Clinical Trials /

Prexasertib (LY2606368), Cytarabine, and Fludarabine in Patients With Relapsed or Refractory Acute Myeloid Leukemia or High-Risk Myelodysplastic Syndrome

NCT02649764

Description:

This phase I trial studies the side effects and determine the best dose of prexasertib (LY2606368) when given together with cytarabine and fludarabine in patients with acute myeloid leukemia or high-risk myelodysplastic syndrome that has returned after a period of improvement or no longer responds to treatment. Prexasertib (LY2606368) may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as cytarabine and fludarabine, 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 (LY2606368) together with cytarabine and fludarabine may work better in treating patients with acute myeloid leukemia or myelodysplastic syndrome.

Related Conditions:
  • Acute Myeloid Leukemia
  • Chronic Myelomonocytic Leukemia
  • Myelodysplastic Syndromes
Recruiting Status:

Active, not recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Prexasertib (LY2606368), Cytarabine, and Fludarabine in Patients With Relapsed or Refractory Acute Myeloid Leukemia or High-Risk Myelodysplastic Syndrome
  • Official Title: Phase 1 A/B Study of LY2606368 in Combination With Cytarabine and Fludarabine in Patients With Relapsed/Refractory Acute Myelogenous Leukemia (AML) and High-Risk Myelodysplastic Syndrome (HRMDS)

Clinical Trial IDs

  • ORG STUDY ID: 2015-0665
  • SECONDARY ID: NCI-2016-00225
  • SECONDARY ID: 2015-0665
  • SECONDARY ID: P30CA016672
  • NCT ID: NCT02649764

Conditions

  • Chronic Myelomonocytic Leukemia
  • Recurrent Acute Myeloid Leukemia
  • Recurrent High Risk Myelodysplastic Syndrome
  • Refractory Acute Myeloid Leukemia
  • Refractory High Risk 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 (fludarabine phosphate, cytarabine, prexasertib)
Fludarabine Phosphate2-F-ara-AMP, 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-, Beneflur, Fludara, SH T 586Treatment (fludarabine phosphate, cytarabine, prexasertib)
PrexasertibLY2606368Treatment (fludarabine phosphate, cytarabine, prexasertib)

Purpose

This phase I trial studies the side effects and determine the best dose of prexasertib (LY2606368) when given together with cytarabine and fludarabine in patients with acute myeloid leukemia or high-risk myelodysplastic syndrome that has returned after a period of improvement or no longer responds to treatment. Prexasertib (LY2606368) may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as cytarabine and fludarabine, 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 (LY2606368) together with cytarabine and fludarabine may work better in treating patients with acute myeloid leukemia or myelodysplastic syndrome.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine the safety and toxicity profile of combination therapy of prexasertib
      (LY2606368), fludarabine and cytarabine in patients with relapsed or refractory (first or
      second salvage) acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (HRMDS).

      SECONDARY OBJECTIVES:

      I. To determine the complete response (CR), CR with incomplete count recovery (CRi),
      morphologic leukemia free state (MLFS) and partial response (PR) rates.

      II. To determine the duration of response. III. To determine the disease-free survival. IV.
      To determine the overall survival with combination therapy of LY2606368, fludarabine and
      cytarabine in patients with relapsed or refractory AML/HRMDS.

      V. To determine the correlative studies including but not limited to total and phosphor
      histone (H2AX), checkpoint kinase-2 (Chk1), checkpoint kinase-2 (Chk2), ras protein specific
      guanine nucleotide releasing factor 1 (Cdc25), retinoblastoma-associated protein (Rb),
      cyclin-dependent kinase (CDK), protein kinase B (AKT) in AML cells by flow cytometry and/or
      Western blot.

      OUTLINE: This is a dose-escalation study of prexasertib (LY2606368).

      Patients =/< 65 years of age: receive fludarabine intravenously (IV) over approximately 2
      hours on days 1-4, cytarabine IV over 4 hours on days 1-4, and prexasertib (LY2606368) IV
      over approximately 2 hours on days 1, 3, and 4 or on days 1-4.

      Patients > 65 years of age: receive fludarabine IV over approximately 2 hours on days 1-3,
      cytarabine IV over 4 hours on days 1-3, and prexasertib (LY2606368) IV over approximately 2
      hours on days 1, 3, and 4 or on days 1-4. Treatment for both age groups repeats every 28 days
      for up to 5 courses in the absence of disease progression or unacceptable toxicity.

      After completion of study treatment, patients in remission who do not start new treatment are
      followed up every 2-3 months for up to 2 years.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (fludarabine phosphate, cytarabine, prexasertib)ExperimentalPatients =/< 65 years of age: receive fludarabine IV over approximately 2 hours on days 1-4, cytarabine IV over 4 hours on days 1-4, and prexasertib (LY2606368) IV over approximately 2 hours on days 1, 3, and 4 or on days 1-4. Patients > 65 years of age: receive fludarabine IV over approximately 2 hours on days 1-3, cytarabine IV over 4 hours on days 1-3, and prexasertib (LY2606368) IV over approximately 2 hours on days 1, 3, and 4 or on days 1-4. Treatment for both age groups repeats every 28 days for up to 5 courses in the absence of disease progression or unacceptable toxicity.
  • Cytarabine
  • Fludarabine Phosphate
  • Prexasertib

Eligibility Criteria

        Inclusion Criteria:

          -  All patients with histologically or cytologically confirmed relapsed or refractory
             acute myeloid leukemia (AML) (except acute promyelocytic leukemia) or relapsed or
             refractory high-risk myelodysplastic syndrome (HRMDS) (intermediate 2 [Int-2] or
             higher risk by International Prognostic Scoring System [IPSS]); patients with chronic
             myelomonocytic leukemia (CMML) can be enrolled if they can be classified as HRMDS
             using MDS criteria; patients should not have received more than one salvage therapy;
             second induction regimen or stem cell transplant in remission will be considered
             salvage therapy; refractory subjects, up to second consecutive salvage

          -  Patients must have a performance status of 0-2 (Eastern Cooperative Oncology Group
             [ECOG] scale)

          -  Serum creatinine less than or equal to 1.3 mg/dL and/or creatinine clearance > 40
             mL/min

          -  Bilirubin less than or equal to 1.5 mg/dl (unless due to Gilbert's syndrome)

          -  Serum glutamic-oxaloacetic transaminase (SGOT)/aspartate transaminase (AST) or serum
             glutamate pyruvate transaminase (SGPT)/alanine transferase (ALT) less than or equal to
             2.5 X the upper limit of normal (ULN) for the reference lab

          -  Patients must have normal cardiac ejection fraction (left ventricular ejection
             fraction [LVEF] >/= 45%)

          -  Corrected QT (QTc) interval =/< 470 msecs, no familial history of QTc prolongation or
             ventricular arrhythmias

          -  Female patients must not be pregnant or lactating; female patients of childbearing
             potential (including those < 1 year post-menopausal) and male patients must agree to
             use contraception

          -  Patients who have received prior stem cell transplantation will be allowed to enroll
             as long as prior transplantation has been at least 3 months before enrollment in the
             trial and any transplant related toxicities have subsided to grade 1 or less

        Exclusion Criteria:

          -  Patients must not have untreated or uncontrolled life-threatening infection

          -  Patients must not have been treated with CHK1/2 inhibitors

          -  Patients must not have received chemotherapy and/or radiation therapy within 2 weeks
             of start of protocol treatment; hydroxyurea is allowed up to 48 hours prior to
             starting therapy in the setting of rapidly proliferating disease

          -  Patients must not have received an investigational anti-cancer drug within two weeks
             of start of protocol treatment

          -  Patients must not have active central nervous system leukemia; patients with history
             of central nervous system (CNS) leukemia with no evidence of active CNS disease may be
             enrolled; maintenance intrathecal chemotherapy for adequately treated CNS involvement
             with leukemia is allowed with approval from the study supporter

          -  Patients must not have significant cardiac co-morbidity including: history of acute
             coronary syndromes (including myocardial infarction and unstable angina) within 12
             months; coronary angioplasty or stenting within 6 months; history or evidence of
             current >/= class III congestive heart failure as defined by the New York Heart
             Association (NYHA); patients with intra-cardiac defibrillators or permanent pacemakers
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of dose-limiting toxicities of prexasertib in combination with cytarabine and fludarabine
Time Frame:Up to 28 days
Safety Issue:
Description:Will be determined.

Secondary Outcome Measures

Measure:Response rates (complete response [CR], CR with incomplete count recovery [CRi], morphologic leukemia free state [MLFS], and partial response [PR])
Time Frame:Up to 2 years
Safety Issue:
Description:Will be determined.
Measure:Duration of response
Time Frame:Up to 2 years
Safety Issue:
Description:Will be determined.
Measure:Disease-free survival
Time Frame:Up to 2 years
Safety Issue:
Description:Will be determined.
Measure:Overall survival
Time Frame:Up to 2 years
Safety Issue:
Description:Will be determined.
Measure:Total and phosphorylated biomarker levels in acute myeloid leukemia cells
Time Frame:Up to 2 years
Safety Issue:
Description:Measured by flow cytometry and/or Western blot.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:M.D. Anderson Cancer Center

Last Updated

May 7, 2019