SL-401 as Consolidation Therapy in Patients With Adverse Risk Acute Myeloid Leukemia in First Complete Remission

This is a non-randomized, open-label, multicenter, dose escalation study designed to determine the maximum tolerated dose (MTD) of SL-401 in adult patients with acute myeloid leukemia, and to evaluate the safety profile of SL-401 at the MTD.

Patients who were in their first or second complete remission (CR) or complete remission with incomplete bone marrow recovery (CRi) after induction therapy were treated with SL-401, which was administered as a brief intravenous infusion for 5 consecutive days every 28 days for 6 or more cycles. Stage 1 consisted of a period in which patients were treated with SL-401 at 3 dose levels. During Stage 2, patients with minimal residual disease (MRD) in their bone marrow were treated at a MTD or maximum tested dose in which multiple dose-limiting toxicities were not observed (identified in Stage 1).

Eligibility Criteria:
Inclusion Criteria:

1. The patient has a diagnosis of AML according to World Health Organization (WHO) criteria.
2. The patient received any induction chemotherapy regimen and may have received post-remission consolidation therapy prior to screening.
3. The patient has achieved a first or second CR or CRi. For patients without evidence of MRD in CR/CRi, CR (or CRi) must have been initially identified within 12 months prior to screening.

   OR The patient has achieved first or second CR or CRi with evidence of MRD as determined locally at least 6 months post stem cell transplant without evidence of acute or chronic graft-versus-host disease post-transplant and has not received immunosuppressant therapy for at least 14 days prior to SL-401 therapy.
4. The patient has adverse risk disease or AML for which there is otherwise a substantial risk of relapse, which includes but is not limited to: adverse karyotype, FLT3 internal tandem duplication (ITD) mutation, history of antecedent hematologic disorder (AHD), therapy-related AML, history of requiring more than 1 cycle of intensive induction chemotherapy to achieve first remission, and/or presence of persistent MRD (detected by cytogenetics, molecular markers, or flow cytometry) at any point after the initial induction cycle.
5. For patients enrolling in Stage 2, the bone marrow evaluation determined locally within the previous 6 months indicates the presence of MRD.
6. The patient is not considered to be an immediate candidate for allogeneic stem cell transplant as determined by the investigator.
7. The patient is ≥18 years old.
8. The patient has an Eastern Cooperative Oncology Group (ECOG) performance score (PS) of 0-2.
9. The patient has adequate organ function, including cardiac, renal, and hepatic function:

   * Left ventricular ejection fraction (LVEF) ≥institutional lower limit of normal as measured by multigated acquisition scan (MUGA) or 2-dimensional (2-D) echocardiography (ECHO) within 28 days prior to start of therapy and no clinically significant abnormalities on a 12-lead electrocardiogram (ECG)
   * Serum creatinine ≤1.5 mg/dL
   * Serum albumin ≥3.2 g/dL in the absence of receipt of (IV) albumin within the previous 72 hours.
   * Bilirubin ≤1.5 mg/dL
   * Aspartate transaminase (AST) and alanine transaminase (ALT) ≤2.5 × the upper limit of normal (ULN)
   * Creatine phosphokinase (CPK) ≤2.5 × the ULN.
10. The patient has adequate bone marrow reserve:

    • Absolute neutrophil count (ANC) \> 0.5 × 10\^9/L
11. The patient is a woman of child bearing potential (WOCBP) who has had a negative serum or urine pregnancy test within 1 week prior to SL-401 treatment (intervals shorter than 1 week are acceptable if required by institutional guidelines).
12. A written and voluntarily signed informed consent must be obtained from the patient or legally authorized representative, in accordance with local regulations, before the initiation of any study related procedures. The patient or legally authorized representative must be able to read and understand the informed consent form (ICF).
13. The patient is able to adhere to the study visit schedule and other protocol requirements, including follow-up for survival assessment.
14. The patient (male and female) agrees to use acceptable contraceptive methods for the duration of time on the study, and continue to use acceptable contraceptive methods for 2 months after the last infusion of SL-401.

Exclusion Criteria:

1. The patient has a diagnosis of AML associated with karyotype t(15;17).
2. The patient has persistent and clinically significant Grade ≥2 toxicities from induction or consolidation therapy (excluding alopecia, nausea, fatigue, and liver function tests \[as mandated in the inclusion criteria\]) not readily managed with supportive measures.
3. The patient received treatment with another investigational agent within 14 days of screening.
4. The patient previously received treatment with SL-401.
5. The patient has an active malignancy and/or cancer history (excluding AML or antecedent myelodysplastic syndrome \[MDS\]) that may confound the assessment of the study endpoints. Patients with a past cancer history (within 2 years of entry) with substantial potential for recurrence and/or ongoing active malignancy must be discussed with the Sponsor before study entry. Patients with the following neoplastic diagnoses are eligible: non-melanoma skin cancer, carcinoma in situ, cervical intraepithelial neoplasia, organ-confined prostate cancer with no evidence of progressive disease.
6. The patient has clinically significant cardiovascular disease (e.g., uncontrolled or any New York Heart Association \[NYHA\] Class 3 or 4 congestive heart failure, uncontrolled angina, history of myocardial infarction, unstable angina or stroke within 6 months prior to study entry, uncontrolled hypertension or clinically significant arrhythmias not controlled by medication).
7. The patient has uncontrolled, clinically significant pulmonary disease (e.g., chronic obstructive pulmonary disease, pulmonary hypertension) that in the opinion of the Investigator would put the patient at significant risk for pulmonary complications during the study.
8. The patient has known active or suspected central nervous system (CNS) leukemia. If suspected, CNS leukemia should be ruled out with relevant imaging and/or examination of cerebrospinal fluid.
9. The patient has uncontrolled intercurrent illness including, but not limited to, uncontrolled infection, disseminated intravascular coagulation (DIC), or psychiatric illness/social situations that would limit compliance with study requirements.
10. The patient is pregnant or breast feeding.
11. The patient has known positive status for human immunodeficiency virus (HIV), active or chronic Hepatitis B or Hepatitis C.
12. The patient is oxygen-dependent.
13. The patient has any medical condition which in the opinion of the Investigator places the patient at an unacceptably high risk for toxicities.