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Acute Myeloid LeukemiaPhase 1NCT04190550

Testing the Addition of an Anti-cancer Drug, Navtemadlin, to the Usual Treatments (Cytarabine and Idarubicin) in Patients With Acute Myeloid Leukemia

A Phase 1 study testing Cytarabine, Idarubicin Hydrochloride and Navtemadlin in people with Acute Myeloid Leukemia and Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome, run by National Cancer Institute (NCI) at 6 sites in United States.

Active, not recruiting

Under way, not looking for participants. Everyone needed has enrolled. The study is still running.

Official record
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Trial summary

This phase Ib trial studies the side effects and best dose of navtemadlin when given together with the standard chemotherapy drugs cytarabine and idarubicin in patients with acute myeloid leukemia. Navtemadlin may stop the growth of cancer cells by blocking a protein called MDM2 that is needed for cell growth. Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Cytarabine, Idarubicin Hydrochloride and Navtemadlin
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
24 participants
Where
6 sitesUnited States
Study dates
4 Feb 2021to 30 Jun 2027
Phase
Phase 1
Are there results?
Not yet: the study is under way

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Newly diagnosed and previously untreated AML (except acute promyelocytic leukemia [APL]) (>= 20% blasts in bone marrow or extramedullary leukemia) according to the World Health Organization (WHO), 2016 criteria. Note that patients who have received treatment with hypomethylating agents alone or in combination with venetoclax, ivosidenib or enasidenib for myelodysplastic syndrome (MDS) and have now transformed to AML are eligible.
  • Eligible patients must show evidence of wild-type (WT) p53 as assessed by deoxyribonucleic acid (DNA) sequencing before initiation of KRT-232 (AMG 232).
  • Patients must be considered candidates for intensive chemotherapy treatment with standard doses of cytarabine and idarubicin ("7+3 regimen").
  • Left ventricular ejection fraction (LVEF) >= 50% as assessed by echocardiogram or radionuclide angiography.
  • All non-hematological adverse events of any prior chemotherapy, surgery, or radiotherapy, except alopecia, must have resolved to National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) grade =< 2 prior to starting therapy.
  • Patient must be willing to submit the blood sampling and bone marrow sampling for the PK and PD analyses and exploratory biomarkers.
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  • Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%).
  • Prothrombin time (PT) or partial thromboplastin time (PTT) < 1.5 x upper limit of normal (ULN), OR international normalized ratio (INR) < 1.5.
  • Total bilirubin =< 2 mg/dl, unless from hemolysis, Gilbert's syndrome or liver infiltration with leukemia.
  • Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT)(serum glutamic pyruvic transaminase [SGPT]) =< 2.5 x institutional ULN (=< 5 x ULN if liver infiltration with leukemia).
  • Alkaline phosphatase (ALP) < 2.0 x ULN (if liver or bone metastases are present, < 3.0 x ULN)
  • Creatinine within reference laboratory ranges OR glomerular filtration rate (GFR) >= 50 mL/min/1.73 m^2 (by the Cockcroft Gault equation), with normalization to the patient's body surface area.
  • Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial.
  • Patients with known leukemic involvement of the central nervous system (CNS) are eligible if, in the opinion of the treating physician, they are eligible for induction chemotherapy. These patients can receive the intrathecal treatment concurrently with the study treatment on protocol.
  • Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial.
  • The effects of KRT-232 (AMG 232) on the developing human fetus are unknown. For this reason and because MDM2 inhibiting agents as well as other therapeutic agents used in this trial are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation through 5 weeks (women) after receiving the last dose of KRT-232 (AMG 232). 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. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 3 months after completion of KRT-232 (AMG 232) administration. Male subjects must agree to refrain from sperm donation from initial study drug administration until 90 days after the last dose of study drug. Adequate methods of effective birth control include sexual abstinence (men, women); vasectomy; or a condom with spermicide (men) in combination with barrier methods, hormonal birth control or intrauterine device (IUD) (women).
  • Female patients with child-bearing potential must have a negative serum pregnancy test within 72 hours prior to the first study drug administration.
  • Ability to understand and the willingness to sign a written informed consent document. Participants with impaired decision-making capacity (IDMC) who have a legally-authorized representative (LAR) and/or family member available will also be eligible.

Who cannot join

  • Patients with evidence of p53 mutation or deletion (e.g. chromosome 17p deletion).
  • Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities > grade 2) with the exception of alopecia.
  • Patients receiving any other investigational or commercial agents or therapies administered with the intention to treat their malignancy within 14 days of first receipt of study drug with the exception of: Hydroxyurea (HU) in patients who need to continue this agent to maintain white blood cell (WBC) count =< 50,000/mm^3.
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to KRT-232 (AMG 232) or other agents used in study.
  • Patients with uncontrolled intercurrent illness including, but not limited to, active infection, symptomatic congestive heart failure, unstable angina pectoris, or cardiac arrhythmia; patients receiving an anti-microbial agent may be eligible if the patient remains hemodynamically stable for 72 hours; patients with myocardial infarction within 6 months of study day 1, symptomatic congestive heart failure (New York Heart Association [NYHA] class III and higher), unstable angina, or cardiac arrhythmia requiring medication are excluded.
  • Patients with psychiatric illness/social situations that would limit compliance with study requirements.
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  • Pregnant women are excluded from this study because KRT-232 (AMG 232) is an MDM2 inhibiting agent with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with KRT-232 (AMG 232), breastfeeding should be discontinued if the mother is treated with KRT-232 (AMG 232). These potential risks may also apply to other agents used in this study.
  • Patients with reproductive potential not willing to use effective methods of contraception.
  • Patients with gastrointestinal (GI) tract disease causing the inability to take oral medication, malabsorption syndrome, requirement for intravenous alimentation, prior surgical procedures affecting absorption, uncontrolled inflammatory GI disease (e.g., Crohn's disease, ulcerative colitis).
  • Patients with history of bleeding diathesis.
  • Positive hepatitis B surface antigen (HepBsAg) (indicative of chronic hepatitis B), positive hepatitis total core antibody with negative HBsAG (suggestive of occult hepatitis B), or detectable hepatitis C virus ribonucleic acid (RNA) by a polymerase-chain reaction (PCR) assay (indicative of active hepatitis C - screening is generally done by hepatitis C antibody [HepCAb], followed by hepatitis C virus RNA by PCR if HepCAb is positive).
  • All herbal medicines (e.g., St. John's wort), vitamins, and supplements consumed by the subject within the 30 days prior to receiving the first dose of AMG 232, and continuing use, if applicable, will be reviewed by the principal investigator. Patients may continue to take all herbal medicines (e.g., St. John's wort), vitamins, and supplements if approved by the principal investigator.
  • Use of any known CYP3A4 substrates with narrow therapeutic window (such as alfentanil, astemizole, cisapride, dihydroergotamine, pimozide, quinidine, sirolimus, or terfanide) within the 14 days prior to receiving the first dose of AMG 232 is not permitted. Other medications (such as fentanyl and oxycodone) may be allowed per investigator's assessment/evaluation. Use of any known CYP2C8 substrates with a narrow therapeutic window within the 14 days prior to receiving the first dose of KRT-232 (AMG 232) is not permitted.
  • Use of any medications considered inhibitors or substrates of UGT1A1, or inhibitors or inducers of P-glycoprotein (gp) are not permitted. Caution should be used with concomitant antacids or proton pump inhibitor (PPI) products.
  • Major surgery within 28 days of study day 1.
  • Current use of warfarin, factor Xa inhibitors and direct thrombin inhibitors. Note: Low molecular weight heparin and prophylactic low dose warfarin are permitted. PT/PTT must meet the inclusion criteria. Subjects taking warfarin must have their INR followed closely.

Trial locations and contacts

6 sites in 1 country.

6 sites in 1 country

United States6 sites

  • University of Maryland/Greenebaum Cancer Center

    Baltimore, Maryland, 21201

  • Northwestern University

    Chicago, Illinois, 60611

  • Los Angeles General Medical Center

    Los Angeles, California, 90033

  • USC / Norris Comprehensive Cancer Center

    Los Angeles, California, 90033

  • Laura and Isaac Perlmutter Cancer Center at NYU Langone

    New York, New York, 10016

  • University of Oklahoma Health Sciences Center

    Oklahoma City, Oklahoma, 73104

Other trials in United States

About this study

Official title: A Phase 1b Study With Expansion Cohort of Escalating Doses of KRT-232 (AMG 232) Administered in Combination With Standard Induction Chemotherapy (Cytarabine and Idarubicin) in Newly Diagnosed Acute Myelogenous Leukemia (AML)

This phase Ib trial studies the side effects and best dose of navtemadlin when given together with the standard chemotherapy drugs cytarabine and idarubicin in patients with acute myeloid leukemia. Navtemadlin may stop the growth of cancer cells by blocking a protein called MDM2 that is needed for cell growth. Chemotherapy drugs, such as cytarabine and idarubicin, 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 navtemadlin with cytarabine and idarubicin may stabilize cancer for longer when compared to giving usual treatments alone.

Read the detailed description

PRIMARY OBJECTIVE:

  1. To evaluate the toxicities of navtemadlin (KRT-232 [AMG 232]), cytarabine and idarubicin hydrochloride (idarubicin), and to determine the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D) of KRT-232 (AMG 232), cytarabine and idarubicin.

SECONDARY OBJECTIVES:

  1. To observe and record anti-tumor activity. II. To evaluate the pharmacokinetic (PK) profiles of KRT-232 (AMG 232), cytarabine and idarubicin when used in combination.

III. To evaluate p53 signaling induced by KRT-232 (AMG 232), cytarabine and idarubicin.

IV. To correlate KRT-232 (AMG 232), cytarabine and idarubicin exposure with pharmacodynamics endpoints (efficacy, toxicity, changes in p53 signaling).

EXPLORATORY OBJECTIVES:

  1. To evaluate the response rate (RR) and progression free survival (PFS) of KRT-232 (AMG 232), cytarabine and idarubicin in acute myeloid leukemia (AML).

II. To evaluate potential predictive biomarkers, including MTF2 and H3K27me3, of response to KRT-232 (AMG 232), cytarabine and idarubicin in AML.

III. To evaluate the pharmacodynamic (PD) effects of KRT-232 and induction chemotherapy in AML blasts.

OUTLINE: This is a dose-escalation study of navtemadlin.

Patients receive navtemadlin orally (PO) once daily (QD) on days 1-7, cytarabine intravenously (IV) twice daily (BID) over 3 hours on days 1-7, and idarubicin IV over 10-15 minutes on days 1-3. Treatment repeats every 28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients with residual disease may receive cytarabine IV BID over 3 hours for 5 days and idarubicin IV over 10-15 minutes for 2 days starting between days 14-21 of cycle 1 or the second cycle of navtemadlin, cytarabine, and idarubicin. Patients who achieve a complete response (CR) or a CR with incomplete hematologic recovery (CRi) in either cycle 1 or 2 may receive cytarabine IV BID over 3 hours on days 1, 3, and 5 for 3-4 additional 28 to 35-day cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days and then every 3 months for 2 years, then every 6 months thereafter.

Being tested
Cytarabine, Idarubicin Hydrochloride, Navtemadlin
Medical subject headings
Leukemia, Myeloid, Acute

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • CytarabineDrug

    Also called .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

    Given IV

  • Idarubicin HydrochlorideDrug

    Also called Idamycin, Idamycin PFS, Idarubicin HCl, IMI-30

    Given IV

  • NavtemadlinDrug

    Also called (3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((1S)-2-methyl-1-(((1-methylethyl)sulfonyl)methyl)propyl)-2-oxo-3-piperidineacetic Acid, AMG 232, AMG-232, KRT 232

    Given PO

Study groups in NCT04190550
Study groupRoleWhat they receive
Treatment (navtemadlin, cytarabine, idarubicin)ExperimentalPatients receive navtemadlin PO QD on days 1-7, cytarabine IV BID over 3 hours on days 1-7, and idarubicin IV over 10-15 minutes on days 1-3. Treatment repeats every 28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients with residual disease may receive cytarabine IV BID over 3 hours for 5 days and idarubicin IV over 10-15 minutes for 2 days starting between days 14-21 of cycle 1 or the second cycle of navtemadlin, cytarabine, and idarubicin. Patients who achieve a CR or a CRi in either cycle 1 or 2 may receive cytarabine IV BID over 3 hours on days 1, 3, and 5 for 3-4 additional 28 to 35-day cycles in the absence of disease progression or unacceptable toxicity.
Receives: Drug: Cytarabine; Drug: Idarubicin Hydrochloride; Drug: Navtemadlin

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Incidence of adverse events

    Toxicity will be coded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Based on the toxicity observed, a derived variable, the occurrence of dose limiting toxicity, will be created. Toxicities will be tabulated and reported according to dose level, grade, type, cycle, and attribution and, if numbers permit, by whether the patient had newly diagnosed or previously treated acute myeloid leukemia (AML). Cumulative incidence curves will be used to estimate the proportion of patients who will discontinue therapy for reasons of toxicity or general inability to tolerate the regimen. The data from all patients treated at the recommended phase 2 dose (RP2D), will be combined for a final summary and listing of toxicities observed.

    Measured: Up to 30 days after the last dose of navtemadlin

Secondary outcomes (1)

  1. Pharmacokinetic (PK) profile of navtemadlin in combination with cytarabine and idarubicin

    Will be quantitatively measured using liquid chromatography/tandem mass spectrometric (LC/MS/MS) method developed by the Analytical Pharmacology Core Laboratory at the Sidney Kimmel Comprehensive Cancer Center (SKCCC) at Johns Hopkins. For navtemadlin, the individual PK parameters from a single dose will be estimated for concentration maximum (Cmax), area under the curve (AUC), half-life (T1/2), apparent clearance (Cl/F), and apparent volume of distribution (V/F) using non-compartmental or compartmental PK methods with the software WinNonlin. Advanced population PK methods may be employed to assess the link between drug exposure and biological effects and efficacy.

    Measured: Pre-treatment and 1, 3, 5, 8, and 24 hours post-treatment on cycle 1, day 1 (1 cycle = 28-35 days)

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted9 Dec 2019
  2. Study start4 Feb 2021
  3. Primary completion30 Jun 2027 (estimated)
  4. Study completion30 Jun 2027 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
24 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04190550
Sponsor's protocol ID
NCI-2019-08137
Other IDs
NCI-2019-08137, PHI-115, 10367, 10367, UM1CA186717
Status last verified
Jun 2026
First submitted
6 Dec 2019
Last updated
11 Jun 2026
Results posted
No
Data monitoring committee
No
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
Yes: NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page.

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing Cytarabine, Idarubicin Hydrochloride and Navtemadlin in people with Acute Myeloid Leukemia and Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome, run by National Cancer Institute (NCI) at 6 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 18 inclusion and 16 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: under way, not looking for participants, as of the sponsor's last update on 11 Jun 2026. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 6 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

This study is still under way. Results are not available in the source record yet.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Incidence of adverse events (time frame: Up to 30 days after the last dose of navtemadlin). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04190550.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 11 Jun 2026.

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