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

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ClinicalTrials.gov Identifier: NCT03041688
Recruitment Status : Recruiting
First Posted : February 3, 2017
Last Update Posted : October 7, 2019
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Brief Summary:
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 (recurrent), does not respond to treatment (refractory), 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.

Condition or disease Intervention/treatment Phase
Acute Myeloid Leukemia Recurrent Acute Myeloid Leukemia Refractory Acute Myeloid Leukemia Secondary Acute Myeloid Leukemia Drug: Decitabine Drug: MDM2 Inhibitor AMG-232 Phase 1

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).

EXPLORATORY 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 cycles in patients with evidence of persistent AML.

Starting cycle 2, patients with no morphologic evidence of AML receive decitabine IV over 1 hour on days 1-5 and AMG-232 PO QD on days 4-10. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

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


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 58 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1B Study of AMG-232 in Combination With Decitabine in Acute Myeloid Leukemia
Actual Study Start Date : October 12, 2017
Estimated Primary Completion Date : October 31, 2019
Estimated Study Completion Date : October 31, 2019


Arm Intervention/treatment
Experimental: Treatment (decitabine, MDM2 inhibitor AMG-232)

Patients 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 cycles in patients with evidence of persistent AML.

Starting cycle 2, patients with no morphologic evidence of AML receive decitabine IV over 1 hour on days 1-5 and AMG-232 PO QD on days 4-10. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Drug: Decitabine
Given IV
Other Names:
  • 5-Aza-2''-deoxycytidine
  • Dacogen
  • Decitabine for Injection
  • Deoxyazacytidine
  • Dezocitidine

Drug: MDM2 Inhibitor AMG-232
Given PO
Other Names:
  • AMG 232
  • AMG-232




Primary Outcome Measures :
  1. Incidence of toxicity [ Time Frame: Up to 4 weeks ]
    Will be evaluated according to National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. 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 :
  1. Pharmacokinetics (PK) profile [ 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 ]
    Will be measured using liquid chromatography/tandem mass spectrometric method. 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.

  2. P53 activation [ Time Frame: Up to 4 weeks ]
    Will be measured by MIC-1 levels. 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.

  3. Change in p53 signaling [ Time Frame: Baseline to 30 days after end of study treatment ]
    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.


Other Outcome Measures:
  1. Complete response (CR) or CR with incomplete blood count recovery [ Time Frame: Up to 112 days ]
    The percent of CR's will be calculated and associated exact 95% confidence intervals will be constructed.

  2. Complete cytogenetic response (CRc or molecular CR [CRm]) [ Time Frame: Up to 112 days ]
    Will be evaluated according to revised International Working Group criteria. The percent of CR's will be calculated and associated exact 95% confidence intervals will be constructed.

  3. Progression-free survival (PFS) [ Time Frame: From start of treatment to progression/recurrence or death, whichever comes first, assessed up to 4 weeks ]
    Kaplan-Meier plots will be used to summarize PFS.

  4. Pharmacodynamic (PD) effects on leukemia blasts [ Time Frame: Up to 4 weeks ]
    PD effects of MDM2 inhibitor AMG232 in combination with decitabine on leukemia blasts will be explored.

  5. Predictive biomarker of sensitivity [ Time Frame: Up to 4 weeks ]
    PD effects of MDM2 inhibitor AMG232 in combination with decitabine on potential predictive biomarker of sensitivity will be explored.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Relapsed/refractory AML (>= 20% 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 measurable disease as defined the presence of >= 20% blasts in bone marrow or extramedullary leukemia
  • Eligible patient must show evidence of wild-type (WT) p53 as assessed by central DNA sequencing; 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
  • The effects of AMG 232 on the developing human fetus are unknown; for this reason and because decitabine is known to be teratogenic, 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 because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events
  • 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 because AMG 232 is an 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 AMG 232, breastfeeding should be discontinued if the mother is treated with AMG 232; these potential risks may also apply to other agents used in this study
  • 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03041688


Locations
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United States, California
City of Hope Comprehensive Cancer Center Recruiting
Duarte, California, United States, 91010
Contact: Site Public Contact    800-826-4673    becomingapatient@coh.org   
Principal Investigator: Samer K. Khaled         
Los Angeles County-USC Medical Center Recruiting
Los Angeles, California, United States, 90033
Contact: Site Public Contact    323-865-0451      
Principal Investigator: Kevin R. Kelly         
USC / Norris Comprehensive Cancer Center Recruiting
Los Angeles, California, United States, 90033
Contact: Site Public Contact    323-865-0451      
Principal Investigator: Kevin R. Kelly         
Keck Medical Center of USC Pasadena Suspended
Pasadena, California, United States, 91105
University of California Davis Comprehensive Cancer Center Recruiting
Sacramento, California, United States, 95817
Contact: Site Public Contact    916-734-3089      
Principal Investigator: Brian A. Jonas         
United States, Kentucky
University of Kentucky/Markey Cancer Center Recruiting
Lexington, Kentucky, United States, 40536
Contact: Site Public Contact    859-257-3379      
Principal Investigator: Reshma Ramlal         
United States, Maryland
Johns Hopkins University/Sidney Kimmel Cancer Center Recruiting
Baltimore, Maryland, United States, 21287
Contact: Site Public Contact    410-955-8804    jhcccro@jhmi.edu   
Principal Investigator: Jonathan A. Webster         
United States, Massachusetts
Massachusetts General Hospital Cancer Center Suspended
Boston, Massachusetts, United States, 02114
Brigham and Women's Hospital Suspended
Boston, Massachusetts, United States, 02115
Beth Israel Deaconess Medical Center Recruiting
Boston, Massachusetts, United States, 02215
Contact: Site Public Contact    617-667-9925      
Principal Investigator: Myrna R. Nahas         
Dana-Farber Cancer Institute Recruiting
Boston, Massachusetts, United States, 02215
Contact: Site Public Contact    877-442-3324      
Principal Investigator: Myrna R. Nahas         
United States, Ohio
Ohio State University Comprehensive Cancer Center Active, not recruiting
Columbus, Ohio, United States, 43210
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Kevin R Kelly City of Hope Comprehensive Cancer Center LAO

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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT03041688     History of Changes
Other Study ID Numbers: NCI-2017-00128
NCI-2017-00128 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
PHI-92
10075 ( Other Identifier: City of Hope Comprehensive Cancer Center LAO )
10075 ( Other Identifier: CTEP )
UM1CA186717 ( U.S. NIH Grant/Contract )
First Posted: February 3, 2017    Key Record Dates
Last Update Posted: October 7, 2019
Last Verified: August 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Neoplasms by Histologic Type
Neoplasms
Decitabine
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Enzyme Inhibitors