Study of TCP-ATRA for Adult Patients With AML and MDS
Status:
Completed
Trial end date:
2020-07-01
Target enrollment:
Participant gender:
Summary
Acute Myeloid Leukemia (AML) is a diverse disease that is fatal in the majority of patients.
Acute promyelocytic leukemia (APL) however, a subtype of AML accounting for 5% of all cases,
is very curable. APL cells are highly sensitive to the retinoid all-trans-retinoic acid
(ATRA), which effectively differentiates the leukemic clone. Over 80% of APL patients can be
cured with ATRA based therapies. For patients with non-APL AML, ATRA has little effect.
Consequently, 85% of these patients will succumb to their disease despite conventional
approaches. Little is known about mechanisms of resistance to ATRA in non-APL AML. This
knowledge gap limits the use of ATRA in a disease that already has few effective therapies.
The investigators' preliminary data suggest that non-APL AML cells can be re-sensitized to
ATRA when combined with lysine-specific demethylase 1 (LSD 1) inhibitors. The investigators'
publication in Nature Medicine showed that LSD1 inhibition with tranylcypromine (TCP),
unlocked the ATRA-driven therapeutic response in non-APL AML. Notably, treatment with ATRA
and TCP markedly diminished the engraftment of primary human AML cells in murine models,
indicating that the combination may target leukemia-initiating cells (LIC). The
investigators' data identify LSD1 as a therapeutic target and strongly suggest that it may
contribute to ATRA resistance in non-APL AML. The investigators' central hypothesis is that
ATRA combined with TCP will be safe and effective in a clinical population, and that this
approach will suppress LICs and restore myeloid differentiation programs in patients with
non-APL AML. Testing this hypothesis with the phase I clinical trial outlined in this
protocol, will establish a new treatment paradigm in AML and extend the important anti-cancer
effects of ATRA to all AML subtypes.
Phase:
Phase 1
Details
Lead Sponsor:
University of Miami
Collaborators:
Gabrielle's Angel Foundation Women's Cancer Association