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Study of Sensitization of Non-M3 AML Blasts to ATRA by Epigenetic Treatment With Tranylcypromine (TCP) (TRANSATRA)

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ClinicalTrials.gov Identifier: NCT02717884
Recruitment Status : Recruiting
First Posted : March 24, 2016
Last Update Posted : October 18, 2018
Sponsor:
Collaborator:
University Hospital Freiburg
Information provided by (Responsible Party):
Michael Luebbert, University Hospital Freiburg

Brief Summary:

The objective of the phase I part of the trial is the determination of the maximum tolerated dose (MTD) of TCP (Tranylcypromine) in combination with fixed-dose ATRA (all-trans-retinoic acid) and with fixed-dose AraC (Cytarabine) and to derive the recommended phase II dose (RP2D) in patients with non-APL AML or MDS for whom no standard treatment is available or who failed azanucleoside treatment.

The objective of the phase II part of the trial is a first evaluation of the efficacy of TCP at the RP2D in combination with fixed-dose ATRA and with fixed-dose AraC as basis for further investigations of TCP


Condition or disease Intervention/treatment Phase
Acute Myeloid Leukemia Myelodysplastic Syndrome Drug: tranylcypromine Drug: all-trans retinoic acid Drug: cytarabine Phase 1 Phase 2

Detailed Description:

Study treatment: TCP + ATRA + AraC Four dose levels of TCP (20 mg, 40 mg, 60 mg, 80 mg on days 1-28) will be examined in combination with fixed dose ATRA (45 mg/m2 on days 10-28) and fixed-dose AraC (40 mg on days 1-10) in the first cycle.

In further cycles patients will be treated in the same manner, except for ATRA which will be administered continuously with a nine-day interruption at the beginning of every fourth cycle.

Follow-up per patient: Until twelve months after registration of the last patient.

Duration of intervention per patient: Until relapse/progression, unacceptable toxicity or until twelve months after registration of the last patient, whatever occurs first


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 60 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase I/II Study of Sensitization of Non-M3 Acute Myeloid Leukemia (AML) Blasts to All-trans Retinoic Acid (ATRA) by Epigenetic Treatment With Tranylcypromine (TCP), an Inhibitor of the Histone Lysine Demethylase 1 (LSD1)
Study Start Date : May 2015
Estimated Primary Completion Date : December 2020
Estimated Study Completion Date : December 2021


Arm Intervention/treatment
Experimental: TCP, ATRA, Cytarabine

Phase I part:

The rolling-six phase I design will be used to determine the MTD of TCP in combination with fixed-dose of ATRA and with fixed-dose AraC in patients with AML/MDS.

Intervention: Four dose levels of TCP (20 mg, 40 mg**, 60 mg**, 80 mg** on days 1-28) will be examined in combination with ATRA (45 mg/m2 on days 10-28) and with fixed-dose AraC (40 mg on days 1-10) in the first cycle. In case of dose-limiting toxicity (DLT) on the starting level 1 of 20 mg a de-escalation to dose level of 10 mg (level -1) will be investigated.

**TCP dose will be slowly increased to achieve the necessary dose level and slowly tapered off at the end of treatment

Drug: tranylcypromine

TCP p.o., daily either 20, 40**, 60**, 80** mg/day, (28d/cycle)

**TCP doses will be slowly increased during cycle 1 and slowly decreased at end of treatment (for details see study protocol)

Other Names:
  • TCP
  • Jatrosom®

Drug: all-trans retinoic acid
45mg/m2 (days 10-28), CAVE: ATRA will be administered without interruption until inclusively cycle 3. At the beginning of the cycle 4 a nine-day break corresponding to the first nine days of the AraC treatment will be performed, thereafter the ATRA-therapy will be continued with a nine-day interruption every fourth cycle. That means that the therapy in cycles 1, 4, 7, 10, 13 etc. In other cycles ATRA will be given without interruption
Other Names:
  • ATRA
  • Vesanoid®

Drug: cytarabine
40mg s.c. (days 1-10)
Other Names:
  • Alexan®
  • AraC




Primary Outcome Measures :
  1. MTD determination of TCP in combination with fixed-dose of ATRA and with fixed-dose Cytarabine; [ Time Frame: first 28 days of treatment ]
    MTD determination of TCP in combination with fixed-dose of ATRA and with fixed-dose Cytarabine;


Secondary Outcome Measures :
  1. Objective best response [ Time Frame: through study completion, an average of one year ]
    (CR complete remission, CRi complete remission with incomplete blood count recovery, PR partial remission)

  2. Overall survival (OS) [ Time Frame: 12 months ]
    Overall survival (OS)



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

Patients eligible for inclusion in this trial must meet all of the following criteria:

  1. Patients >18 years (no upper age limit);
  2. AML (WHO) or intermediate or higher risk MDS/ Chronic Myelomonocytic Leukemia (CMML) (IPSS-R >3.0);
  3. No standard treatment available (comorbidities, higher age, refractoriness to standard or salvage chemotherapy and allografting, azanucleosides failure*);
  4. Patients with < 30.000 leukocytes/µl;
  5. Eastern Cooperative Oncology Group (ECOG) 0,1,2;
  6. Written informed consent obtained according to international guidelines and local laws;
  7. Ability to understand the nature of the trial and the trial related procedures and to comply with them.

    • Azanucleosides failure is defined as 1) no response after at least three (AML) or six (MDS) cycles of azacitidine or decitabine, 2) disease progression under treatment or 3) grade 3-4 non-hematologic toxicity.

Exclusion Criteria:

Patients eligible for this trial must not meet any of the following criteria:

  1. Acute promyelocytic leukemia (APL, French-American-British classification system (FAB) M3);
  2. Eligibility for standard induction or consolidation chemotherapy, immediate allografting, or a hypomethylating agent;
  3. AML with central nervous system (CNS) involvement;
  4. AraC treatment within one month prior to registration;
  5. Prior exposure to histone deacetylase inhibitors, including sodium valproate within one month prior to registration;
  6. Stem cell transplant patient with graft-versus-host disease (GvHD) or under systemic immunosuppression;
  7. Previous gastrointestinal surgery that might interfere with drug absorption;
  8. Pheochromocytoma;
  9. Carcinoid tumor;
  10. Confirmed or suspected cerebrovascular disease;
  11. Vascular malformations including aneurysm;
  12. Severe renal insufficiency;
  13. Severe or poorly controlled hypertension;
  14. Severe cardiovascular disease;
  15. Hepatic insufficiency/liver disease;
  16. Porphyria;
  17. Diabetes insipidus;
  18. History or presence of malignant hyperthermia;
  19. Known psychiatric disorders;
  20. Known allergy against soy beans or peanuts;
  21. Known hypersensitivity to or intolerance of one of the trial drugs or its constituents (e.g. lactose, corn starch, indigocarmine (TCP), corn starch (AraC), other retinoids (ATRA));
  22. Simultaneous intake of the prohibited medication, incl. linezolid, that is likely to cause interactions (see detailed list study protocol);
  23. Patients who refuse to follow study-specific dietary guidelines;
  24. Known or persistent abuse of medication, drugs or alcohol;
  25. Current or planned pregnancy, nursing period;
  26. Failure to use safe methods of contraception;
  27. Simultaneous participation in other interventional trials which could interfere with this trial and/or participation before the end of a required restriction period;
  28. Participation in a clinical trial within the last 30 days before the start of this trial
  29. Persons who are in a relationship of dependence/employment with the sponsor or the investigator;

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02717884


Contacts
Contact: Michael Lübbert, MD, Prof. +49 761 270 ext 35340 michael.luebbert@uniklinik-freiburg.de
Contact: Alexandra Schulz, MSc +49 761 270 ext 36710 alexandra.schulz@uniklinik-freiburg.de

Locations
Germany
Universitätsklinikum Heidelberg Recruiting
Heidelberg, Baden-Wuerttemberg, Germany, 69120
Contact: Alwin Krämer, MD, Prof.    +49 6221 ext 5637750    a.kraemer@Dkfz-Heidelberg.de   
Contact: Anne-Marie Geueke    +49 6221 ext 568006    anne-marie.geueke@med.uni-heidelberg.de   
Principal Investigator: Alwin Krämer, MD,Prof.         
Sub-Investigator: Tilmann Bochtler, MD,PD Dr         
Universitätsklinik Düsseldorf, Medical School Duesseldorf Recruiting
Düsseldorf, Germany, 40225
Contact: Andrea Kündgen, MD, PD Dr.    +49 211 811 ext 6338    kuendgen@med.uni-duesseldorf.de   
Contact: Ulrike Spiegelberg    +49 211 811 ext 7714    spiegelberg@med.uni-duesseldorf.de   
Principal Investigator: Andrea Kündgen, MD, PD Dr.         
Sub-Investigator: Ulrich Germing, MD, Prof.         
Universitätsklinikum Frankfurt Main, Medical School Frankfurt Recruiting
Frankfurt Main, Germany, 60590
Contact: Tobias Berg, MD, Dr.    +49 69 6301 ext 84004    tobias.berg@kgu.de   
Contact: Gesine Bug, MD, PD Dr.    +49 69 6301 ext 7369    gesine.bug@kgu.de   
Principal Investigator: Tobias Berg, MD, Dr.         
Sub-Investigator: Gesine Bug, MD, PD Dr.         
Universitätsklinikum Freiburg, Medical School Freiburg Recruiting
Freiburg, Germany, 79106
Contact: Michael Lübbert, MD, Prof.    +49 761 270 ext 35340    michael.luebbert@uniklinik-freiburg.de   
Contact: Alexandra Schulz, MSc    +49 761 270 ext 36710    alexandra.schulz@uniklinik-freiburg.de   
Sub-Investigator: Ralph Wäsch, MD, Prof.         
Klinikum München rechts der Isar, Medical School Munich rechts der Isar Recruiting
München, Munich, Germany, 81675
Contact: Katharina Götze, MD, Prof.    +49 89 4140 ext 5618    katharina.goetze@mri.tum.de   
Contact: Sandra Eckert    +49 89 4140 ext 5637    sandra.eckert@mri.tum.de   
Principal Investigator: Katharina Götze, MD, Prof.         
Sub-Investigator: Mareike Verbeek, MD, Dr.         
Universitätsklinikum Tübingen, Medical School Tuebingen Recruiting
Tübingen, Tuebingen, Germany, 72076
Contact: Helmut R Salih, MD, Prof.    +49 7071 29 ext 83275    helmut.salih@med.uni-tuebingen.de   
Contact: Heinz Schwarz, SN    +49 7071 29 ext 82883    heinz.schwarz@med.uni-tuebingen.de   
Principal Investigator: Helmut R Salih, MD, Prof.         
Sub-Investigator: Marcus M Schittenhelm, MD, Dr.         
Sponsors and Collaborators
Michael Luebbert
University Hospital Freiburg
Investigators
Principal Investigator: Michael Lübbert, MD, Prof. Medical Center - University of Freiburg

Responsible Party: Michael Luebbert, Prof. Dr. med., University Hospital Freiburg
ClinicalTrials.gov Identifier: NCT02717884     History of Changes
Other Study ID Numbers: 00806 UKF
First Posted: March 24, 2016    Key Record Dates
Last Update Posted: October 18, 2018
Last Verified: October 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Keywords provided by Michael Luebbert, University Hospital Freiburg:
AML
MDS
relapsed
trans-retinoic acid ATRA
epigenetic treatment
non-M3 AML blasts
tranylcypromine TCP
LSD1
refractory

Additional relevant MeSH terms:
Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Myelodysplastic Syndromes
Preleukemia
Neoplasms by Histologic Type
Neoplasms
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Cytarabine
Tretinoin
Tranylcypromine
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antiviral Agents
Anti-Infective Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Keratolytic Agents
Dermatologic Agents
Antidepressive Agents
Psychotropic Drugs
Monoamine Oxidase Inhibitors
Enzyme Inhibitors
Anti-Anxiety Agents
Tranquilizing Agents