Acute Myeloid Leukemia, Relapsed/Refractory Acute Myeloid Leukemia
Conditions
Keywords
Arsenic Trioxide, Cyclophosphamide
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.
Interventions
DRUGCyclophosphamide 500 MG
ATO at a fixed dose of 0.15 mg/kg/d IV followed by Cyclophosphamide 500 mg/m2 on day 4 as a single IV dose along with hydration for a maximum of 6 doses
DRUGCyclophosphamide 1000 MG
Enrolled subjects will receive 3 consecutive days of ATO at a fixed dose of 0.15 mg/kg/d IV followed by Cyclophosphamide 1000 mg/m2on day 4 as a single IV dose along with Mesna (in subjects receiving ≥1000mg/m2 Cy) and hydration for a maximum of 6 doses
DRUGCyclophosphamide 2000 MG
Enrolled subjects will receive 3 consecutive days of ATO at a fixed dose of 0.15 mg/kg/d IV followed by Cyclophosphamide 2000 mg/m2on day 4 as a single IV dose along with Mesna (in subjects receiving ≥1000mg/m2 Cy) and hydration for a maximum of 6 doses
DRUGCyclophosphamide 3000 MG
Enrolled subjects will receive 3 consecutive days of ATO at a fixed dose of 0.15 mg/kg/d IV followed by Cyclophosphamide 3000 mg/m2on day 4 as a single IV dose along with Mesna (in subjects receiving ≥1000mg/m2 Cy) and hydration for a maximum of 6 doses
DRUGCyclophosphamide 4000 MG
Enrolled subjects will receive 3 consecutive days of ATO at a fixed dose of 0.15 mg/kg/d IV followed by Cyclophosphamide 4000 mg/m2on day 4 as a single IV dose along with Mesna (in subjects receiving ≥1000mg/m2 Cy) and hydration for a maximum of 6 doses
Sponsors
University of Colorado, Denver
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention 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.
Eligibility
Sex/Gender
ALL
Age
18 Years to 99 Years
Healthy volunteers
No
Inclusion criteria
1. WHO-confirmed AML, other than APL, with no standard treatment options available 2. Age 18 years or older 3. Relapsed or refractory (resistant) disease, as defined by standard criteria * 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 4. \>14 days since any prior therapy for AML excluding hydroxyurea 5. Willing and able to understand and voluntarily sign a written informed consent 6. Able to adhere to the study visit schedule and other protocol requirements 7. 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
1. New York Heart Association Class III or IV heart failure 2. Unstable angina pectoris 3. 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 4. QTc \>500 ms, uncorrectable by managing electrolytes and medications, using the QTcF formula in Appendix D. 5. Active acute graft vs. host disease ≥ grade 2 or active extensive chronic GVHD 6. Relapse after allogeneic stem cell transplantation prior to post-transplant day 30 7. Active central nervous system (CNS) involvement of leukemia (lumbar puncture not required to rule out CNS involvement if not suspected) 8. Uncontrolled psychiatric illness that would limit compliance with requirements 9. Pregnant or breast feeding females 10. 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 11. 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants That Reached Maximally Tolerated Dose (MTD) of Cyclophosphamide and ATO | 26 months | Number of Participants that were treated in each Cohort in attempt to establish Maximally Tolerated Dose (MTD) of cyclophosphamide with ATO is defined as the highest dose level of 1000 mg/m2. MTD is established when at least 6 participants within a Cohort have responded without toxicity. The trial is organized in a standard, phase I, 3+3 design. The first 3 subjects will be assigned to cohort 1. Per standard trial design, if there are 0/3 dose-limiting toxicities (DLT) in this cohort, the next three subjects will be assigned to cohort 2. This will continue until MTD is established. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate (ORR) Using ATO and Cyclophosphamide | 26 months | ORR defined by complete remission/complete remission with incomplete recovery of blood counts (CR/CRi), morphologic leukemia free state (MLFS) and partial responses (PR) |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Cohort -1 ATO at a fixed dose of 0.15 mg/kg/d IV followed by Cyclophosphamide 500 mg/m2 on day 4 as a single IV dose along with hydration for a maximum of 6 doses | 0 |
| Cohort 1 ATO at a fixed dose of 0.15 mg/kg/d IV followed by Cyclophosphamide 1000 mg/m2 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 | 3 |
| Cohort 2 ATO at a fixed dose of 0.15 mg/kg/d IV followed by Cyclophosphamide 2000 mg/m2 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 | 2 |
| Cohort 3 ATO at a fixed dose of 0.15 mg/kg/d IV followed by Cyclophosphamide 3000 mg/m2 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 | 0 |
| Cohort 4 ATO at a fixed dose of 0.15 mg/kg/d IV followed by Cyclophosphamide 4000 mg/m2 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 | 0 |
| Total | 5 |
Baseline characteristics
| Characteristic | Cohort -1 | Cohort 1 | Cohort 2 | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 3 Participants | 2 Participants | 5 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Continuous | — | 72 years | 68 years | 78 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | — | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | — | 3 Participants | 2 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | — | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | — | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | — | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | — | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | — | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | — | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | — | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | — | 3 Participants | 2 Participants | 5 Participants |
| Region of Enrollment United States | — | 3 participants | 2 participants | 5 participants |
| Sex: Female, Male Female | — | 3 Participants | 0 Participants | 3 Participants |
| Sex: Female, Male Male | — | 0 Participants | 2 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 0 | 0 / 3 | 0 / 2 | 0 / 0 | 0 / 0 |
| other Total, other adverse events | 0 / 0 | 3 / 3 | 2 / 2 | 0 / 0 | 0 / 0 |
| serious Total, serious adverse events | 0 / 0 | 1 / 3 | 0 / 2 | 0 / 0 | 0 / 0 |
Outcome results
Primary
Number of Participants That Reached Maximally Tolerated Dose (MTD) of Cyclophosphamide and ATO
Number of Participants that were treated in each Cohort in attempt to establish Maximally Tolerated Dose (MTD) of cyclophosphamide with ATO is defined as the highest dose level of 1000 mg/m2. MTD is established when at least 6 participants within a Cohort have responded without toxicity. The trial is organized in a standard, phase I, 3+3 design. The first 3 subjects will be assigned to cohort 1. Per standard trial design, if there are 0/3 dose-limiting toxicities (DLT) in this cohort, the next three subjects will be assigned to cohort 2. This will continue until MTD is established.
Time frame: 26 months
Population: Patients With Relapsed/Refractory Acute Myeloid Leukemia
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort -1 | Number of Participants That Reached Maximally Tolerated Dose (MTD) of Cyclophosphamide and ATO | 0 Participants |
| Cohort 1 | Number of Participants That Reached Maximally Tolerated Dose (MTD) of Cyclophosphamide and ATO | 0 Participants |
| Cohort 2 | Number of Participants That Reached Maximally Tolerated Dose (MTD) of Cyclophosphamide and ATO | 0 Participants |
| Cohort 3 | Number of Participants That Reached Maximally Tolerated Dose (MTD) of Cyclophosphamide and ATO | 0 Participants |
| Cohort 4 | Number of Participants That Reached Maximally Tolerated Dose (MTD) of Cyclophosphamide and ATO | 0 Participants |
Secondary
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)
Time frame: 26 months
Population: Subjects provided both ATO and Cyclophosphamide
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1 | Overall Response Rate (ORR) Using ATO and Cyclophosphamide | 3 Participants |
| Cohort 2 | Overall Response Rate (ORR) Using ATO and Cyclophosphamide | 2 Participants |