This phase I trial identifies the best dose and clinical benefit of giving pemigatinib
following standard induction chemotherapy in patients with newly diagnosed acute myeloid
leukemia. Pemigatinib selectively inhibits FGFR (fibroblast growth factor receptor) activity,
a receptor that may contribute to the growth of leukemia cells. The genetic changes
responsible for activating the growth of leukemia cells can be unique to each patient and can
change during the course of the disease. Chemotherapy drugs, such as cytarabine and
daunorubicin work in different ways to stop the growth of cancer cells, either by killing the
cells, by stopping them from dividing, or by stopping them from spreading.
PRIMARY OBJECTIVE:
I. To determine the maximum tolerated dose of pemigatinib (INC054828) following standard of
care induction chemotherapy.
SECONDARY OBJECTIVES:
I. To assess preliminary efficacy associated with study intervention. II. To assess the
safety profile of the study intervention. III. To evaluate time-to- marrow recovery between
cycles of pemigatinib.
EXPLORATORY OBJECTIVES:
I. Assess minimal residual disease (MRD) by fluorescent in situ hybridization (FISH), reverse
transcriptase-polymerase chain reaction (RT-PCR), and/or next-generation sequencing of acute
myeloid leukemia (AML) genetic abnormalities in bone marrow and blood.
II. Quantify FGF2/FGFR immunohistochemical staining of marrow core biopsies and compare to
historical controls at various timepoints.
III. Assess ex vivo sensitivity of patient-derived mononuclear cells to pemigatinib with and
without FGF2 supplementation.
IV. Evaluate pemigatinib-induced changes in stromal expression using cultured bone marrow
samples and compare to historical controls.
V. Evaluate the impact of pemigatinib on the need for intravenous (IV) phosphate replacement
after chemotherapy.
OUTLINE: This is a dose-escalation study of pemigatinib.
INDUCTION: Patients receive cytarabine IV on days 1-7, daunorubicin IV on days 1-3, and
pemigatinib orally (PO) once daily (QD) on days 8-21 in the absence of disease progression or
unacceptable toxicity. Patients with hematologic count recovery (assessed between days 25-42)
after induction proceed to consolidation therapy.
CONSOLIDATION: Patients receive high dose cytarabine IV twice daily (BID) on days 1, 3, and
5, and pemigatinib PO QD on days 8-21. Treatment repeats every 28 days for up to 4 cycles in
the absence of disease progression of unacceptable toxicity.
After completion of study treatment, patients are followed up every 3 months for up to 24
months.
Inclusion Criteria:
- PRE-SCREENING INCLUSION CRITERIA:
- Ability to understand and the willingness to sign a written informed consent document
- For dose-determining portion of study, study population is limited to: Newly
diagnosed, morphologically documented primary AML, based on the World Health
Organization (WHO) 2008 classification, with cytogenetics associated with the adverse
prognostic risk group per European Leukemia Net (ELN) guidelines. These include:
- t(6;9)(p23;q34.1); DEK-NUP214
- t(v;11q23.3); KMT2A rearranged
- t(9;22)(q34.1;q11.2); BCR-ABL1
- inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2); GATA2,MECOM(EVI1)
- -5 or del(5q); -7; -17/abn(17p)
- Complex karyotype - defined as three or more unrelated chromosome abnormalities
in the absence of 1 of the WHO-designated recurring translocations or inversions,
that is, t(8;21), inv(16) or t(16;16), t(9;11), t(v;11)(v;q23.3), t(6;9), inv(3)
or t(3;3); AML with BCR-ABL1
- Monosomal karyotype - defined by the presence of 1 single monosomy (excluding
loss of X or Y) in association with at least 1 additional monosomy or structural
chromosome abnormality (excluding core-binding factor AML)
- Mutated RUNX1
- Mutated ASXL1
- Mutated TP53
- For the dose-expansion portion of the study, study population is limited to: Newly
diagnosed, morphologically documented primary AML, based on the World Health
Organization (WHO) 2008 classification, with a cytogenetic profile encompassing the
intermediate prognostic risk groups per European Leukemia Net (ELN) guidelines.2 These
include:
- Wild-type or NPM1
- t(9;11)(p21.3;q23.3); MLLT3-KMT2A
- Cytogenetic abnormalities not classified as favorable or adverse
- Participants must consent to a bone marrow aspirate/biopsy that will be collected
prior to start of planned 7+3 induction therapy
- Concurrent active malignancy with expected survival of < 1 year
- TREATMENT INCLUSION CRITERIA:
- Eastern Cooperative Oncology Group (ECOG) performance status 0-2
- Serum creatinine clearance >= 30 mL/min (as calculated by Cockcroft-Gault formula) (on
or by day 8 of induction therapy, prior to starting pemigatinib)
- Serum phosphate within institutional upper limit of normal (ULN) or can be corrected
with supplementation/ phosphate binders to be within institutional ULN (on or by day 8
of induction therapy, prior to starting pemigatinib)
- Serum electrolytes within institutional ULN: potassium, calcium (total, or corrected
for serum albumin in case of hypoalbuminemia) and magnesium. If outside of normal
limits, participant will be eligible when electrolytes are corrected (on or by day 8
of induction therapy, prior to starting pemigatinib)
- Total serum bilirubin =< 3 x ULN (on or by day 8 of induction therapy, prior to
starting pemigatinib)
- Serum aspartate transaminase (AST) and/or alanine transaminase (ALT) =< 3 x ULN (on or
by day 8 of induction therapy, prior to starting pemigatinib)
- As part of institutional standard of care, participants must consent to bone marrow
aspirate/biopsies on day 14 (+3 days), after recovery from induction therapy, and at
the end of consolidation
- Female participants of childbearing potential must agree to use effective
contraception (2 forms of contraception or abstinence) from the screening visit until
6 months following the last dose of study treatment. Should a woman become pregnant or
suspect she is pregnant while she or her partner is participating in this study, she
should inform her treating physician immediately
- Male patients of childbearing potential having intercourse with females of
childbearing potential must agree to abstain from heterosexual intercourse or have
their partner use 2 forms of contraception from the screening visit until 3 months
following the last dose of study treatment. The male participant must also refrain
from sperm donation from the screening visit until 3 months following the last dose of
study treatment
Exclusion Criteria:
- PRE-SCREENING EXCLUSION CRITERIA:
- Diagnosis of acute promyelocytic leukemia (APL, or AML M3 subtype) per WHO
classification
- AML with FLT3 mutations
- Favorable risk AML: inv(16), t(8;21) or NPM1 mutations without FLT3 ITD mutations
- Any cancer-directed therapy within 2 weeks prior to starting planned 7+3 induction
regimen, with the exception of hydroxyurea, which is allowed to control white blood
cell count, or empiric all-trans retinoic acid (ATRA) for suspected APL
- Prior receipt of a selective FGFR inhibitor
- Known liver disease
- History of calcium and phosphate hemostasis disorder or systemic mineral imbalance
with ectopic calcification of soft tissues
- Except for commonly observed calcifications in soft tissues such as the skin,
kidney tendon, or vessels due to injury, disease, or aging in the absence of
systemic mineral imbalance)
- History of hypovitaminosis D requiring supraphysiologic doses (e.g., 50,000 IU/weekly)
to replenish the deficiency. Vitamin D supplements are allowed
- Untreated human immunodeficiency virus (HIV) or active hepatitis C detectable by PCR,
or chronic hepatitis B
- Individuals positive for hepatitis B core antibody who are receiving intravenous
immunoglobulin (IVIg) are eligible if HepB PCR is negative
- History of cerebrovascular accident or intracranial hemorrhage within 2 months of
enrollment
- Unwillingness to receive infusion of blood products
- Inability to take oral medication
- Gastrointestinal condition/disorders that may raise gastric and/or small intestinal pH
that could interfere with absorption, metabolism, or excretion of pemigatinib
- Known history and/or current evidence of ectopic mineralization/calcification,
including (but not limited to): soft tissue, kidneys, intestine, myocardia, or lung,
excepting calcified lymph nodes and asymptomatic arterial or cartilage/tendon
calcification
- Current evidence of corneal disorder/keratopathy, including (but not limited to):
bullous/band keratopathy, corneal abrasion, inflammation/ulceration,
keratoconjunctivitis, etc., as confirmed by ophthalmologic examination
- TREATMENT EXCLUSION CRITERIA:
- Clinically significant coagulation abnormality (e.g., disseminated intravascular
coagulation) that is present on or by day 8 of induction therapy prior to starting
pemigatinib
- Clinically significant or uncontrolled cardiac disease, including unstable angina,
acute myocardial infarction within 6 months from day 1 of planned induction therapy,
New York Heart Association class III or IV congestive heart failure, and uncontrolled
arrhythmia (participants with pacemaker or with atrial fibrillation and well
controlled heart rate are allowed). History or presence of an abnormal
electrocardiogram (ECG) that, in the investigator's opinion, is clinically meaningful.
- A screening QT interval by Fridericia's Correction Formula (QTcF) interval > 480
ms will result in exclusion.
- For participants with an intraventricular conduction delay (QRS interval > 120
ms), the JTc interval may be used in place of the QTc with approval from
Sponsor-Investigator. The JTc must be =< 340 ms if JTc is used in place of the
QTc.
- Left ventricular ejection fraction (LVEF) by echocardiogram < 45% prior to initiating
pemigatinib
- Active infection that is not well-controlled by antibacterial or antiviral therapy
- Current use of prohibited medications including use of any potent CYP3A4 inducers
within 14 days or five half-lives (whichever is longer) before the first dose of study
drug.
- Use of CYP3A4 inhibitors should be avoided but, if medically necessary, is
permitted with a dose reduction of study drug
- Use of moderate CYP3A4 inhibitors are permitted.
- Based on the low overall bioavailability of topical ketoconazole, there are no
restrictions on topical ketoconazole
- Current use of prohibited medication
- Hypersensitivity to pemigatinib, or its excipients, when administered alone
- Pregnancy or breastfeeding at the time of enrollment
- Any concurrent condition that, in the investigator's opinion, would jeopardize the
safety of the participant or compliance with the protocol
