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Phase I/II Trial of ATRA and TCP in Patients With Relapsed or Refractory AML and no Intensive Treatment is Possible (TCP-AML)

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. Identifier: NCT02261779
Recruitment Status : Unknown
Verified July 2015 by Dr. Petra Tschanter, Martin-Luther-Universität Halle-Wittenberg.
Recruitment status was:  Recruiting
First Posted : October 10, 2014
Last Update Posted : July 7, 2015
Information provided by (Responsible Party):
Dr. Petra Tschanter, Martin-Luther-Universität Halle-Wittenberg

Tracking Information
First Submitted Date  ICMJE September 23, 2014
First Posted Date  ICMJE October 10, 2014
Last Update Posted Date July 7, 2015
Study Start Date  ICMJE September 2014
Estimated Primary Completion Date September 2017   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 9, 2014)
Analysis of the cumulative response rate (CR,CRp, CRi, PR) [ Time Frame: every 28 day cycle ]
Disease status will be assessed by bone marrow analyses
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: October 9, 2014)
  • number of participants with adverse events as a measure of safety and tolerability [ Time Frame: one year ]
  • overall survival [ Time Frame: 2 years ]
  • treatment effects of promotor genes [ Time Frame: 2 Years ]
    To assess the cumulative incidence and degree of histone methylation of promotor genes in AML blasts after treatment with Tretinoin and tranylcpromine
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
Descriptive Information
Brief Title  ICMJE Phase I/II Trial of ATRA and TCP in Patients With Relapsed or Refractory AML and no Intensive Treatment is Possible
Official Title  ICMJE Phase I/II Pilot Trial of ATRA (Tretinoin) and TCP (Tranylcypromine) in Patients With Relapsed or Refractory Acute Myeloid Leukemia (AML) and no Intensive Treatment is Possible
Brief Summary

Longterm disease-free survival (DFS) of older patients with acute myeloid leukemia (AML) remains poor. The vast majority of AML patients relapses within two years after start of therapy1,2. In Acute Promyelocytic Leukemia (APL, AML M3), all-trans-retinoic-acid (ATRA; Tretinoin) induces differentiation and subsequently clinical remission. So far effective differentiation therapy does not exist in other AML subtypes. Recent preclinical data suggest that the combinatorial use of ATRA and tranylcypromine (TCP), an irreversible Monoamine-Oxidase (MAO) and Lysin-specific demethylase (LSD) inhibitor that also inhibits LSD1 (a histone H3 Lysine 4 demethylase), induces leukemia cell differentiation and leukemic stem cell exhaustion in vitro and in vivo in non-APL AML subtypes.

In this Phase I/II study the investigators will explore the feasibility, safety, as well as efficacy and of Tretinoin/TCP treatment in patients with relapsed or refractory AML or in patients with AML who are not eligible for intensive treatment. Patients will be treated with daily increasing doses of TCP (initially 10 mg/day, then +10 mg each day up to 80mg/d). After 7 days, ATRA will be added at a fixed dose (45 mg/sqm/day). Overall, 16 evaluable patients are going to be treated. The primary endpoint is the fraction of patients that achieve CR, CRp( complete response with incomplete recovery of platelets), CRi (complete response with incomplete recovery of granulocytes) and PR. Secondary endpoints are tolerability, safety as well as progression-free survival and overall survival. Serum levels of TCP will be regularly analyzed. Pharmacodynamic analyses will be performed with analyses of the inhibition of LSD1 by TCP. Further analyses will address the changes in Histone H3 lysine 4 tri demethylase (H3K4me3) levels in AML blasts and the differentiation status of AML blasts.

Taken together, this Phase I/II study will analyze feasibility, pharmacodynamics and effectivity of ATRA and TCP as differentiation therapy in AML.

Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE AML
Intervention  ICMJE
  • Drug: Tranylcypromine
    Other Name: Jatrosom
  • Drug: Tretinoin
    Other Name: Vesanoid
Study Arms  ICMJE Experimental: Tretinoin & Tranylcypromine
Tretinoin started with 45mg/m2 on day 7 for one year, administered orally as soft capsules, Tranylcypromine started with 10mg/d up to a maximum dose of 60mg/d for on year, administered orally as tablets
  • Drug: Tranylcypromine
  • Drug: Tretinoin
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status  ICMJE Unknown status
Estimated Enrollment  ICMJE
 (submitted: October 9, 2014)
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE September 2017
Estimated Primary Completion Date September 2017   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Subjects must provide written informed consent prior to performance of study-specific procedures or assessments which are not routinely performed for diagnosis or monitoring of AML, and the subjects must be willing to comply with treatment and to follow up assessments and procedures
  2. Histologically or cytologically confirmed diagnosis of AML relapsed after or refractory to at least one induction regimen, or patients with AML at initial diagnosis who are not eligible for allogeneic transplant or intensive induction chemotherapy (investigator´s choice; for example reduced general state), except for AML M3 (acute promyelocytic leukemia).
  3. Age > 18 years
  4. Eastern Cooperative Oncology Group (ECOG) performance status of ≤3 (see Appendix, 3.2)
  5. Measurable disease burden (blasts in bonemarrow (BM) and/or peripheral blood (PB), extramedullary blasts [chloroma])
  6. Able to swallow and retain oral medication
  7. A life expectancy of at least 4 weeks
  8. Adequate contraception methods
  9. Adequate organ function

Exclusion Criteria:

  1. Patients with more than 20.000/µl leukocytes in the peripheral blood that cannot be controlled by Hydroxyurea.
  2. Patients with a valid option for intensive chemotherapy and/ or stem cell transplantation. (Patients after allogeneic stem cell transplant must be off immunosuppressive agents for at least 2 weeks prior to study entry and Graft- versus host disease must have resolved to Grade <= 2)
  3. Patients with less than 30% blasts in the bone marrow at the time of diagnosis. They should receive Azacytidine monotherapy.
  4. History of cancer that according to the Investigator might confound the assessment of the endpoints of the study
  5. Uncontrolled peptic ulcer disease or clinically significant gastrointestinal abnormalities which interfere with oral dosing or any unstable or serious concurrent condition (e.g., active uncontrolled infection)
  6. Poorly controlled hypertension (defined as systolic blood pressure (SBP) of ≥170 mmHg). Note: Initiation or adjustment of antihypertensive medication is permitted prior to study entry. BP must be re-assessed on two occasions that are separated by a minimum of 1 hour; on each of these occasions, the mean (of 3 readings) SBP/ DBP(diastolic blood pressure) values from each BP assessment must be <140/90 mmHg in order for a subject to be eligible for he study.
  7. Prolongation of corrected QT interval (QTc) > 480 ms
  8. History of any one or more of the following cardiovascular conditions within the past 6 months: cardiac angioplasty or stenting, myocardial infarction (MI), unstable angina, symptomatic peripheral vascular disease, class 3 or 4 congestive heart failure, as defined by the New York Heart Association (NYHA)
  9. Left ventricular ejection fraction (LVEF) at least 40% by multiple gated acquisition (MUGA) scan or echocardiogram (ECHO)
  10. History of cerebrovascular infarction or bleeding, pulmonary embolism (PE), or untreated deep venous thrombosis (DVT) within the past 6 months. Note: Subjects with recent DVT who have been treated with therapeutic anti- coagulant agents for at least 6 weeks are eligible
  11. Evidence of serious active bleeding or bleeding diathesis (except for bleeding or petechiae due to AML- related thrombocytopenia which will be treated using platelet transfusions). Also, patients with known endobronchial lesions and/ or lesions infiltrating major pulmonary vessels will be excluded from the study due to excess risk of bleeding.
  12. Prior major surgery or trauma within 28 days prior to first dose of study drug
  13. Treatment with an investigational agent within 21 days or 5 half-life, whichever is longer prior to the first dose of study drug.
  14. Concurrent cytoreductive chemotherapy except hydroxyurea.
  15. Known immediate or delayed hypersensitivity reaction or idiosyncrasy to Tretinoin, Retinoids, soya, peanuts or Tranylcypromine.
  16. Patients with psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol
  17. Patients with known epilepsy or patients with known psychiatric affections (bipolar disorder, schizophrenia, suicidal patients)
  18. Pregnant or lactating and actively breastfeeding patients
  19. Patients who are indignant to comply with nutritional conditions (see Protocol)
  20. Poorly adjusted diabetes mellitus
  21. Patients with hereditary Galactose-Intolerance, Lactase-Intolerance or Glucose-Galactose-Malabsorption
  22. Known drug or alcohol abuse
  23. Phaeochromocytoma or carcinoid tumor
  24. Known cerebral vascular disease or other malformation of vessels (e.g. aneurysma)
  25. Diabetes insipidus
  26. Patients taking any of the following prohibited medication due to interaction with a) tretinoin and b) TCP.
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 Germany
Removed Location Countries  
Administrative Information
NCT Number  ICMJE NCT02261779
Other Study ID Numbers  ICMJE UKM_04_12_TCP_ATRA_AML
2012-002154-23 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Dr. Petra Tschanter, Martin-Luther-Universität Halle-Wittenberg
Study Sponsor  ICMJE Martin-Luther-Universität Halle-Wittenberg
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Carsten Mueller-Tidow, Prof. Martin-Luther-Universität Halle-Wittenberg
PRS Account Martin-Luther-Universität Halle-Wittenberg
Verification Date July 2015

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