Clinical Trials /

Phase I Study of Mitoxantrone and Etoposide Combined With Hydroxychloroquine, for Relapsed Acute Myelogenous Leukemia

NCT02631252

Description:

This is an open label phase I clinical trial of hydroxychloroquine (HCQ) ,when it is combined with the usual medications for acute myeloid leukemia, mitoxantrone and etoposide. The purpose of this study is to find the safest and most effective dose of hydroxychloroquine with these medications. The investigators will be testing to see if it can increase the effectiveness of mitoxantrone and etoposide.

Related Conditions:
  • Acute Myeloid Leukemia
Recruiting Status:

Terminated

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Phase I Study of Mitoxantrone and Etoposide Combined With Hydroxychloroquine, for Relapsed Acute Myelogenous Leukemia
  • Official Title: A Phase I Study of Combination Chemotherapy With Mitoxantrone and Etoposide (VP-16) Combined With an Autophagy Inhibitor, Hydroxychloroquine (HCQ), for the Treatment of Patients With Relapsed Acute Myelogenous Leukemia (AML)

Clinical Trial IDs

  • ORG STUDY ID: 14-133
  • NCT ID: NCT02631252

Conditions

  • Leukemia, Acute Myelogenous

Interventions

DrugSynonymsArms
HydroxychloroquinePlaquenilOpen-label, Single-arm
MitoxantroneDihydroxyanthracenedione, DHADOpen-label, Single-arm
EtoposideToposar®, EPEGOpen-label, Single-arm

Purpose

This is an open label phase I clinical trial of hydroxychloroquine (HCQ) ,when it is combined with the usual medications for acute myeloid leukemia, mitoxantrone and etoposide. The purpose of this study is to find the safest and most effective dose of hydroxychloroquine with these medications. The investigators will be testing to see if it can increase the effectiveness of mitoxantrone and etoposide.

Detailed Description

      Hydroxychloroquine is not FDA (United States Food and Drug Administration) approved for AML
      and is considered an investigational drug in this study. It has helped make chemotherapy
      more effective in animals. The investigators will be testing to see if it can increase the
      effectiveness of mitoxantrone and etoposide. It has been combined with other types of
      chemotherapy for humans with other types of cancer. Most of the patients were able to take
      hydroxychloroquine safely at the doses studied in this clinical trial.

      Hydroxychloroquine is approved by the FDA for malaria, rheumatoid arthritis, and other
      autoimmune diseases. Mitoxantrone is approved by the FDA for use in AML, and it is one of
      the most common drugs used in the treatment of AML. Etoposide is not approved by the FDA for
      AML. It is approved for small cell lung cancer and testicular cancer. It is commonly used in
      AML.

      The primary objective of this trial is to determine the recommend phase 2 dose (RP2D) for
      HCQ combined with mitoxantrone and etoposide, while secondary objectives include efficacy
      estimates of this combination at the RP2D, a safety and tolerability profile of this
      combination, as well as the correlation of pharmacodynamic assessments of autophagy
      inhibition with dose and clinical response.
    

Trial Arms

NameTypeDescriptionInterventions
Open-label, Single-armExperimentalHydroxychloroquine + Mitoxantrone + Etoposide Hydroxychloroquine is given up to 21 days, started concurrently with both Mitoxantrone, administered by IVPB over 15 minutes each day for 5 days and Etoposide, administered intravenously over 2 hours each day for 5 days
  • Hydroxychloroquine
  • Mitoxantrone
  • Etoposide

Eligibility Criteria

        Inclusion Criteria:

          1. Able to understand and have the ability to provide written consent

          2. Age > 18 years old to <80 years old

          3. Patients with AML in the first morphologic relapse as defined by >5% reappearance of
             leukemia blasts in the bone marrow not attributable to any other cause (Appendix I)
             who have not yet received chemotherapy for the current relapse

          4. Eastern Cooperative Oncology Group Performance Status of 0 -2 (see Appendix II)

          5. Adequate organ function

               1. Serum creatinine ≤ 1.5 mg/dl and calculated creatinine clearance ≥ 50 mL/min
                  (using the Cockcroft-Gault equation CL creatinine = (140-age) x body mass X 0.85
                  if female)/72 x creatinine where age is given in years, body mass is given in kg
                  and creatinine is given in mg/dL)

               2. Aspartate aminotransferase (AST) ≤ 5x the upper limit of normal Alanine
                  aminotransferase (ALT) < 5x the upper limit of normal

               3. Direct bilirubin ≤ 1.5 mg/dl Note: As many eligible patients will be
                  pancytopenic secondary to their disease or prior treatments, hematologic
                  abnormalities will not be used as a criteria for entry or exclusion

          6. Left ventricular ejection fraction (LVEF) ≥50 %

          7. Females of child-bearing potential must have a negative pregnancy test during
             screening and all subjects must agree to use an effective method of contraception. A
             woman is eligible to enter and participate in the study if she is of:

               1. Non-childbearing potential (i.e., physiologically incapable of becoming
                  pregnant) including any female who has had a hysterectomy or has had a bilateral
                  oophorectomy (ovariectomy).

               2. Childbearing potential, has a negative serum pregnancy test during the screening
                  period and agrees to avoid sexual activity or use accepted methods of
                  contraception from screening through follow-up.

        Men with a female partner of childbearing potential are eligible to enroll and participate
        in the study if they have had either a prior vasectomy or agree to avoid sexual activity
        or use appropriate barrier contraception from screening through post-treatment follow-up.

        Exclusion Criteria:

          1. Acute promyelocytic leukemia

          2. Prior chemotherapy regimen given for 1st relapse, not including the use of
             hydroxyurea or plasmapheresis that is used prior to the initiation of chemotherapy.

          3. Previous use of mitoxantrone and etoposide combination therapy within the preceding
             180 days of screening.

          4. Symptomatic central nervous system (CNS) involvement

          5. Uncontrolled, life-threatening infection that is not responding to antimicrobial
             therapy

          6. History of psychiatric disorder which may compromise compliance with the protocol or
             which does not allow for appropriate informed consent

          7. Current receiving any other anti neoplastic investigational agents

          8. Prior autologous or allogeneic stem cell transplantation

          9. Concurrent malignancy. Exceptions: Patients who have been disease-free for 5 years,
             or subjects with a history of completely resected non-melanoma skin cancer or
             successfully treated in situ carcinoma are eligible. Subjects with concurrent
             malignancies that are indolent or definitely treated may be enrolled.

         10. Women who are pregnant or breastfeeding

         11. Evidence of severe or uncontrolled systemic disease (e.g., unstable or uncompensated
             respiratory or cardiac disease)

         12. Inability to take oral medications, due to impaired swallowing ability or poor
             absorption capacity

         13. Known glucose-6-phosphate dehydrogenase (G-6PD) deficiency
      
Maximum Eligible Age:80 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Select a recommended phase 2 dose (RP2D) for hydroxychloroquine
Time Frame:during the first 7 weeks after initiating therapy
Safety Issue:
Description:Dose limiting toxicity (DLT) that occurs during the first 7 weeks after initiating therapy and is at least possibly related

Secondary Outcome Measures

Measure:Complete Remission (CR)
Time Frame:up to 4 weeks after completion of therapy
Safety Issue:
Description:
Measure:Overall Survival (OS)
Time Frame:until death or last patient contact, up to 5 years
Safety Issue:
Description:
Measure:Relapse Free Survival (RFS)
Time Frame:until relapse or death, whichever occurs first, or last patient contact, for up to 5 years
Safety Issue:
Description:
Measure:Pharmacodynamic Endpoint - Measurement of LC3-1
Time Frame:up to 4 weeks after completion of therapy
Safety Issue:
Description:
Measure:Pharmacodynamic Endpoint - Measurement of LC3-2
Time Frame:up to 4 weeks after completion of therapy
Safety Issue:
Description:
Measure:Pharmacodynamic Endpoint - Measurement of p62
Time Frame:up to 4 weeks after completion of therapy
Safety Issue:
Description:
Measure:Pharmacodynamic Endpoint - Measurement of HMGB1
Time Frame:up to 4 weeks after completion of therapy
Safety Issue:
Description:
Measure:Pharmacodynamic Endpoint - Measurement of RAGE
Time Frame:up to 4 weeks after completion of therapy
Safety Issue:
Description:

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Alison Sehgal, MD, MS

Trial Keywords

  • Leukemia
  • Acute Myelogenous
  • Phase I
  • Mitoxantrone
  • Etoposide
  • Hydroxychloroquine
  • Relapsed
  • Autophagy inhibitor
  • AML
  • Relapsed AML

Last Updated

January 21, 2016