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Study of TCP-ATRA for Adult Patients With AML and MDS | Clinical Trials | Clareo Health

COMPLETEDPHASE1

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

A Phase 1 Dose Escalation Study of Tranylcypromine (TCP) in Combination With ATRA (Tretinoin) for Adult Patients With Relapsed/Refractory Acute Myelogenous Leukemia (AML) and Myelodysplastic Syndromes (MDS)

NCT02273102•University of Miami

View on ClinicalTrials.gov

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.

Eligibility

Age

18 - No limit years

Sex

ALL

Healthy Volunteers

Inclusion Criteria

•1. Confirmed diagnosis of one of the following:
•* Relapsed/refractory Acute Myelogenous Leukemia (AML) as defined by the World Health Organization (WHO) criteria \[therapy-related AML and/or secondary AML from an antecedent hematologic disorder not excluded\].
•* Relapsed/refractory Myelodysplasic Syndrome (MDS) as defined by the World Health Organization (WHO) criteria.
•2. Adult patients 18 years of age or older.
•3. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1, or 2.
•4. Adequate organ function as defined as:
•* Total bilirubin ≤ 1.5 x upper limited of normal (ULN)
•* ALT and AST must be ≤ 3 × ULN
•* Creatinine ≤ 1.5 x ULN or calculated creatinine clearance \> 50ml/min or
•* PT and aPTT ≤ 1.5 × ULN
+3 more criteria

Exclusion Criteria

•1. Therapy with moderate or strong CYP3A4 inhibitors or CYP3A4 inducers within 14 days prior to Cycle1 Day1.
•2. Therapy with Monoamine Oxidase Inhibitors (MAOIs), dibenzazepine derivatives, sympathomimetics, or Selective Serotonin Reuptake Inhibitors (SSRIs) within 14 days prior to Cycle1 Day1. (Patients actively receiving a safe substitute in the judgment of the Principal Investigator are eligible and may continue to receive the safe substitute during protocol treatment)
•3. Therapy with any investigational products, antineoplastic therapy, or radiotherapy within 14 days prior to Cycle1 Day1. Patients actively receiving hydroxyurea are eligible and may continue to receive hydroxyurea during protocol treatment.
•4. Candidates for standard and/or potentially curative treatments. (Candidate defined as a patient that is both eligible and willing)
•5. Major surgery within 28 days prior to Cycle1 Day1.
•6. Grade 2 or higher diarrhea as defined by NCI CTCAE Version 4.03 despite optimal antidiarrheal supportive care within 7 days prior to Cycle1, Day1.
•7. Myocardial infarction within 6 months (24 weeks) prior to Cycle1, Day1.
•8. Class III or IV heart failure as defined by the New York Heart Association (NYHA), uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities. (Any ECG abnormality at screening has to be documented by the investigator as not medically relevant and confirmed by the Principal Investigator)
•9. Active and uncontrolled infection.
•10. Known human immunodeficiency virus (HIV) positive.
+10 more criteria

Locations (1)

University of Miami

Miami, Florida, United States

Key Dates

Start Date

March 2, 2015

Primary Completion Date

November 8, 2018

Completion Date

July 1, 2020

Last Updated

July 21, 2020

Enrollment

ACTUAL participants

Conditions

Acute Myelogenous LeukemiaMyelodysplastic SyndromesLeukemia

Interventions

Tranylcypromine

DRUG

Tretinoin

DRUG

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RECRUITINGPHASE2

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Data Source & Attribution

This clinical trial information is sourced from ClinicalTrials.gov, a service of the U.S. National Institutes of Health.

ClinicalTrials.gov last update: July 21, 2020Data synced to Clareo: March 29, 2026

Modifications: This data has been reformatted for display purposes. Eligibility criteria have been parsed into inclusion/exclusion sections. Location data has been geocoded to enable distance-based search. For the authoritative and most current information, please visit ClinicalTrials.gov.

Neither the United States Government nor Clareo Health make any warranties regarding the data. Check ClinicalTrials.gov frequently for updates.

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

Inclusion Criteria

Exclusion Criteria

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