Clinical Trials /

Low Dose Daunorubicin in Pediatric Relapsed/Refractory Acute Leukemia

NCT04562792

Description:

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.

Related Conditions:
  • Acute Lymphoblastic Leukemia
  • Acute Myeloid Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Low Dose Daunorubicin in Pediatric Relapsed/Refractory Acute Leukemia
  • Official Title: A Pilot Study of Targeted Daunorubicin Dosing to Overcome Chemotherapeutic Resistance in Children With Relapsed or Refractory Acute Leukemia

Clinical Trial IDs

  • ORG STUDY ID: LDDAUNO20
  • NCT ID: NCT04562792

Conditions

  • Relapsed Pediatric ALL
  • Relapsed Pediatric AML
  • Refractory Acute Myeloid Leukemia
  • Refractory Acute Lymphoblastic Leukemia

Interventions

DrugSynonymsArms
DaunorubicinPatients with relapsed/refractory ALL and AML

Purpose

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.
    

Trial Arms

NameTypeDescriptionInterventions
Patients with relapsed/refractory ALL and AMLExperimentalPatients in this arm will receive daunorubicin 6.75mg/m2 daily for 5 consecutive days.
  • Daunorubicin

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.
      
Maximum Eligible Age:21 Years
Minimum Eligible Age:1 Year
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of low dose daunorubicin feasbility as assessed by absolute blast count
Time Frame:24 months
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure:Pharmacokinetic parameters of low dose daunorubicin in children with relapsed/refractory AML and ALL as assessed by maximum concentration.
Time Frame:24 months
Safety Issue:
Description: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.
Measure:Pharmacokinetic parameters of low dose daunorubicin in children with relapsed/refractory AML and ALL as assessed by time at maximum concentration.
Time Frame:24 months
Safety Issue:
Description: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.
Measure:Pharmacokinetic parameters of low dose daunorubicin in children with relapsed/refractory AML and ALL as assessed by area under the curve.
Time Frame:24 months
Safety Issue:
Description: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.
Measure:Pharmacokinetic parameters of low dose daunorubicin in children with relapsed/refractory AML and ALL as assessed by elimination half-life
Time Frame:24 months
Safety Issue:
Description: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.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Children's Mercy Hospital Kansas City

Last Updated

September 18, 2020