Clinical Trials /

6,8-Bis(Benzylthio)Octanoic Acid, Cytarabine, and Daunorubicin Hydrochloride in Treating Older Patients With Newly Diagnosed Acute Myeloid Leukemia

NCT02472626

Description:

This phase I/II trial studies the side effects and the best dose of 6,8-bis(benzylthio)octanoic acid (CPI-613) when given together with cytarabine and daunorubicin hydrochloride and to see how well it works in treating older patients with newly diagnosed acute myeloid leukemia. CPI-613 may kill tumor cells by turning off mitochondria (small structures in the cancer cells that are found in the cytoplasm [fluid that surrounds the cell nucleus]). Mitochondria are used by cancer cells to produce energy and are the building blocks needed to make more tumor cells. By shutting off mitochondria, CPI-613 may deprive the cancer cells of energy and other supplies that they need to survive and grow. Drugs used in chemotherapy, such as cytarabine and daunorubicin hydrochloride, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving CPI-613 together with cytarabine and daunorubicin hydrochloride may kill more cancer cells.

Related Conditions:
  • Acute Myeloid Leukemia
Recruiting Status:

Withdrawn

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: 6,8-Bis(Benzylthio)Octanoic Acid, Cytarabine, and Daunorubicin Hydrochloride in Treating Older Patients With Newly Diagnosed Acute Myeloid Leukemia
  • Official Title: A Phase I/II Study of CPI-613 in Combination With Induction/Consolidation in Older AML Patients

Clinical Trial IDs

  • ORG STUDY ID: IRB00033422
  • SECONDARY ID: NCI-2015-00890
  • SECONDARY ID: IRB00033422
  • SECONDARY ID: CCCWFU 22115
  • SECONDARY ID: P30CA012197
  • NCT ID: NCT02472626

Conditions

  • Untreated Adult Acute Myeloid Leukemia

Interventions

DrugSynonymsArms
6,8-Bis(benzylthio)octanoic AcidAlpha-Lipoic Acid Analogue CPI-613, CPI 613, CPI-613Treatment (CPI-613, cytarabine, daunorubicin hydrochloride)
Cytarabine.beta.-Cytosine arabinoside, 1-.beta.-D-Arabinofuranosyl-4-amino-2(1H)pyrimidinone, 1-.beta.-D-Arabinofuranosylcytosine, 1.beta.-D-Arabinofuranosylcytosine, 2(1H)-Pyrimidinone, 4-amino-1.beta.-D-arabinofuranosyl-, Alexan, Ara-C, ARA-cell, Arabine, Arabinofuranosylcytosine, Arabinosylcytosine, Aracytidine, Aracytin, Aracytine, Beta-Cytosine Arabinoside, CHX-3311, Cytarabinum, Cytarbel, Cytosar, Cytosar-U, Cytosine Arabinoside, Cytosine-.beta.-arabinoside, Erpalfa, Starasid, Tarabine PFS, U 19920, U-19920, Udicil, WR-28453Treatment (CPI-613, cytarabine, daunorubicin hydrochloride)
Daunorubicin HydrochlorideCerubidin, Cerubidine, Cloridrato de Daunorubicina, Daunoblastin, Daunoblastina, Daunoblastine, Daunomycin Hydrochloride, Daunomycin, hydrochloride, Daunorubicin.HCl, Daunorubicini Hydrochloridum, FI-6339, Ondena, RP-13057, Rubidomycin, Rubidomycin Hydrochloride, RubilemTreatment (CPI-613, cytarabine, daunorubicin hydrochloride)

Purpose

This phase I/II trial studies the side effects and the best dose of 6,8-bis(benzylthio)octanoic acid (CPI-613) when given together with cytarabine and daunorubicin hydrochloride and to see how well it works in treating older patients with newly diagnosed acute myeloid leukemia. CPI-613 may kill tumor cells by turning off mitochondria (small structures in the cancer cells that are found in the cytoplasm [fluid that surrounds the cell nucleus]). Mitochondria are used by cancer cells to produce energy and are the building blocks needed to make more tumor cells. By shutting off mitochondria, CPI-613 may deprive the cancer cells of energy and other supplies that they need to survive and grow. Drugs used in chemotherapy, such as cytarabine and daunorubicin hydrochloride, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving CPI-613 together with cytarabine and daunorubicin hydrochloride may kill more cancer cells.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine the maximum tolerated dose (MTD). (Phase I) II. To determine treatment
      response with the addition of CPI-613 to induction therapy in patients with newly diagnosed
      acute myeloid leukemia (AML). (Phase II)

      SECONDARY OBJECTIVES:

      I. To assess the safety of administering CPI-613 under the proposed study regimen. (Phase
      I/II) II. To assess survival endpoints of patients receiving the proposed study regimen.
      (Phase II) III. To assess the rate of allogeneic stem cell transplantation. (Phase II)

      OUTLINE: This is a phase I, dose-escalation study of 6,8-bis(benzylthio)octanoic acid
      followed by a phase II study.

      INDUCTION: Patients receive cytarabine intravenously (IV) continuously on days 1-7,
      daunorubicin hydrochloride IV on days 1-3, and 6,8-bis(benzylthio)octanoic acid IV over 2
      hours on days 3-7. Patients then undergo biopsy on day 14. Patients experiencing significant
      residual disease receive cytarabine IV continuously on days 1-5, daunorubicin hydrochloride
      IV on days 1-2, and 6,8-bis(benzylthio)octanoic acid IV over 2 hours on days 1-5.

      CONSOLIDATION: Beginning 42 days later, patients receive cytarabine IV continuously on days
      1-16 and 6,8-bis(benzylthio)octanoic acid IV over 2 hours on days 2-6. Treatment repeats
      every 14 days for 3 courses in the absence of disease progression or unacceptable toxicity.

      MAINTENANCE: Patients not undergoing transplant after consolidation receive
      6,8-bis(benzylthio)octanoic acid IV over 2 hours on days 1-5. Treatment repeats every 4 weeks
      for up to 1 year in the absence of disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up for 14 days and then every 3
      months for 2 years.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (CPI-613, cytarabine, daunorubicin hydrochloride)ExperimentalINDUCTION: Patients receive cytarabine IV continuously on days 1-7, daunorubicin hydrochloride IV on days 1-3, and 6,8-bis(benzylthio)octanoic acid IV over 2 hours on days 3-7. Patients then undergo biopsy on day 14. Patients experiencing significant residual disease receive cytarabine IV continuously on days 1-5, daunorubicin hydrochloride IV on days 1-2, and 6,8-bis(benzylthio)octanoic acid IV over 2 hours on days 1-5. CONSOLIDATION: Beginning 42 days later, patients receive cytarabine IV continuously on days 1-16 and 6,8-bis(benzylthio)octanoic acid IV over 2 hours on days 2-6. Treatment repeats every 14 days for 3 courses in the absence of disease progression or unacceptable toxicity. MAINTENANCE: Patients not undergoing transplant after consolidation receive 6,8-bis(benzylthio)octanoic acid IV over 2 hours on days 1-5. Treatment repeats every 4 weeks for up to 1 year in the absence of disease progression or unacceptable toxicity.
  • 6,8-Bis(benzylthio)octanoic Acid
  • Cytarabine
  • Daunorubicin Hydrochloride

Eligibility Criteria

        Inclusion Criteria:

          -  Patients must have histologically or cytologically documented newly diagnosed acute
             myeloid leukemia (non-acute promyelocytic leukemia [APL]) that has not yet been
             treated; hydroxyurea (Hydrea) and tretinoin (ATRA) previous treatments are acceptable

          -  Hydroxyurea may be used to control leukocytosis and can be taken until day 1 of
             therapy; patients with persisting, non-hematologic, non-infectious toxicities from
             prior treatment =< grade 2 are eligible, but must be documented as such

          -  Eastern Cooperative Oncology Group (ECOG) performance status of =< 3 and fit for
             induction therapy in the opinion of the treating physician

          -  Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase
             [SGOT])/alanine aminotransferase (ALT)(serum glutamate pyruvate transaminase [SGPT])
             =< 3 X institutional upper limit of normal (=< 5 X upper limit of normal [ULN] if
             liver metastases present)

          -  Bilirubin =< 1.5 X ULN

          -  Creatinine =< 1.5 mg/dL or 133 umol/L

          -  International normalized ration (INR) < 1.5

          -  Albumin >= 2.0 g/dL

          -  Women of child-bearing potential and men must agree to use adequate contraception
             (hormonal or barrier method of birth control; abstinence) prior to study entry and for
             the duration of study participation; should a woman become pregnant or suspect she is
             pregnant while participating in this study, she should inform her treating physician
             immediately

          -  Ability to understand and the willingness to sign an Institutional Review Board
             (IRB)-approved informed consent document

        Exclusion Criteria:

          -  Patients who have received any therapy other than hydroxyurea with the purpose of
             treating their AML are not eligible

          -  Patients having received prior radiotherapy, treatment with cytotoxic agents (except
             CPI-613), treatment with biologic agents or any anti-cancer therapy for a non-AML
             malignancy within the 2 weeks prior to treatment with CPI-613, or those who have not
             fully recovered from the acute, non-hematological, non-infectious toxicities of any
             prior treatment with cytotoxic drugs, radiotherapy or other anti-cancer modalities
             (returned to baseline status as noted before most recent treatment)

          -  Patients that have received a chemotherapy regimen with stem cell support in the
             previous 6 months

          -  Patients with known central nervous system involvement should be excluded from this
             clinical trial

          -  History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to CPI-613

          -  Uncontrolled concurrent illness including, but not limited to symptomatic congestive
             heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric
             illness/social situations that would limit compliance with study requirements

          -  Patients with large and recurrent pleural or peritoneal effusions requiring frequent
             drainage (e.g. weekly); patients with any amount of clinically significant pericardial
             effusion

          -  Patients with known human immunodeficiency virus (HIV) infection

          -  A history of additional risk factors for Torsade de Pointes (e.g., clinically
             significant heart failure, hypokalemia, family history of long QT syndrome)

          -  Pregnant women are excluded from this study; breastfeeding should be discontinued
      
Maximum Eligible Age:N/A
Minimum Eligible Age:60 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:MTD based on the number of observed dose-limiting toxicities as graded by the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 (Phase I)
Time Frame:14 days
Safety Issue:
Description:Dose-limiting toxicity is defined as the occurrence of any clinically relevant, grade >= 3, non-hematologic, non-infectious toxicity attributed as probably or definitely related to 6,8-bis(benzylthio)octanoic acid.

Secondary Outcome Measures

Measure:Incidence of adverse events as assessed by the CTCAE version 4.0 (Phase I/II)
Time Frame:Up to 14 days post-treatment
Safety Issue:
Description:
Measure:Overall survival (OS) (Phase II)
Time Frame:Up to 2 years
Safety Issue:
Description:Kaplan-Meier plots will be produced for OS.
Measure:Progression-free survival (Phase II)
Time Frame:Up to 2 years
Safety Issue:
Description:Kaplan-Meier plots will be produced for disease free survival.
Measure:Rate of allogeneic stem cell transplantation (Phase II)
Time Frame:After day 42 post-consolidation therapy
Safety Issue:
Description:The rate of allogeneic stem cell transplantation will be estimated by the number of transplants as the numerator and all study eligible subjects as the denominator.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Withdrawn
Lead Sponsor:Wake Forest University Health Sciences

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