Ivosidenib and Combination Chemotherapy for the Treatment of IDH1 Mutant Relapsed or Refractory Acute Myeloid Leukemia

Phase 1 Trial of Ivosidenib and FLAG Chemotherapy in Relapsed/Refractory IDH1+ Acute Myeloid Leukemia (AML)

This phase I trial studies the side effects and best dose of ivosidenib when given together with combination chemotherapy for the treatment of 1DH1 mutant acute myeloid leukemia that is newly diagnosed (previously untreated), has come back (relapsed), or does not respond to treatment (refractory). Ivosidenib may stop the growth of cancer cells by blocking the IDH1 mutation and some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as fludarabine phosphate, cytarabine, and filgrastim, 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. Giving ivosidenib with combination chemotherapy may work better in treating patients with acute myeloid leukemia compared to chemotherapy alone.

Study Overview

• Status: Terminated
• Conditions: Recurrent Acute Myeloid Leukemia; Recurrent Myelodysplastic Syndrome; Refractory Acute Myeloid Leukemia; Refractory Myelodysplastic Syndrome; Acute Myeloid Leukemia (AML); Newly Diagnosed Acute Myeloid Leukemia (AML); Recurrent Myeloproliferative Neoplasm; IDH1 Mutation Myeloid Neoplasms
• Intervention / Treatment: Drug: Cytarabine; Drug: Fludarabine; Biological: Filgrastim; Drug: Ivosidenib; Drug: Fludarabine Phosphate; Drug: Idarubicin

Detailed Description

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) ± Idarubicin chemotherapy.

SECONDARY OBJECTIVES:

I. To evaluate the safety profile of ivosidenib in combination with FLAG ± Idarubicin 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 ± Idarubicin 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 ± Idarubicin 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 ± Idarubicin 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. The addition of idarubicin to FLAG (FLAG ± IDA) will be per treating investigator and is to be to be administered at 8 mg/m2 by IV infusion over 30 minutes on days 4-6 of cycle 1, when given in combination with FLAG. Treatment continues for 28 days in the absence of disease progression or unacceptable toxicity.

CONSOLIDATION: Patients that complete the induction cycle are eligible to receive consolidation therapy with 1 cycle of FLAG ± IDA and ivosidenib based on treating physician discretion. Eligible patients for consolidation therapy are those who have CR, CRi, CRp, or PR. Patients are not required to receive consolidation therapy. 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. The addition of idarubicin to FLAG (FLAG ± IDA) will be per treating investigator and is to be to be administered at 8 mg/m2 by IV infusion over 30 minutes on days 4-6. Treatment continues for 28 days for 1 cycle in the absence of disease progression or unacceptable toxicity.

MAINTENANCE: Patients that have completed 1 cycle of induction with ivosidenib and FLAG ± IDA may start maintenance. Patients are not required to receive consolidation treatment in order to proceed to 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 complete follow up at 30 days and then every month for up to 1 year from start of study treatment to document survival and disease progression.

• Study Type: Interventional
• Enrollment (Actual): 2
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Patients must have newly diagnosed previously untreated AML or relapsed/refractory primary (ie, de novo) or secondary (progression of MDS or myeloproliferative neoplasms [MPN], or therapy-related) AML according to the WHO classification with ≥ 5% leukemic blasts in the bone marrow.

• Patients with relapsed/refractory primary (ie, de novo) or secondary (progression of MDS or myeloproliferative neoplasms [MPN], or therapy-related) AML 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.
• Patients with newly diagnosed or relapsed/refractory high-risk MDS or MDS/MPN (defined as ≥ 10% bone marrow blasts, or intermediate or high risk by International Prognostic Scoring System [IPSS], revised [R]-IPSS or dynamic [D]-IPSS) may also be eligible after discussion with the PI.
• Patient must have documentation of an IDH1 R132 mutation obtained prior to registration. IDH mutational status will be assessed locally.
• Patients must be ≥ 18 years of age at the time of signing the informed consent form (ICF).
• 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.

• Patients of childbearing potential (POCBP) 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 POCBP 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 POCBP is any person of childbearing potential (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)

• POCBP 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)

• Patients of sperm producing potential 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 for relapsed/refractory primary (ie, de novo) or secondary (progression of MDS or myeloproliferative neoplasms [MPN], or therapy-related) AML patients.
• 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.
• Patients of child bearing potential (POCBP) 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Treatment (combination chemotherapy, ivosidenib); 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. The addition of idarubicin to FLAG (FLAG ± IDA) will be per treating investigator and is to be to be administered at 8 mg/m2 by IV infusion over 30 minutes on days 4-6 of cycle 1. CONSOLIDATION: Patients are not required to receive consolidation therapy. 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. The addition of idarubicin to FLAG (FLAG ± IDA) will be per treating investigator and is to be to be administered at 8 mg/m2 by IV infusion over 30 minutes on days 4-6. MAINTENANCE: Patients receive ivosidenib PO QD on days 1-28. Treatment repeats every 28 days for up to 26 cycles in the absence of progression.

Drug: Cytarabine; Given IV; Other Names: .beta.-Cytosine arabinoside; 1-.beta.-D-Arabinofuranosyl-4-amino-2(1H)pyrimidinone; 1-.beta.-D-Arabinofuranosylcytosine; 1-Beta-D-arabinofuranosyl-4-amino-2(1H)pyrimidinone; 1-Beta-D-arabinofuranosylcytosine; 1.beta.-D-Arabinofuranosylcytosine; 2(1H)-Pyrimidinone, 4-Amino-1-beta-D-arabinofuranosyl-; 2(1H)-Pyrimidinone, 4-amino-1.beta.-D-arabinofuranosyl-; Alexan; Ara-C; ARA-cell; Arabine; Arabinofuranosylcytosine; Arabinosylcytosine; Aracytidine; Aracytin; Aracytine; CHX-3311; Cytarabinum; Cytarbel; Cytosar; Cytosine Arabinoside; Cytosine-.beta.-arabinoside; Cytosine-beta-arabinoside; Erpalfa; Starasid; Tarabine PFS; U 19920; U-19920; Udicil; WR-28453; Beta-cytosine Arabinoside; Drug: Fludarabine; Given IV; Other Names: Fluradosa; Biological: Filgrastim; Given SC; Other Names: G-CSF; r-metHuG-CSF; Neupogen; Recombinant Methionyl Human Granulocyte Colony Stimulating Factor; rG-CSF; Tevagrastim; Drug: Ivosidenib; Given PO; Other Names: AG-120; Tibsovo; Drug: Fludarabine Phosphate; Given IV; Other Names: 2-F-ara-AMP; Beneflur; Fludara; 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-; SH T 586; Drug: Idarubicin; 8 mg/m2 IV on days 4-6 of induction (cycle 1) and 8 g/m2 IV on days 4-6 of consolidation. Idarubicin will be administered per treating physician discretion. Idarubicin is a drug that belongs to a group of anti-cancer drugs called anthracyclines. These drugs were originally used as antibiotics, but it was subsequently found that they were effective anti-cancer drugs. Idarubicin hydrochloride is a DNA-intercalating analog of daunorubicin which has an inhibitory effect on nucleic acid synthesis and interacts with the enzyme topoisomerase II. The absence of a methoxy group at position 4 of the anthracycline structure gives the compound a high lipophilicity which results in an increased rate of cellular uptake compared with other anthracyclines.; Other Names: Idamycin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum tolerated dose of ivosidenib in combination with FLAG (± IDA) chemotherapy	Will be assessed for a DLT per the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Patients that complete the induction cycle will be eligible for assessment.	Up to day 42 of the first treatment cycle

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression free survival	Will be estimated using Kaplan-Meier curves.	At 1 year
Overall survival	Will be estimated using Kaplan-Meier curves.	At 1 year
Number of patients that receive hematopoietic stem cell transplant after induction treatment	Patients that complete the induction cycle will be eligible for assessment.	Up to 1 year
Rates of complete remission (CR + complete remission with incomplete hematological recovery [CRi] + complete remission with incomplete platelet recovery [CRp])	Patients that complete the induction cycle will be eligible for assessment. The rate of complete remission (CR + CRi + CRp) with ivosidenib in combination with FLAG (± IDA) chemotherapy will be assessed after induction or upon count recovery.	After induction on day 28 or upon count recovery, up to 1 year
Review of adverse events of ivosidenib in combination with FLAG (± IDA) chemotherapy	Will be assessed by the CTCAE version 5.0. Toxicity profiles will be summarized for toxicities of any grade, with rates of >= grade 3 toxicities also analyzed separately. Adverse events rates will be summarized and accompanied by 95% exact binomial confidence intervals.	Up to 30 days after last dose

Collaborators and Investigators

• Sponsor: Northwestern University
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Shira N Dinner, M.D., Northwestern University

Study record dates

Study Major Dates

• Study Start (Actual): December 21, 2020
• Primary Completion (Actual): January 16, 2022
• Study Completion (Actual): December 20, 2022

Study Registration Dates

• First Submitted: January 29, 2020
• First Submitted That Met QC Criteria: January 30, 2020
• First Posted (Actual): January 31, 2020

Study Record Updates

• Last Update Posted (Actual): June 1, 2026
• Last Update Submitted That Met QC Criteria: May 28, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Histologic Type; Hematologic Diseases; Leukemia, Myeloid; Bone Marrow Diseases; Leukemia; Hemic and Lymphatic Diseases; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes; Myeloproliferative Disorders; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleic Acids, Nucleotides, and Nucleosides; Hydrocarbons; Hydrocarbons, Cyclic; Biological Factors; Carbohydrates; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Polycyclic Compounds; Glycosides; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Nucleosides; Intercellular Signaling Peptides and Proteins; Arabinonucleosides; Anthracyclines; Naphthacenes; Aminoglycosides; Glycoproteins; Glycoconjugates; Daunorubicin; Colony-Stimulating Factors; Hematopoietic Cell Growth Factors; Cytokines; Cytarabine; Idarubicin; fludarabine; fludarabine phosphate; Granulocyte Colony-Stimulating Factor; Filgrastim; ivosidenib
• Other Study ID Numbers: NU 19H05 (Other Identifier: Northwestern University); P30CA060553 (U.S. NIH Grant/Contract); STU00210558 (CTRP (Clinical Trial Reporting Program)); NCI-2019-08390 (Registry Identifier: CTRP (Clinical Trial Reporting Program))

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No