Adavosertib Alone or Combined with Cytarabine in Treating Patients with Acute Myeloid Leukemia, Myelodysplastic Syndrome, or Myelofibrosis

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 * Note: previous therapy with a hypomethylating agent (HMA) for a diagnosis of MDS is allowed.
• Dose expansion part of trial for combined AraC + AZD1775 (Arm A) * Untreated elderly (> 60 years) AML if in the intermediate and poor-risk cytogenetic group * 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 progressed on lenalidomide in addition to having failed or been intolerant to HMA treatment. * Note: Patients with chronic myelomonocytic leukemia (CMML) and MDS/myeloproliferative neoplasm (MPN) overlap are allowed if meeting other study eligibility criteria.
• 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 * Note: ** If appropriate, patients can have failed other prior therapies for their disease (i.e. JAK2 inhibitor, interferon, hydroxyurea or immunomodulatory imide drug [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). ** Primary (PMF) and secondary MF (post polycythemia vera [PV]/post essential thrombocythemia [ET]) are allowed.
• Failure/ intolerance of ruxolitinib is defined as loss of optimal response in a responder to ruxolitinib, based on growth of the spleen [appearance of a new splenomegaly that is palpable at least 5 cm below the LCM, or a >= 100% increase in palpable distance, below LCM, for baseline splenomegaly of 5–10 cm, or a 50% increase in palpable distance, below least common multiple (LCM), for baseline splenomegaly of >10 cm], loss of symptom improvement (Myeloproliferative Neoplasm Symptom Assessment Form [MPN-SAF]), worsening cytopenias [currently or previously treated with ruxolitinib for at least 28 days and either required RBC transfusion on ruxolitinib, or required a dose adjustment of ruxolitinib to less than 20 mg twice a day and also had anemia; grade 3 thrombocytopenia] or intolerable side effects [in the assessment of the treating physician]. Further increase of blood or marrow blasts to > 5% if previously < 2% and > 10% if previously < 7% qualify as progression to ruxolitinib.
• 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) (obtained =< 7 days prior to registration).
• 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 (obtained =< 7 days prior to registration).
• Alkaline phosphatase < 5 x ULN (obtained =< 7 days prior to registration).
• 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) (obtained =< 7 days prior to registration).
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1.
• 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 who agree to use adequate contraceptive measures from 2 weeks prior to the study and until 1 month after study treatment discontinuation, who are not breastfeeding, and who have a negative serum or urine pregnancy test within 3 days prior to the start of study treatment.
• 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 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 longer) * For steroids or other non-cytotoxics (exception, hydroxyurea [HU]) given for blast count control, patient must be off for > 24 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 =< 28 days prior to registration * Patients with persistent toxicities of >= grade 1 from prior AML treatment (including chemotherapy, kinase inhibitors, immunotherapy, experimental agents, radiation, or surgery).
• 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 treatment will all available therapies known to be active for treatment of APL.
• 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
• 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 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 as listed 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.
• 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 due to potential CYP3A4 interaction with the study medication. NOTE: Orange juice is allowed.
• 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 are generally not allowed throughout the study. These herbal medications include, but are not limited to: St. John’s wort, kava, ephedra (ma huang), gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, and ginseng. Patients should stop using these herbal medications 7-14 days prior to first dose of AZD1775. If there is no known potential interaction between an herbal medication and AZD1775, the protocol principal investigator can give a waiver to continue such medication, with the exception of St. John’s wort, kava, ephedra (ma huang), gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, and ginseng, that are not allowed at any stage.