Clinical Trials /

Testing a New Chemotherapy Drug, KRT-232 (AMG 232) in Combination With Standard Chemotherapy (Cytarabine and Idarubicin) in Patients With Acute Myeloid Leukemia

NCT04190550

Description:

This phase Ib trial studies the side effects and best dose of KRT-232 (AMG 232) when given together with the standard chemotherapy drugs cytarabine and idarubicin in patients with acute myeloid leukemia. KRT-232 (AMG 232) may stop the growth of cancer cells by blocking a protein called MDM2 that is needed for cell growth. Drugs used in chemotherapy, 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 KRT-232 (AMG 232) with cytarabine and idarubicin may stabilize cancer for longer when compared to giving usual treatments alone.

Related Conditions:
  • Acute Myeloid Leukemia
Recruiting Status:

Not yet recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Testing a New Chemotherapy Drug, KRT-232 (AMG 232) in Combination With Standard Chemotherapy (Cytarabine and Idarubicin) in Patients With Acute Myeloid Leukemia
  • 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)

Clinical Trial IDs

  • ORG STUDY ID: NCI-2019-08137
  • SECONDARY ID: NCI-2019-08137
  • SECONDARY ID: PHI-115
  • SECONDARY ID: 10367
  • SECONDARY ID: 10367
  • SECONDARY ID: UM1CA186717
  • NCT ID: NCT04190550

Conditions

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

Interventions

DrugSynonymsArms
Cytarabine.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-28453Treatment (AMG 232, cytarabine, idarubicin)
Idarubicin4-Demethoxydaunomycin, 4-demethoxydaunorubicin, 4-DMDRTreatment (AMG 232, cytarabine, idarubicin)
Idarubicin HydrochlorideIdamycin, Idamycin PFS, Idarubicin HCl, IMI-30, SC-33428, ZavedosTreatment (AMG 232, cytarabine, idarubicin)
MDM2 Inhibitor AMG-232AMG 232, AMG-232Treatment (AMG 232, cytarabine, idarubicin)

Purpose

This phase Ib trial studies the side effects and best dose of KRT-232 (AMG 232) when given together with the standard chemotherapy drugs cytarabine and idarubicin in patients with acute myeloid leukemia. KRT-232 (AMG 232) may stop the growth of cancer cells by blocking a protein called MDM2 that is needed for cell growth. Drugs used in chemotherapy, 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 KRT-232 (AMG 232) with cytarabine and idarubicin may stabilize cancer for longer when compared to giving usual treatments alone.

Detailed Description

      PRIMARY OBJECTIVE:

      I. To evaluate the toxicities of MDM2 inhibitor AMG-232 (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:

      I. 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:

      I. 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 AMG 232.

      Patients receive AMG 232 orally (PO) once daily (QD) on days 1-7, cytarabine intravenously
      (IV) 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 benefiting from treatment but with signs of AML may receive cytarabine for 5 days
      and idarubicin for 2 days in the middle of cycle 1. Patients who have no signs of AML may
      then receive cytarabine IV 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.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (AMG 232, cytarabine, idarubicin)ExperimentalPatients receive AMG 232 PO QD on days 1-7, cytarabine IV 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 benefiting from treatment but with signs of AML may receive cytarabine for 5 days and idarubicin for 2 days in the middle of cycle 1. Patients who have no signs of AML may then receive cytarabine IV on days 1, 3, and 5 for 3-4 additional 28 to 35-day cycles in the absence of disease progression or unacceptable toxicity.
  • Cytarabine
  • Idarubicin
  • Idarubicin Hydrochloride
  • MDM2 Inhibitor AMG-232

Eligibility Criteria

        Inclusion Criteria:

          -  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.

          -  Corrected QT interval (QTc) =< 470 msec (based on average of screening triplicates).

          -  Leukocytes >= 3,000/mcL.

          -  Absolute neutrophil count >= 1,500/mcL.

          -  Platelets >= 100,000/mcL.

          -  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 treated brain metastases are eligible if follow-up brain imaging after
             central nervous system (CNS)-directed therapy shows no evidence of progression.

          -  Patients with new or progressive brain metastases (active brain metastases) or
             leptomeningeal disease are eligible if the treating physician determines that
             immediate CNS specific treatment is not required and is unlikely to be required during
             the first cycle of therapy.

          -  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.

        Exclusion Criteria:

          -  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 1) 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 afebrile and 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.

          -  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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of adverse events
Time Frame:Up to 30 days after the last dose of KRT-232 (AMG 232)
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure:Pharmacokinetic (PK) profile of KRT-232 (AMG 232) in combination with cytarabine and idarubicin
Time Frame:Pre-treatment and 1, 3, 5, 8, and 24 hours post-treatment on cycle 1, day 1
Safety Issue:
Description: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 KRT -232, 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.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:National Cancer Institute (NCI)

Last Updated

December 9, 2019