WEE1 Inhibitor AZD1775 With or Without Cytarabine in Treating Patients With Advanced Acute Myeloid Leukemia or Myelodysplastic Syndrome
Condition: 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
MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Preleukemia; Leukemia, Myelomonocytic, Chronic; Leukemia, Myelomonocytic, Juvenile; Myelodysplastic Syndromes; Myeloproliferative Disorders; Myelodysplastic-Myeloproliferative Diseases; Syndrome
Intervention: Cytarabine; Laboratory Biomarker Analysis; Pharmacological Study; Quality-of-Life Assessment; Questionnaire Administration; WEE1 Inhibitor AZD1775
Intervention description: Given SC; Correlative studies; Correlative studies; Ancillary studies; Ancillary studies; Given PO
Intervention MeSH terms: Cytarabine; Adavosertib
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 3.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      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.
    

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