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Trial record 15 of 91 for:    gemtuzumab ozogamicin

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

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ClinicalTrials.gov Identifier: NCT03848754
Recruitment Status : Recruiting
First Posted : February 21, 2019
Last Update Posted : June 10, 2019
Sponsor:
Information provided by (Responsible Party):
Sameem M. Abedin, MD, Medical College of Wisconsin

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Relapsed Adult AML Drug: Gemtuzumab Ozogamicin Drug: Pracinostat Phase 1

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 18 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Pracinostat in Combination With Gemtuzumab Ozogamicin (PraGO) in Patients With Relapsed/Refractory Acute Myeloid Leukemia (AML)
Actual Study Start Date : May 24, 2019
Estimated Primary Completion Date : May 2020
Estimated Study Completion Date : March 2021


Arm Intervention/treatment
Experimental: Pracinostat with Gemtuzumab Ozogamicin Drug: Gemtuzumab Ozogamicin

Induction: GO 3mg/m2 on Day 1, 4, and 7

Maintenance: 2mg/m2 intravenous administration on day 1, in a 28-day cycle.


Drug: Pracinostat

Induction: 45mg or 60mg administered orally 3 days a week with 48 hours between dosing (e.g. Monday, Wednesday, and Friday) for three consecutive weeks, followed by 1 week of rest, in 28-day cycles.

Maintenance: (In addition to GO, only if induction dose escalation occurs) 45mg orally 3 days a week with 48 hours between dosing, for three consecutive weeks, followed by 1 week of rest, in a 28-day cycle.





Primary Outcome Measures :
  1. Maximum-tolerated dose [ Time Frame: First 28-day cycle ]
    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 :
  1. Overall Response [ Time Frame: Day 28 ]
    Measurement of response (complete response, complete response with incomplete count recovery, morphologic leukemia-free state, partial response) determined by bone marrow biopsy.

  2. Progression-Free Survival [ Time Frame: 6 Months ]
    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.

  3. Overall Survival [ Time Frame: 6 Months ]
    Time from the first day of study drug administration (Day 1) to death on study up to a period of six months.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03848754


Contacts
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Contact: Medical College of Wisconsin Cancer Center Clinical Trials Office 414-805-8900 cccto@mcw.edu

Locations
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United States, Wisconsin
Froedtert Hospital & the Medical College of Wisconsin Recruiting
Milwaukee, Wisconsin, United States, 53226
Contact: Medical College of Wisconsin Cancer Center Clinical Trials Office    414-805-8900    cccto@mcw.edu   
Sponsors and Collaborators
Medical College of Wisconsin
Investigators
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Principal Investigator: Sameem Abedin, MD Medical College of Wisconsin

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Responsible Party: Sameem M. Abedin, MD, Assistant Professor, Medical College of Wisconsin
ClinicalTrials.gov Identifier: NCT03848754     History of Changes
Other Study ID Numbers: PRO 33922
First Posted: February 21, 2019    Key Record Dates
Last Update Posted: June 10, 2019
Last Verified: June 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Leukemia, Myeloid, Acute
Leukemia
Neoplasms by Histologic Type
Neoplasms
Leukemia, Myeloid
Gemtuzumab
Antineoplastic Agents, Immunological
Antineoplastic Agents