Phase I Study of Pracinostat in Combination with Gemtuzumab Ozogamicin (PraGO) in Patients with Relapsed/Refractory Acute Myeloid Leukemia (AML)
Authors: Badar Talha , Guru Murthy Guru Subramanian , Runaas Lyndsey , Carlson Karen-Sue B. , Michaelis Laura C. , Harrington Alexandra M. , Atallah Ehab L. , Abedin Sameem 
Published: November 2019

Background:
Relapsed/Refractory AML (RR-AML) represents an area in urgent need for new treatments, particularly among patients ineligible for intensive chemotherapy. Newer options exist for AML with mutations involving IDH1, IDH2, or FLT3, but in AML without these mutations, only gemtuzumab ozogamicin (GO) is currently approved. GO is a calicheamicin-conjugated antibody directed against the CD33 antigen, commonly found on AML. Mechanistically, GO binds to the CD33 antigen on AML forming a complex which is internalized, resulting in intracellular delivery of calicheamicin, DNA double-strand breaks and cell death.GO recently received re-approval for patients with RR-AML on the basis of the Mylofrance-1 trial, which demonstrated a CR rate estimated at 26%.
This clinical trial was designed to assess the safety of adding pracinostat, a histone deacetylase inhibitor (HDACi) to GO. Inhibition of histone deacetylases has been shown to induce an open chromatin structure and potentially restore transcription of critically silenced genes. In AML, single agent pracinostat has demonstrated potential anti-leukemic activity (Abaza et al. Cancer 2017). We hypothesize that, HDACi may mediate histone unwinding, a more open chromatin structure, and potentiate DNA-targeted delivery of calicheamicin within AML blasts. 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 (ten Cate et al. Leukemia 2007). Previously, vorinostat, another HDACi, has been used in combination with GO and azacitidine in AML. While that trial reported limited efficacy, this trial will incorporate a fractionated GO dosing schedule, as well as the use of a more potent HDACi, both of which may improve efficacy.
Study Design and Methods:
This is a prospective, investigator-initiated, phase 1 clinical study that is aimed at determining the safety of pracinostat + GO (PraGO) combination in patients with R/R AML (ClinicalTrial.gov identifier NCT03848754). Secondary end points are to evaluate response rates, 6-month progression free survival (PFS) and overall survival (OS). Eligible patients are either aged ≥ 60 years with RR- AML to at least one line of therapy, or patients 18-59 years with RR-AML to at least two lines of intensive induction chemotherapy, or one line of therapy if deemed unsuitable for further intensive chemotherapy. Diagnosis of acute promyelocytic leukemia (APL), hematopoietic stem cell transplantation (HCT) within 60 days of enrollment, evidence of veno-occlusive disease (VOD) at any time post-transplant, or active graft versus host disease (GVHD) requiring systemic immunosuppressive therapy are major exclusion criteria.
Patients will be enrolled into two potential dosing cohorts. Cohort 1 will receive pracinostat at 45mg orally, three times weekly for three weeks. GO will be administered at 3 mg/m2 on Days 1, 4, and 7. The first dose of GO will be administered two hours after the first pracinostat dose. Responding patients will subsequently receive maintenance with GO alone at 2 mg/m2 on Day 1. Up to 5 cycles of GO will be administered to responders. Cohort 2 will receive pracinostat at 60 mg orally, three times weekly for three weeks. GO administration will remain the same for induction. Responding patients in this cohort will be eligible for maintenance with pracinostat at 45 mg orally, three times weekly for three weeks. GO will still only be given D1 in each maintenance cycle. A standard 3+3 design will be utilized to determine escalation to Cohort 2. DLTs will be assessed during the 1st cycle only. The study schema is diagrammatically illustrated in figure 1.
With the hypothesis that HDAC inhibition may lead to increased CD33 expression, RNA seq will be performed on blasts isolated on BM aspirate, pre- and post pracinostat treatment. Other potential antibody targets will also be assessed, including CD22 and CD38.
To date, one patient has been enrolled. This 72 years old male with MPN/MF transformed to AML, refractory to CLAG (cladribine, cytarabine, G-CSF) induction. On study, he achieved a partial remission after 1st induction cycle (bone marrow blast from 20% --> 6.4%), with normalization of counts albeit with very short follow up, no SAE or DLTs were observed.
Figure 1

Disclosures
Runaas: Agios: Honoraria; Blueprint Medicine: Honoraria. Michaelis:Novartis: Consultancy; TG Therapeutics: Consultancy, Research Funding; JAZZ: Other: Data Safety Monitoring Board, uncompensated, Research Funding; Macrogeneics: Research Funding; Pfizer: Equity Ownership, Research Funding; ASTEX: Research Funding; Bioline: Research Funding; BMS: Research Funding; Celgene: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Millenium: Research Funding; Janssen: Research Funding. Atallah:Helsinn: Consultancy; Novartis: Consultancy; Jazz: Consultancy; Takeda: Consultancy, Research Funding; Pfizer: Consultancy; Jazz: Consultancy; Helsinn: Consultancy. Abedin:Agios: Honoraria; Jazz Pharmaceuticals: Honoraria; Actinium Pharmaceuticals: Research Funding; Pfizer Inc: Research Funding; Helsinn Healthcare: Research Funding.