NCT03848754

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

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

• Status: Completed
• Phase: Phase 1
• Study type: Interventional
• Enrollment: 14 (actual)
• Sponsor: Medical College of Wisconsin · Academic / Other
• Sex: All
• Age: 18 Years
• Healthy volunteers: Not accepted

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.

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 cluster of differentiation 33 (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 complete response (CR) rate of 26% \[95% confidence interval (CI) 16-40%\]. 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.

Conditions

• Relapsed Adult AML

Interventions

Type	Name	Description
DRUG	Gemtuzumab Ozogamicin 3 mg/m^2	GO 3 mg/m\^2 on Day 1, 4, and 7 Maintenance: 2mg/m2 intravenous administration on day 1, in a 28-day cycle.
DRUG	Gemtuzumab Ozogamicin 2 mg/m^2	GO 2 mg/m\^2 on Day 1 of a 28-day cycle.
DRUG	Pracinostat - 45 mg	Induction: 45mg 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.
DRUG	Pracinostat - 60 mg	Escalation: 60 mg administered orally three days a week with 48 hours between dosing (e.g., Monday, Wednesday, and Friday) for three consecutive weeks, followed by one week of rest, in 28-day cycles.

Timeline

• Start date: 2019-05-24
• Primary completion: 2021-05-05
• Completion: 2021-05-05
• First posted: 2019-02-21
• Last updated: 2022-06-30

Locations

1 site across 1 country: United States

Regulatory

• FDA-regulated drug study