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Low-Dose Daunorubicin in Relapsed/Refractory Acute Leukemia

Primary Purpose

Acute Lymphocytic Leukemia, Acute Myeloid Leukemia

Status

Completed

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

Daunorubicin

About this trial

This is an interventional treatment trial for Acute Lymphocytic Leukemia focused on measuring Relapsed, Refractory

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Ability to understand and the willingness to sign a written informed consent or have parental consent.
Age ≥ 18 years
Pathological confirmation by bone marrow documenting the following:
1. AML which has relapsed after Complete Remission
2. AML which has been refractory to two prior induction attempts
3. ALL which has relapsed after Complete Remission
4. ALL which has been refractory to two prior induction attempts
Disease status allows delay of additional anti-leukemia therapy for the duration of the study (hydroxyurea is allowed for control of WBC throughout study)
Eastern Cooperative Oncology Group (ECOG) performance status score of 0-3
Able to adhere to the study visit schedule and other protocol requirements
Cardiac ejection fraction ≥45% by ECHO
Serum alanine aminotransferase or aspartate aminotransferase < 3 times the ULN
Women of child-bearing potential and men with partners of child-bearing potential must agree to use adequate contraception prior to study entry, for the duration of study participation, and for 90 days following completion of therapy.

Exclusion Criteria:

Concurrent use of conventional or investigational anticancer agents, except hydroxyurea (Standard prophylactic anti-infectives and medications to prevent/treat tumor lysis syndrome are allowed. Hydroxyurea may be used to keep the WBC<25,000. Additional anti-leukemia therapy is prohibited during the study.).
Patient has received chemotherapy or radiotherapy within 2 weeks prior to entering the study or has not recovered from adverse events due to agents administered more than 2 weeks earlier, with the exception of hydroxyurea.
Patients with known active uncontrolled central nervous system (CNS) leukemia
History of allergic reactions attributed to compounds of similar chemical or biologic composition to daunorubicin
Patients with a total lifetime anthracycline exposure exceeding the equivalent of 900 mg/m2 of daunorubicin
Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
Unwilling or unable to undergo serial bone marrow aspirate/biopsy
Pregnant or nursing

Sites / Locations

University of Kansas Cancer Center - Clinical Research Center

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Low-dose daunorubicin (DNR)

Arm Description

Eligible patients will be treated with 5 days of low dose daunorubicin (DNR) for one cycle only.

Outcomes

Primary Outcome Measures

Molecular pharmacodynamic effect of low dose daunorubicin on beta-catenin phosphorylation as assessed by quantitative immunohistochemistry assay performed on serial bone marrow samples of patients with relapsed leukemia.

Secondary Outcome Measures

Number of participants with treatment-related adverse events and/or toxicity as assessed by CTCAE 4.03.

Analyses will be performed for all patients having received at least one dose of study drug. Each patient will be assessed for the development of toxicity at all scheduled visits (Days 1-5).

Maximum Plasma Concentration [Cmax]

Area Under the Curve [AUC]

Full Information

NCT ID

NCT02914977

First Posted

July 25, 2016

Last Updated

January 12, 2022

Sponsor

Tara Lin

1. Study Identification

Unique Protocol Identification Number

NCT02914977

Brief Title

Low-Dose Daunorubicin in Relapsed/Refractory Acute Leukemia

Official Title

A Pilot Study of Low-Dose Daunorubicin in Patients With Relapsed/Refractory Acute Leukemia

Study Type

Interventional

2. Study Status

Record Verification Date

January 2022

Overall Recruitment Status

Completed

Study Start Date

November 2016 (Actual)

Primary Completion Date

April 3, 2019 (Actual)

Study Completion Date

July 15, 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor-Investigator

Name of the Sponsor

Tara Lin

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

In this pilot study, eligible patients will be treated with 5 days of low dose daunorubicin for one cycle only. Any patient who receives treatment on this protocol will be evaluable for toxicity. Each patient will be assessed for the development of toxicity at all scheduled visits (Days 1-5). Following participation on this brief pharmacodynamic trial, patients can then proceed to other conventional or investigational therapies, as clinically indicated.

Detailed Description

Disease relapse remains the primary challenge in the treatment of acute myeloid leukemia (AML) and acute lymphocytic leukemia (ALL). There is no standard of care treatment option for relapsed acute leukemia, and investigational therapies are recommended. Clinically targeting the leukemia stem cell (LSC) remains an unmet need in both AML and ALL. Therefore, a primary objective of this trial is to determine the molecular pharmacodynamic effects of low dose daunorubicin (DNR) on beta-catenin phosphorylation in serial bone marrow samples of patients with relapsed leukemia. Prior to studying low-dose DNR in complex, multi-agent regimens, it is essential to confirm that it inhibits p-beta-catenin S552 in humans. This pilot study is designed to assess the feasibility and tolerability of low dose DNR administration to patients with relapsed/refractory AML and ALL, and obtain preliminary data regarding target engagement. A second objective is to demonstrate the safety and feasibility of low-dose daunorubicin administration in patients with relapsed/refractory acute leukemia. Beta-catenin phosphorylation will be measured by immunohistochemistry assay in bone marrow samples taken from patients at study entry and at Day 8 following study therapy with low-dose DNR. The investigators will also measure the pharmacokinetics of low dose DNR in these patients, to enable preliminary PK-PD analyses and because there are essentially no PK data for DNR at comparable doses using modern analytical methodologies. Following participation on this brief pharmacodynamic proof-of-concept trial, patients can then proceed to other conventional or investigational therapies, as clinically indicated.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Acute Lymphocytic Leukemia, Acute Myeloid Leukemia

Keywords

Relapsed, Refractory

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

18 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Low-dose daunorubicin (DNR)

Arm Type

Experimental

Arm Description

Eligible patients will be treated with 5 days of low dose daunorubicin (DNR) for one cycle only.

Intervention Type

Drug

Intervention Name(s)

Daunorubicin

Other Intervention Name(s)

Cerubidine, Daunoxome

Intervention Description

Agent: Daunorubicin Dose: 6.75 mg/m2/day Route: IV Schedule: Days 1-5 Duration: One cycle

Primary Outcome Measure Information:

Title

Time Frame

12 months

Secondary Outcome Measure Information:

Title

Number of participants with treatment-related adverse events and/or toxicity as assessed by CTCAE 4.03.

Description

Analyses will be performed for all patients having received at least one dose of study drug. Each patient will be assessed for the development of toxicity at all scheduled visits (Days 1-5).

Time Frame

12 months

Title

Maximum Plasma Concentration [Cmax]

Time Frame

prior to dosing and 5, 20, and 40 min and 1, 2, 4, 8, and 24 hrs after dosing

Title

Area Under the Curve [AUC]

Time Frame

prior to dosing and 5, 20, and 40 min and 1, 2, 4, 8, and 24 hrs after dosing

Other Pre-specified Outcome Measures:

Title

Test for additional validated markers for leukemia and/or stem cells (such as anti-CD34 and CD38, CD45 and/or CD19) assessed by flow cytometry of serial bone marrow samples.

Time Frame

12 months

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Ability to understand and the willingness to sign a written informed consent or have parental consent. Age ≥ 18 years Pathological confirmation by bone marrow documenting the following: AML which has relapsed after Complete Remission AML which has been refractory to two prior induction attempts ALL which has relapsed after Complete Remission ALL which has been refractory to two prior induction attempts Disease status allows delay of additional anti-leukemia therapy for the duration of the study (hydroxyurea is allowed for control of WBC throughout study) Eastern Cooperative Oncology Group (ECOG) performance status score of 0-3 Able to adhere to the study visit schedule and other protocol requirements Cardiac ejection fraction ≥45% by ECHO Serum alanine aminotransferase or aspartate aminotransferase < 3 times the ULN Women of child-bearing potential and men with partners of child-bearing potential must agree to use adequate contraception prior to study entry, for the duration of study participation, and for 90 days following completion of therapy. Exclusion Criteria: Concurrent use of conventional or investigational anticancer agents, except hydroxyurea (Standard prophylactic anti-infectives and medications to prevent/treat tumor lysis syndrome are allowed. Hydroxyurea may be used to keep the WBC<25,000. Additional anti-leukemia therapy is prohibited during the study.). Patient has received chemotherapy or radiotherapy within 2 weeks prior to entering the study or has not recovered from adverse events due to agents administered more than 2 weeks earlier, with the exception of hydroxyurea. Patients with known active uncontrolled central nervous system (CNS) leukemia History of allergic reactions attributed to compounds of similar chemical or biologic composition to daunorubicin Patients with a total lifetime anthracycline exposure exceeding the equivalent of 900 mg/m2 of daunorubicin Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. Unwilling or unable to undergo serial bone marrow aspirate/biopsy Pregnant or nursing

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Tara Lin, MD

Organizational Affiliation

University of Kansas Medical Center

Official's Role

Principal Investigator

Facility Information:

Facility Name

University of Kansas Cancer Center - Clinical Research Center

City

Fairway

State/Province

Kansas

ZIP/Postal Code

66205

Country

United States

12. IPD Sharing Statement

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Low-Dose Daunorubicin in Relapsed/Refractory Acute Leukemia

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