Prexasertib, Mitoxantrone Hydrochloride, Etoposide, and Cytarabine in Treating Patients with Recurrent or Refractory Acute Myeloid Leukemia or High Risk Myelodysplastic Syndrome

Status: Active

Description

This phase I trial studies the side effects and best dose of prexasertib when given together with mitoxantrone hydrochloride, etoposide, and cytarabine in treating patients with acute myeloid leukemia or high risk myelodysplastic syndrome that has come back or does not respond to treatment. Prexasertib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as mitoxantrone hydrochloride, etoposide, and cytarabine, 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 prexasertib, mitoxantrone hydrochloride, etoposide, and cytarabine may work better in treating patients with acute myeloid leukemia or high risk myelodysplastic syndrome compared to mitoxantrone hydrochloride, etoposide, and cytarabine.

Eligibility Criteria

Inclusion Criteria

  • Patients must have histologically confirmed relapsed or refractory acute myeloid leukemia (AML) or high risk myelodysplastic syndrome (MDS) diagnosed per World Health Organization (WHO) criteria
  • For refractory AML: refractory as defined per International Working Group (IWG) criteria. Refractory patients must have had =< 2 prior induction regimens (hydroxyurea is not considered a prior treatment regimen). “5+2” reinduction at day 14 is not considered a second regimen
  • For relapsed AML: relapse as defined by IWG criteria. Relapsed patients must be first or second relapse (hydroxyurea is not considered a prior treatment regimen)
  • For patients with MDS, >= 10% myeloblasts in the bone marrow, and no more than 2 prior treatment regimens (hydroxyurea is not considered a prior treatment regimen)
  • Patients must be medically eligible to receive mitoxantrone, etoposide, and cytarabine (MEC) therapy
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
  • Total bilirubin =< 1.5 x institutional upper limit of normal (ULN), OR
  • Total bilirubin =< 2 x institutional ULN if the participant has a history of Gilbert’s syndrome
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional ULN, OR
  • AST(SGOT)/ALT(SGPT) =< 5 x institutional ULN if elevation is a result of leukemia
  • Serum creatinine =< 1.5 x institutional ULN, OR
  • Creatinine clearance >= 60 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal (calculated via the Cockcroft-Gault equation)
  • Left ventricular ejection fraction (LVEF) >= 50% on screening echocardiogram (ECHO) or multigated acquisition scan (MUGA)
  • Corrected QT interval by Fridericia (QTcF) value of =< 450 msec on screening electrocardiogram (ECG)
  • Women of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 4 months after treatment. 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 4 months after completion of study therapy administration. A negative serum pregnancy test is required for women of child-bearing potential
  • Ability to understand and the willingness to sign a written informed consent document
  • Patients may have had a prior autologous or allogeneic transplant if there is at least 100 days between transplant and screening, and there is no evidence of active graft-versus-host-disease (GvHD) or ongoing requirement for immunosuppressive therapy

Exclusion Criteria

  • Patients who have had chemotherapy, other investigational therapy, radiotherapy, or immune therapy within 2 weeks prior to the first dose of study medication. Hydroxyurea is allowed with no required washout and may be administered up to day 5 of protocol therapy
  • Patients previously treated with MEC chemotherapy
  • Patients who have received a tyrosine kinase inhibitor (TKI) within 5 half-lives of day 1
  • Patients who have had major surgery within 4 weeks prior to the first dose of study medication
  • Patients with acute promyelocytic leukemia
  • Patients with a known personal or family history of long QT syndrome
  • Patients with known central nervous system (CNS) leukemia involvement
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to prexasertib, mitoxantrone, etoposide, or cytarabine
  • Patients with a history of a secondary malignancy, with the following exceptions: * Malignancies that have been curatively treated and have not recurred within the past 2 years * Adequately treated carcinoma in situ of any type * Curatively treated non-melanoma skin cancers * Any other malignancy that has been curatively treated with a low likelihood of recurrence as judged by the treating investigator and agreed upon with the overall principal investigator prior to study entry * Patients with other secondary malignancies may be allowed to enroll with agreement from the overall principal investigator
  • Uncontrolled intercurrent illness including, but not limited to: uncontrolled active infection, symptomatic congestive heart failure, unstable angina pectoris, uncontrolled cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
  • Pregnant women are excluded from this study because prexasertib, mitoxantrone, etoposide, and cytarabine are anti-cancer agents 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 the study agents, breastfeeding should be discontinued if the mother is treated with prexasertib, mitoxantrone, etoposide, or cytarabine
  • Patients who are known to be seropositive for human immunodeficiency virus (HIV) or hepatitis B or C

Locations & Contacts

Massachusetts

Boston
Brigham and Women's Hospital
Status: Active
Contact: Eric Stephen Winer
Phone: 617-632-2053
Email: EricS_Winer@DFCI.HARVARD.EDU
Dana-Farber Cancer Institute
Status: Active
Contact: Eric Stephen Winer
Phone: 617-632-2053
Email: EricS_Winer@DFCI.HARVARD.EDU

Trial Objectives and Outline

PRIMARY OBJECTIVES:

I. To determine the safety and tolerability of the combination of prexasertib and standard mitoxantrone hydrochloride, etoposide, and cytarabine (MEC) therapy.

SECONDARY OBJECTIVES:

I. To determine the maximum-tolerated dose (MTD) and recommended phase II dose (RPIID) for the combination of prexasertib and standard MEC therapy.

II. To preliminarily evaluate the overall response rate (ORR), defined as the rate of complete remission (CR), CR with incomplete count recovery (CRi), and partial remission (PR).

III. To assess the overall survival (OS) rate for the combination.

IV. To assess the duration of remission (DoR), defined as the time from achievement of CR or CRi until relapse, death, or one year, whichever is first.

EXPLORATORY OBJECTIVES:

I. To evaluate potential biomarkers of clinical benefit for the combination via analysis of peripheral blood samples and bone marrow biopsies and aspirates.

OUTLINE: This is a dose-escalation study of prexasertib.

Patients receive mitoxantrone hydrochloride intravenously (IV) over 10 minutes, etoposide IV over 60 minutes, and cytarabine IV over 60 minutes on days 1-5 and prexasertib IV over 60 minutes on days 1, 3, and 5 in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 42 days and then up to 1 year.

Trial Phase & Type

Trial Phase

Phase I

Trial Type

Treatment

Lead Organization

Lead Organization
Dana-Farber Harvard Cancer Center

Principal Investigator
Eric Stephen Winer

Trial IDs

Primary ID 18-468
Secondary IDs NCI-2019-01758
Clinicaltrials.gov ID NCT03735446