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

NCT04250051 | Terminated Phase 1 DMC FDA Drug

• 4 other identifiers: NU 19H05STU00210558P30CA060553NCI-2019-08390
• Study Type: interventional
• Target: 2
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Recurrent Acute Myeloid Leukemia; Recurrent Myeloproliferative Neoplasm; Recurrent Myelodysplastic Syndrome; IDH1 Mutation Myeloid Neoplasms; Refractory Acute Myeloid Leukemia; Refractory Myelodysplastic Syndrome; Newly Diagnosed Acute Myeloid Leukemia (AML); Acute Myeloid Leukemia (AML)

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (5)

• Review of adverse events of ivosidenib in combination with FLAG (± IDA) chemotherapy

  Up to 30 days after last dose

• Rates of complete remission (CR + complete remission with incomplete hematological recovery [CRi] + complete remission with incomplete platelet recovery [CRp])

  After induction on day 28 or upon count recovery, up to 1 year

• Progression free survival

  At 1 year

• Overall survival

  At 1 year

• Number of patients that receive hematopoietic stem cell transplant after induction treatment

  Up to 1 year

Study Arms (1)

Treatment (combination chemotherapy, ivosidenib)

EXPERIMENTAL

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; Biological: Filgrastim; Drug: Fludarabine; Drug: Fludarabine Phosphate; Drug: Ivosidenib; Drug: Idarubicin

Interventions

Cytarabine DRUG

Given IV

Also known as: .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, Beta-cytosine Arabinoside, CHX-3311, Cytarabinum, Cytarbel, Cytosar, Cytosine Arabinoside, Cytosine-.beta.-arabinoside, Cytosine-beta-arabinoside, Erpalfa, Starasid, Tarabine PFS, U 19920, U-19920, Udicil, WR-28453

Treatment (combination chemotherapy, ivosidenib)

Filgrastim BIOLOGICAL

Given SC

Also known as: G-CSF, Neupogen, r-metHuG-CSF, Recombinant Methionyl Human Granulocyte Colony Stimulating Factor, rG-CSF, Tevagrastim

Treatment (combination chemotherapy, ivosidenib)

Fludarabine DRUG

Given IV

Also known as: Fluradosa

Treatment (combination chemotherapy, ivosidenib)

Fludarabine Phosphate DRUG

Given IV

Also known as: 2-F-ara-AMP, 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-, Beneflur, Fludara, SH T 586

Treatment (combination chemotherapy, ivosidenib)

Ivosidenib DRUG

Given PO

Also known as: AG-120, Tibsovo

Treatment (combination chemotherapy, ivosidenib)

Idarubicin DRUG

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.

Also known as: Idamycin

Treatment (combination chemotherapy, ivosidenib)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Northwestern University: lead
• National Cancer Institute (NCI): collaborator

Study Sites (1)

Northwestern University

Chicago, Illinois, 60611, United States

Location

MeSH Terms

Conditions

Leukemia, Myeloid, Acute; Myelodysplastic Syndromes; Myeloproliferative Disorders

Interventions

Cytarabine; Filgrastim; Granulocyte Colony-Stimulating Factor; fludarabine; fludarabine phosphate; ivosidenib; Idarubicin

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Bone Marrow Diseases

Intervention Hierarchy (Ancestors)

Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Arabinonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Colony-Stimulating Factors; Glycoproteins; Glycoconjugates; Carbohydrates; Hematopoietic Cell Growth Factors; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Biological Factors; Daunorubicin; Anthracyclines; Naphthacenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Polycyclic Compounds; Aminoglycosides; Glycosides

Study Officials

• Shira N Dinner, M.D.

  Northwestern University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 29, 2020
• First Posted: January 31, 2020
• Study Start: December 21, 2020
• Primary Completion: January 16, 2022
• Study Completion: December 20, 2022
• Last Updated: June 1, 2026

Record last verified: 2026-05

Locations

US (1)