Safety concerns

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.

A phase II study testing the clinical efficacy of combined AZD1775 with AraC or single agent activity of AZD1775 in three patient strata: Elderly(> 60 years) newly diagnosed AML patients (Arm A) will only receive the combination; whereas relapsed/refractory AML patients and HMA failure MDS patients will be allocated to either the combination (Arm B) or single agent AZD1775 (Arm C). The study will have a run in safety cohort of six patients in each of the three arms to determine the safe use of combined AraC /AZD1775 or single agent AZD1775 in the patient populations. This will be followed by an expansion phase of up to 20 and 21 eligible patients in each arm respectively where elderly patients with newly diagnosed AML will receive a combination of AZD1775 and AraC (Arm A) while patients with relapsed or refractory AML or HMA failure MDS will be allocated to receive either AZD1775 with AraC (Arm B) or AZD1775 alone (Arm C). An early toxicity check will be conducted to determine safety and tolerability. If indicated, dose levels will be reduced. The study will continue to enroll the rest of the patients at the tolerated dose.

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

Individual participant data that underlie the results reported in this article, after deidentification (text, tables, figures, and appendices). Upon reasonable request.

Beginning 9 months and ending 36 months following article publication or as required by a condition of awards and agreements supporting the research.

The investigator who proposed to use the data.

4 months