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Arsenic Trioxide With Cyclophosphamide in Patients With Relapsed/Refractory Acute Myeloid Leukemia

Primary Purpose

Acute Myeloid Leukemia, Relapsed/Refractory Acute Myeloid Leukemia

Status

Completed

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

Cyclophosphamide

About this trial

This is an interventional treatment trial for Acute Myeloid Leukemia focused on measuring Arsenic Trioxide, Cyclophosphamide

Eligibility Criteria

18 Years - 99 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

WHO-confirmed AML, other than APL, with no standard treatment options available
Age 18 years or older
Relapsed or refractory (resistant) disease, as defined by standard criteria7
- Relapsed: Bone marrow blasts ≥5%, reappearance of blasts in the blood, or development of extramedullary disease following achievement of CR/CRi/CRp/MLFS
- Refractory (resistant): Failure to achieve CR/CRi/MLFS in subjects who survive ≥7 days following completion of initial treatment, with evidence of persistent leukemia by blood and/or bone marrow examination
>14 days since any prior therapy for AML excluding hydroxyurea
Willing and able to understand and voluntarily sign a written informed consent
Able to adhere to the study visit schedule and other protocol requirements
Women of childbearing potential must use an acceptable form of birth control for 28 days prior to beginning study treatment, through the duration of study treatment, and for 3 months after discontinuing study treatment.

Exclusion Criteria:

New York Heart Association Class III or IV heart failure
Unstable angina pectoris
Significant uncontrolled cardiac arrhythmias, including ventricular arrhythmias, congenital long QT syndrome, symptomatic atrial fibrillation, symptomatic bradycardia, right bundle branch block plus left anterior hemiblock or bifasicular block
QTc >500 ms, uncorrectable by managing electrolytes and medications, using the QTcF formula in Appendix D.
Active acute graft vs. host disease ≥ grade 2 or active extensive chronic GVHD
Relapse after allogeneic stem cell transplantation prior to post-transplant day 30
Active central nervous system (CNS) involvement of leukemia (lumbar puncture not required to rule out CNS involvement if not suspected)
Uncontrolled psychiatric illness that would limit compliance with requirements
Pregnant or breast feeding females
Laboratory abnormalities:
1. Either creatinine >2.0 mg/dL or creatinine clearance <30 mL/min
2. Total bilirubin > 3 x institutional upper limit of normal (ULN) (unless documented Gilbert's syndrome)
3. AST or ALT > 3 x institutional ULN, unless felt to be due to disease involvement
Other medical or psychiatric illness or organ dysfunction or laboratory abnormality which, in the opinion of the investigator, would compromise the subject's safety or interfere with data interpretation.

Sites / Locations

University of Colorado Denver

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Cyclophosphamide

Arm Description

Cohort -1: Cyclophosphamide 500 mg/m2 Cohort 1: Cyclophosphamide 1000 mg/m2 Cohort 2: Cyclophosphamide 2000 mg/m2 Cohort 3: Cyclophosphamide 3000 mg/m2 Cohort 4: Cyclophosphamide 4000 mg/m2

Outcomes

Primary Outcome Measures

Maximally Tolerated Dose (MTD) of Cyclophosphamide and ATO

MTD is defined as the highest dose level with no more than 1 DLT reported out of 6 DLT-evaluable subjects.

Secondary Outcome Measures

Overall Response Rate (ORR) using ATO and Cyclophosphamide

ORR defined by complete remission/complete remission with incomplete recovery of blood counts (CR/CRi), morphologic leukemia free state (MLFS) and partial responses (PR)

Full Information

NCT ID

NCT03318016

First Posted

October 18, 2017

Last Updated

April 28, 2021

Sponsor

University of Colorado, Denver

1. Study Identification

Unique Protocol Identification Number

NCT03318016

Brief Title

Arsenic Trioxide With Cyclophosphamide in Patients With Relapsed/Refractory Acute Myeloid Leukemia

Official Title

Phase I Trial of Arsenic Trioxide With Cyclophosphamide in Patients With Relapsed/Refractory Acute Myeloid Leukemia

Study Type

Interventional

2. Study Status

Record Verification Date

April 2021

Overall Recruitment Status

Completed

Study Start Date

December 15, 2017 (Actual)

Primary Completion Date

January 15, 2020 (Actual)

Study Completion Date

January 20, 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

University of Colorado, Denver

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

Determine the maximum tolerated dose (MTD) and toxicity profile of the combination of cyclophosphamide and ATO (Arsenic Trioxide) in subjects with relapsed refractory AML. Determine the efficacy of ATO and cyclophosphamide in this population, as defined by response rate, response duration, event-free survival (EFS) and overall survival (OS). Determine the number of transplant-eligible subjects who are successfully bridged to stem cell transplantation or donor lymphocyte infusion.

Detailed Description

This is an open label phase 1 study of fixed dose ATO (Arsenic Trioxide) and escalating doses of cyclophosphamide using a standard 3+3 dose escalation design. All subjects will be treated with sequential cycles of 3 days of ATO at 0.15 mg/kg/d IV followed by Cyclophosphamide as a single IV dose on day 4 along with mesna at a dose equal to the cyclophosphamide (for doses ≥1000 mg/m2) and hydration for a maximum of 6 cycles. ATO and Cyclophosphamide will be repeated every 28-42 days. Treatment will be given inpatient for the first cycle, with the option of outpatient treatment for subsequent cycles. Subjects may remain on study in the absence of disease progression or unacceptable toxicity for a maximum six cycles. Toxicity assessments will be performed continuously; DLT determination will be made based on adverse events (AEs) that occur during cycle 1 (day 1-28). An expansion cohort of ten subjects at the maximum tolerated dose will occur at the conclusion of dose escalation.

6. Conditions and Keywords

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

Acute Myeloid Leukemia, Relapsed/Refractory Acute Myeloid Leukemia

Keywords

Arsenic Trioxide, Cyclophosphamide

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Single Group Assignment

Model Description

Cohort -1 (3-6 subjects, if needed): Cyclophosphamide 500 mg/m2 Cohort 1 (3-6 subjects): Cyclophosphamide 1000 mg/m2 Cohort 2 (3-6 subjects): Cyclophosphamide 2000 mg/m2 Cohort 3 (3-6 subjects): Cyclophosphamide 3000 mg/m2 Cohort 4 (3 subjects): Cyclophosphamide 4000 mg/m2 ATO and Cyclophosphamide will be repeated every 28 days.

Masking

None (Open Label)

Allocation

N/A

Enrollment

5 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Cyclophosphamide

Arm Type

Experimental

Arm Description

Cohort -1: Cyclophosphamide 500 mg/m2 Cohort 1: Cyclophosphamide 1000 mg/m2 Cohort 2: Cyclophosphamide 2000 mg/m2 Cohort 3: Cyclophosphamide 3000 mg/m2 Cohort 4: Cyclophosphamide 4000 mg/m2

Intervention Type

Drug

Intervention Name(s)

Cyclophosphamide

Intervention Description

ATO at a fixed dose of 0.15 mg/kg/d IV followed by Cyclophosphamide on day 4 as a single IV dose along with Mesna (in subjects receiving >1000mg/m2 Cy) and hydration for a maximum of 6 doses in the following dose escalation schema: Cohort -1 (3-6 subjects, if needed): Cyclophosphamide 500 mg/m2 Cohort 1 (3-6 subjects): Cyclophosphamide 1000 mg/m2 Cohort 2 (3-6 subjects): Cyclophosphamide 2000 mg/m2 Cohort 3 (3-6 subjects): Cyclophosphamide 3000 mg/m2 Cohort 4 (3 subjects): Cyclophosphamide 4000 mg/m2

Primary Outcome Measure Information:

Title

Maximally Tolerated Dose (MTD) of Cyclophosphamide and ATO

Description

MTD is defined as the highest dose level with no more than 1 DLT reported out of 6 DLT-evaluable subjects.

Time Frame

6 months

Secondary Outcome Measure Information:

Title

Overall Response Rate (ORR) using ATO and Cyclophosphamide

Description

ORR defined by complete remission/complete remission with incomplete recovery of blood counts (CR/CRi), morphologic leukemia free state (MLFS) and partial responses (PR)

Time Frame

minimum 5 years

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

99 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: WHO-confirmed AML, other than APL, with no standard treatment options available Age 18 years or older Relapsed or refractory (resistant) disease, as defined by standard criteria7 Relapsed: Bone marrow blasts ≥5%, reappearance of blasts in the blood, or development of extramedullary disease following achievement of CR/CRi/CRp/MLFS Refractory (resistant): Failure to achieve CR/CRi/MLFS in subjects who survive ≥7 days following completion of initial treatment, with evidence of persistent leukemia by blood and/or bone marrow examination >14 days since any prior therapy for AML excluding hydroxyurea Willing and able to understand and voluntarily sign a written informed consent Able to adhere to the study visit schedule and other protocol requirements Women of childbearing potential must use an acceptable form of birth control for 28 days prior to beginning study treatment, through the duration of study treatment, and for 3 months after discontinuing study treatment. Exclusion Criteria: New York Heart Association Class III or IV heart failure Unstable angina pectoris Significant uncontrolled cardiac arrhythmias, including ventricular arrhythmias, congenital long QT syndrome, symptomatic atrial fibrillation, symptomatic bradycardia, right bundle branch block plus left anterior hemiblock or bifasicular block QTc >500 ms, uncorrectable by managing electrolytes and medications, using the QTcF formula in Appendix D. Active acute graft vs. host disease ≥ grade 2 or active extensive chronic GVHD Relapse after allogeneic stem cell transplantation prior to post-transplant day 30 Active central nervous system (CNS) involvement of leukemia (lumbar puncture not required to rule out CNS involvement if not suspected) Uncontrolled psychiatric illness that would limit compliance with requirements Pregnant or breast feeding females Laboratory abnormalities: Either creatinine >2.0 mg/dL or creatinine clearance <30 mL/min Total bilirubin > 3 x institutional upper limit of normal (ULN) (unless documented Gilbert's syndrome) AST or ALT > 3 x institutional ULN, unless felt to be due to disease involvement Other medical or psychiatric illness or organ dysfunction or laboratory abnormality which, in the opinion of the investigator, would compromise the subject's safety or interfere with data interpretation.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Daniel Pollyea, MD

Organizational Affiliation

University of Colorado, Denver

Official's Role

Principal Investigator

Facility Information:

Facility Name

University of Colorado Denver

City

Aurora

State/Province

Colorado

ZIP/Postal Code

80045

Country

United States

12. IPD Sharing Statement

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Arsenic Trioxide With Cyclophosphamide in Patients With Relapsed/Refractory Acute Myeloid Leukemia

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