Clinical Trials /

MDM2 Inhibitor AMG-232 and Decitabine in Treating Patients With Relapsed, Refractory, or Newly-Diagnosed Acute Myeloid Leukemia

NCT03041688

Description:

This phase Ib trial studies the side effects and best dose of murine double minute chromosome 2 (MDM2) inhibitor AMG-232 when given together with decitabine in treating patients with acute myeloid leukemia that has come back, does not respond to treatment, or is newly diagnosed. MDM2 inhibitor AMG-232 may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as decitabine, 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 MDM2 inhibitor AMG-232 and decitabine together may work better than decitabine alone in treating patients with acute myeloid leukemia.

Related Conditions:
  • Acute Myeloid Leukemia
Recruiting Status:

Suspended

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: MDM2 Inhibitor AMG-232 and Decitabine in Treating Patients With Relapsed, Refractory, or Newly-Diagnosed Acute Myeloid Leukemia
  • Official Title: A Phase 1B Study of AMG-232 in Combination With Decitabine in Acute Myeloid Leukemia

Clinical Trial IDs

  • ORG STUDY ID: NCI-2017-00128
  • SECONDARY ID: NCI-2017-00128
  • SECONDARY ID: PHI-92
  • SECONDARY ID: 10075
  • SECONDARY ID: 10075
  • SECONDARY ID: UM1CA186717
  • NCT ID: NCT03041688

Conditions

  • Acute Myeloid Leukemia
  • Blasts 5 Percent or More of Bone Marrow Nucleated Cells
  • Recurrent Adult Acute Myeloid Leukemia
  • Refractory Acute Myeloid Leukemia
  • Secondary Acute Myeloid Leukemia
  • TP53 wt Allele
  • Untreated Adult Acute Myeloid Leukemia

Interventions

DrugSynonymsArms
Decitabine5-Aza-2'-deoxycytidine, Aza-TdC, Dacogen, Decitabine for Injection, Deoxyazacytidine, DezocitidineTreatment (decitabine, MDM2 inhibitor AMG-232)
MDM2 Inhibitor AMG-232AMG 232, AMG-232Treatment (decitabine, MDM2 inhibitor AMG-232)

Purpose

This phase Ib trial studies the side effects and best dose of murine double minute chromosome 2 (MDM2) inhibitor AMG-232 when given together with decitabine in treating patients with acute myeloid leukemia that has come back, does not respond to treatment, or is newly diagnosed. MDM2 inhibitor AMG-232 may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as decitabine, 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 MDM2 inhibitor AMG-232 together and decitabine together may work better in treating patients with acute myeloid leukemia.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To evaluate the toxicities of MDM2 inhibitor AMG-232 (AMG-232) in combination with
      decitabine (20 mg/m^2 for 10 days), and to determine the maximum tolerated dose
      (MTD)/recommended phase 2 dose (RP2D) of AMG-232 in combination with a standard dose of
      decitabine.

      SECONDARY OBJECTIVES:

      I. To evaluate the pharmacokinetic (PK) profiles of AMG-232 and decitabine when used in
      combination.

      II. To evaluate tumor suppressor protein 53 (p53) signaling induced by AMG-232 and decitabine
      as measured by macrophage inhibitory cytokine-1 (MIC-1) induction.

      III. To correlate AMG-232 and decitabine exposure with pharmacodynamics endpoints (efficacy,
      toxicity, changes in p53 signaling).

      TERTIARY OBJECTIVES:

      I. To evaluate the response rate (RR) and progression free survival (PFS) of AMG-232 and
      decitabine in acute myeloid leukemia (AML).

      II. To evaluate potential predictive biomarkers of response to AMG-232 and decitabine in AML.

      III. To evaluate the pharmacodynamic (PD) effects of AMG-232 and decitabine in AML blasts.

      IV. To determine the variability of decitabine incorporation into genomic deoxyribonucleic
      acid (DNA) and correlate with systemic pharmacokinetics and exposure-response relationships.

      OUTLINE: This is a dose-escalation study of MDM2 inhibitor AMG-232.

      Patients receive decitabine intravenously (IV) over 1 hour on days 1-10 and MDM2 inhibitor
      AMG-232 orally (PO) once daily (QD) on days 4-10 and 18-24. Treatment repeats every 28 days
      for up to 4 courses in the absence of disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up for 30 days.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (decitabine, MDM2 inhibitor AMG-232)ExperimentalPatients receive decitabine IV over 1 hour on days 1-10 and MDM2 inhibitor AMG-232 PO QD on days 4-10 and 18-24. Treatment repeats every 28 days for up to 4 courses in the absence of disease progression or unacceptable toxicity.
  • Decitabine
  • MDM2 Inhibitor AMG-232

Eligibility Criteria

        Inclusion Criteria:

          -  Relapsed/refractory AML (>= 5% blasts in bone marrow or extramedullary leukemia) or
             newly diagnosed AML patients who are not candidates for (age >= 70 years; adverse
             cytogenetics, e.g., as defined by the Medical Research Council [MRC] Prognostic
             Groupings; secondary AML; organ dysfunction arising from significant co-morbidities
             not directly linked to leukemia; Eastern Cooperative Oncology Group [ECOG] = 2) or not
             willing to undergo intensive chemotherapy; Note that both relapsed/refractory and
             newly diagnosed AML patients will be eligible for the dose escalation part of the
             study, but only newly diagnosed patients will be eligible for the dose expansion
             cohort

          -  Patients must have measureable disease as defined the presence of >= 5% blasts in bone
             marrow or extramedullary leukemia

          -  Eligible patient must show evidence of wild-type (WT) p53 as assessed by central DNA
             sequencing conducted at Dr. Jeffrey Sklar's laboratory at Yale University Cancer
             Center; note, that since patients with AML have a rapidly proliferating disease,
             patient can be enrolled and begin treatment prior to obtaining the results of this
             test; patients who are found to the TP53 mutated will be removed from study and can
             continue on single agent decitabine; however patients will continue to be followed for
             toxicity

          -  ECOG performance status =< 2 (Karnofsky >= 60%)

          -  Total bilirubin < 1.5 x institutional upper limit of normal (ULN) (< 2.0 x ULN for
             subjects with documented Gilbert's syndrome or < 3.0 x ULN for subjects for whom the
             indirect bilirubin level suggests an extrahepatic source of elevation)

          -  Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and
             alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =< 2.5 x
             ULN

          -  Alkaline phosphatase < 2.0 x ULN (if liver or bone metastases are present, < 3.0 x
             ULN)

          -  Body surface area (BSA)-normalized creatinine clearance >= 30 mL/min/1.73 m^2 (using
             Cockcroft-Gault creatinine clearance [CrCl])

          -  Prothrombin time (PT) or partial thromboplastin time (PTT) < 1.5 x upper limit of
             normal (ULN), OR international normalized ratio (INR) < 1.5

          -  Patient must be willing to submit the blood sampling and bone marrow sampling for the
             PK and PD analyses and exploratory biomarkers

          -  Women of child-bearing potential must agree to use adequate contraception prior to
             study entry and for the duration of study participation through 5 weeks (women) after
             receiving the last dose of 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 AMG 232 administration

               -  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)

          -  Ability to understand and the willingness to sign a written informed consent document

        Exclusion Criteria:

          -  Acute promyelocytic leukemia with t(15;17)(q22;q12) and/or PML-RARA molecular
             rearrangement

          -  Patients with previously untreated AML with core binding factor (CBF) chromosomal
             aberrations (inv[16]/t[16;16] or t[8;21]); Note that patients with relapsed or
             refractory AML with CBF chromosomal aberrations will be eligible

          -  Unresolved toxicities from prior anti-tumor therapy, defined as not having resolved to
             Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 grade 0 or 1, or to
             levels dictated in the eligibility criteria with the exception of alopecia (grade 2 or
             3 toxicities from prior antitumor therapy that are considered irreversible [defined as
             having been present and stable for > 6 months], such as ifosfamide-related
             proteinuria, may be allowed if they are not otherwise described in the exclusion
             criteria AND there is agreement to allow by both the investigator and sponsor)

          -  Patients who are receiving any other investigational agents

          -  Major surgery within 28 days of study day 1

          -  Patients with known central nervous system involvement at the time of study entry will
             be excluded from this clinical trial

          -  History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to AMG 232 or decitabine

          -  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

          -  Use of any known CYP2C8 substrates with a narrow therapeutic window is not allowed
             during the study and patients must come off 14 days prior to receiving the first dose
             of AMG 232

          -  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; other
             medications (such as fentanyl and oxycodone) may be allowed per investigator's
             assessment/evaluation

          -  Treatment with medications known to cause corrected QT (QTc) interval prolongation
             within 7 days of study day 1 is not permitted unless approved by the sponsor; use of
             ondansetron is permitted for treatment of nausea and vomiting

          -  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

          -  Uncontrolled intercurrent illness including, but not limited to, active infection,
             symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or
             psychiatric illness/social situations that would limit compliance with study
             requirements; 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 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)

          -  Human immunodeficiency virus (HIV)-patients positive for human immunodeficiency virus
             (HIV) are NOT excluded from this study, but HIV-positive patients must have:

               -  A stable regimen of highly active anti-retroviral therapy (HAART)

               -  No requirement for concurrent antibiotics or antifungal agents for the prevention
                  of opportunistic infections

               -  A CD4 count above 250 cells/mcL and an undetectable HIV viral load on standard
                  PCR-based test

          -  Men and women of reproductive potential who are unwilling to practice acceptable
             methods of effective birth control while on study through 5 weeks (women) or 3 months
             (men) after receiving the last dose of AMG 232; acceptable 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)

          -  Pregnant women are excluded from this study; breastfeeding should be discontinued if
             the mother is treated with AMG 232

          -  Women who are lactating/breast feeding or who plan to breastfeed while on study
             through 1 week after receiving the last dose of study drug

          -  Patients with a baseline QTc > 500 msec and patients with a family history of
             prolonged QT syndrome

          -  Patients with known TP53 mutations or chromosome 17 or 17p deletions
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of toxicity evaluated according to National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5.0
Time Frame:Up to 4 weeks
Safety Issue:
Description:The maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) will be determined. Based on the toxicity observed, a derived variable, the occurrence of dose limiting toxicity, will be created. Will be correlated with MDM2 inhibitor AMG-232 and decitabine exposure. 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 RP2D, will be combined for a final summary and listing of toxicities observed.

Secondary Outcome Measures

Measure:Pharmacokinetics (PK) profile measured using liquid chromatography/tandem mass spectrometric method
Time Frame:Baseline, 1, 3, 5, 8 and 24 hours post dose on days 4 and 18 of course 1; baseline, 0.5 hour, prior to end of infusion, 0.25, 0.5, and 1 hour post infusion on days 1 and 4 of course 1
Safety Issue:
Description:Standard descriptive methods (point estimates and confidence intervals, scatterplots) will be used to summarize the baseline levels and the changes from baseline (i.e. after treatment). The individual PK parameters from a single dose will be estimated maximum concentration (Cmax), area under the curve (AUC), half-life (T1/2), apparent clearance, and apparent volume of distribution using non-compartmental or compartmental PK methods with the software WinNonlin. Cmax and AUC will be calculated for decitabine systemic exposure.
Measure:P53 activation measured by MIC-1 levels
Time Frame:Up to 4 weeks
Safety Issue:
Description:For serum MIC-1 levels, each individual level will be normalized to the baseline level for that patient. Will be analyzed using nonparametric statistics. Significance for comparisons will be at the p < 0.05 level.
Measure:Change in p53 signaling
Time Frame:Baseline to 30 days after end of study treatment
Safety Issue:
Description:Will be correlated with MDM2 inhibitor AMG-232 and decitabine exposure. Will be analyzed using nonparametric statistics. Significance for comparisons will be at the p < 0.05 level.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Suspended
Lead Sponsor:National Cancer Institute (NCI)

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