) score (for subjects <16 years of age) of >=80%.
8. Have expected survival of >=12 months.
9. Have adequate bone marrow function
10. Have adequate hepatic function
11. Have adequate renal function
12. Have recovered from any clinically relevant toxicities associated with any
prior surgery for the treatment of glioma unless stabilized under medical
management.
For the complete and extended list, see protocol section 4.2 Inclusion Criteria
Exclusion criteria
1. Have had any prior anticancer therapy other than surgery (biopsy, sub-total
resection, gross-total resection) for treatment of glioma including systemic
chemotherapy, radiotherapy, vaccines, small-molecules, IDH inhibitors,
investigational agents, laser ablation etc.
2. Have features assessed as high-risk by the Investigator, including brainstem
involvement either as primary location or by tumor extension, clinically
relevant functional or neurocognitive deficits due to the tumor in the opinion
of the Investigator (deficits resulting from surgery are allowed), or
uncontrolled seizures (defined as persistent seizures interfering with
activities of daily life AND failed 3 lines of antiepileptic drug regimens
including at least 1 combination regimen).
3. Concurrent active malignancy except for a) curatively resected nonmelanoma
skin cancer or b) curatively treated carcinoma in situ. Subjects with
previously treated malignancies are eligible provided they have been
disease-free for 3 years at Screening.
4. Are pregnant or breastfeeding.
5. Have an active infection that requires systemic anti-infective therapy or
with an unexplained fever >38.5°C within 7 days of C1D1.
6. Have a known hypersensitivity to any of the components of AG-881.
7. Have significant active cardiac disease within 6 months before the start of
study treatment, including New York Heart Association Class III or IV
congestive heart failure (Appendix 11.2), myocardial infarction, unstable
angina, and/or stroke.
8. Have LVEF <40% by echocardiogram (ECHO) (or by other methods according to
institutional practice) obtained within 28 days before the start of study
treatment.
9. Have a heart-rate corrected QT interval using Fridericia*s formula (QTcF)
>=450 msec or other factors that increase the risk of QT prolongation or
arrhythmic events (eg, heart failure, hypokalemia, family history of long QT
interval syndrome). Subjects with bundle branch block and prolonged QTcF are
permitted with approval of the Medical Monitor.
10. Are taking therapeutic doses of steroids for signs/symptoms of glioma.
Subjects taking physiologic doses (defined as equivalent of <=10 mg prednisone
daily) for medical conditions not related to glioma will be permitted.
11. Exclusion Criterion 11 removed in Protocol Amendment 1 (v2.0).
12. Are taking any medications that are CYP3A or CYP2C9 substrates with a
narrow therapeutic index as listed in Appendix 11.4. (Subjects should be
transferred to other medications before receiving the first dose of study drug.)
13. Have known active hepatitis B virus (HBV) or hepatitis C virus (HCV)
infection, known positive human immunodeficiency virus antibody results, or
AIDS-related illness. Subjects with a sustained viral response to HCV treatment
or immunity to prior HBV infection will be permitted. Subjects with chronic HBV
that is adequately suppressed by institutional practice will be permitted.
14. Have known active inflammatory gastrointestinal disease, chronic diarrhea,
previous gastric resection or lap band dysphagia, short-gut syndrome,
gastroparesis, or other condition that limits the ingestion or gastrointestinal
absorption of drugs administered orally. Gastroesophageal reflux disease under
medical treatment is allowed (assuming no drug interaction potential).
15. Have any other acute or chronic medical or psychiatric condition, including
recent (within 12 months of C1D1) or active suicidal ideation or behavior, or a
laboratory abnormality that may increase the risk associated with study
participation or investigational product administration or may interfere with
the interpretation of study results and, in the judgment of the Investigator,
would make the subject inappropriate for entry into this study.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EU-CTR | CTIS2024-512961-15-00 |
| EudraCT | EUCTR2019-002481-13-NL |
| ClinicalTrials.gov | NCT04164901 |
| CCMO | NL73641.056.20 |