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A Phase 1B Study of AMG-232 in Combination With Decitabine in Acute Myeloid Leukemia

Description

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, 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.


Detailed Description
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 the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up for 30 days.

Phase

N/A

Inclusion and Exclusion 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 measureable 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

  • 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
  • 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

Sites

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