Niclosamide in Pediatric Patients With Relapsed and Refractory AML

Inclusion criteria

• Prior morphologically-confirmed diagnosis of AML based on WHO Criteria 2. Has previously failed all available and suitable therapies for AML. Disease relapse or the presence of refractory disease after ≥ 2 cycles of intensive chemotherapy; or ≥ 4 cycles of non-intensive chemotherapy or hypomethylating agents (HMAs) must be documented by bone marrow (BM) examination demonstrating ≥ 5% blasts in the BM by morphology or ≥ 1% blasts by flow cytometry,

• 5% blasts in the peripheral blood (confirmed by flow cytometry, cytogenetics or FISH), ≥ 1% MRD

+ by flow cytometry, FISH, PCR or NGS, and not attributable to another cause (EXCEPTION: subjects with frank disease progression in the face of treatment with HMA with or without venetoclax will be considered eligible regardless of treatment cycles administered if they meet the other eligibility criteria). No prior treatment with niclosamide. 3. Age ≥ 2 and ≤ 30 years 4. Body surface area (BSA) ≤ 2.10 m2

, calculated per the Mostellar formula 5. Must be able to tolerate po or ng medications. 6. Performance status: Subject ≤ 16 years old: Lansky ≥ 50 Subject > 16 years old: Karnofsky ≥ 50% 7. Life expectancy of greater than 4 weeks 8. Platelets ≥ 10,000/mm3 (for subjects with platelets < 10,000/mm3 at baseline, platelet transfusion support is allowed) 9. Measured or calculated creatinine clearance

• 60 mL/min/1.73 m2 (by the Cockcroft-Gault method) within 14 days prior to treatment initiation 10. Total bilirubin ≤ 2.0 x institutional upper limit of normal (ULN) within 14 days prior to treatment initiation (EXCEPTION: Subjects with Gilbert's syndrome may be included if the total bilirubin is

• 3.0 x ULN) 11. SGOT (AST) ≤ 3.0 x ULN and SGPT (ALT)
• 3.0 x ULN within 14 days prior to treatment initiation 12. Patients must have received their last dose of anti-cancer therapy (chemotherapy, immunotherapy, targeted agents, radiotherapy or investigational therapy) at least 2 weeks or 3 half-lives prior to the start of study treatment, whichever is longer. 13. For patients who have received prior hematopoietic stem cell transplants (HSCT), no evidence of GvHD and must be > 60 days since the HSCT. HSCT recipients must have completed their last course of tacrolimus, cyclosporine, or mycophenolate > 4 weeks before initiation of niclosamide 14. Females of reproductive potential (WOCBP) must have a negative pregnancy test within 14 days prior to study treatment. WOCBP must agree to use adequate contraception (eg, hormonal or barrier methods of birth control; abstinence; sterilized partner) from date of consent through the treatment period, and for 30 days after completion of niclosamide administration 15. Men only: Men must agree to use adequate contraception (eg, hormonal or barrier methods of birth control; abstinence; sterilized partner) from date of consent through the treatment period, and for 30 days after completion of niclosamide administration 16. Ability to understand the purpose and risks of the study and the willingness to sign a written informed consent document containing an authorization to use protected health information (in accordance with national and local subject privacy regulations

Exclusion criteria

• Received anticancer therapy (chemotherapy, immunotherapy, radiotherapy, or investigational therapy) within 2 weeks prior to starting study treatment. Administration of hydroxyurea 10 to 20 mg/kg/day PO (maximum 1000 mg PO BID) to control high WBC > 50 x 103

/mm3 is permitted at MD discretion (however, hydroxyurea should be stopped at least 24 hours prior to protocol therapy start).

• Receiving any other investigational agents, including niclosamide.
• Unresolved toxicities due to prior anticancer therapy, defined as not having resolved to Grade 0 or 1 (by CTCAE version 5 criteria), unless otherwise defined in the inclusion/exclusion criteria with the exception of alopecia
• Acute promyelocytic leukemia (French-American-British Class M3-AML)
• Known active central nervous system (CNS) leukemia; subjects can enroll on study if CNS disease can be cleared with intrathecal chemotherapy, in the judgement of the treating physician
• Known congenital bleeding disorders, including but not limited to hemophilia
• Known active uncontrolled systemic infection
• Malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel, uncontrolled symptomatic inflammatory bowel disease or ulcerative colitis, or partial or complete bowel obstruction, at the time of study entry
• Inability to receive administration of niclosamide in the available formulation(s)
• Uncontrolled intercurrent illness including, but not limited to, uncontrolled active infection, or psychiatric illness/social situations that would limit compliance with study requirements
• Lactating or pregnant female
• Known active hepatitis C