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

NCT04190550 | Active Not Recruiting Phase 1 FDA Drug

• 4 other identifiers: NCI-2019-08137PHI-11510367UM1CA186717
• Study Type: interventional
• Target: 24
• Locations: 1 country
• Sites: 6

Brief 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. 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.

Conditions

Acute Myeloid Leukemia; Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome

Outcome Measures

Primary Outcomes (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.

  Up to 30 days after the last dose of navtemadlin

Secondary Outcomes (1)

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

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

Other Outcomes (5)

• Complete response rate to navtemadlin, cytarabine and idarubicin

  Up to 2 years

• Complete cytogenetic response to navtemadlin, cytarabine and idarubicin

  Up to 2 years

• Progression-free survival (PFS)

  From start of treatment to progression/recurrence or death - whichever comes first, assessed up to 2 years

Study Arms (1)

Treatment (navtemadlin, cytarabine, idarubicin)

EXPERIMENTAL

Patients 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.

Drug: Cytarabine; Drug: Idarubicin Hydrochloride; Drug: Navtemadlin

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 (navtemadlin, cytarabine, idarubicin)

Navtemadlin DRUG

Given PO

Also known as: (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, KRT-232, KRT232, MDM2 Inhibitor KRT-232

Treatment (navtemadlin, cytarabine, idarubicin)

Idarubicin Hydrochloride DRUG

Given IV

Also known as: Idamycin, Idamycin PFS, Idarubicin HCl, IMI-30, SC-33428, Zavedos

Treatment (navtemadlin, cytarabine, idarubicin)

Eligibility Criteria

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

You may qualify if:

• 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.
• 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.

You may not qualify if:

• 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.
• 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.

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (6)

Los Angeles General Medical Center

Los Angeles, California, 90033, United States

Location

USC / Norris Comprehensive Cancer Center

Los Angeles, California, 90033, United States

Location

Northwestern University

Chicago, Illinois, 60611, United States

Location

University of Maryland/Greenebaum Cancer Center

Baltimore, Maryland, 21201, United States

Location

Laura and Isaac Perlmutter Cancer Center at NYU Langone

New York, New York, 10016, United States

Location

University of Oklahoma Health Sciences Center

Oklahoma City, Oklahoma, 73104, United States

Location

MeSH Terms

Conditions

Leukemia, Myeloid, Acute

Interventions

Cytarabine; Idarubicin; 4-demethoxydaunorubicin bis(hydrazone); navtemadlin; 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsulfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; 2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-(isopropylsulfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Arabinonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Daunorubicin; Anthracyclines; Naphthacenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Polycyclic Compounds; Aminoglycosides; Glycosides; Carbohydrates

Study Officials

• Kevin R Kelly

  City of Hope Comprehensive Cancer Center LAO

  PRINCIPAL INVESTIGATOR

Study Design

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

Study Record Dates

• First Submitted: December 6, 2019
• First Posted: December 9, 2019
• Study Start: February 4, 2021
• Primary Completion (Estimated): June 30, 2026
• Study Completion (Estimated): June 30, 2026
• Last Updated: April 13, 2026

Record last verified: 2025-12

Data Sharing

• IPD Sharing: Will share

Locations

US (6)