Working…
COVID-19 is an emerging, rapidly evolving situation.
Get the latest public health information from CDC: https://www.coronavirus.gov.

Get the latest research information from NIH: https://www.nih.gov/coronavirus.
ClinicalTrials.gov
ClinicalTrials.gov Menu

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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02273102
Recruitment Status : Completed
First Posted : October 23, 2014
Last Update Posted : July 21, 2020
Sponsor:
Collaborators:
Women’s Cancer Association
Gabrielle's Angel Foundation
Information provided by (Responsible Party):
Justin Watts, MD, University of Miami

Tracking Information
First Submitted Date  ICMJE October 20, 2014
First Posted Date  ICMJE October 23, 2014
Last Update Posted Date July 21, 2020
Actual Study Start Date  ICMJE March 2, 2015
Actual Primary Completion Date November 8, 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 16, 2016)
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.
Original Primary Outcome Measures  ICMJE
 (submitted: October 21, 2014)
Number of subjects experiencing adverse events [ Time Frame: 24 months ]
The safety and tolerability of TCP/ATRA combination therapy in patients with Acute Myelogenous Leukemia (AML) and Myelodysplastic Syndromes (MDS).
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: February 27, 2018)
  • 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
  • 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).
  • 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.
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Study of TCP-ATRA for Adult Patients With AML and MDS
Official Title  ICMJE 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)
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.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Acute Myelogenous Leukemia
  • Myelodysplastic Syndromes
  • Leukemia
Intervention  ICMJE
  • 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
Study Arms  ICMJE
  • 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.
    Interventions:
    • Drug: Tranylcypromine
    • Drug: Tretinoin
  • 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.
    Interventions:
    • Drug: Tranylcypromine
    • Drug: Tretinoin
  • 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.
    Interventions:
    • Drug: Tranylcypromine
    • Drug: Tretinoin
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: December 21, 2018)
17
Original Estimated Enrollment  ICMJE
 (submitted: October 21, 2014)
24
Actual Study Completion Date  ICMJE July 1, 2020
Actual Primary Completion Date November 8, 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02273102
Other Study ID Numbers  ICMJE 20140328
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
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
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Justin Watts, MD, University of Miami
Study Sponsor  ICMJE University of Miami
Collaborators  ICMJE
  • Women’s Cancer Association
  • Gabrielle's Angel Foundation
Investigators  ICMJE
Principal Investigator: Justin Watts, MD University of Miami
PRS Account University of Miami
Verification Date July 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP