The primary objective of this study is to:• Determine the safety and tolerability of AG-120 and AG-221 when administered with induction and consolidation therapy in patients with newly diagnosed acute myeloid leukemia (AML) with an isocitrate…
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Brief title
Condition
- Leukaemias
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Safety Outcome Measures
Safety will be evaluated by:
• Dose-limiting toxicities (DLTs)
• Adverse events (AEs), serious adverse events (SAEs), and AEs leading to
discontinuation
• Safety laboratory test results, physical examination, vital signs, 12-lead
electrocardiograms (ECGs), left ventricular ejection fraction (LVEF), and
Eastern Cooperative Oncology Group (ECOG) performance status (PS)
• Drug exposure, including dose intensities and dose modifications
Secondary outcome
Pharmacokinetic and Pharmacodynamic Outcome Measures
The PK and PD profile of AG-120 and AG-221 will be evaluated by:
• Plasma concentrations and PK parameters of AG-120 or AG-221 and its major
metabolite, AGI-16903;
• 2-HG concentrations in plasma and bone marrow;
• PK/PD relationship of AG-120 or AG-221 and 2-HG in plasma.
Clinical Activity Outcome Measures
The clinical activity of AG-120 and AG-221 in combination with AML
induction and consolidation therapy will be evaluated by:
• Complete remission rate (CRR)
• Objective response rate (ORR), assessed by the Investigator, including
complete remission (CR), CR with incomplete hematologic recovery - neutrophil
and/or platelet (CRi [includes CR with incomplete platelet recovery (CRp)]),
partial remission (PR), and morphologic leukemia-free state (MLFS)
• Study Sponsor-derived CR + morphologic complete remission with partial
hematologic recovery (CRh) rate, defined as peripheral blood counts (< 5% bone
marrow blasts, platelets > 50,000/µL, ANC > 500/µL);
• Duration of response (DOR) and duration of CR (DOCR)
• Duration of CR + CRh
• Time to response (TTR) and time to CR (TTCR)
• Time to CR + CRh
• Event-free survival (EFS)
• Overall survival (OS)
Exploratory Outcome Measures
• Molecular MRD by IDH1 or IDH2 VAF
• MRD by multiparameter flow cytometry
• Evaluation of a variety of established and exploratory biomarkers for
morphologic, functional, metabolic, and biologic changes over the course of
treatment
• Plasma concentrations and PK parameters of the anthracyclines and their
metabolites.
Background summary
AG-120 and AG-221 are novel compounds that are potent inhibitors of IDH mutant
proteins (IDH1 and IDH2, respectively). Small molecule inhibition of the
mutant IDH protein represents a targeted approach to cancer treatment. Direct
inhibition of the gain-of-function activity of the IDH mutated protein is
intended to inhibit the production of the oncogenic metabolite 2-HG. AG-120
and AG-221 have been extensively evaluated in nonclinical studies and have
been shown to effectively inhibit the gain-of-function activity of the mutated
protein leading to >90% reduction of the potential oncometabolite 2-HG in
tumor.
Preliminary clinical data have shown the compounds to be safe and well
tolerated at the doses evaluated. Substantial reductions in mean plasma 2-HG
concentrations have been observed in patients treated with AG-120 and AG-221,
as well as evidence of clinical activity.
This Phase 1 study is designed to determine if AG-120 and AG-221 are safe and
show clinical activity in patients when administered with AML induction and
consolidation therapy, and to determine the recommended phase 2 dose (RP2D)
for combination treatment.
Study objective
The primary objective of this study is to:
• Determine the safety and tolerability of AG-120 and AG-221 when administered
with induction and consolidation therapy in patients with newly diagnosed acute
myeloid leukemia (AML) with an isocitrate dehydrogenase-1 (IDH1) and/or
isocitrate dehydrogenase-2 (IDH2) mutation.
Secondary objectives of this study are to:
• Characterize the pharmacokinetics (PK) of AG-120 and AG-221 in plasma samples
when administered with AML induction therapy and consolidation therapy;
• Establish the recommended Phase 2 dose (RP2D) of AG-120 and AG-221 when
administered with AML induction and consolidation therapy;
• Evaluate 2-hydroxyglutarate (2-HG) levels in plasma;
• Evaluate the clinical activity of AG-120 and AG-221 in combination with AML
induction and consolidation therapy.
Exploratory objectives of this study are to:
• Evaluate the PK and pharmacodynamic (PD) relationship of AG-120 or AG-221 and
2*HG inhibition in plasma;
• Evaluate the PK of the anthracyclines and their metabolites in plasma when
administered with AG-120 or AG-221;
• Characterize the effects of AG-120 and AG-221 (when administered with
induction and consolidation therapy) in AML by the assessment of changes in
cellular differentiation and changes in methylation profiles of IDH1- and/or
IDH2-mutated and wild-type leukemic cells;
• Evaluate gene mutation status, global gene expression profiles, and other
potential prognostic markers (eg, cytogenetics) in IDH1- and/or IDH2-mutated
leukemic cells and plasma, as well as populations of IDH wild-type leukemic
cells, to explore predictors of anti- leukemic activity and/or resistance;
• Evaluate minimal residual disease (MRD)/leukemic stem cells (LSCs) using
multiparameter flow cytometry (MFC) and molecular techniques;
• Assess IDH1 or IDH2 variant allele fraction (VAF) in blood or bone marrow
samples before and after induction, treatment, and consolidation cycles.
Study design
AG120-221-C-001 is an open-label, multicenter, Phase 1 clinical trial to
evaluate the safety of AG-120 and AG-221 in combination with AML induction and
consolidation therapy. The study will evaluate up to 2 dose levels of AG-120
in subjects with an IDH1 mutation and up to 2 dose levels of AG-221 in subjects
with an IDH2 mutation. AG-120 or AG-221 will be administered with
2 types of AML induction therapies (cytarabine with either daunorubicin or
idarubicin) and 2 types of AML consolidation therapies (mitoxantrone with
etoposide [ME] or cytarabine). For subjects who have a dual IDH1 and IDH2
mutation, assignment to AG-120 or AG-221 will be based on Investigator and
study sponsor decision.
Intervention
A single dose of AG-120 or AG-221 will be administered orally starting on Day 1
of induction prior to daunorubicin/idarubicin and cytarabine and will be
administered daily through treatment discontinuation or end of study.
Alternative dosing schedules of AG-120 or AG-221 in induction and consolidation
cycles (e.g. starting AG-120 or AG-221 after anthracycline administration in
induction is complete) may be explored with study sponsor approval. Doses of
AG-120 or AG-221 must be taken within ±4 hours before or after of the scheduled
dose at approximately the same time each day. Each AG-221 daily dose should be
taken 2 hours after fasting (water is allowed), and food intake should be
avoided for at least 1 hour after administration of AG-221. Subjects may take
AG-120 tablets with or without food. Subjects should be advised that if AG-120
tablets are taken with food, they should avoid consuming a high-fat meal.
Subjects should be instructed to swallow tablets whole and to not chew the
tablets. All subjects are advised to avoid grapefruit and grapefruit products.
The dose of AG-120 administered to subjects with IDH1 mutation will be 500 mg
(unless there is a dose reduction to 250 mg due to DLTs, as described above).
The dose of AG-221 administered to subjects with an IDH2 mutation will be 100
mg (unless there is a dose reduction to 50 mg due to DLT's). No intra- patient
dose escalation will be permitted during induction or consolidation therapy for
AG-120 or AG-221.
Subjects who continue onto maintenance therapy following consolidation may
receive single-agent AG-120 or AG-221 daily for up to 2 year from Day 1 of the
first induction cycle or until relapse, development of an unacceptable toxicity
or HSCT. Subjects will continue on treatment at their current dose.
Alternative dosing schedules for AG-120 or AG-221, including administration of
the different dosing schedules in concurrent cohorts, may be explored as agreed
upon by the Clinical Study Team.
Study burden and risks
Burden:
The subject will need to make additional visits to the clinic, follow the
instructions for participation in the trial and have additional trial
procedures/tests.
Risks:
AG-120 Side Effects
AG-120 has been given to experimental animals to find out what possible side
effects might be expected when given to people. AG120 has also been given to a
total of 66 healthy volunteers and no serious side effects were noted. AG-120
has also been studied in about 412 patients with cancers.
AG-120 may cause changes in the electrical activity of the heart called QT
prolongation. QT prolongation can cause irregular heartbeats that can be
life-threatening.
AG-120 alone has been given to patients with advanced blood cancers in a
clinical study. A notable side effect of AG-120 is Differentiation syndrome,
which has been described with other targeted agents for leukemia.
Differentiation syndrome is a condition which may include one or more of the
following symptoms: unexplained fever, shortness of breath, high white blood
cells 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.
Additional serious and possibly life-threatening side effects may include
weakness, loss of muscle function, numbness, tingling or burning caused by
damage to nerves and the nervous system.
The following information applies to patients being treated for advanced blood
cancers only: Tumor Lysis Syndrome (TLS) has occurred in patients receiving
AG-120. TLS results from the rapid breakdown of cancer cells in response to
treatment. This can result in problems with many of the body*s normal functions
and may cause weakness, low blood pressure, muscle cramps, kidney damage,
irregular heartbeat and/or other organ damage. TLS can be life-threatening.
Some patients have experienced elevations of liver function tests. Abnormal
liver function tests may mean that your liver is not functioning properly and
may be associated with fatigue, and jaundice (yellowing of the skin and eyes).
Side effects reported very commonly (occurred in 10% or greater in patients) in
the advanced blood cancers clinical study are listed below.
• fatigue (very tired)
• diarrhea
• nausea
• increase in number of white blood cells (blood cells that help fight
infection)
• fever and fever with very low white blood cell counts
• swelling of arms and legs
• a decrease in number of red blood cells in blood which may make you feel weak
or tired (anemia)
• shortness of breath
• constipation
• pain in joints
• vomiting
• cough
• decreased appetite
• rash
• weakness
• pneumonia
• low blood pressure
• mouth sores
• a decrease in number of platelets (blood cells that help with clotting)
Frequently serious (may require hospitalization) side effects occurring in more
than 5 % of the patients who took AG-120 in the advanced blood cancers study:
• Increase in number of white blood cells (blood cells that help fight
infection)
• Fever and fever with very low white blood cell counts
• Pneumonia
• A severe infection throughout the body (sepsis)
Other serious side effects included respiratory failure (2.5%) and low blood
pressure (3.4%).
AG-120 alone has been given to patients with solid tumors, including glioma (a
type of brain cancer). Side effects reported very commonly (occurred in 10% or
greater in patients) in this clinical study are listed below.
• nausea
• fatigue
• diarrhea
Other side effects that occurred in less than 10% of patients in the solid
tumors, including glioma study included:
• vomiting
• a decrease in number of red blood cells in blood which may make you feel weak
or tired (anemia)
• headache
• abdominal pain
• build-up of fluid in the abdomen
• low sodium counts (a type of body salt or chemical that helps control blood
pressure and the function of muscles and nerves)
Long- term (28-day) safety studies have been conducted in two non-human species
to further understand any potential side effects that may be relevant to
humans. A thorough plan is outlined in this study to identify and treat any
expected and/or unexpected side effects that may emerge. Based on the 28-day
safety studies conducted, key functions that will be monitored include but are
not limited to:
• Heart rhythm and function
• Liver function
• Kidney function
• Bone Marrow Function: White blood cell, red blood cell, and platelet counts
The effects of AG-120 when combined with medications, food or alcohol are not
known. Please discuss with your study doctor the use of alcohol or any drugs
(over the counter, prescription, illegal) with your study doctor prior to
taking AG-120. You should avoid consuming grapefruit or drinking grapefruit
juice while taking AG-120.
AG-221 Side Effects
Differentiation Syndrome (very common or greater than 10% chance this will
happen):
Differentiation syndrome has only been reported in subjects with blood cancers
and was not observed in subjects with other types of cancers or in healthy
volunteers.
Symptoms of differentiation syndrome include shortness of breath (dyspnea) or
difficulty breathing that might require supplemental oxygen (respiratory
distress); fever (pyrexia), rash, swelling in legs (oedema peripheral), an
accumulation of fluid in lungs (pulmonary infiltrates), around the lungs
(pleural effusion) and around the heart (pericardial effusions), and increase
in blood creatinine (blood creatinine increase). This syndrome is treated by
giving additional medication (steroids).
Leukocytosis not caused by infections (very common, occurs in at least 1 in 10
people):
Leukocytosis has been reported in subjects with blood cancers who were treated
with enasidenib (AG221) and was not observed in subjects with other types of
cancers or in healthy volunteers. Leukocytosis is higher than normal amount of
white blood cells in your blood (cells that fight infection) which normally
occurs with infections. With this study medication, leukocytosis sometimes
occurred without any infection.
Tumor Lysis Syndrome (common, in at least 1 in 100 people):
Tumor Lysis Syndrome (TLS) has been reported in subjects with blood cancers
treated with enasidenib, and causes chemical abnormalities in your blood such
as higher than normal levels of potassium and phosphorus or low levels of
calcium with increase in uric acid levels (hyperuricaemia). Tumor Lysis
Syndrome can occur subsequent to Differentiation Syndrome. Tumor Lysis Syndrome
may affect kidney function and is treated with additional fluids (hydration) or
other medications.
Diarrhea, Nausea, Vomiting, Decreased Appetite, and Alterations in Taste (very
common, occurs in at least 1 in 10 people):
Diarrhea, nausea, vomiting, decreased appetite, and alterations in taste
(dysgeusia), were usually reported in the beginning of the treatment.
Increased blood bilirubin (very common occurs in at least 1 in 10 people):
The study drug slows breakdown of bilirubin (a liver lab test) in the blood,
causing higher than normal bilirubin blood levels (blood bilirubin increased)
that may cause skin yellowing. This condition is not due to liver damage and
usually does not required any additional treatment.
Other Very Common Side Effects (Greater than 10% chance this will happen):
Other very common side effects reported by subjects participating in clinical
trials are listed below. Currently, it isn*t known if these side effects are
caused by AG-221 or are effects related to cancers.
Very common side effects reported by subjects who have taken AG-221 in blood
cancer or other types o
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Age
Inclusion criteria
1. >=18 years of age
2. Previously untreated AML (de novo or secondary) defined according to
WHO criteria, excluding APL [AML with t(15;17)], with locally
documented IDH1 and/or IDH2 gene mutation scheduled for induction
therapy followed by consolidation therapy. Secondary AML is defined as
AML arising after MDS or another antecedent hematologic disorder (AHD) or AML
arising after exposure to genotoxic injury including radiation and/or
chemotherapy. Patients may have had previous treatment with
hypomethylating agents (HMAs) for MDS, provided that the last dose of
administration was >14 days prior to study drug initiation.
3. ECOG PS score of 0 to 2
4. Adequate hepatic function as evidenced by:
a. Serum total bilirubin <=1.5 × upper limit of normal (ULN) unless
considered due to Gilbert's disease, a gene mutation in UGT1A1 (only for
subjects who will be receiving AG-221), or leukemic involvement
following approval by the Medical Monitor
b. AST, ALT, and ALP <=3.0 × ULN, unless considered due to leukemic
involvement following approval by the study sponsor
5. Adequate renal function as evidenced by serum creatinine <=2.0 × ULN
or creatinine clearance >40 mL/min based on the Cockroft-Gault
glomerular filtration rate (GFR)
6. Agree to serial blood and bone marrow sampling
7. Meet any criteria necessary for the safe and proper use of the
induction and consolidation agents involved in this trial
8. Able to understand and willing to sign an informed consent form. A
legally authorized representative may consent on behalf of a subject
who is otherwise unable to provide informed consent, if acceptable to,
and approved by, the site's Institutional Review Board
(IRB)/Independent Ethics Committee (IEC)
9. Female subjects with reproductive potential must agree to undergo a
medically supervised pregnancy test prior to starting study drug. The
first pregnancy test will be performed at screening (within 7 days prior
to first study drug administration). A pregnancy test should also be
performed on the day of the first study drug administration and
confirmed negative prior to dosing as well as before dosing on Day 1 of
all subsequent cycles.
10. Female subjects with reproductive potential must have a negative
serum pregnancy test within 7 days prior to the start of the therapy.
Subjects with reproductive potential are defined as sexually mature
women who have not undergone a hysterectomy, bilateral oophorectomy
or tubal occlusion or who have not been naturally postmenopausal for at
least 24 consecutive months. Females of reproductive potential as well
as fertile men and their partners who are females of reproductive
potential must agree to abstain from sexual intercourse or to use one
highly effective form (for subjects receiving AG-221) or two highly
effective forms (for subjects receiving AG-120) of contraception from
the time of giving informed consent, during the study, and for 2 months
(for subjects receiving AG-221) and for 4 months (for subjects receiving
AG-120) following the last dose of AG-120 or AG-221 (females and
males). A highly effective form of contraception is defined as hormonal
oral contraceptives, injectables, patches, intrauterine devices, doublebarrier
methods (e.g., synthetic condoms, diaphragm or cervical cap
with spermicidal foam, cream, or gel) or male partner sterilization.
Exclusion criteria
1. Have received prior chemotherapy for AML. Hydroxyurea is allowed prior to
enrollment for the control of peripheral leukemic blasts in subjects with
leukocytosis; hydroxyurea may be allowed on study with study sponsor approval.
2. Taking medications with narrow therapeutic windows listed in
Appendix 15.6 (for subjects taking AG-221) or Appendix 15.7 (for subjects
taking AG-120), unless they can be transferred to other medications prior
to enrolling or unless the medications can be properly monitored during
the study.
3. Taking known strong cytochrome P450 (CYP) 3A4 inducers or
inhibitors unless they can be transferred to other medications prior to
enrolling. For subjects taking AG-120, systemic administration of a moderate or
strong CYP3A4 inhibitor requires careful monitoring of the heart rate-corrected
QT interval (QTc) interval using Fridericia*s formula (QTcF).
4. Taking P-glycoprotein (P-gp) or BCRP transporter-sensitive substrate
medications unless they can be transferred to alternative medications within
>= 5 half-lives prior to administration of AG-221, or unless the
medications can be properly monitored during the study. There are no
restrictions regarding the co-administration of such medications with AG-120.
5. Pregnant or breast feeding
6. Uncontrolled active infection or uncontrolled invasive fungal infection
(positive blood or tissue culture). An infection controlled with an
approved or closely monitored antibiotic/antifungal treatment is
allowed.
7. Prior history of malignancy, other than MDS or AML, unless the subject
has been free of the disease for >=1 year prior to the start of study
treatment. However, subjects with the following history/concurrent
conditions are allowed:
a. Basal or squamous cell carcinoma of the skin
b. Carcinoma in situ of the cervix
c. Carcinoma in situ of the breast
d. Incidental histologic finding of prostate cancer
8. Significant active cardiac disease within 6 months prior to the start of
study treatment, including New York Heart Association (NYHA) Class III
or IV congestive heart failure; myocardial infarction, unstable angina
and/or stroke; or LVEF <40% by echocardiogram (ECHO) or multi-gated
acquisition (MUGA) scan obtained within 28 days prior to the start of
study treatment
9. QTc interval >450 msec or other
factors that increase the risk of QT prolongation or arrhythmic events
(e.g., heart failure, hypokalemia, family history of long QT interval
syndrome). Bundle branch block and prolonged QTc interval are
permitted with approval of the study sponsor.
10. Taking medications that are known to prolong the QT interval unless
they can be transferred to other medications within >=5 half-lives prior to
dosing (If equivalent medication is not available QTc will be closely
monitored)
11. Known infection caused by human immunodeficiency virus (HIV) or active
hepatitis B or C
12. Dysphagia, short-gut syndrome, gastroparesis, or other conditions
that limit the ingestion or gastrointestinal absorption of orally
administered drugs
13. Clinical symptoms suggestive of active central nervous system (CNS)
leukemia or known CNS leukemia. Evaluation of cerebrospinal fluid (CSF)
during screening is only required if there is a clinical suspicion of CNS
involvement by leukemia during screening.
14. Immediate life-threatening, severe complications of leukemia such
as uncontrolled bleeding, pneumonia with hypoxia or shock, and/or
disseminated intravascular coagulation
15. Any other medical or psychological condition deemed by the
Investigator to be likely to interfere with a subject's ability to give
informed consent or participate in the 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 |
|---|---|
| EudraCT | EUCTR2015-004290-33-NL |
| ClinicalTrials.gov | NCT02632708 |
| CCMO | NL56481.078.16 |