Phase 1 Study of TCP-ATRA for Adult Patients With AML and MDS (TCP-ATRA) | Aplastic Anemia and MDS International Foundation

Clinical Trial: NCT02273102

Phase 1 Study of TCP-ATRA for Adult Patients With AML and MDS (TCP-ATRA)
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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.

Study Date: 
Sun, 02/01/2015 to Fri, 12/01/2017
Bone Marrow Disease(s): 
myelodysplastic syndromes (MDS)
Drug: Tranylcypromine Tranylcypromine (TCP) to be administered orally twice a day (12 hours apart) for up to 16 cycles of 21 days each. Other Name: TCP Drug: Tretinoin 45 mg/m2 of ATRA to be administered orally twice a day (12 hours apart), beginning on day 4 for up to 16 cycles of 21 days each. Other Name: ATRA