NCT02273102: TCP-ATRA

Study of TCP-ATRA for Adult Patients With AML and MDS

Completed Phase 1 Last updated 21 July 2020

What this trial tests

Phase 1 trial testing Tranylcypromine in Acute Myelogenous Leukemia in 17 participants. Completed in 1 July 2020.

Timeline

2 March 2015

Primary endpoint
8 November 2018

1 July 2020

Quick facts

Lead sponsor	University of Miami
Phase	Phase 1
Status	Completed
Study type	INTERVENTIONAL
Allocation	non randomized
Design	parallel
Masking	none
Primary purpose	treatment
Enrollment	17
Start date	2 March 2015
Primary completion	8 November 2018
Estimated completion	1 July 2020
Sites	1 location across United States

Drugs / interventions tested

• Tranylcypromine (TRANYLCYPROMINE) — full drug profile →
• Tretinoin (TRETINOIN) — full drug profile →

Conditions studied

• Acute Myelogenous Leukemia — all drugs for Acute Myelogenous Leukemia →
• Myelodysplastic Syndromes — all drugs for Myelodysplastic Syndromes →
• Leukemia — all drugs for Leukemia →

Sponsor

University of Miami

Who can join

18 and older, any sex, with Acute Myelogenous Leukemia or Myelodysplastic Syndromes. Patients with the condition only — healthy volunteers not accepted.

Sponsor's own description

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.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

1. Targeting epigenetic regulators for cancer therapy: mechanisms and advances in clinical trials.
   Cheng Y, He C, Wang M, Ma X, et al · · 2019 · cited 760× · PMID 31871779 · DOI 10.1038/s41392-019-0095-0
2. LSD1/KDM1A inhibitors in clinical trials: advances and prospects.
   Fang Y, Liao G, Yu B, Yu B. · · 2019 · cited 316× · PMID 31801559 · DOI 10.1186/s13045-019-0811-9
3. MLL-Rearranged Leukemias-An Update on Science and Clinical Approaches.
   Winters AC, Bernt KM. · · 2017 · cited 289× · PMID 28232907 · DOI 10.3389/fped.2017.00004
4. Epigenetics in cancer stem cells.
   Toh TB, Lim JJ, Chow EK. · · 2017 · cited 286× · PMID 28148257 · DOI 10.1186/s12943-017-0596-9
5. Targeting histone methyltransferases and demethylases in clinical trials for cancer therapy.
   Morera L, Lübbert M, Jung M. · · 2016 · cited 283× · PMID 27222667 · DOI 10.1186/s13148-016-0223-4
6. Cancer cell plasticity during tumor progression, metastasis and response to therapy.
   Pérez-González A, Bévant K, Blanpain C. · · 2023 · cited 254× · PMID 37537300 · DOI 10.1038/s43018-023-00595-y
7. The timeline of epigenetic drug discovery: from reality to dreams.
   Ganesan A, Arimondo PB, Rots MG, Jeronimo C, et al · · 2019 · cited 234× · PMID 31791394 · DOI 10.1186/s13148-019-0776-0
8. Targeting epigenetic regulators to overcome drug resistance in cancers.
   Wang N, Ma T, Yu B, Yu B. · · 2023 · cited 213× · PMID 36797239 · DOI 10.1038/s41392-023-01341-7