Study of TCP-ATRA for Adult Patients With AML and MDS
TCP-ATRA
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)
1 other identifier
interventional
17
1 country
1
Brief 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.
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at below P25 for phase_1
Started Mar 2015
Longer than P75 for phase_1
1 active site
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
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Study Timeline
Key milestones and dates
First Submitted
Initial submission to the registry
October 20, 2014
CompletedFirst Posted
Study publicly available on registry
October 23, 2014
CompletedStudy Start
First participant enrolled
March 2, 2015
CompletedPrimary Completion
Last participant's last visit for primary outcome
November 8, 2018
CompletedStudy Completion
Last participant's last visit for all outcomes
July 1, 2020
CompletedJuly 21, 2020
July 1, 2020
3.7 years
October 20, 2014
July 20, 2020
Conditions
Keywords
Outcome Measures
Primary Outcomes (1)
Rate of Toxicity in Study Participants Receiving TCP/ATRA Combination Therapy
The safety and tolerability of TCP/ATRA combination therapy in patients with Acute Myelogenous Leukemia (AML) and Myelodysplastic Syndromes (MDS). This will be measured by the rate of adverse events, serious adverse events and other toxicities in study participants receiving protocol therapy.
24 months
Secondary Outcomes (3)
Rate of Preliminary Efficacy of TCP/ATRA Combination Therapy
24 months
Pharmacokinetics (PK) effects of TCP in plasma when combined with ATRA
Baseline, Cycle 1, Cycle 2, 30 Days (+/-10 days) Post-End of Treatment
Pharmacodynamic (PD) effects of TCP in peripheral blood and bone marrow when combined with ATRA.
Baseline, Cycle 1, Cycle 2, 30 Days (+/-10 days) Post-End of Treatment
Study Arms (3)
TCP Dose Level 1
EXPERIMENTAL20mg of Tranylcypromine (TCP) to be administered orally twice a day (12 hours apart) for up to 16 cycles of 21 days each. 45 mg/m2 of Tretinoin (ATRA) to be administered orally twice a day (12 hours apart) beginning on day 4 of each 21 day cycle, for up to 16 cycles.
TCP Dose Level 2
EXPERIMENTAL40mg of Tranylcypromine (TCP) to be administered orally twice a day (12 hours apart) for up to 16 cycles of 21 days each. 45 mg/m2 of Tretinoin (ATRA) to be administered orally twice a day (12 hours apart) beginning on day 4 of each 21 day cycle, for up to 16 cycles.
TCP Dose Level 3
EXPERIMENTAL60mg of Tranylcypromine (TCP) to be administered orally twice a day (12 hours apart) for up to 16 cycles of 21 days each. 45 mg/m2 of Tretinoin (ATRA) to be administered orally twice a day (12 hours apart) beginning on day 4 of each 21 day cycle, for up to 16 cycles.
Interventions
Tranylcypromine (TCP) to be administered orally twice a day (12 hours apart) for up to 16 cycles of 21 days each.
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.
Eligibility Criteria
You may qualify if:
- 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.
- Adult patients 18 years of age or older.
- Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1, or 2.
- 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
- Patients with total bilirubin, Alanine transaminase (ALT), Aspartate transaminase (AST), Creatinine, prothrombin time (PT), and activated partial thromboplastin time (aPTT) levels outside the permitted range are eligible if, in the judgment of the Principal Investigator, the levels are related to the patient's AML or MDS.
- Suitable venous access to allow for all study related blood sampling (safety and research).
- Estimated life expectancy, in the judgment of the Investigator, which will permit receipt of at least 6 weeks of treatment.
- Able to understand and willing to signed the written informed consent and HIPAA document/s.
You may not qualify if:
- Therapy with moderate or strong CYP3A4 inhibitors or CYP3A4 inducers within 14 days prior to Cycle1 Day1.
- 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)
- 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.
- Candidates for standard and/or potentially curative treatments. (Candidate defined as a patient that is both eligible and willing)
- Major surgery within 28 days prior to Cycle1 Day1.
- 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.
- Myocardial infarction within 6 months (24 weeks) prior to Cycle1, Day1.
- 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)
- Active and uncontrolled infection.
- Known human immunodeficiency virus (HIV) positive.
- Known hepatitis B surface antigen-positive.
- Known or suspected active hepatitis C infections (Patients who are hepatitis C surface antigen-positive are eligible).
- Female patients who are pregnant women or breast feeding. Confirmation that the patient is not pregnant will require a negative serum β-human chorionic gonadotropin (β-hCG) pregnancy test result obtained during screening; pregnancy testing is not required for post-menopausal or surgically sterilized women.
- Females of child bearing potential who refused to either practice 2 effective methods of contraception at the same time or abstain from heterosexual intercourse from the time of signing the informed consent through 30 days after the last dose of study drug.
- Males of child bearing potential who refuse to practice effective barrier contraception during the entire study treatment period and through 4 months after the last dose of study drug (includes males surgically sterilized - i.e. status post vasectomy).
- +5 more criteria
Contact the study team to confirm eligibility.
Sponsors & Collaborators
- University of Miamilead
- Women's Cancer Associationcollaborator
- Gabrielle's Angel Foundationcollaborator
Study Sites (1)
University of Miami
Miami, Florida, 33136, United States
Related Publications (1)
Tayari MM, Santos HGD, Kwon D, Bradley TJ, Thomassen A, Chen C, Dinh Y, Perez A, Zelent A, Morey L, Cimmino L, Shiekhattar R, Swords RT, Watts JM. Clinical Responsiveness to All-trans Retinoic Acid Is Potentiated by LSD1 Inhibition and Associated with a Quiescent Transcriptome in Myeloid Malignancies. Clin Cancer Res. 2021 Apr 1;27(7):1893-1903. doi: 10.1158/1078-0432.CCR-20-4054. Epub 2021 Jan 25.
PMID: 33495312DERIVED
MeSH Terms
Conditions
Interventions
Condition Hierarchy (Ancestors)
Intervention Hierarchy (Ancestors)
Study Officials
- PRINCIPAL INVESTIGATOR
Justin Watts, MD
University of Miami
Study Design
- Study Type
- interventional
- Phase
- phase 1
- Allocation
- NON RANDOMIZED
- Masking
- NONE
- Purpose
- TREATMENT
- Intervention Model
- PARALLEL
- Sponsor Type
- OTHER
- Responsible Party
- PRINCIPAL INVESTIGATOR
- PI Title
- Assistant Professor
Study Record Dates
First Submitted
October 20, 2014
First Posted
October 23, 2014
Study Start
March 2, 2015
Primary Completion
November 8, 2018
Study Completion
July 1, 2020
Last Updated
July 21, 2020
Record last verified: 2020-07
Data Sharing
- IPD Sharing
- Will not share