Clinical Trials /

WEE1 Inhibitor AZD1775 With or Without Cytarabine in Treating Patients With Advanced Acute Myeloid Leukemia or Myelodysplastic Syndrome

NCT02666950

Description:

This randomized phase II trial studies how well WEE1 inhibitor AZD1775 with or without cytarabine works in treating patients with acute myeloid leukemia or myelodysplastic syndrome that has spread to other places in the body and usually cannot be cured or controlled with treatment. WEE1 inhibitor AZD1775 may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as 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. It is not yet known whether giving WEE1 inhibitor AZD1775 works better with or without cytarabine in treating patients with advanced acute myeloid leukemia or myelodysplastic syndrome.

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

Completed

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: WEE1 Inhibitor AZD1775 With or Without Cytarabine in Treating Patients With Advanced Acute Myeloid Leukemia or Myelodysplastic Syndrome
  • Official Title: A Phase 2 Study of WEE1 Inhibition With AZD1775 Alone or Combined With Cytarabine in Patients With Advanced Acute Myeloid Leukemia and Myelodysplastic Syndrome

Clinical Trial IDs

  • ORG STUDY ID: MC1488
  • SECONDARY ID: NCI-2015-02136
  • SECONDARY ID: MC1488
  • SECONDARY ID: P30CA015083
  • NCT ID: NCT02666950

Conditions

  • Chronic Myelomonocytic Leukemia
  • Myelodysplastic Syndrome With Isolated Del(5q)
  • Myelodysplastic/Myeloproliferative Neoplasm
  • Previously Treated Myelodysplastic Syndrome
  • Recurrent Adult Acute Myeloid Leukemia
  • Untreated Adult Acute Myeloid Leukemia

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, Cytosar-U, Cytosine Arabinoside, Cytosine-.beta.-arabinoside, Cytosine-beta-arabinoside, Erpalfa, Starasid, Tarabine PFS, U 19920, U-19920, Udicil, WR-28453Arm B (cytarabine and WEE1 inhibitor AZD1775
WEE1 Inhibitor AZD1775AZD-1775, AZD1775, MK-1775, MK1775Arm B (cytarabine and WEE1 inhibitor AZD1775

Purpose

This randomized phase II trial studies how well WEE1 inhibitor AZD1775 with or without cytarabine works in treating patients with acute myeloid leukemia or myelodysplastic syndrome that has spread to other places in the body and usually cannot be cured or controlled with treatment. WEE1 inhibitor AZD1775 may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as 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. It is not yet known whether giving WEE1 inhibitor AZD1775 works better with or without cytarabine in treating patients with advanced acute myeloid leukemia or myelodysplastic syndrome.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To estimate the clinical efficacy of AZD1775 (WEE1 inhibitor AZD1775) in combination with
      AraC (cytarabine) in patients with newly diagnosed acute myeloid leukemia (AML) by assessing
      complete response (complete remission [CR] plus CR with incomplete blood count recovery
      [CRi]) rates.

      II. To estimate the clinical efficacy of AZD1775 alone or in combination with AraC in
      patients with relapsed/refractory AML and hypomethylating agent failure myelodysplastic
      syndrome (MDS) by assessing complete response (CR plus CRi) rates.

      SECONDARY OBJECTIVES:

      I. To determine the safety and tolerability of AZD1775 alone or combined with AraC in the
      study population.

      II. To estimate additional measures of clinical benefit (i.e. hematological improvements,
      transfusion requirements).

      III. To measure the duration of response of AZD1775 alone or combined with AraC.

      IV. To measure time to response of AZD1775 alone or combined with AraC. V. To measure time to
      progression of AZD1775 alone or combined with AraC. VI. To measure overall survival of
      AZD1775 alone or combined with AraC. VII. To measure time to AML (for MDS subjects) of
      AZD1775 alone or combined with AraC.

      TERTIARY OBJECTIVES:

      I. To determine the pharmacokinetics (PK) of AZD1775 alone or combined with AraC in the study
      population.

      II. To conduct correlative research studies characterizing underlying molecular events and
      solidifying putative mechanism of action in vivo and to identify potential
      pharmacodynamic/biomarkers of response to AZD1775 alone or combined with AraC.

      III. To evaluate quality of life (QOL) and patient-reported symptoms in subjects treated with
      AZD1775 alone or combined with AraC.

      OUTLINE: Elderly newly diagnosed patients are assigned to arm A.

      ARM A (ELDERLY NEWLY DIAGNOSED PATIENTS): Patients receive cytarabine subcutaneously (SC)
      twice daily (BID) on days 1-5 and 8-12 and WEE inhibitor AZD1775 orally (PO) daily on days
      1-5 and 8-12.

      Patients are randomized to 1 of 2 treatment arms.

      ARM B: Patients receive cytarabine and WEE1 inhibitor AZD1775 as in Arm A.

      ARM C: Patients receive WEE inhibitor AZD1775 PO daily on days 1-5, 8-12, 15-19, and 22-26.

      In all arms, courses repeat every 28 days in the absence of disease progression or
      unacceptable toxicity.

      After completion of study treatment, patients are followed up every 3-6 months for 2 years.
    

Trial Arms

NameTypeDescriptionInterventions
Arm B (cytarabine and WEE1 inhibitor AZD1775ExperimentalPatients receive cytarabine and WEE1 inhibitor AZD1775 as in Arm A.
  • Cytarabine
  • WEE1 Inhibitor AZD1775
Arm C (WEE inhibitor AZD1775)ExperimentalPatients receive WEE inhibitor AZD1775 PO daily on days 1-5, 8-12, 15-19, and 22-26.
  • WEE1 Inhibitor AZD1775

Eligibility Criteria

        Inclusion Criteria:

          -  Patient population (histological or cytologically confirmed diagnosis):

               -  Untreated elderly (> 60 years) AML if in the intermediate and poor-risk
                  cytogenetic group and not candidates (as judged by treating doctor of medicine
                  [MD]) for or willing to undergo standard induction therapy (i.e. elderly
                  unfavorable cytogenetic AML) or any untreated AML age > 65 years

                    -  Note: previous therapy with a hypomethylating agent (HMA) for a diagnosis of
                       MDS is allowed

               -  Relapsed or refractory AML (>= 18 years)

               -  Any MDS (>= 18 years) having failed or been intolerant to prior hypomethylating
                  agent (HMA) treatment

                    -  Failure is defined as any disease progression while on HMA, relapse after
                       HMA treatment or no response after 4 cycles of 5-Azacitidine or decitabine

                    -  Patients with isolated 5q-/5q- syndrome must have failed, not tolerated, or
                       lenalidomide in addition to having failed or been intolerant to HMA
                       treatment

                         -  Note: patients with chronic myelomonocytic leukemia (CMML) and
                            MDS/myeloproliferative neoplasms (MPN) overlap are allowed if meeting
                            other study eligibility criteria

                         -  Note: for all patient groups, therapy as part of a plan as a bridge to
                            transplant is allowed

          -  Total bilirubin =< 1.5 mg/dL (except Gilbert's syndrome or known hemolysis or leukemic
             infiltration)

          -  Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase [SGOT]) and
             alanine aminotransferase (ALT)(serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x
             upper limit normal (ULN) or < 5 x ULN if organ involvement

          -  Alkaline phosphatase < 5 x ULN

          -  Serum creatinine =< 2 x ULN or 24 hour creatinine (Cr) clearance > 30 ml/min

          -  Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1 or 2

          -  Ability to provide informed written consent and be able to adhere to the study visit
             schedule and other protocol requirements

          -  Willing to return to enrolling institution for follow-up (during the active monitoring
             phase of the study)

          -  Willing to provide blood and bone marrow aspirate samples for correlative research
             purposes

          -  Negative serum pregnancy test done =< 7 days prior to registration, for women of
             childbearing potential only

          -  Men and women must be willing to use appropriate contraception throughout study and
             for 6 months after

          -  Male patients who are sexually active with a female partner of childbearing potential
             must be either surgically sterilized or agree to use barrier contraception (ie,
             condoms) for the duration of study participation, and for 90 days after the final dose
             of study drug; cessation of birth control after this point should be discussed with a
             responsible physician

          -  Patients who have undergone stem cell transplantation (SCT), autologous or allogeneic,
             are eligible provided that they are > 60 days from stem cell infusion, have
             graft-versus-host disease (GVHD) =< grade 1 and are off immunosuppressive agents for >
             28 days at time of registration

        Exclusion Criteria:

          -  Uncontrolled intercurrent illness including, but not limited to, active uncontrolled
             infection, known positive for active infectious hepatitis, type A, B or C (past
             infection allowed), or psychiatric illness/social situations that would limit
             compliance with study requirements; Note: ongoing infection controlled on
             antibiotics/antifungal/antiviral medications are allowed

          -  Any of the following prior therapies:

               -  Cytotoxic chemotherapy =<14 days prior to registration

               -  Immunotherapy =< 14 days prior to registration

               -  Biologic therapy (i.e. antibody therapies) =< 14 days prior to registration

               -  Radiation therapy =<14 days prior to registration

               -  Targeted therapies (i.e. kinase inhibitors, =< 7 days or 5 half-life's whichever
                  is shorter)

                  • For steroids or other non-cytotoxics given for blast count control, patient
                  must be off for > 24 hours (hrs) before starting therapy; NOTE: hydroxyurea (HU)
                  is allowed for blast count control throughout study

               -  Receiving any other investigational agent which would be considered as a
                  treatment for the primary neoplasm =< 14 days prior to registration

          -  Active uncontrolled central nervous system (CNS) leukemia; NOTE: positive
             (cyto)pathology is allowed and patient can receive intrathecal chemotherapy

          -  Immunocompromised patients and patients known to be human immunodeficiency virus (HIV)
             positive and currently receiving antiretroviral therapy; NOTE: patients known to be
             HIV positive, but without clinical evidence of an immunocompromised state, are
             eligible for this trial

          -  Any previous treatment with AZD1775 or allergic reactions to excipients of AZD1775

          -  Acute promyelocytic leukemia (APL, M3) unless failed regimens that included tretinoin,
             arsenic trioxide, anthracyclines and cytarabine and currently NOT candidates for stem
             cell transplantation

          -  Major surgery =< 28 days prior to registration

          -  Clinically significant heart disease, including the following:

               -  Active severe angina pectoris within 3 months prior to registration

               -  Acute myocardial infarction within 3 months prior to registration

               -  New York Heart Association classification IV cardiovascular disease or
                  symptomatic class III disease

                    -  Note: patients with any of the above may be allowed after discussion amongst
                       the investigators including the principal investigator

          -  Any of the following:

               -  Pregnant women

               -  Nursing women

               -  Men or women of childbearing potential who are unwilling to employ adequate
                  contraception

          -  Subject has had prescription or non-prescription drugs or other products known to be
             sensitive cytochrome P450 family 3, subfamily A, polypeptide 4 (CYP3A4) substrates or
             CYP3A4 substrates with a narrow therapeutic index, or to be moderate to strong
             inhibitors/inducers of CYP3A4 which cannot be discontinued two weeks prior
             (alternatively 5 half lives if T1/2 is known) prior to day 1 of dosing and withheld
             throughout the study until 2 weeks after the last dose of study drug

               -  NOTE: co-administration of aprepitant or fosaprepitant during this study is
                  prohibited

               -  Note: individual drugs exerting CYP interactions may be continued on a case by
                  case basis if felt essential for patient management, after discussions and
                  discretion of the treating physician

               -  The preferred azole anti-fungal medication is fluconazole (alternatively
                  posaconazole) which can be given during treatment with AZD1775 at the treating
                  physician's discretion, however with dose reductions of AZD1775 by 25-75% (i.e.
                  from AZD1775 200mg to 150 or 100mg)

          -  Patients may not be on an inhibitor of breast cancer resistance protein (BCRP)

               -  NOTE: AZD1775 is an inhibitor of breast cancer resistance protein (BCRP); the use
                  of statins including atorvastatin which are substrates for BCRP are therefore
                  prohibited and patients should be moved on to non-BCRP alternatives

          -  Not willing to avoid grapefruit, grapefruit juices, grapefruit hybrids, Seville
             oranges, pummelos, and exotic citrus fruits from 7 days prior to the dose of study
             medication and during the entire study; NOTE: orange juice is allowed

          -  Corrected QT interval (QTc) > 470 msec (as calculated per institutional standards) at
             study entry or congenital long QT syndrome
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Complete response rate (CR or CRi) per the National Comprehensive Cancer Network (NCCN) guidelines or according to specific criteria from expert panels (Arm A)
Time Frame:Up to 2 years
Safety Issue:
Description:Complete response rate will be evaluated over all courses of study treatment. The proportion of CR/CRi responses will be estimated by the number of CR/CRi responses divided by the total number of evaluable patients. Two-sided 95% confidence intervals will be computed using an exact binomial confidence interval. The frequency and relative frequency of individual response categories will also be computed.

Secondary Outcome Measures

Measure:Clinical benefit (i.e. hematological improvements, transfusion requirements)
Time Frame:Up to 2 years
Safety Issue:
Description:Summary statistics for clinical benefit (mean and standard deviations for continuous variables and frequencies and percentages for discrete variables) will be compiled for hematologic improvements and transfusion requirements.
Measure:Duration of response defined for all evaluable patients who have achieved a response as the date at which the patient's earliest best objective status is first noted to be a CR/CRi response to the earliest date progression is documented
Time Frame:Up to 2 years
Safety Issue:
Description:The distribution of duration of response will be estimated using the method of Kaplan-Meier.
Measure:Incidence of adverse events as assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0
Time Frame:Up to 30 days post-treatment
Safety Issue:
Description:Safety and tolerability data will be compiled. The maximum grade for each type of adverse event will be recorded for each patient, and frequency tables will be reviewed to determine patterns (by arm, disease and overall). Additionally, the relationship of the adverse event(s) to the study treatment will be taken into consideration. The rate of grade 3 or higher non-hematologic adverse events, and the rate of grade 4 or higher adverse event (hematologic and non-hematologic) will be computed each with a 95% exact binomial confidence interval.
Measure:Overall survival
Time Frame:From registration to death due to any cause, assessed up to 2 years
Safety Issue:
Description:The distribution of survival time will be estimated using the method of Kaplan-Meier.
Measure:Time to AML or death
Time Frame:From registration to leukemic transformation or death due to any cause, assessed up to 2 years
Safety Issue:
Description:The distribution of time to AML or death will be estimated using the method of Kaplan-Meier.
Measure:Time to progression, defined as the time from registration to the earliest date of documentation of disease progression
Time Frame:Up to 2 years
Safety Issue:
Description:The distribution of time to progression will be estimated using the method of Kaplan-Meier.
Measure:Time to response, defined as the time from registration to the earliest date of documentation of response
Time Frame:Up to 2 years
Safety Issue:
Description:The distribution of time to progression will be estimated using the method of Kaplan-Meier.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Suspended
Lead Sponsor:Mayo Clinic

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