Acute Myeloid Leukemia
Conditions
Brief summary
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.
Detailed description
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 followed by a dose-expansion study. 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. Patients undergo echocardiography (ECHO) during screening and as clinically indicated on study. Patients undergo blood sample collection and bone marrow aspirate and biopsy during screening and cycle 11 day 21 on study. CONSOLIDATION: Patients receive high dose cytarabine IV twice daily (BID) on days 1, 3, and 5 of each cycle, and pemigatinib PO QD on days 8-21 of each cycle. Treatment repeats every 28 days for up to 4 cycles in the absence of disease progression of unacceptable toxicity. Patients undergo ECHO as clinically indicated and blood sample collection and bone marrow biopsy and aspirate at the end of consolidation. After completion of study treatment, patients are followed up every 3 months for up to 24 months.
Interventions
PROCEDUREBiospecimen Collection
Undergo blood sample collection
PROCEDUREBone Marrow Aspirate
Undergo bone marrow biopsy and aspirate
PROCEDUREBone Marrow Biopsy
Undergo bone marrow biopsy and aspiratie
DRUGCytarabine
Given IV
DRUGDaunorubicin
Given IV
PROCEDUREElectrocardiography
Undergo ECHO
DRUGPemigatinib
Given PO
Sponsors
OHSU Knight Cancer Institute
Incyte Corporation
Oregon Health and Science University
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* PRE-SCREENING INCLUSION CRITERIA: Ability to understand and the willingness to sign a written informed consent document * PRE-SCREENING INCLUSION CRITERIA: Age \>= 18 years at time of informed consent. Both men and women of all races and ethnic groups will be included * PRE-SCREENING INCLUSION CRITERIA: Participants must consent to a bone marrow aspirate/biopsy that will be collected prior to start of planned 7+3 induction therapy. Patients with known favorable risk AML (2022 European Leukemia Net \[ELN\] Guidelines) or FLT3 mutations should not be pre-screened. If the risk category is unknown, then it is okay to pre-screen patients for study. Adverse or intermediate risk needs to be confirmed prior to treatment with pemigatinib (during screening period) as outlined below * TREATMENT INCLUSION CRITERIA: Eastern Cooperative Oncology Group (ECOG) performance status 0-2 * TREATMENT INCLUSION CRITERIA: For both the dose-determining and dose-expansion cohort, study population is limited to: Newly diagnosed, morphologically documented AML, based on the World Health Organization (WHO) 2008 classification, with wild-type FLT3 and cytogenetics or mutations associated with intermediate or adverse prognostic risk per European Leukemia Net (ELN) guidelines. These include: * t(9;11)(p21.3;q23.3); MLLT3-KMT2A * Cytogenetic abnormalities not classified as favorable * 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 (without favorable risk cytogenetics/mutations) * Mutated BCOR (without favorable risk cytogenetics/mutations) * Mutated EZH2 (without favorable risk cytogenetics/mutations) * Mutated ASXL1 (without favorable risk cytogenetics/mutations) * Mutated SF3B1 (without favorable risk cytogenetics/mutations) * Mutated SRSF2 (without favorable risk cytogenetics/mutations) * Mutated STAG2 (without favorable risk cytogenetics/mutations) * Mutated U2AF1, (without favorable risk cytogenetics/mutations) * Mutated ZRSR2 (without favorable risk cytogenetics/mutations) * Mutated TP53 (mono- or biallelic) at a variant allele fraction of at least 10% * TREATMENT INCLUSION CRITERIA: Serum creatinine clearance \>= 30 mL/min (as calculated by Cockcroft-Gault formula) (on or by day 8 of induction therapy, prior to starting pemigatinib) * TREATMENT INCLUSION CRITERIA: 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) * TREATMENT INCLUSION CRITERIA: 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) * TREATMENT INCLUSION CRITERIA: Total serum bilirubin =\< 3 x ULN (on or by day 8 of induction therapy, prior to starting pemigatinib) * TREATMENT INCLUSION CRITERIA: Serum aspartate transaminase (AST) and/or alanine transaminase (ALT) =\< 3 x ULN (on or by day 8 of induction therapy, prior to starting pemigatinib) * TREATMENT INCLUSION CRITERIA: Participants must consent to standard of care bone marrow aspirate/biopsies during treatment. Bone marrow biopsies will be obtained prior to study, on day 21 (+/- 3 days, if considered institutional standard of care), after recovery from induction therapy, and at the end of consolidation and/or prior to allogeneic stem cell transplant * TREATMENT INCLUSION CRITERIA: 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 * TREATMENT INCLUSION CRITERIA: 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of dose limiting toxicities (DLTs) | From cycle 1 day 8, until 14 days after cycle 1 day 28 (up to 42 days) | Will be summarized using the proportion and exact binomial confidence interval. DLTs will be summarized at each dose level by severity and major organ site according to the Common Terminology Criteria for Adverse Events (CTCAE) version (v)5.0. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Rate of composite complete remission (cCR) | From cycle 1 day 1, until blood cell count recovery after induction (day 25-42) | — |
| Duration of remission (DOR) | Date of first response (>= immune complete remission) till date of documented relapse assessed up to 2 years from last dose of study intervention | — |
| Event-free survival (EFS) | From cycle 1 day 1, until date of primary refractory disease, progression, relapse, or death from any cause, assessed up to 2 years from last dose of study intervention | — |
| Relapse-free survival (RFS) | Date of first response (>= complete remission with incomplete blood count recovery [CRi]), until date of relapse or death from any cause, assessed up to 2 years from last dose of study intervention | — |
| Overall survival (OS) | From cycle 1 day 1, until date of death from any cause, assessed up to 2 years from last dose of study intervention | Estimated with the Kaplan-Meier method. |
| Incidence of treatment-emergent adverse events (TEAEs) | From cycle 1 day 8, until 90 days after last dose of study intervention | Will be determined for the safety analysis set (i.e., study participants who receive at least one dose of pemigatinib) and the subset of safety evaluable patients treated at the MTD. The point estimate and 95% confidence interval will be reported. Each toxicity event will be tabulated and summarized by severity and major organ site according to the CTCAE v5.0. Will be evaluated in the dose determining and dose expansion cohorts separately as well as combined. |
| Incidence of non-treatment related adverse events (AEs) | From cycle 1 day 8, until 90 days after last dose of study intervention | Will be determined for the safety analysis set (i.e., study participants who receive at least one dose of pemigatinib) and the subset of safety evaluable patients treated at the MTD. The point estimate and 95% confidence interval will be reported. Each toxicity event will be tabulated and summarized by severity and major organ site according to the CTCAE v5.0. Will be evaluated in the dose determining and dose expansion cohorts separately as well as combined |
| Time-to-marrow recovery | Baseline (cycle 1 day 1), until time of count recovery | Defined as absolute neutrophil count (ANC) \>= 1 x 10\^9 /L and platelets \>= 100 x 10\^9/L. |
Countries
United States
Contacts
CONTACTOHSU Knight Cancer Institute Clinical Trials Information
PRINCIPAL_INVESTIGATORElie Traer, MD PhD
OHSU Knight Cancer Institute
Outcome results
None listed