A randomized, double-blindphase 3 study of vadastuximab talirine (SGN-CD33A)versus placebo in combination with azacitidine or decitabine in the treatment of older patients with newly diagnosed acute myeloid leukemia (AML)

1. Patients with newly diagnosed, previously untreated, cytologically or histologically confirmed de novo or secondary AML according to WHO classification (except for acute promyelocytic leukemia [APL]).
2. Age >=18 years.
3. Life expectancy of at least 12 weeks.
4. Patient is eligible for therapy with either decitabine or azacitidine.
5. For patients <80 years, an ECOG performance status <=2 (Appendix C). Patients >=80 years must be have an ECOG performance status of 0 or 1.
6. The following baseline laboratory data:
* White blood cell (WBC) count <30,000/µL; use of hydroxyurea to control WBC is acceptable.
* Serum bilirubin <=1.5 x upper limit of normal (ULN) or <=3 x ULN for patients with Gilbert*s disease, or direct bilirubin <= 2 x ULN if total bilirubin is abnormal.
* Serum creatinine <=2.5 x ULN and estimated creatinine clearance >=30 mL/min.
* Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) <=3 x ULN.
7. Female patients (for those of childbearing potential as defined in Section 4.3), the following stipulations apply:
a. Must have a negative serum or urine pregnancy test (minimum sensitivity 25 mIU/mL or equivalent units of beta human chorionic gonadotropin [β-hCG]) result within 7 days prior to the first dose of study treatment. Females with false positive results and documented verification that the patient is not pregnant are eligible for participation.
b. Must agree not to try to become pregnant during the study and for at least 6 months after the final dose of study drug administration.
c. Must agree not to breastfeed or donate ova, starting at time of informed consent and continuing through 6 months after the final dose of study drug administration.
d. If heterosexually active, must consistently use 2 highly effective methods of birth control (as defined in Appendix G) starting at time of informed consent and continuing throughout the study and for at least 6 months after the final dose of study drug administration.
8. Male patients under the following conditions:
a. Must agree not to donate sperm starting at time of informed consent and continuing throughout the study period and for at least 6 months after the final study drug administration.
b. If heterosexually active with non-pregnant, pregnant, or breastfeeding partner, must consistently use 2 highly effective methods of birth control (as defined in Appendix G) starting at time of informed consent and continuing throughout the study and for at least 6 months after the final dose of study drug administration.
9. Patients must provide written informed consent.

1. AML associated with favorable risk karyotypes including inv(16), t(8;21), t(16;16), or t(15;17).
2. Patients who are medically fit and willing to receive standard intensive induction chemotherapy.
3. Patients who are candidates for allogeneic stem cell transplant at the time of enrollment.
4. Patients with a history of one of the following myeloproliferative neoplasms: essential thrombocythemia, polycythemia vera, and primary myelofibrosis.
5. Received prior treatment with HMA or chemotherapy for antecedent MDS. Prior hydroxyurea or 6-mercaptopurine is permitted, as is prior lenalidomide treatment for MDS.
6. History of allogeneic stem cell transplant.
7. History of clinically significant chronic liver disease (e.g. liver cirrhosis) and/or ongoing alcohol abuse.
8. Patient with supplemental oxygen requirement or resting oxygen saturation of <90%.
9. Concurrent active malignancy other than nonmelanoma skin cancer or carcinoma in situ of the following: bladder, stomach, colon, cervix, endometrium, melanoma, or breast. Patients with previous malignancies are eligible if the malignancy has been confined and surgically resected (or treated with other modalities) with curative intent. Any active systemic therapy must have been completed > 1 year from enrollment (except for hormonal/anti hormonal treatment, e.g., breast cancer).
10. Central nervous system leukemia based on imaging or documented positive cytology in cerebral spinal fluid.
11. Any uncontrolled Grade 3 or higher (per NCI CTCAE, Version 4.03) viral, bacterial, or fungal infection within 14 days prior to the first dose of study treatment. Antimicrobial prophylaxis or ongoing treatment of resolving/controlled infection is permitted.
12. Patients with any of the following:
* Known positive hepatitis B polymerase chain reaction (PCR) assay who have also tested positive for hepatitis B surface antigen and/or anti-hepatitis B core antibody; patients with a negative PCR assay are permitted with appropriate antiviral prophylaxis.
* Known or suspected active hepatitis C infection (positive by PCR or on antiviral therapy within the last 6 months).
* Known human immunodeficiency virus (HIV) infection.
13. Documented history of a cerebral vascular event (stroke or transient ischemic attack), unstable angina, or myocardial infarction within 6 months prior to their first dose of study drug, or cardiac symptoms consistent with New York Heart Association (NYHA) Class III-IV within 6 months prior to the first dose of study treatment (see Appendix F).
14. Current therapy with other systemic anti-neoplastic or investigational agents, with the exception of hydroxyurea.
15. Females who are breastfeeding.
16. Known hypersensitivity to any excipient contained in the drug formulation of any study treatment.
17. Significant history of pulmonary, renal, neurologic, psychiatric, endocrine, metabolic, immunologic, hepatic, cardiovascular disease, or any other condition which, in the opinion of the investigator, would adversely affect participation in this study, compromise patient safety or interfere with data interpretation.