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
|Condition or disease||Intervention/treatment||Phase|
|Relapsed Adult AML||Drug: Gemtuzumab Ozogamicin Drug: Pracinostat||Phase 1|
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.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||18 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|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|
|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.
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.
- 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.
- 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.
- 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.
- 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.
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
|Contact: Medical College of Wisconsin Cancer Center Clinical Trials Officeemail@example.com|
|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 firstname.lastname@example.org|
|Principal Investigator:||Sameem Abedin, MD||Medical College of Wisconsin|