AZD1775 in Advanced Acute Myeloid Leukemia, Myelodysplastic Syndrome and Myelofibrosis
Condition: Myelofibroses; Acute Myeloid Leukemia; Myelodysplastic Syndromes
MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Preleukemia; Myelodysplastic Syndromes; Primary Myelofibrosis; Syndrome
Intervention: Combination AZD1775 with AraC; AZD1775 only
Intervention description: AZD1775 days 1-5 & 8-12 AraC days 1-5 & 8-12; AZD1775 days 1-5 & 8-12
Intervention MeSH terms: Adavosertib
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 6.0
Sex: All
Minimum age: 18 Years
Maximum age: 99 Years
Healthy volunteers: No

Summary:

      A phase II study testing the efficacy of combined AZD1775 with AraC or single agent activity
      of AZD1775 in three arms: Arm A has subjects age 60 years or older who are newly diagnosed
      with AML receiving the combination of the drugs; Arm B has subjects who are have
      relapsed/refractory AML and HMA failure MDS patients being allocated to either the
      combination Arm B or single agent AZD1775 Arm C.
    

Eligibility criteria:

        Inclusion:

        Inclusion Criteria

          -  Dose escalation part of trial for combined AraC + AZD1775 (Arm A)

          -  untreated elderly (>60 years) AML if in the poor-risk cytogenetic group (please
             reference Appendix V).

          -  untreated elderly (>60 years) AML if in the intermediate and poor-risk cytogenetic
             group (please reference Appendix V)

          -  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 progressed
             on lenalidomide in addition to having failed or been intolerant to HMA treatment.

          -  advanced progressive MF, defined as intermediate and high risk primary and secondary
             MF, or any other MF failed or intolerant to JAK2 inhibitor therapy requiring medical
             therapy

          -  If appropriate, patients can have failed other prior therapies for their disease (i.e.
             JAK2 inhibitor, interferon, hydroxyurea or IMIDs). Patients may have failed more than
             one JAK2 inhibitor and JAK2 inhibitor must not have been the most recent treatment
             (e.g. other therapies as last therapy prior to study given after failure of previous
             JAK2 inhibitor).

          -  Failure/ intolerance of Ruxolitinib

          -  The following laboratory values obtained 7 days prior to registration.

          -  Total bilirubin ≤ 1.5 mg/dL (except Gilbert's syndrome or known hemolysis or leukemic
             infiltration)

          -  AST (SGOT) and ALT (SGPT) ≤ 2.5 x Upper Limit normal (ULN) or < 5 x ULN if organ
             involvement

          -  Alkaline Phosphatase < 5 x ULN - Serum creatinine ≤1.5 x ULN, or measured creatinine
             clearance (CrCl) ≥45 mL/min as calculated by the Cockcroft-Gault method (confirmation
             of creatinine clearance is only required when creatinine is >1.5 x institutional ULN)
             CrCl (glomerular filtration rate [GFR]) = (140-age) x (weight/kg) x Fa (72 x serum
             creatinine mg/dL) a where F= 0.85 for females and F=1 for males

          -  ECOG Performance Status (PS) 0, 1 (Appendix I).

          -  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.

          -  Female patients who are not of child-bearing potential and fertile females of
             childbearing potential

          -  Male patients should be willing to abstain or use barrier contraception (i.e.,
             condoms) for the duration of the study drug exposure and for 3 months after study
             treatment discontinuation.

          -  Patients who have undergone stem cell transplantation (SCT), autologous or allogeneic,
             are eligible provided that they are > 60 days from stem cell infusion, have GVHD <
             grade 1 and are off immunosuppressive agents for > 28 days at time of registration.

        Exclusion:

          -  AML patients who are suitable for and willing to receive intensive chemotherapy

          -  Any of the following because this study involves an investigational agent whose
             genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are
             unknown:

               -  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 CYP3A4 substrates or CYP3A4 substrates

          -  The preferred azole anti-fungal medication is Fluconazole (alternatively Posaconazole)
             which can be given during treatment with AZD1775 (section 9.5).

          -  Pateints may not be on an inhibitor of BCRP as outlined in Appendix VI.

          -  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

          -  Mean resting corrected QTc interval using the Fridericia formula (QTcF) >450 msec/male
             and >470 msec/female (as calculated per institutional standards) obtained from 3
             electrocardiograms (ECGs) 2-5 minutes apart at study entry, or congenital long QT
             syndrome

          -  Herbal preparations/medications