A Phase 3, Multicenter, Double-Blind, Randomized, Placebo-Controlled Study of AG-120 in Combination with Azacitidine in Subjects * 18 Years of Age with Previously Untreated Acute Myeloid Leukemia with an IDH1 Mutation

Acute myeloid leukemia is an aggressive hematologic malignancy with a poor
prognosis. Patients not considered candidates for standard IC because of older
age with comorbid conditions, poor performance status, or disease-related
adverse prognostic risk factors have an especially poor prognosis with a median
survival of 2 to 10 months; these patients are commonly treated with BSC or low
intensity therapies such as LDAC or hypomethylating agents, including
azacitidine. Azacitidine, an analog of the pyrimidine nucleoside cytidine, is a
DNA methyltransferase inhibitor that has been shown to be associated with
sustained decreases in promoter DNA methylation and altered gene expression at
critical regulatory pathways. In addition, azacitidine is a cytotoxic agent.
Treatment with azacitidine has demonstrated clinical activity in AML and an
encouraging median OS of 9 to 10 months in patients not considered to be
eligible for standard IC.

Mutations of the IDH1 enzyme have been identified in several tumors, including
AML. The resulting mutant IDH proteins convert alpha ketoglutarate (*-KG) to
the oncometabolite 2-HG, which has been shown to cause DNA hypermethylation by
inhibition of methylcytosine dioxygenase TET2 and histone hypermethylation
through competitive inhibition of * KG dependent Jumonji-C histone
demethylases, thereby leading to broad epigenetic changes and a block in
myeloid differentiation. AG 120 is a specific inhibitor of IDH1 mutant protein;
nonclinical studies have demonstrated that AG-120 effectively inhibits the
activity of IDH mutant proteins leading to the reduction of 2-HG in tumors and
the reversal of IDH mutation-induced histone and DNA hypermethylation.
Preliminary clinical data from the ongoing, open-label, single-agent Phase 1
study in subjects with R/R AML (AG120-C-001) have shown that AG-120 is
generally well-tolerated and has triggered the differentiation of leukemic
blast cells that ultimately lead to reductions in mean plasma 2-HG
concentrations and evidence of substantial clinical activity.

These data raise the possibility that the combination of an inhibitor of the
IDH1 mutant protein with a DNA methyltransferase inhibitor such as azacitidine
may lead to an additive or synergistic antitumor effect. Azacitidine reduces
DNA methylation levels non-specifically, as it inhibits DNA methyltransferase
activity, while AG-120 indirectly reduces DNA methylation levels by depleting
2-HG and restoring enzyme function to *-KG-dependent enzymes. A synergistic
interaction between azacitidine and AG-120 could have a combined impact on DNA
methylation, either at the same DNA loci or potentially at different loci.
Furthermore, the combination of AG-120 + azacitidine has been shown to enhance
the differentiation and apoptosis of a leukemic cell line (TF-1) that harbors
an IDH1 R132 mutation.

Primary Objective:
* To compare event-free survival (EFS) between AG-120 + azacitidine and
placebo + azacitidine.

Key Secondary Objectives:
* To compare the complete remission (CR) rate between AG-120 + azacitidine and
placebo + azacitidine. EFS is defined as the time from randomization until the
occurrence of death from any cause, disease relapse after remission or MLFS,
progressive disease, or failure to achieve complete remission (CR) or CR with
incomplete hematologic (neutrophil and/or platelet) recovery (CRi) (including
CR with incomplete platelet recovery [CRp]) at 24 weeks, whichever occurs
first, based on responses assessed by the Investigator. Remission is defined as
CR or CRi (including CRp). If a subject fails to achieve CR or CRi (including
CRp) at 24 weeks, the subject will be considered as an EFS event at that time.
EFS will be censored in the event of initiation of a new anticancer therapy
should it occur prior to any EFS event.
* To compare overall survival (OS) between AG-120 + azacitidine and placebo +
azacitidin. CR is defined as: bone marrow blasts < 5% and no Auer rods; absence
of extramedullary disease; absolute neutrophil count (ANC) > 1.0 × 109/L
(1000/µL); platelet count > 100 × 109/L (100,000/µL); and independence of red
cell transfusions.
* To compare the CR (based on Investigator-assessed IWG Response Criteria for
AML) + complete remission with partial hematologic recovery (CRh) rate between
AG-120 + azacitidine and placebo + azacitidine. CRh is defined as a CR with
partial recovery of peripheral blood counts (< 5% bone marrow blasts, platelets
> 50,000/µL, ANC > 500/µL) and will be derived by the Sponsor.
* To compare the objective response rate (ORR) between AG-120 + azacitidine and
placebo + azacitidine, as assessed by the Investigator. ORR is defined as the
rate of CR, complete remission with incomplete hematologic (neutrophil and/or
platelet) recovery (CRi, including complete remission with incomplete platelet
recovery [CRp]), partial remission (PR), and morphologic leukemia-free state
(MLFS). The best response is calculated using the following hierarchy: 1) CR;
2) CRi (including CRp); 3) PR; and 4) MLFS.

Study AG120-C-009 is a global, Phase 3, multicenter, double-blind, randomized,
placebo-controlled clinical trial to evaluate the efficacy and safety of AG-120
+ azacitidine vs placebo + azacitidine in adult subjects with previously
untreated IDH1m AML who are considered appropriate candidates for non intensive
therapy.

The primary endpoint of OS is defined as the time from date of randomization to
the date of death due to any cause. The key secondary efficacy endpoints are
EFS, CR rate, CR + CRh rate (with CRh derived by Sponsor), and ORR.
Following provision of signed informed consent, all subjects will undergo
Screening procedures within 4 weeks (28 days) prior to randomization to
determine eligibility. Gene mutation analysis for confirmation of IDH1m disease
from a bone marrow and/or peripheral blood sample and germ-line mutation
analysis from a buccal swab will be conducted for all subjects, and can be
conducted prior to the 28-day Screening window. Central laboratory confirmation
of IDH1m status is required for study entry. Additional Screening procedures
include, but are not limited to: medical and medication history; bone marrow
aspirate/biopsy for morphologic analyses and cytogenetics; complete physical
examination; vital signs; 12 lead electrocardiogram (ECG); Eastern Cooperative
Oncology Group (ECOG) performance status (PS); echocardiogram (ECHO) or
multi-gated acquisition (MUGA; not permitted for subjects in Germany) scan for
left ventricular ejection fraction (LVEF); clinical laboratory assessments
(hematology, chemistry, coagulation, and serum pregnancy test); quality of life
(QoL) assessments; and exploratory biomarker assessments.

Subjects eligible for study treatment based on Screening assessments will be
randomized 1:1 to receive oral AG-120 or matched placebo, both administered in
combination with subcutaneous (SC) or intravenous (IV) azacitidine.
Randomization will be stratified by de novo status (de novo AML and secondary
AML) and geographic region (United States/Canada; Western Europe, Israel, and
Australia; and rest of world [ROW]).
Subjects should be treated for a minimum of 6 cycles of combination therapy
unless they experience relapse after achieving a CR, CRi (including CRp), or
MLFS; disease progression after having previously attained PR or stable
disease; unacceptable toxicity (adverse event); confirmed pregnancy; withdrawal
by subject; physician*s decision to end treatment; protocol violation; death;
or End of Study.

Treatment will be administered as follows:
* All subjects will receive azacitidine 75 mg/m2/day SC or IV for the first 1
week (7 days) (or on a 5 2-2 schedule) of each 4-week (28-day) cycle in
combination with AG 120 or placebo once daily (QD) on each day of the 4-week
cycle. The same schedule should be used for each subject throughout the
duration of treatment, when possible.
* Subjects should continue to receive therapy with AG 120 or placebo +
azacitidine until death, disease relapse, disease progression, development of
unacceptable toxicity (adverse event), confirmed pregnancy, withdrawal by
subject, physician*s decision to end treatment, protocol violation, or End of
Study.
o Disease progression (defined only for subjects who have previously attained
PR or stable disease) is defined as evidence for an increase in bone marrow
blast percentage and/or increase of absolute blast counts in the blood: 1) >
50% increase in bone marrow blast count over baseline (a minimum 15% point
increase is required in cases with < 30% blasts at baseline); or persistent
marrow blast percentage of > 70% over at least 3 months; without at least a
100% improvement in ANC to an absolute level (> 500/µL, and/or platelet count
to > 50,000/µL non-transfused); 2)> 50% increase in peripheral blasts (WBC × %
blasts) to > 25,000/µL in the absence of treatment-related differentiation
syndrome; or 3) new extramedullary disease. All bone marrow blasts, peripheral
blood blasts, and extramedullary disease assessments should be confirmed by 2
consecutive assessments separated by at least 4 weeks.
o Subjects with a response less than CR or CRi (including CRp) at 24 weeks or
beyond can continue on treatment if demonstrating treatment benefit, defined as
any 1 of the following: 1) Transfusion-independence while on study treatment;
2) ANC > 500/µL; or 3) platelets > 50,000/µL.

All subjects will have the extent of their disease assessed by bone marrow
aspirate (and biopsy if standard of care) and peripheral blood samples at
Screening and Day 1 (± 7 days) of Week 9 and every eighth week thereafter
(Weeks 17, 25, etc.); at End of Treatment (EOT); every eighth week during EFS
follow-up; as clinically indicated; and/or any time that disease progression is
suspected. The disease assessment schedule should not be altered due to changes
in the start of treatment cycles (eg, in the case of a treatment interruption
that resulted in a delay to the start of subsequent cycles).

During treatment, response will be evaluated by the Investigator based on
modified IWG Response Criteria for AML and European LeukemiaNet (ELN)
guidelines to determine subject status and continuation on study treatment.
Investigator response assessments will be used for the analysis of all efficacy
endpoints, unless otherwise defined.

All subjects will undergo safety assessments throughout the treatment period,
to include physical examination, vital signs, ECOG PS, ECG, ECHO or MUGA for
LVEF as clinically indicated (method per institutional standard of care, with
the same method used for an individual subject throughout the study; sites in
Germany may only use ECHO), clinical laboratory assessments (hematology,
chemistry, and coagulation), and assessment of adverse events (AEs), AEs of
special interest (AESIs), serious AEs (SAEs), AEs leading to discontinuation or
death, and concomitant medication use. Toxicity severity will be graded
according to the National Cancer Institute Common Terminology Criteria for AEs
(NCI CTCAE) version 4.03.

Safety data will be reviewed regularly by an Independent Data Monitoring
Committee (IDMC) to ensure the safety of the combination therapy. These reviews
will occur after the first 6, 12, 24, and 36 subjects have completed 1 cycle of
therapy or discontinued, whichever should occur first. Thereafter, safety
reviews will be conducted approximately every 6 months until the study is
unblinded for the final efficacy analysis.
There are 2 planned interim analyses for OS. The first is a futility analysis
that will be performed when approximately 93 OS events have occurred
(approximately 26 months after the first subject is randomized). Consideration
to terminate the study will be based on evaluation by the IDMC of the overall
safety and efficacy data available at that time, including an observed hazard
ratio (HR) of OS > 1.05 (in favor of the placebo + azacitidine arm), based on
the gamma (*2) error spending function. The second interim analysis, for
superiority, will be performed when approximately 185 OS events have occurred
(approximately 39 months after the first subject is randomized). At this
interim analysis, the study could be stopped for efficacy reasons if the
observed HR of OS is * 0.691 (1 sided p value * 0.006) in favor of the AG-120 +
azacitidine arm, based on the O*Brien-Fleming alpha spending function using the
Lan-DeMets method. The overall enrollment period is expected to be
approximately 44 months and the study duration is expected to be approximately
54 months. The final analysis of OS will take place when 278 OS events have
occurred (approximately 54 months after the first subject is randomized).

All subjects are to undergo an EOT assessment within 1 week of their last dose
of study treatment (AG 120/placebo + azacitidine). If a subject discontinues
study treatment at a regularly scheduled visit, EOT assessments may be
performed at that visit. A post-treatment safety assessment is to be scheduled
4 weeks (± 3 days) after the last dose of study treatment. All subjects who
discontinue study treatment without experiencing any one of the following*
death, disease relapse, disease progression, failure to achieve CR or CRi
(including CRp) at 24 weeks, withdrawal of consent, or start of subsequent
anticancer therapy*will be followed every 8 weeks for EFS until the occurrence
of 278 OS events.
All subjects who are alive after an EFS event will be contacted every 8 weeks
for survival follow-up until death, withdrawal by subject, subject completed
study, physician*s decision to end treatment, or loss to follow-up, or until
278 OS events have occurred.

AG-120 (500 mg) or matched placebo will be administered orally QD
(approximately every 24 hours) during Weeks 1 to 4 in continuous 4 week (28
day) cycles. Subjects may take AG-120 or placebo tablets with or without food.
Subjects should be advised that if AG-120/placebo tablets are taken with food,
they should avoid consuming a high-fat meal. All subjects will also be advised
to avoid grapefruit and grapefruit products.
Azacitidine will be administered SC or IV at a dose of 75 mg/m2/day for 1 week
every 4 weeks until the end of the study (unless they are discontinued from
treatment), starting on Day 1 (± 3 days). In the event that 2 or fewer doses
are missed during the 7 day dosing period, dosing should continue so that the
subject receives the full 7 days of therapy. If 3 or more doses are missed
during the 7 day dosing period, the Investigator should contact the Medical
Monitor and a decision on dosing will be made on an individual case basis. A
full 7 days of azacitidine are required, but as per institutional practice, a
schedule of 5 days of daily dosing, followed by no dose received on the weekend
and 2 daily doses given again at the start of the next week, is allowed. The
same schedule should be used for each subject throughout the duration of
treatment, when possible.
On days when both AG-120/placebo and azacitidine are given, AG 120/placebo will
be given prior to azacitidine.

The required study drug can cause side effects.
- Risks (adverse events) related to Vidaza (Azacitidine) are described in the
SmPC Vidaza.
- Risks (adverse events) related to AG-120 are described in the Investigator
Brochure AG-120 section 6.5 Potential risks.

Blood Drawing Risks
During this study, small amounts of blood will be drawn from a vein to perform
tests that allow your doctors to see 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.

Bone Marrow Aspirate and/or Biopsy Risks
Risks associated with bone marrow aspirate and/or biopsy include pain, redness,
swelling, excessive bleeding, bruising or infection at the needle site. An
allergic reaction to the local anesthetic medication used to numb the skin over
the biopsy site may occur.
For more information about side effects and risks, ask your study doctor.

Exposure to radiation
Multigated Acquisition (MUGA) scan during the screening assessments involves
using radioactive markers. The total amount of radiation you will be exposed to
in this study is 10 mSv. To compare: the background radiation in the
Netherlands is ~2.5 mSv per year.
If you participate in scientific research involving exposure to radiation more
often, you should discuss with the investigator whether participation now would
be safe.
The radiation used during the study may lead to damage to your health. However,
this risk is small. We nevertheless advise you not to participate in another
scientific study involving exposure to radiation in the near future.
Examinations or procedures involving radiation for medical reasons are not a
problem.

Benefit
Isocitrate dehydrogenase 1 (IDH1) is a type of protein involved in normal cell
metabolism, the process of providing your body*s cells with energy. In certain
types of diseases such as AML, an abnormal form of the IDH1 protein is present
in the cancer cells. When IDH1 is present in this form, it produces too much
2-hydroxyglutarate (2-HG), which is a substance that is present in low levels
in normal cells. When too much 2-HG is present, it may prevent immature cells
from becoming normal functioning cells, which may result in leukemia.
AG-120 may block the abnormal IDH1 protein and may reduce 2-HG levels in
diseased cells to normal levels.

Cumulatively, as of 16 January 2020, an estimated 2,187 subjects/patients have
been exposed to 1 or more doses of ivosidenib (AG-120), with most
subjects/patients exposed in clinical studies and the post-marketed setting.
Ivosidenib (AG-120) has been given to approximately 171 healthy volunteers and
no serious side effects determined to be related to ivosidenib (AG-120) were
noted. In the clinical setting, 897 subjects have received ivosidenib (AG-120),
along with 189 subjects who have received ivosidenib in expanded/compassionate
use programs, investigator-sponsored studies, and partner studies.
Additionally, 1,101 patients received ivosidenib (AG-120) in the post-marketing
setting.