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Olutasidenib Combined with Co-targeted Therapy for the Treatment of Myeloid Cell Cancers in Patients with IDH1 and Co-signaling Gene Mutations
Trial Status: active
This phase II trial studies the side effects of olutasidenib when given together with different co-targeted therapies and to see how well it works in treating myeloid cell cancers in patients with a change (mutation) in the IDH1 gene and in a second gene (either the RAS, FLT3, or JAK-STAT pathway) (co-signaling mutation). The co-targeted therapy drug combinations studied in this trial include olutasidenib in combination with cladribine and cytarabine with or without venetoclax, olutasidenib in combination with gilteritinib with or without venetoclax, and olutasidenib in combination with ruxolitinib. Olutasidenib, gilteritinib, and ruxolitinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Chemotherapy drugs, such as cladribine and cytarabine, 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. Venetoclax is in a class of medications called B-cell lymphoma-2 (BCL-2) inhibitors. It may stop the growth of cancer cells by blocking Bcl-2, a protein needed for cancer cell survival. Giving olutasidenib with co-targeted therapy may be safe, tolerable, and/or effective in treating myeloid cell cancers in patients with IDH1 and co-signaling gene mutations.
Inclusion Criteria
Age ≥ 18 years
Participants with a diagnosis of relapsed and/or refractory acute myeloid leukemia (AML) (including biphenotypic or bilineage leukemia including a myeloid component) OR high-risk myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), or MDS/MPN (defined as ≥ 10% blasts on peripheral flow cytometry or bone marrow biopsy)
Subjects must have a documented IDH1 mutation
Subjects must also have a documented co-signaling mutation in one or more of the following: KRAS, NRAS, PTPN11, CBL, NF1, FLT3-ITD, FLT3-TKD, KIT, JAK2, MPL, CALR, CSF3R
Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
Adequate renal function with estimated glomerular filtration rate (GFR) ≥ 30 by the 2021 Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI)
Adequate hepatic function, defined as direct bilirubin ≤ 2x upper limit of normal (ULN) and aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3x ULN unless the increase is due to Gilbert’s disease or leukemic involvement, in which case direct bilirubin, AST, and ALT ≤ 5x ULN will be considered eligible
The interval from prior treatment to time of initiation will be at least 14 days OR five half-lives for both cytotoxic and non-cytotoxic (e.g. immunotherapy agent[s]) to avoid potential delayed anti-leukemic effect of prior therapy on efficacy outcomes. Oral hydroxyurea and/or cytarabine (up to 2g/m^2) is allowed for participants with rapidly proliferative disease prior to the start and during the first two cycles of therapy, for clinical benefit and after discussion with the principal investigator (PI). Continuation of concurrent intrathecal therapy for controlled central nervous system (CNS) disease is permitted
Ability to understand and the willingness to sign an informed consent document
Exclusion Criteria
Participants who have received prior olutasidenib (Rezlidhiai, previously FT-2102)
Participants with translocation t(15;17) or acute promyelocytic leukemia (French-American British [FAB] class M3-AML)
Participants with any concurrent uncontrolled clinically significant medical condition, including life-threatening infection, which could place the patient at unacceptable risk of study treatment
Participants with any uncontrolled psychiatric illness that would limit compliance with study requirements
Participants with a New York Heart Association (NYHA) Functional Classification of III or IV
Participants with active graft-versus-host-disease (GVHD) status post stem cell transplant. Patients must have discontinued calcineurin inhibitors at least 4 weeks prior to the start of study treatment
Participants with active, uncontrolled CNS leukemia
Participants with any severe gastrointestinal or metabolic condition which could interfere with the absorption of oral study medications
Known active hepatitis B (HBV), hepatitis C (HCV), or human immunodeficiency virus (HIV) infection. For participants with evidence of chronic HBV or HIV infection, the HBV or HIV viral load must be undetectable, respectively. For participants with a history of HCV, it must be treated and cured with an undetectable HCV viral load
Subject has white blood cell count > 25 x 10^9/L (Note: Hydroxyurea and cytarabine are permitted to mean this criterion)
The effects of the study drug on the developing human fetus or transmission through breast feeding are unknown. Therefore, nursing women and women with a positive urine pregnancy test and excluded. Additionally, women of child-bearing potential (WOCBP) and men who are sexually active with WOCBP who are not willing to maintain adequate contraception are excluded
* WOCBP includes all female participants between the onset of menses (as early as 8 years of age) to 55 years unless the patient presents with an applicable exclusionary factor which may be one of the following:
** Postmenopausal (no menses in greater than or equal to 12 consecutive months)
** History of hysterectomy or bilateral salpingo-oophorectomy
** Ovarian failure (follicle stimulating hormone and estradiol in menopausal range, who have received whole pelvic radiation therapy)
** History of bilateral tubal ligation or another surgical sterilization procedure
* Approved methods of birth control are as follows: hormonal contraception (i.e. birth control pills, injection, transdermal patch, vaginal ring, hormonal implant), intrauterine device (IUD), tubal ligation or hysterectomy, subject/partner post-vasectomy, double barrier methods (e.g. condom in combination with spermicide). Abstinence for the duration of the trial and drug washout period is an acceptable practice; however periodic abstinence, the rhythm method, and the withdrawal method are not acceptable methods of birth control. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform the treating physician immediately
* Adequate contraception must be maintained from initiation of the study drug until 90 days after the last dose of the study drug
History of an allergic reaction to venetoclax, gilteritinib, ruxolitinib, cladribine, or cytarabine
Study sponsor and potential other locations can be found on ClinicalTrials.gov for NCT07032727.
Locations matching your search criteria
United States
Florida
Miami
University of Miami Miller School of Medicine-Sylvester Cancer Center
I. To determine the safety and tolerability of olutasidenib in combination with cladribine + low-dose cytarabine (LDAC) ± venetoclax (Arm 1), gilteritinib ± venetoclax (Arm 2), and ruxolitinib (Arm 3) for patients with relapsed/refractory IDH1-mutated myeloid malignancies with a co-signaling mutation.
II. To quantify the composite complete remission rate (CRc; complete response [CR] + complete response with partial hematologic recovery [CRh] + compete response with incomplete count recovery [CRi]) in patients with relapsed/refractory IDH1-mutated myeloid malignancies with a co-signaling mutation treated with olutasidenib in combination with cladribine + LDAC ± venetoclax (Arm 1), gilteritinib ± venetoclax (Arm 2), and ruxolitinib (Arm 3).
SECONDARY OBJECTIVES:
I. To determine overall survival (OS), event free survival (EFS), and duration of response (DOR) with olutasidenib in combination with a co-targeting chemotherapeutic agent.
II. To determine the overall response rate (ORR; CR + CRh + CRi + morphologic leukemia free state [MLFS] + partial response [PR]) of olutasidenib in combination with a co-targeting chemotherapeutic agent.
III. To evaluate occurrence of measurable residual disease (MRD) negative status by multiparameter flow cytometry and molecular evaluation by polymerase chain reaction (PCR) and next generation sequencing (NGS)-based assays (e.g. IDH1 and FLT3 if applicable).
IV. To characterize the pharmacokinetic (PK) profiles of olutasidenib and venetoclax in plasma samples.
EXPLORATORY OBJECTIVE:
I. To investigate the clonal evolution in response to multiple targeted therapeutic agents using single cell sequencing of plasma and bone marrow samples at select sites.
OUTLINE: Patients with a RAS pathway co-mutation are assigned to arm 1, patients with a FLT3 pathway co-mutation are assigned to arm 2, and patients with a JAK-STAT pathway co-mutation are assigned to arm 3.
ARM 1: The first 16 patients enrolled are assigned to arm 1a and subsequent patients enrolled are assigned to arm 1b.
ARM 1A: Patients receive olutasidenib orally (PO) twice daily (BID) on days 1-28, cladribine intravenously (IV) on days 1-5, and LDAC subcutaneously (SC) on days 1-10 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
ARM 1B: Patients receive olutasidenib PO BID on days 1-28, cladribine IV on days 1-5, LDAC SC on days 1-10, and venetoclax PO once daily (QD) on days 1-14 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
ARM 2: The first 16 patients enrolled are assigned to arm 2a and subsequent patients enrolled are assigned to arm 2b.
ARM 2A: Patients receive olutasidenib PO BID and gilteritinib PO QD on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
ARM 2B: Patients receive olutasidenib PO BID on days 1-28, gilteritinib PO QD on days 1-28, and venetoclax PO QD on days 1-14 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
ARM 3: Patients receive olutasidenib PO BID and ruxolitinib PO BID on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Additionally, all patients undergo bone marrow aspiration and biopsy and blood sample collection throughout the trial.
After completion of study treatment, patients are followed up at 30-60 days and then every 3 months for 3 years.
