Low Dose Daunorubicin in Pediatric Relapsed/Refractory Acute Leukemia

NCT04562792 | Completed Phase 2 Results DMC FDA Drug

• 1 other identifier: STUDY00001114
• Study Type: interventional
• Target: 1
• Locations: 1 country
• Sites: 1

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.

Conditions

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

Outcome Measures

Primary Outcomes (5)

• 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 Outcomes (4)

• Pharmacokinetic Parameters of Low Dose Daunorubicin in Children With Relapsed/Refractory AML and ALL as Assessed by Maximum Concentration.

  24 months

• Pharmacokinetic Parameters of Low Dose Daunorubicin in Children With Relapsed/Refractory AML and ALL as Assessed by Time at Maximum Concentration.

  24 months

• Pharmacokinetic Parameters of Low Dose Daunorubicin in Children With Relapsed/Refractory AML and ALL as Assessed by Area Under the Curve.

  24 months

• Pharmacokinetic Parameters of Low Dose Daunorubicin in Children With Relapsed/Refractory AML and ALL as Assessed by Elimination Half-life

  24 months

Study Arms (1)

Patients with relapsed/refractory ALL and AML

EXPERIMENTAL

Patients in this arm will receive daunorubicin 6.75mg/m2 daily for 5 consecutive days.

Drug: Daunorubicin

Interventions

Daunorubicin DRUG

Eligible patients with relapsed and/or refractory acute leukemia will receive daunorubicin 6.75mg/m2 daily for 5 consecutive days.

Patients with relapsed/refractory ALL and AML

Eligibility Criteria

• Age: 1 Year - 21 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• Children's Mercy Hospital Kansas City: lead

Study Sites (1)

Children's Mercy Hospital

Kansas City, Missouri, 64108, United States

Location

Related Publications (11)

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  PMID: 24488779 BACKGROUND

• Nguyen K, Devidas M, Cheng SC, La M, Raetz EA, Carroll WL, Winick NJ, Hunger SP, Gaynon PS, Loh ML; Children's Oncology Group. Factors influencing survival after relapse from acute lymphoblastic leukemia: a Children's Oncology Group study. Leukemia. 2008 Dec;22(12):2142-50. doi: 10.1038/leu.2008.251. Epub 2008 Sep 25.

  PMID: 18818707 BACKGROUND

• Borowitz MJ, Devidas M, Hunger SP, Bowman WP, Carroll AJ, Carroll WL, Linda S, Martin PL, Pullen DJ, Viswanatha D, Willman CL, Winick N, Camitta BM; Children's Oncology Group. Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia and its relationship to other prognostic factors: a Children's Oncology Group study. Blood. 2008 Jun 15;111(12):5477-85. doi: 10.1182/blood-2008-01-132837. Epub 2008 Apr 3.

  PMID: 18388178 BACKGROUND

• Armenian SH. Improving screening practices in childhood cancer survivors at risk for treatment-related heart failure. J Clin Oncol. 2014 Dec 10;32(35):3923-5. doi: 10.1200/JCO.2014.58.5562. Epub 2014 Nov 3. No abstract available.

  PMID: 25366690 BACKGROUND

• Oeffinger KC, Mertens AC, Sklar CA, Kawashima T, Hudson MM, Meadows AT, Friedman DL, Marina N, Hobbie W, Kadan-Lottick NS, Schwartz CL, Leisenring W, Robison LL; Childhood Cancer Survivor Study. Chronic health conditions in adult survivors of childhood cancer. N Engl J Med. 2006 Oct 12;355(15):1572-82. doi: 10.1056/NEJMsa060185.

  PMID: 17035650 BACKGROUND

• Reulen RC, Winter DL, Frobisher C, Lancashire ER, Stiller CA, Jenney ME, Skinner R, Stevens MC, Hawkins MM; British Childhood Cancer Survivor Study Steering Group. Long-term cause-specific mortality among survivors of childhood cancer. JAMA. 2010 Jul 14;304(2):172-9. doi: 10.1001/jama.2010.923.

  PMID: 20628130 BACKGROUND

• Blanco JG, Sun CL, Landier W, Chen L, Esparza-Duran D, Leisenring W, Mays A, Friedman DL, Ginsberg JP, Hudson MM, Neglia JP, Oeffinger KC, Ritchey AK, Villaluna D, Relling MV, Bhatia S. Anthracycline-related cardiomyopathy after childhood cancer: role of polymorphisms in carbonyl reductase genes--a report from the Children's Oncology Group. J Clin Oncol. 2012 May 1;30(13):1415-21. doi: 10.1200/JCO.2011.34.8987. Epub 2011 Nov 28.

  PMID: 22124095 BACKGROUND

• van Nimwegen FA, Ntentas G, Darby SC, Schaapveld M, Hauptmann M, Lugtenburg PJ, Janus CPM, Daniels L, van Leeuwen FE, Cutter DJ, Aleman BMP. Risk of heart failure in survivors of Hodgkin lymphoma: effects of cardiac exposure to radiation and anthracyclines. Blood. 2017 Apr 20;129(16):2257-2265. doi: 10.1182/blood-2016-09-740332. Epub 2017 Jan 31.

  PMID: 28143884 BACKGROUND

• Felker GM, Thompson RE, Hare JM, Hruban RH, Clemetson DE, Howard DL, Baughman KL, Kasper EK. Underlying causes and long-term survival in patients with initially unexplained cardiomyopathy. N Engl J Med. 2000 Apr 13;342(15):1077-84. doi: 10.1056/NEJM200004133421502.

  PMID: 10760308 BACKGROUND

• Huang J, Nguyen-McCarty M, Hexner EO, Danet-Desnoyers G, Klein PS. Maintenance of hematopoietic stem cells through regulation of Wnt and mTOR pathways. Nat Med. 2012 Dec;18(12):1778-85. doi: 10.1038/nm.2984. Epub 2012 Nov 11.

  PMID: 23142822 BACKGROUND

• Korkaya H, Paulson A, Charafe-Jauffret E, Ginestier C, Brown M, Dutcher J, Clouthier SG, Wicha MS. Regulation of mammary stem/progenitor cells by PTEN/Akt/beta-catenin signaling. PLoS Biol. 2009 Jun 2;7(6):e1000121. doi: 10.1371/journal.pbio.1000121. Epub 2009 Jun 2.

  PMID: 19492080 BACKGROUND

MeSH Terms

Conditions

Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Myeloid, Acute

Interventions

Daunorubicin

Condition Hierarchy (Ancestors)

Leukemia, Lymphoid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Leukemia, Myeloid

Intervention Hierarchy (Ancestors)

Anthracyclines; Naphthacenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Polycyclic Compounds; Aminoglycosides; Glycosides; Carbohydrates

Results Point of Contact

• Title: Dr. Alan Gamis
• Organization: Children's Mercy

agamis@cmh.edu

816-302-6808

Study Officials

• Chandni Dargan, MD

  Children's Mercy Hospital Kansas City

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 28, 2020
• First Posted: September 24, 2020
• Study Start: May 8, 2020
• Primary Completion: June 30, 2022
• Study Completion: June 30, 2022
• Last Updated: June 28, 2023
• Results First Posted: May 6, 2023

Record last verified: 2023-06

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)