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

July 20, 2020 updated by: Justin Watts, MD, University of Miami

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)

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 Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Completed

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
17

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Florida
      • Miami, Florida, United States, 33136
        • University of Miami

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

14 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

      • 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.
  5. Suitable venous access to allow for all study related blood sampling (safety and research).
  6. Estimated life expectancy, in the judgment of the Investigator, which will permit receipt of at least 6 weeks of treatment.
  7. Able to understand and willing to signed the written informed consent and HIPAA document/s.

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.
  11. Known hepatitis B surface antigen-positive.
  12. Known or suspected active hepatitis C infections (Patients who are hepatitis C surface antigen-positive are eligible).
  13. 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.
  14. 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.
  15. 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).
  16. Serious medical or psychiatric illness/condition likely in the judgment of the Investigator to interfere with compliance to protocol treatment/research.
  17. Known history of allergic reaction to TCP or ATRA.
  18. Symptomatic central nervous system (CNS) involvement.
  19. A concurrent second active and non-stable malignancy (Patients with a concurrent second active but stable malignancy are eligible).
  20. Patients with proliferative AML will be excluded defined by a white blood cell count (WBC) > 5 x ULN UNLESS, the white count has been suppressed to < 5 x ULN with hydroxurea and has remained below this level for at least 2 weeks prior to enrollment on study.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Non-Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Experimental: TCP Dose Level 1
20mg 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.
Drug: Tranylcypromine
Tranylcypromine (TCP) to be administered orally twice a day (12 hours apart) for up to 16 cycles of 21 days each.
Other Names:
  • 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 Names:
  • ATRA
Experimental: TCP Dose Level 2
40mg 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.
Drug: Tranylcypromine
Tranylcypromine (TCP) to be administered orally twice a day (12 hours apart) for up to 16 cycles of 21 days each.
Other Names:
  • 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 Names:
  • ATRA
Experimental: TCP Dose Level 3
60mg 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.
Drug: Tranylcypromine
Tranylcypromine (TCP) to be administered orally twice a day (12 hours apart) for up to 16 cycles of 21 days each.
Other Names:
  • 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 Names:
  • ATRA

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Rate of Toxicity in Study Participants Receiving TCP/ATRA Combination Therapy
Time Frame: 24 months
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 Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Rate of Preliminary Efficacy of TCP/ATRA Combination Therapy
Time Frame: 24 months
Best response to TCP/ATRA combination therapy will be determined using serial blood and bone marrow sampling throughout the course of treatment. Responses will be documented according to revised/modified International Working Group (IWG) Response Criteria - Cheson et al. 2003 for AML and Cheson et al. 2006 for MDS. Morphologic complete remission (CR), cytogenetic CR, and molecular CR will be assessed by blood counts and simultaneous examination of the bone marrow fpr percentage of bone marrow blasts, as well as cytogenetics and molecular studies of bone marrow mononuclear cells
24 months
Pharmacokinetics (PK) effects of TCP in plasma when combined with ATRA
Time Frame: Baseline, Cycle 1, Cycle 2, 30 Days (+/-10 days) Post-End of Treatment
Pharmacokinetics (PK) parameters will be determined using serial blood sampling at specified time points to determine PK effects of TCP in plasma when combined with ATRA. Non-compartmental methods of analysis will be used to determine TCP PK parameters following oral dosing of patients in Cycle 1. The following will be calculated: Observed maximum concentration (Cmax), the time at which Cmax occurred (Tmax), the area under the plasma concentration-time curve from time 0 to 24 hours post-dose (AUC24hr), the terminal disposition phase half-life (t1/2).
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.
Time Frame: Baseline, Cycle 1, Cycle 2, 30 Days (+/-10 days) Post-End of Treatment
Pharmacodynamics (PD) measurements will be obtained from serial blood and bone marrow sampling at specified time points to describe the PD effects of TCP when combined with ATRA. The following will be measured: Expression of CD11b by flow cytometry, gene expression analysis of leukemic blasts, measurement of Retinoic acid receptor alpha (RARα) and lysine (K)-specific demethylase 1A (LSD1) within leukemic blasts, leukemic engraftment of treated cells in immunodeficient mice.
Baseline, Cycle 1, Cycle 2, 30 Days (+/-10 days) Post-End of Treatment

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
University of Miami

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
Gabrielle's Angel Foundation
Women's Cancer Association

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
March 2, 2015

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
November 8, 2018

Study Completion (Actual)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
July 1, 2020

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
October 20, 2014

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
October 21, 2014

First Posted (Estimate)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
October 23, 2014

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
July 21, 2020

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
July 20, 2020

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
July 1, 2020

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • 20140328

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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