Low Dose Daunorubicin in Pediatric Relapsed/Refractory Acute Leukemia

Study Overview
=================
Brief Summary
-----------------
In this pilot study, eligible pediatric patients will be treated with 5 consecutive days of low dose daunorubicin. All patients who receive low dose daunorubicin will be evaluated daily for potential toxicity during those 5 days. Once the patient has received 5 doses of daunorubicin, subsequent therapy will be at the discretion of the primary oncology team.

Detailed Description
-----------------
Cancer remains the number one cause of non-accidental death in children with leukemia being the most common type of childhood cancer. Although cure rates for pediatric leukemia have greatly improved over the last few years, relapsed disease still carries a poor prognosis. Outcomes for children with multiply relapsed leukemia are dismal ranging from a remission rate of 25% in AML after 2 relapses falling to 17% after 3 or more relapses and 44% in ALL after 2 relapses and 27% after 3 or more relapses. Leukemia stem cells that are resistant to chemotherapy primarily contribute to treatment failure and targeting these cells remains a challenge. Anthracyclines such as daunorubicin and doxorubicin have been the mainstays of childhood leukemia therapy for over 50 years. Prior investigations found that very low doses, significantly less than traditionally given, of doxorubicin and daunorubicin inhibit the interaction of Akt and beta catenin pathways which is known to drive the development of leukemia stem cells and chemoresistance. Mice models showed that treatment with these very low dose anthracyclines does not suppress the immune system but rather expands cancer targeting T cells while inhibiting populations known to help cancer cells evade the immune system. In addition, targeted treatment reduced immune checkpoint expression, a known cause of resistance, on leukemia stem cells, thus further sensitizing them to cytotoxic T cells. Standard doses of anthracyclines suppress hematopoiesis and in turn the immune system and thus do not permit the expression of these immunologic benefits. Patients with relapsed and/or refractory acute lymphoblastic leukemia or acute myeloid leukemia, ages 1-21 years, will be approached to participate in this study. These patients must have pathologically confirmed ALL or AML, whose disease is refractory to two induction therapeutic attempts, or who are in 2nd or greater relapse, or who are in 1st relapse or refractory to a single therapeutic attempt but are unable to receive intensive therapy due to other comorbidities. Patients will receive daunorubicin at 6.75mg/m2 daily for 5 consecutive days for a total dose of 33.75mg/m2. The primary objective of this study is to assess the feasibility and tolerability of low dose daunorubicin. Another objective of the study is to validate if T cell based immune responses against chemoresistant leukemia stem cells are stimulated at these lower doses of daunorubicin, in hopes to provide preliminary pediatric data for further research with the hypothesis being that targeted anthracycline treatment does in fact stimulate T cell based immune responses against chemoresistant leukemia stem cells. Samples will be analyzed by flow cytometry for stem cell and immune markers. The third primary objective is to identify pro vs anti-cancer cellular immune responses of targeted anthracycline treatment in these patients. The mechanism of low dose DNR treatment on activating immunogenic cell death (ICD) will be investigated by determining relative levels of damage-associated molecular patterns. The tumorigenic capacity of resistant populations such as LSCs expressing high levels of immune checkpoints will be tested. The secondary objective of this study is to evaluate the pharmacokinetic parameters of low dose daunorubicin in children with relapsed/refractory AML and ALL. Blood samples for evaluation of low dose daunorubicin pharmacokinetics (area under the time concentration curve, maximum concentration, elimination half-life, clearance) will be drawn prior to dosing and 5min, 20min, 40min, 1hr, 2hrs, 4hrs, 8hrs, and 24hrs only after the first day of dosing. Once the patient has received 5 doses of daunorubicin, subsequent therapy will be at the discretion of the primary oncology team.

Official Title
-----------------
A Pilot Study of Targeted Daunorubicin Dosing to Overcome Chemotherapeutic Resistance in Children With Relapsed or Refractory Acute Leukemia

Conditions
-----------------
Relapsed Pediatric ALL, Relapsed Pediatric AML, Refractory Acute Myeloid Leukemia, Refractory Acute Lymphoblastic Leukemia

Intervention / Treatment
-----------------
* Drug: Daunorubicin


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients with pathologically confirmed ALL or AML, whose disease is refractory to two induction therapeutic attempts, or who are in 2nd or greater relapse, or who are in 1st relapse or refractory to a single therapeutic attempt but are unable to receive intensive therapy at the time of consent. All prior upfront therapies including bone marrow transplant are acceptable. Pulse steroids (of 5 days duration or less in the prior month) administered as part of a routine maintenance therapy are acceptable. Age 1 to 21 years of age, inclusive Established central catheter IV access Exclusion Criteria: Females who are known to be pregnant or lactating Any Grade 3 or higher Cardiac Disorder per CTCAE version 5 Patients with echocardiographic evidence of cardiomyopathy (shortening fraction <27% or ejection fraction <50%) Uncontrolled sepsis Absolute Blast Count >50 x10(3)/mcL at enrollment or on day 1 of study Direct hyperbilirubinemia >5mg/dL Grade 3 or higher anaphylaxis to daunorubicin Non-English speaking Patients, who in the opinion of the PI, are unable to tolerate any study-specific procedures Patients who have received cyclosporine, tacrolimus or other agents to prevent or treat graft-vs-host disease post bone marrow transplant in the last 14 days Concurrent investigational drugs or other chemotherapeutic agents (excluding hydroxyurea), immunotherapies or biosimilars during the 5 days of daunorubicin. Prior cumulative doses of anthracyclines will not be an exclusion regardless of the total cumulative dose previously received.

Ages Eligible for Study
-----------------
Minimum Age: 1 Year
Maximum Age: 21 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Patients with relapsed/refractory ALL and AML<br>Patients in this arm will receive daunorubicin 6.75mg/m2 daily for 5 consecutive days. | Drug: Daunorubicin<br>* Eligible patients with relapsed and/or refractory acute leukemia will receive daunorubicin 6.75mg/m2 daily for 5 consecutive days.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Low Dose Daunorubicin Feasbility as Assessed by Absolute Blast Count | Feasibility failure due to progressive leukemia is defined as a rise in absolute blast count (ABC) of >10,000/day on two consecutive days that continues to increase >10,000/day after starting hydroxyurea. | 24 months | 
| Incidence of Low Dose Daunorubicin Feasbility as Assessed by Extramedullary Leukemia Progression | Low dose daunorubicin will also be deemed not feasible if there is evidence of progression of extramedullary leukemia such progression of chloroma or leukemia cutis. or if the patient experiences uncontrollable nausea and/or vomiting. | 24 months | 
| Incidence of Low Dose Daunorubicin Feasbility as Assessed by Patient Symptoms | Low dose daunorubicin will also be deemed not feasible if the patient experiences uncontrollable nausea and/or vomiting. | 24 months | 
| T-cell Based Immune Responses Against Chemoresistant Leukemia Stem Cells (LSC) Are Stimulated at Lower Doses of Daunorubicin to Provide Preliminary Data for Further Research. | Leukemia stem cells (LSCs) are known to be resistant to chemotherapy which may lead to treatment failure. In vitro studies have shown that targeted anthracycline treatment reduces immune checkpoint expression on LSCs, potentially sensitizing LSCs to cytotoxic T-cells. This will be measured in our study. | 24 months | 
| The Pro- vs. Anti-cancer Cellular Immune Response of Targeted Anthracycline Treatment in Patients With Relapsed/Refractory Acute Leukemia | Chemotherapy is typically administered at maximum tolerated doses which leads to secondary immunosuppression. In other words, beneficial immunologic side effects can be weakened if chemotherapy is given at high doses. The Wnt pathway (which plays a key role in chemoresistance of LSCs) reduces T cell recruitment to tumors. Available data in murine models indicates that targeted anthracycline treatment expands cancer-targeting T-cells while inhibiting populations known to help cancer cells evade the immune system. This will be measured in our study. | 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetic Parameters of Low Dose Daunorubicin in Children With Relapsed/Refractory AML and ALL as Assessed by Maximum Concentration. | Serial daunorubicin levels for evaluation of maximum concentration will be drawn prior to infusion and at 5, 20 and 40 minutes and at hours 1,2,4,8 and 24 post infusion. | 24 months | 
| Pharmacokinetic Parameters of Low Dose Daunorubicin in Children With Relapsed/Refractory AML and ALL as Assessed by Time at Maximum Concentration. | Serial daunorubicin levels for evaluation of time at maximum concentration will be drawn prior to infusion and at 5, 20 and 40 minutes and hours 1,2,4,8 and 24 post infusion. | 24 months | 
| Pharmacokinetic Parameters of Low Dose Daunorubicin in Children With Relapsed/Refractory AML and ALL as Assessed by Area Under the Curve. | Serial daunorubicin levels for evaluation of exposure by measuring area under the curve will be drawn prior to infusion and at 5, 20 and 40 minutes and hours 1,2,4,8 and 24 post infusion. | 24 months | 
| Pharmacokinetic Parameters of Low Dose Daunorubicin in Children With Relapsed/Refractory AML and ALL as Assessed by Elimination Half-life | Serial daunorubicin levels for evaluation of exposure by measuring elimination half-life will be drawn prior to infusion and at 5, 20 and 40 minutes and hours 1,2,4,8 and 24 post infusion. | 24 months |