This study has been transitioned to CTIS with ID 2024-511722-31-00 check the CTIS register for the current data. Phase 1b Dose-finding Stage Primary Objectives· To assess the safety and tolerability of the combination treatments of oral AG-120 when…
ID
Source
Brief title
Condition
- Leukaemias
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Efficacy
Secondary outcome
Safety
Plasma PK/PD of AG-120 and AG-221
Exploratory Biomarkers
Investigational product accountability
Background summary
The combination of inhibitors of IDH mutant proteins with a DNA
methyltransferase inhibitor such as azacitidine may lead to an additive or
synergistic antitumor effect. Furthermore, the combination of AG-221 and
azacitidine has been shown to enhance the differentiation and apoptosis of a
leukemic cell line (TF-1) that harbors an IDH2R140Q mutation.
Study objective
This study has been transitioned to CTIS with ID 2024-511722-31-00 check the CTIS register for the current data.
Phase 1b Dose-finding Stage
Primary Objectives
· To assess the safety and tolerability of the combination treatments of oral
AG-120 when administered with subcutaneous (SC) azacitidine and oral AG-221
when administered with SC azacitidine in subjects with newly diagnosed AML with
an IDH1 or an IDH2 mutation, respectively, who are not candidates to receive
intensive IC.
· To establish the recommended combination dose (RCD) of oral AG-120 and oral
AG-221 when administered with SC azacitidine.
Secondary Objective
• To assess the preliminary efficacy of the combination treatments of oral
AG-120 when administered with SC azacitidine and oral AG-221 when administered
with SC azacitidine in subjects with newly diagnosed AML with an IDH1 or an
IDH2 mutation, respectively, who are not candidates to receive intensive IC.
Phase 1b AG-120 Expansion Stage
Primary Objectives
· To assess the safety and tolerability of the combination treatments of oral
AG-120 when administered with SC azacitidine in subjects with newly diagnosed
AML with an IDH1 mutation who are not candidates to receive intensive IC.
Secondary Objective
• To assess the preliminary efficacy of the combination treatments of oral
AG-120 when administered with SC azacitidine in subjects with newly diagnosed
AML with an IDH1 mutation, who are not candidates to receive intensive IC.
• To characterize the pharmacokinetics (PK) of oral AG-120 when administered
with SC azacitidine.
Phase 2 AG-221 Randomized Stage
Primary Objective
· To assess the efficacy of oral AG-221 when administered with SC azacitidine
versus SC azacitidine alone in subjects with newly diagnosed AML with an IDH2
mutation, who are not candidates to receive intensive IC.
Secondary Objectives
· To evaluate the safety of oral AG-221 when administered with SC azacitidine.
· To characterize the PK of oral AG-221 when administered with SC azacitidine.
· To evaluate the effect of oral AG-221 when administered with SC azacitidine
versus SC azacitidine alone on health-related quality-of-life (HRQoL) outcomes.
Study design
This Phase 1b/2 study is an open-label, randomized, multicenter trial to
evaluate the safety and efficacy of oral AG-120 + SC azacitidine and oral
AG-221 + SC azacitidine in subjects with newly diagnosed AML with an IDH1 or an
IDH2 mutation, respectively. The study population consists of subjects who are
not candidates to receive intensive IC. The study comprises a Phase 1b
dose-finding and AG-120 expansion stage and a Phase 2 randomized stage.
Intervention
Phase 1b (Dose-finding and AG-120 Expansion) Stage:
Phase 1b dose finding will use a 3 + 3 design. For AG-120 one dose level will
be explored enrolling a minimum of 3 subjects. Cohort 1 will be initiated with
oral AG-120 500 mg once a day and azacitidine 75 mg/m2/day SC for 7 days of
each 28-day cycle starting on Day 1 of each cycle. A Cohort -1 will be
explored with AG-120 250 mg once a day and azacitidine 75 mg/m2/day SC for 7
days of each 28-day cycle if 2 or more subjects in Cohort 1 have a
dose-limiting toxicity (DLT) in cycle 1. Upon declaration of the RCD by the DRT
an expansion cohort of up to 15 patients will be enrolled at the RCD for
further safety evaluation and PK sampling.
For AG-221 two dose levels will be explored. Cohort 1 will be initiated with
oral AG-221 100 mg once a day and azacitidine 75 mg/m2/day SC for 7 days of
each 28-day cycle starting on Day 1 of each cycle. If no DLTs are observed,
the RCD will be confirmed by the DRT and the 100 mg dose will be used as the
starting dose for Phase 2 of the study. Dose escalation to Cohort 2 will be
initiated with oral AG-221 200 mg once a day and azacitidine 75 mg/m2/day SC
for 7 days of each 28-day cycle starting on Day 1 of each cycle to explore the
tolerability of AG-221 + SC azacitidine at this dose level. A Cohort -1 with
oral AG-221 50 mg daily and azacitidine 75 mg/m2/day SC for 7 days of each
28-day cycle starting on Day 1 of each cycle will be explored if 2 or more
subjects have a DLT in Cohort 1.
The DRT will evaluate all toxicities of each subject after 1 cycle and
determine whether further dose modifications are needed for individual subjects.
Phase 2 AG-221 Randomized Stage:
AG-221 + Azacitidine Arm (Arm 1):
· Subjects with an IDH2 mutation will receive AG-221 at the RCD orally QD on
Days 1-28 of each 28-day cycle + azacitidine 75 mg/m2/day SC for 7 days of each
28-day cycle.
Azacitidine Arm (Arm 2):
• Subjects with IDH2 mutation will receive azacitidine 75 mg/m2/day SC for 7
days of each 28-day cycle.
Study burden and risks
Burden
- Questionnaires: 1x per cycle and during EOT visit
- ECHO/MUGA scan: at least 1x
- ECG: 1x per cycle en during screening and EOT visit
- Blood sampling: every visit
- Bone marow aspiration/biopsy: 1x per cycle and during screening, EOT visit
and follow up
- Subcutaneous administration Azacitidine: Once daily, during 7 days per cycle
- 2 hours before and 1 hour after AG-120 or AG-221 administration, the patient
needs to be fasting. Water is allowed.
See also protocol section 5 (Table of Events).
AG-120
very common in blood cancer patients and solid tumor patients:
AG-120 may cause changes inthe electrical activity of your heart ( QT
prolongation)
Blood Cancers, common
-IDH Differentiation Syndrome: swelling in the arms or legs, an abnormally high
number of white blood cells circulating in the blood, unexplained fever,
shortness of breath, build-up of fluid around the lungs, low blood pressure, or
unexplained weight gain
-Leukocytosis is higher than normal amount of white blood cells in your blood
-Tumor Lysis Syndrome (TLS): weakness, low blood pressure, muscle cramps,
kidney damage, irregular heartbeat and/or other organ damage.
Risks that may or may not be caused by AG-120 treatment:
Both blood and solid cancer clinical studies: Very Common
Diarrhea; Nausea; Fatigue; Low number of red blood cells that can cause
tiredness and shortness of breath. May require a blood transfusion; Arm/leg
swelling; Fever; Decreased appetite; Constipation; Vomiting; Headache; Low
blood levels of magnesium (symptoms may include weakness, muscle cramps and/or
irregular heartbeat); Abdominal pain.
Blood cancer clinical studies: Very Common
Fever with dangerously low white blood cell counts Shortness of breath Cough
Low blood level of potassium (possible weakness); Joint pain; Dizziness; Nose
bleed; A low number of platelets, which may cause bleeding and bruising.
Bleeding may be serious or life threatening. Back pain; rash; Low blood
pressure (symptoms dizziness / fainting); Difficulty sleeping; Chest pain;
Build-up of fluid around the lungs (difficulty breathing or shortness of
breath); Itching; Mouth blisters/sores
In blood cancer clinical studies: Common (very serious)
Low white blood cell counts (increase the risk of infection. It may become
life-threatening. Symptomps: fever, pain, redness and/or difficulty
breathing); An abnormally high number of white blood cells; A serious condition
known as sepsis that occurs in response to an infection and causes widespread
inflammation, resulting in poor blood supply to vital organs Symptoms: fast
heart rate, fever, confusion, and rapid breathing.
Advanced blood cancer clinical studies: Very Common
An abnormally high number of white blood cells circulating in the blood;
increased risk of infection, such as pneumonia (an infection of the lungs). A
low number of white blood cells may increase the risk of infection. It may
become life-threatening. Symptoms of infection may include fever, pain, redness
and/or difficulty breathing. Loss of strength; High blood levels of uric acid
(possible painful joints and/or kidney failure); Arm/leg pain
AG-221
constipation; weight decrease; dizziness; feeling unwell, tired and weak
(asthenia and fatigue); back pain, abdominal pain, joint aches (arthralgia);
anxiety and difficulty sleeping (insomnia); headache; rash; decreased blood
pressure (hypotension); swelling in extremities (oedema peripheral); shortness
of breath (dyspnea); cough; lung infection (pneumonia); infection in the blood
(sepsis); decrease in number of red blood cells in blood which may make you
feel weak or tired (anemia); decrease in number of platelets which are cells
that help your blood clot (thrombocytopenia); nose bleeds (epistaxis), fever
with low number of white blood cells in blood that help fight infection
(febrile neutropenia); fever (pyexia), decrease kidney function (acute renal
failure and increased blood creatinine).
Azacitidine
• anemia (a decrease in the number of red blood cells which may make you feel
weak or tired)
• low number of white blood cells with or without fever
• a decrease in the number of platelets, the cells that help your blood to clot
• infections, including pneumonia or of the lung, mouth, skin, or urinary tract
(which may be bacterial, fungal or viral)
• nausea
• vomiting
• diarrhea
• stomach pain
• constipation
• feeling tired, unwell, or weak
• fever
• sore throat with swelling or pain of the nasal membranes or nose
• decreased appetite
• weight loss
• low blood levels of potassium
• pain (including muscle, joints, back, and chest pain)
• dizziness
• headache
• difficulty sleeping
• shortness of breath with or without exercise
• rash
• itchiness
• bruising, including, tiny red or purple spots under the skin or other tissue
• nosebleed
• injection site reaction, including itching, pain, rash, redness, bleeding,
bruising, swelling or damage where the injection/infusion was given
Morris Avenue 86
NJ Summit, NJ 07901
US
Morris Avenue 86
NJ Summit, NJ 07901
US
Listed location countries
Age
Inclusion criteria
Subjects must satisfy the following criteria to be enrolled in the study:
1. Subject is >= 18 years of age at the time of signing the informed consent
form (ICF).
2. Subject must understand and voluntarily sign an ICF prior to any
study-related
assessments/procedures being conducted.
3. Subject is willing and able to adhere to the study visit schedule and other
protocol
requirements.
4. Subject has newly diagnosed, primary (ie, de novo) or secondary (progression
of
MDS or myeloproliferative neoplasms [MPN], or therapy-related) AML according to
the
WHO classification (Appendix B) with >= 20% leukemic blasts in the bone marrow:
a. Have an IDH1 or IDH2 gene mutation (R132, R140, or R172)
o IDH mutational status will be assessed locally; for sites without local
testing
capabilities, a referral lab will be identified.
b. By the investigator*s assessment who are not candidates to receive intensive
IC.
5. Subject has an Eastern Cooperative Oncology Group (ECOG) performance status
of 0, 1
or 2 (Appendix D).
6. Subject has adequate organ function defined as:
• Serum aspartate aminotransferase/serum glutamic oxaloacetic transaminase
(AST/SGOT) and alanine aminotransferase (ALT/SGPT) <= 3 x ULN, unless
considered due to leukemic organ involvement.
• Serum total bilirubin < 1.5 x ULN. Higher levels are acceptable if these can
be
attributed to ineffective erythropoiesis, 3 times the upper limit of normal for
Gilbert*s
syndrome (eg, a gene mutation in UGT1A1), or leukemic organ involvement.
• Serum creatinine < 2 x ULN or creatinine clearance * 30 mL/min based on the
Modification of Diet in Renal Disease (MDRD) glomerular filtration rate (GFR):
GFR (ml/min/1.73 m2) = 175 x (Scr)-1.154 x (Age)-0.0203 x (0.742 if female) x
(1.1212 if African American)
7. Agree to serial bone marrow aspirate/biopsies.
8. Females of childbearing potential (FCBP)* may participate, providing they
meet the
following conditions:
• Agree to practice true abstinence or to use at least two highly effective
contraceptive methods (eg, combined [containing estrogen and progestogen] or
progestogen only associated with inhibition of ovulation, oral, injectable,
intravaginal, patch, or
implantable hormonal contraceptive; bilateral tubal occlusion; intra-uterine
device;
intrauterine hormone-releasing system; or male partner sterilization [note that
a vasectomized partner is a highly effective birth control method provided that
partner is the sole sexual partner of the FCBP trial participant and that a
vasectomized partner has received medical assessment of the surgical success])
at screening and
throughout the study, and for 4 months following the last study treatment; and
• Have a negative serum β-subunit of human chorionic gonadotropin (β-hCG)
pregnancy test (sensitivity of at least 25 mIU/mL) at screening; and
• Have a negative serum or urine (investigator's discretion under local
regulations) β-hCG pregnancy test (sensitivity of at least 25 mIU/mL)
within 72 hours prior to the start of study treatment in the Treatment Period
(note that
the screening serum pregnancy test can be used as the test prior to the start
of study
treatment in the Treatment Period if it is performed within the 72-hour
timeframe).
9. Male subjects (with a female partner of childbearing potential who must
agree to
conditions in criterion 8) must agree to practice true abstinence from sexual
intercourse or agree to the
use of highly effective contraceptive methods (as described above) with
non-pregnant female partneres of child bearing potential at screening and
throughout the course of
the study and should avoid conception with their partners during the course of
the study and for
4 months following the last study treatment (6 months following the last dose of
azacitidine in Canada). Furthermore, the male subject must agree to use a
condom while treated with azacitidine and for at least 4 months following the
last azacitidine dose.
Exclusion criteria
The presence of any of the following will exclude a subject from enrollment:
1. Subject is suspected or proven to have acute promyelocytic leukemia based on
morphology, immunophenotype, molecular assay, or karyotype.
2. Subject has AML secondary to chronic myelogenous leukemia (CML).
3. Subject has received a targeted agent against an IDH1 or IDH2 mutation.
4. Subject has received prior systemic anticancer therapy, HSCT, or
radiotherapy for AML.
Note that hydroxyurea is allowed prior to enrollment for the control of
peripheral leukemic blasts in subjects with leukocytosis (however,
hydroxyurea should not be given within 72 hours prior to and after
administration of azacitidine). For subjects with secondary AML (eg, MDS or
MPN) treatment for prior
cancer is not exclusionary; full treatment information will be collected within
the CRF. The use of all trans retinoic acid (ATRA) for suspected APL is not
exclusionary provided it is discontinued prior to initiation of treatment in
the protocol
5. Subject has received more than 1 cycle of prior treatment with azacitidine
or subject has received any prior treatment with decitabine for MDS.
6. Subject has or is suspected of having central nervous system (CNS) leukemia.
Evaluation of cerebrospinal fluid is only required if CNS involvement by
leukemia is
suspected during screening.
7. Subject has immediate life-threatening, severe complications of leukemia
such as
uncontrolled bleeding, pneumonia with hypoxia or shock, and/or disseminated
intravascular coagulation.
8. Subject has 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; acute coronary syndrome (ACS); and/or stroke; or left
ventricular ejection fraction (LVEF) < 40% by echocardiogram (ECHO) or
multi-gated
acquisition (MUGA) scan obtained within 28 days prior to the start of study
treatment.
9. Subject has prior history of malignancy, other than MDS, MPN, 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:
• Basal or squamous cell carcinoma of the skin
• Carcinoma in situ of the cervix
• Carcinoma in situ of the breast
• Incidental histologic finding of prostate cancer (T1a or T1b using the tumor,
node,
metastasis clinical staging system)
10. Subject is known seropositive for or has active viral infection with human
immunodeficiency virus (HIV), or active infection with hepatitis B virus (HBV)
or
hepatitis C virus (HCV)
11. Subject is known to have dysphagia, short-gut syndrome, gastroparesis, or
other
conditions that limit the ingestion or gastrointestinal absorption of drugs
administered
orally
12. Subject has uncontrolled hypertension (systolic blood pressure [BP] > 180
mmHg or
diastolic BP > 100 mmHg)
13. Subject is taking the following sensitive CYP substrate medications that
have a narrow
therapeutic range are excluded from the study unless the subject can be
transferred to
other medications at least 5 half-lives prior to the start of study treatment:
phenytoin
(CYP2C9), S-mephenytoin (CYP2C19), thioridazine (CYP2D6), theophylline, and
tizanidine (CYP1A2).
14. Subject is taking the breast cancer resistance protein (BCRP)
transporter-sensitive
substrate rosuvastatin; subject should be excluded from the study unless he/she
can be
transferred to other medications at least 5 half-lives prior to the start of
study treatment.
15. Subject has active uncontrolled systemic fungal, bacterial, or viral
infection (defined as
ongoing signs/symptoms related to the infection without improvement despite
appropriate antibiotics, antiviral therapy, and/or other treatment).
16. Subject has known or suspected hypersensitivity to any of the components of
study
therapy.
17. Subject is taking medications that are known to prolong the QT interval
unless he/she can be transferred to other medications within >= 5 half-lives
prior to the start of
study treatment. (If equivalent medication is not available, QTc will be
closely monitored)
18. Subject has QTc interval (ie, Fridericia*s correction [QTcF]) >= 450 ms or
other factors
that increase the risk of QT prolongation or arrhythmic events (eg, heart
failure,
hypokalemia, family history of long QT interval syndrome) at screening.
19. Female subject who is pregnant or lactating.
20. Subject has any significant medical condition, laboratory abnormality, or
psychiatric
illness that would prevent the subject from participating in the study.
21. Subject has any condition, including the presence of laboratory
abnormalities, that places
the subject at unacceptable risk if he/she were to participate in the study.
22. Subject has any condition that confounds the ability to interpret data from
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 |
|---|---|
| EU-CTR | CTIS2024-511722-31-00 |
| EudraCT | EUCTR2015-003951-23-NL |
| ClinicalTrials.gov | NCT02677922 |
| CCMO | NL56633.029.16 |