PRIMARY OBJECTIVE:
I. To determine the maximum tolerated dose (MTD) of ivosidenib in combination with
fludarabine, cytarabine, plus granulocyte-colony stimulating factor (G-CSF) (FLAG)
chemotherapy.
SECONDARY OBJECTIVES:
I. To evaluate the safety profile of ivosidenib in combination with FLAG chemotherapy.
II. To determine the rate of complete remission (CR + complete remission with incomplete
hematological recovery [CRi] + complete remission with incomplete platelet recovery [CRp])
with ivosidenib in combination with FLAG chemotherapy.
III. To evaluate the 1 year progression free survival. IV. To evaluate the 1 year overall
survival. V. To assess the number of patients that receive allogeneic stem cell transplant
after ivosidenib in combination with FLAG chemotherapy.
EXPLORATORY OBJECTIVES:
I. To assess for minimal residual disease negativity by polymerase chain reaction (PCR) for
IDH1 mutations after treatment with ivosidenib in combination with FLAG chemotherapy.
II. To assess for minimal residual disease negativity by PCR for IDH1 mutations after 3
cycles of maintenance therapy.
OUTLINE:
INDUCTION: Patients receive filgrastim subcutaneously (SC) once daily (QD) on days 0-6,
fludarabine phosphate intravenously (IV) QD over 30 minutes on days 1-5, cytarabine IV QD
over 4 hours on days 1-5, and ivosidenib orally (PO) QD on days 7-28. Treatment continues for
28 days in the absence of disease progression or unacceptable toxicity.
CONSOLIDATION: Patients receive filgrastim SC QD on days 0-5, fludarabine phosphate IV QD
over 30 minutes on days 1-4, cytarabine IV QD over 4 hours on days 1-4, and ivosidenib PO QD
on days 1-28. Treatment continues for 28 days for 1 cycle in the absence of disease
progression or unacceptable toxicity.
MAINTENANCE: Patients receive ivosidenib PO QD on days 1-28. Treatment repeats every 28 days
for up to 26 cycles in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 30 days and then every month
for up to 1 year.
Inclusion Criteria:
- Patients must have relapsed/refractory primary (ie, de novo) or secondary (progression
of myelodysplastic syndrome [MDS] or myeloproliferative neoplasms [MPN], or
therapy-related) acute myeloid leukemia (AML) according to the World Health
Organization (WHO) classification with >= 5% leukemic blasts in the bone marrow
- Patients may have received prior therapies and there are no limits on number of
therapies
- Note: There is a requirement of 7 day washout from prior therapy or 5 half-lives,
whichever is shorter
- Patient must have documentation of an IDH1 R132 mutation obtained prior to
registration. IDH mutational status will be assessed locally
- Patients must understand and voluntarily sign an informed consent form (ICF) prior to
any study-related assessments/procedures being conducted
- Patient is willing and able to adhere to the study visit schedule and other protocol
requirements
- Patient has an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or
2
- Serum aspartate aminotransferase/serum glutamic oxaloacetic transaminase (AST/SGOT)
and alanine aminotransferase (ALT/serum glutamate pyruvate transaminase [SGPT]) =< 3 x
upper limit of normal (ULN), unless considered due to leukemic organ involvement
(within 28 days prior to registration)
- Serum total bilirubin < 1.5 x ULN (within 28 days prior to registration)
- 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 or creatinine clearance < 2 x ULN or >= 30 mL/min based on the
Modification of Diet in Renal Disease (MDRD) glomerular filtration rate (GFR) (within
28 days prior to registration)
- Patients must agree to serial bone marrow aspirate/biopsies
- Females of childbearing potential (FOCBP) may participate, providing they meet the
following conditions: Agree to practice true abstinence from sexual intercourse or to
use two highly effective contraceptive methods, of which one must be a barrier method
(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 FOCBP trial participant and that a vasectomized partner has
received medical assessment of the surgical success]) at screening and throughout the
study, and for at least 4 months following the last study treatment.
- NOTE: A FOCBP is any woman (regardless of sexual orientation, having undergone a
tubal ligation, or remaining celibate by choice) who meets the following
criteria:
- Has not undergone a hysterectomy or bilateral oophorectomy
- Has had menses at any time in the preceding 12 consecutive months (and
therefore has not been naturally postmenopausal for > 12 months)
- Female patients must have a negative serum beta-subunit of human chorionic
gonadotropin (beta-hCG) pregnancy test (sensitivity of at least 25 mIU/mL) 28 days
prior to registration on study 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: 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 time frame)
- Male patients 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 partners 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 at least 4 months following the last study treatment.
- Furthermore, the male subject must agree to use a condom while treated with
ivosidenib and for at least 4 months following the last ivosidenib dose
Exclusion Criteria:
- Patients who are suspected or proven to have acute promyelocytic leukemia based on
morphology, immunophenotype, molecular assay, or karyotype are not eligible
- Patients who have had prior therapy with ivosidenib are not eligible.
- Note: prior treatment with other IDH inhibitors are allowed
- Patients who have immediate life-threatening, uncontrolled medical problem that would
prevent treatment on a clinical trial per investigator's discretion are not eligible
- Patients who have significant active cardiac disease within 28 days prior to study
registration, 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 study registration are not eligible
- Patients who have prior history of malignancy, other than MDS, MPN, or AML are not
eligible 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)
- Patients who are known to have short-gut syndrome, gastroparesis, or other conditions
that limit the ingestion or gastrointestinal absorption of drugs administered orally
are not eligible
- Patients who are 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 or 14 days whichever is shorter
prior to the start of study treatment: phenytoin (CYP2C9), S-mephenytoin (CYP2C19),
thioridazine (CYP2D6), theophylline, tizanidine (CYP1A2), CYP2C8, CYP3A4/5, and CYP2B6
- Patients who are known to be taking strong CYP3A4 inducers or sensitive CYP3A4
substrate medications that have a narrow therapeutic window are not eligible, unless
they can be transferred to other medications within >= 5 half-lives prior to dosing or
unless the medications can be properly monitored during the study
- Patients with an 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) are not
eligible
- Patients who have known or suspected hypersensitivity to any of the components of
study therapy are not eligible
- Patient who has corrected QT (QTc) interval (Frederica's correction [QTcF]) >= 480 ms)
at screening unless attributable to bundle branch block or pacemaker are not eligible.
If prolonged QTc is attributed to medications the patient must be transferred to other
medications and QTc corrected to selection parameters prior to enrollment
- Female patients who are pregnant or nursing are not eligible
- Patients who have any significant medical condition, laboratory abnormality, or
psychiatric illness that the treating physician believes would prevent the subject
from participating in the study are not eligible
