Clinical Trials /

Pracinostat in Combination With Gemtuzumab Ozogamicin (PraGO) in Patients With Relapsed/Refractory Acute Myeloid Leukemia (AML)

NCT03848754

Description:

This is a prospective, single-center phase 1 clinical study aimed at determining the maximum-tolerated dose and safety of the combination of gemtuzumab ozogamicin (GO) and pracinostat (P) in patients with relapsed/refractory acute myeloid leukemia.

Related Conditions:
  • Acute Myeloid Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Pracinostat in Combination With Gemtuzumab Ozogamicin (PraGO) in Patients With Relapsed/Refractory Acute Myeloid Leukemia (AML)
  • Official Title: Pracinostat in Combination With Gemtuzumab Ozogamicin (PraGO) in Patients With Relapsed/Refractory Acute Myeloid Leukemia (AML)

Clinical Trial IDs

  • ORG STUDY ID: PRO 33922
  • NCT ID: NCT03848754

Conditions

  • Relapsed Adult AML

Interventions

DrugSynonymsArms
Gemtuzumab OzogamicinPracinostat with Gemtuzumab Ozogamicin
PracinostatPracinostat with Gemtuzumab Ozogamicin

Purpose

This is a prospective, single-center phase 1 clinical study aimed at determining the maximum-tolerated dose and safety of the combination of gemtuzumab ozogamicin (GO) and pracinostat (P) in patients with relapsed/refractory acute myeloid leukemia.

Detailed Description

      Relapsed/Refractory AML (RR-AML) is a serious medical condition where overall less than 10%
      survive beyond five years. Among RR-AML patients ineligible for intensive chemotherapy, this
      problem is magnified, and survival is measured in months. Hence, there is an urgent need for
      more efficacious and tolerable therapies for RR-AML.

      The majority of AML expresses the CD33 surface antigen. Gemtuzumab Ozogamicin (GO) is a
      recombinant, humanized anti-CD33 monoclonal antibody covalently attached to the cytotoxic
      antitumor antibiotic calicheamicin. GO binds to the CD33 antigen on AML cells forming a
      complex which is internalized, resulting in the intracellular delivery of calicheamicin.
      Calicheamicin then binds to DNA in the minor groove, inciting DNA double strand breaks and
      triggering cell death. GO was recently FDA approved for patients with AML who cannot tolerate
      intensive chemotherapy, and additionally received FDA approval in the RR-AML setting on the
      basis of a modest CR rate of 26% (95% CI 16-40%).

      The investigators are studying whether the addition of the Histone deacetylase (HDAC)
      inhibitor pracinostat to GO is safe, and effective. HDACs plays important role in
      transcription regulation and in the pathogenesis of cancer. HDAC inhibitors induces histone
      hyperacetylation, resulting in an open chromatin structure and restore transcription of
      critically silenced genes. In AML, early clinical trials using single agent Pracinostat have
      demonstrated potential activity against the disease.

      In the context of GO, the investigators hypothesize HDAC inhibition may potentially synergize
      with GO to improve response against AML. Through HDAC inhibition mediated histone unwinding,
      open chromatin could allow for increased DNA delivery of calicheamicin within AML blasts and
      increased apoptosis. Further, pre-clinical data suggests HDAC inhibition could also increase
      CD33 expression in myeloid leukemia cells, thereby allowing for increased GO binding to AML
      blasts. This is the basis for the combination of these agents.
    

Trial Arms

NameTypeDescriptionInterventions
Pracinostat with Gemtuzumab OzogamicinExperimental
  • Gemtuzumab Ozogamicin
  • Pracinostat

Eligibility Criteria

        Inclusion Criteria:

          1. Morphologically documented AML or secondary AML [from prior conditions such as
             myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN)] or therapy related
             AML (t-AML), as defined by World Health Organization (WHO) criteria.

          2. Age ≥60 years, with relapsed/refractory AML to at least one line of therapy. Patients
             with antecedent MDS who progressed to AML while on hypomethylating agent therapy will
             also be eligible.

          3. Age 18-59 years with relapsed/refractory AML to at least two lines of intensive
             induction chemotherapy, or one line of therapy if deemed unsuitable for further
             intensive chemotherapy.

          4. Patients aged 18 years or older with relapsed AML after allogeneic hematopoietic cell
             transplantation, if deemed unsuitable for further intensive chemotherapy.

          5. Detectable CD33 expression on AML blasts confirmed by flow cytometry.

          6. Karnofsky performance status ≥ 60 (or ECOG PS of 2 or less).

          7. Adequate organ system function as outlined below:

               -  Total bilirubin ≤ 2 x ULN, AST and ALT ≤ 2.5 x ULN.

               -  Serum creatinine ≤ 2 or a serum creatinine clearance ≤ 1.5 x ULN.

               -  Baseline EKG with QT-interval corrected (QTcF) ≤ 450ms.

          8. Females should be using adequate contraception, should not be breast feeding and must
             have a negative pregnancy test prior to start of dosing if of child-bearing potential.
             Male patient should avoid impregnating a female partner.

             It is not known what effects this treatment has on human pregnancy or development of
             the embryo or fetus. Therefore, female patients participating in this study should
             avoid becoming pregnant, and male patients should avoid impregnating a female partner.
             Non-sterilized female patients of reproductive age and male patients should use
             effective methods of contraception through defined periods during and after study
             treatment as specified below.

             Female patients must meet one of the following:

               -  Postmenopausal for at least one year before the screening visit, or

               -  Surgically sterile, or

               -  If they are of childbearing potential, agree to practice two effective methods of
                  contraception from the time of signing of the informed consent form through three
                  months after the last dose of study drug, AND

               -  Must also adhere to the guidelines of any treatment-specific pregnancy prevention
                  program, if applicable, or

               -  Agree to practice true abstinence when this is in line with the preferred and
                  usual lifestyle of the subject. (Periodic abstinence [e.g., calendar, ovulation,
                  symptothermal, post ovulation methods] and withdrawal are not acceptable
                  contraception methods.)

             Male patients, even if surgically sterilized (i.e., status post vasectomy), must agree
             to one of the following:

               -  Practice effective barrier contraception during the entire study treatment period
                  and through 90 days after the last study drug dose, OR

               -  Must also adhere to the guidelines of any treatment-specific pregnancy prevention
                  program, if applicable, OR

               -  Agree to practice true abstinence when this is in line with the preferred and
                  usual lifestyle of the subject. (Periodic abstinence (e.g., calendar, ovulation,
                  symptothermal, postovulation methods] and withdrawal are not acceptable methods
                  of contraception.)

          9. Ability to understand a written informed consent document, and the willingness to sign
             it.

        Exclusion Criteria:

          1. Acute promyelocytic leukemia (APL).

          2. Prior chemotherapy, radiotherapy, or investigative agent within 14 days, or within
             five half-lives of study entry.

               -  Subjects must have recovered from side effects of prior treatment.

               -  The use of hydroxyurea for leukoreduction prior to start of dosing is permitted.

          3. Hematopoietic Stem Cell Transplantation (HCT) within 60 days of enrollment, or
             evidence of veno-occlusive disease (VOD) at any time post-transplant, or active
             graft-versus-host disease requiring systemic immunosuppressive therapy.

          4. Life-threatening illness unrelated to AML, or any serious medical or psychiatric
             illness that could potentially interfere with participation in this study.

          5. Active and uncontrolled human immunodeficiency virus (HIV), or chronic Hepatitis B, or
             Hepatitis C.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum-tolerated dose
Time Frame:First 28-day cycle
Safety Issue:
Description:Maximum-tolerated dose of pracinostat in combination with fixed dose GO induction will be determined by the 3+3 design rules. If there are no dose-limiting toxicities (DLTs) in the first three patients, the dose of pracinostat will be escalated to 60mg. Escalation to the next dose level will be done only after the third patient on the previous dose level has been observed for 28 days, and no DLTs were noticed. If there is 1 DLT, an additional 3 patients will be tested at same dose level. If there are ≥ 2 DLTs in three or six patients, the study will be placed on hold. If there is < 2 DLTs in the first three or six patients, the dose of pracinostat will be escalated to 60mg. If there are no DLTs in the first three patients at 60mg, an additional three patients will be enrolled to ensure six patients are treated at the MTD.

Secondary Outcome Measures

Measure:Overall Response
Time Frame:Day 28
Safety Issue:
Description:Measurement of response (complete response, complete response with incomplete count recovery, morphologic leukemia-free state, partial response) determined by bone marrow biopsy.
Measure:Progression-Free Survival
Time Frame:6 Months
Safety Issue:
Description:Time from the first day of study drug administration (Day 1) to disease recurrence or progression as defined by the IWG criteria, or death on study up to a period of six months.
Measure:Overall Survival
Time Frame:6 Months
Safety Issue:
Description:Time from the first day of study drug administration (Day 1) to death on study up to a period of six months.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Medical College of Wisconsin

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