Niclosamide in Pediatric Patients With Relapsed and Refractory AML

Study Overview
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Brief Summary
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Protocol is designed to evaluate a niclosamide dose escalation scale in combination with cytarabine as a therapeutic modality for pediatric subjects with relapsed/refractory acute myeloid leukemia.

Official Title
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Phase 1 Study of Niclosamide (ANA001) in Pediatric Patients With Relapsed and Refractory AML

Conditions
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Acute Myeloid Leukemia (AML)

Intervention / Treatment
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* Drug: Niclosamide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Prior morphologically confirmed diagnosis of AML based on WHO Criteria Has previously failed all available and suitable therapies for AML Disease relapse or the presence of refractory disease after ≥ 2 cycles of chemotherapy must be documented by bone marrow (BM) examination demonstrating > 5% blasts in the BM not attributable to another cause. Administration of hydroxyurea 10 to 20 mg/kg/day PO (maximum 1000 mg PO BID) to control high WBC count is permitted. Age ≥ 2 and ≤ 25 years Body surface area (BSA) ≤ 2.10 m2, calculated per the Mostellar formula Must be able to tolerate po or ng medications. Performance status: Subject age ≤ 16 years old: Lansky score ≥ 50 > 16 years old: Karnofsky score ≥ 50% Life expectancy of greater than 4 weeks Platelets ≥ 10,000/mm3 (for subjects with platelets < 10,000/mm3 at baseline, platelet transfusion support is allowed) Serum creatinine ≤ 2.0 mg/dL or estimated creatinine clearance ≥ 30 mL/min (Cockcroft Gault) within 14 days prior to treatment initiation Total bilirubin ≤ 2.0 x Institutional upper limit of normal (ULN) within 14 days prior to treatment initiation, unless the elevation is due primarily to elevated unconjugated hyperbilirubinemia secondary to Gilbert's syndrome or hemolysis or non hepatic origin, and not to liver dysfunction SGOT (AST) ≤ 3.0 x ULN and SGPT (ALT) ≤ 3.0 x ULN within 14 days prior to treatment initiation 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) for the duration of study participation Men only: Men must agree to use adequate contraception (eg, hormonal or barrier methods of birth control; abstinence; sterilized partner) prior to the study treatment (from date of consent), for the duration of study participation, and 30 days after completion of niclosamide administration 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 is permitted. Receiving any other investigational agents. 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 Prior bone marrow transplant presenting with active uncontrolled graft versus host disease (GvHD) 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

Ages Eligible for Study
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Minimum Age: 2 Years
Maximum Age: 25 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Niclosamide 250 mg/m2 /day divided BID<br> | Drug: Niclosamide<br>* Niclosamide will be administered orally for 14 days. Each dose will be followed by backbone chemotherapy<br>|
| Experimental: Niclosamide 500 mg/m2 /day divided BID<br> | Drug: Niclosamide<br>* Niclosamide will be administered orally for 14 days. Each dose will be followed by backbone chemotherapy<br>|
| Experimental: Niclosamide 800 mg/m2 /day divided BID<br> | Drug: Niclosamide<br>* Niclosamide will be administered orally for 14 days. Each dose will be followed by backbone chemotherapy<br>|
| Experimental: Niclosamide 1200 mg/m2 /day divided BID<br> | Drug: Niclosamide<br>* Niclosamide will be administered orally for 14 days. Each dose will be followed by backbone chemotherapy<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose-limiting toxicity | Dose-limiting toxicities (DLTs) are defined as any events ≥ Grade 3 that are at least possibly, probably, or definitely related to niclosamide treatment | 30 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy of niclosamide treatment clinical response | Clinical response is defined as any of the following. Complete response (CR) = < 5% blasts in BM, with no evidence of extramedullary disease. Partial response (PR) = ≥ 5% to ≤ 25% blasts in BM with decrease in BM blast percentage by 50%, and no evidence of extramedullary disease. Resistant disease with clinical benefit (RD-CB) = either ≥ 5% to ≤ 25% blasts in BM OR a decrease in blast percentage by 50%, either with no evidence of extramedullary disease. No response (NR) is defined as BM disease that does not fall into the above categories | 8 weeks |