Clinical Trials /

CPI-613 and Hydroxychloroquine for Patients With High Risk Myelodysplastic Syndrome

NCT03929211

Description:

This is a phase 1/2 study of the combination of CPI-613 and hydroxychloroquine for the treatment of high risk myelodysplastic syndrome patients who have failed a hypomethylating agent.

Related Conditions:
  • Myelodysplastic Syndromes
Recruiting Status:

Not yet recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: CPI-613 and Hydroxychloroquine for Patients With High Risk Myelodysplastic Syndrome
  • Official Title: A Phase I/II Study of CPI-613 and Hydroxychloroquine for Patients With High Risk MDS Who Have Failed Hypomethylating Therapy

Clinical Trial IDs

  • ORG STUDY ID: IRB00057945
  • SECONDARY ID: WFBCCC 99119
  • SECONDARY ID: P30CA012197
  • SECONDARY ID: NCI-2019-02787
  • NCT ID: NCT03929211

Conditions

  • Myelodysplastic Syndromes
  • Progressive Disease

Interventions

DrugSynonymsArms
CPI-6136,8-Bis(benzylthio)octanoic AcidCPI-613 and hydroxychloroquine
Hydroxychloroquine118-42-3, hydroxychloroquine, HYDROXYCHLOROQUINE, HydroxychloroquineCPI-613 and hydroxychloroquine

Purpose

This is a phase 1/2 study of the combination of CPI-613 and hydroxychloroquine for the treatment of high risk myelodysplastic syndrome patients who have failed a hypomethylating agent.

Detailed Description

      Primary Objective(s):

        -  To determine the Maximum Tolerated Dose (MTD) of the combination of CPI-613 and
           Hydroxychloroquine therapy for patients with high risk MDS who have failed
           hypomethylating therapy.

        -  To determine the overall response rate (complete remission (CR), marrow CR, partial
           remission (PR), Hematologic improvement (HI)) of high risk MDS patients who have failed
           hypomethylating agents, treated with the combination of CPI-613 and the maximally
           tolerated dose of hydroxychloroquine

      Secondary Objective(s):

        -  To assess the safety of the combination

        -  To assess progression-free-survival (PFS)

        -  To assess the overall survival of MDS patients who have failed hypomethylating agents
           treated with the combination of CPI-613 and hydroxychloroquine defined as the time from
           enrolment on study to death from any cause.

        -  To assess any changes in the frequency of blood transfusions

      OUTLINE: This is a phase I, dose-escalation study of hydroxychloroquine, followed by a phase
      II study.

      Patients receive hydroxychloroquine orally (PO) and 6,8-bis(benzylthio)octanoic acid
      intravenously (IV) over 2 hours on days 1-5. Treatments repeat every 14 days for 2 cycles in
      the absence of disease progression or unacceptable toxicity. Beginning cycle 3, patients
      receive hydroxychloroquine PO and 6,8-bis(benzylthio)octanoic acid IV over 2 hours on days
      1-5. Cycles repeat every 28 days in the absence of disease progression or unacceptable
      toxicity.

      After completion of study treatment, patients are followed up for 5 years.
    

Trial Arms

NameTypeDescriptionInterventions
CPI-613 and hydroxychloroquineExperimentalThe initial phase of the study will be a dose escalation of hydroxychloroquine from 600 mg to 1,200 mg orally flat dose given 2 hours before the CPI-613 infusion on days 1-5 of every 28 days. CPI-dose will be 2,000 mg/m² and will not be escalated.
  • CPI-613
  • Hydroxychloroquine

Eligibility Criteria

        Inclusion Criteria:

        Patients must meet all of the following inclusion criteria before enrollment:

          -  Histologically documented high risk MDS whose disease has failed to respond,
             progressed or relapsed while on a hypomethylating agent.

          -  IPSS-R score of Intermediate, high or very high at time of enrollment

          -  ECOG Performance Status of ≤3.

          -  Men and women 18 years of age or older.

          -  Expected survival >2 months.

          -  Women of child-bearing potential (i.e., women who are pre-menopausal or not surgically
             sterile) must use accepted contraceptive methods (abstinence, intrauterine device
             [IUD], oral contraceptive or double barrier device) during the study, and must have a
             negative serum or urine pregnancy test within 1 week prior to treatment initiation.

          -  Fertile men must practice effective contraceptive methods during the study, unless
             documentation of infertility exists.

          -  Patients must have fully recovered from the acute, non-hematological, non-infectious
             toxicities of any prior treatment with cytotoxic drugs, radiotherapy or other
             anti-cancer modalities. Patients with persisting, non-hematologic, non-infectious
             toxicities from prior treatment ≤ Grade 2 are eligible, but must be documented as
             such.

          -  Laboratory values obtained ≤2 weeks prior to enrollment must demonstrate adequate
             hepatic function, renal function, and coagulation as defined below:

          -  Aspartate aminotransferase [AST/SGOT] ≤3x upper normal limit [UNL]

          -  Alanine aminotransferase [ALT/SGPT] ≤3x UNL

          -  Bilirubin ≤1.5x UNL

          -  Serum creatinine ≤1.5 mg/dL or 133 μmol/L

          -  Albumin ≥ 2.0 g/dL or ≥ 20 g/L.

          -  Mentally competent, ability to understand and willingness to sign an IRB-approved
             written informed consent form.

          -  Have access via central line (e.g., portacath).

        Exclusion Criteria:

          -  Patients with the following characteristics are excluded:

          -  Serious medical illness, such as significant cardiac disease (e.g. symptomatic
             congestive heart failure, unstable angina pectoris, symptomatic coronary artery
             disease, myocardial infarction within the past 3 months, uncontrolled cardiac
             arrhythmia, pericardial disease or New York Heart Association Class III or IV), or
             severe debilitating pulmonary disease, that would potentially increase patients' risk
             for toxicity.

          -  Patients with active central nervous system (CNS) or epidural tumor.

          -  Any active uncontrolled bleeding or bleeding diathesis (e.g., active peptic ulcer
             disease).

          -  Any condition or abnormality which may, in the opinion of the investigator, compromise
             his or her safety.

          -  Pregnant women, or women of child-bearing potential not using reliable means of
             contraception.

          -  Fertile men unwilling to practice contraceptive methods during the study period.

          -  Lactating females.

          -  Life expectancy less than 2 months.

          -  Unwilling or unable to follow protocol requirements.

          -  Evidence of ongoing uncontrolled serious infection.

          -  Requirement for immediate palliative treatment of any kind including surgery.

          -  Patients with uncontrolled HIV infection. (Note: Patients with known HIV infection are
             excluded because patients with an immune deficiency are at increased risk of lethal
             infections when treated with marrow-suppressive therapy, and because there may be
             unknown or dangerous drug interactions between CPI-613 and anti-retroviral agents used
             to treat HIV infections).

          -  Patients who have received radiotherapy, surgery, treatment with cytotoxic agents
             (except a hypomethylating agent, i.e. azacytidine or decitabine), treatment with
             biologic agents, immunotherapy, or any other anti-cancer therapy of any kind, or any
             other standard or investigational treatment for their cancer, or any other
             investigational agent for any indication, within the past 2 weeks prior to initiation
             of CPI-613 treatment.

          -  Patients that have received a chemotherapy regimen with stem cell support in the
             previous 6 months.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Number of Dose Limiting Toxicities
Time Frame:4 weeks
Safety Issue:
Description:Dose-limiting toxicities assessed in order to be able to establish the maximum tolerable dose for the combination of CPI-613 and Hydroxychloroquine therapy for patients with high risk myelodysplastic syndrome who have failed hypomethylating therapy. Using the descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 for adverse event reporting (Grade 1 (Mild) - 5 (Death) as well as expectedness (unexpected/expected) and attribution (definitely related to study treatment to unrelated to study treatment).

Secondary Outcome Measures

Measure:Proportion of Patients with Toxicities
Time Frame:4 weeks
Safety Issue:
Description:Toxicity profiles of participants during the trial to assess the safety of the combination of CPI-613 and hydroxychloroquine will be presented in tables that describe the number and proportion of patients observed with toxicities.
Measure:Progression-free-survival
Time Frame:Up to 5 years or until death
Safety Issue:
Description:Progression-free-survival is defined as the duration of time from the start of treatment to the time of progression, death, or date of last contact; those lost to follow-up will be censored. Kaplan-Meier survival curves to examine progression free survival in participants will be created.
Measure:Overall Survival
Time Frame:Up to 5 years or until death
Safety Issue:
Description:Overall survival of myelodysplastic syndrome patients who have failed hypomethylating agents treated with the combination of CPI-613 and hydroxychloroquine defined as the time from enrollment on study to death from any cause.
Measure:Changes in the Frequency of Blood Transfusions
Time Frame:Baseline to approximately 6 months
Safety Issue:
Description:The investigators will assess for each participant the number of blood transfusions needed and create tables to display the number and timing of blood transfusions that occur.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Wake Forest University Health Sciences

Trial Keywords

  • Relapsed/refractory myelodysplastic syndrome
  • Failed hypomethylating therapy

Last Updated

November 21, 2019