Clinical Trials /

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

NCT03318016

Description:

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.

Related Conditions:
  • Acute Myeloid Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • 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

Clinical Trial IDs

  • ORG STUDY ID: 17-0754.cc
  • NCT ID: NCT03318016

Conditions

  • Acute Myeloid Leukemia
  • Relapsed/Refractory Acute Myeloid Leukemia

Interventions

DrugSynonymsArms
CyclophosphamideCyclophosphamide

Purpose

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.
    

Trial Arms

NameTypeDescriptionInterventions
CyclophosphamideExperimentalCohort -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
  • Cyclophosphamide

Eligibility Criteria

        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 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

          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.
      
Maximum Eligible Age:99 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximally Tolerated Dose (MTD) of Cyclophosphamide and ATO
Time Frame:6 months
Safety Issue:
Description:MTD is defined as the highest dose level with no more than 1 DLT reported out of 6 DLT-evaluable subjects.

Secondary Outcome Measures

Measure:Overall Response Rate (ORR) using ATO and Cyclophosphamide
Time Frame:minimum 5 years
Safety Issue:
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)

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:University of Colorado, Denver

Trial Keywords

  • Arsenic Trioxide
  • Cyclophosphamide

Last Updated

September 24, 2019