Trial document




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  DRKS00006055

Trial Description

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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)

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Trial Acronym

TRANSATRA

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URL of the Trial

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Brief Summary in Lay Language

The treatment for acute myeloid leukemia or a myelodyplastic syndrome usually requires an intensive chemotherapy , with the goal to heal the present disease . Sometimes, however, chemotherapy does not work , or is not possible due to advanced age of the patient, or after initial improvement, a relapse occurs.For these patients new treatment approaches are sought .
The TRANSATRA study has the objective of improving the treatment options for these patients with acute myeloid leukemia and myelodysplastic syndromes . The study medications obtained all patients are tranylcypromine ( TCP ) , retinoic acid ( ATRA ) and chemotherapy as cytarabine ( ARA - C )

The TRANSATRA Studie has the goal, to improve the treatment of Patients with AML/MDS.The studymedication, every patient gets, is Tranylcypromin(TCP), ATRA and as chemotherapy Cytarabin( ARA-C)

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Brief Summary in Scientific Language

Phase I/II study of sensitization of non-M3 acute myeloid leukemia (AML) blasts to alltrans retinoic acid (ATRA) by epigenetic treatment with tranylcypromine (TCP), an inhibitor of the histone lysine demethylase 1 (LSD1)

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Organizational Data

  •   DRKS00006055
  •   2015/07/09
  •   2016/02/04
  •   yes
  •   Approved
  •   15/15, Ethik-Kommission der Albert-Ludwigs-Universität Freiburg
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Secondary IDs

  •   2014-001479-30 
  •   NCT02717884   (clinicaltrials.gov)
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Health Condition or Problem studied

  •   C92.0 -  Acute myeloblastic leukaemia [AML]
  •   D46.9 -  Myelodysplastic syndrome, unspecified
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Interventions/Observational Groups

  •   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
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Characteristics

  •   Interventional
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  •   Single arm study
  •   Open (masking not used)
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  •   Uncontrolled/Single arm
  •   Treatment
  •   Single (group)
  •   I-II
  •   Yes
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Primary Outcome

The primary endpoint of the phase I part of the study is DLT in the first 28 days of treatment. DLT is defined as a toxicity that is considered by the investigator to be related to the combination TCP+ATRA or TCP+AraC+ATRA and necessitates to reduce the dose of the investigational product or to even stop treatment. The aim is the determination of the maximum tolerated dose (MTD) and the recommended phase II dose (RP2D).The primary endpoint of the phase II part of the study is objective best response (CR, CRi, PR).

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Secondary Outcome

Safety:
- Adverse events and serious adverse events
- Vital signs (pulse rate and blood pressure)
- Laboratory data including hematologic parameters

Efficacy (phase II part):
- Overall survival
- EORTC QLQ C30
- HADS-D

Translational endpoints:
- in vivo target validation and functional evaluation of LSD1 inhibition

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Countries of Recruitment

  •   Germany
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Locations of Recruitment

  • University Medical Center 
  • University Medical Center 
  • University Medical Center 
  • University Medical Center 
  • University Medical Center 
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Recruitment

  •   Actual
  •   2015/08/26
  •   60
  •   Multicenter trial
  •   National
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Inclusion Criteria

  •   Both, male and female
  •   18   Years
  •   no maximum age
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Additional Inclusion Criteria

1. Patients >18 years (no upper age limit);
2. AML (WHO) or intermediate or higher risk MDS/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. 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.

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Exclusion Criteria

Acute promyelocytic leukemia (APL, FAB M3);
2. Eligibility for standard induction or consolidation chemotherapy, immediate
allografting, or a hypomethylating agent;
3. AML with 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 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, indigocarmin (TCP), corn starch
(AraC), other retinoids (ATRA));
22. Simultaneous intake of the prohibited medication, incl. linezolid, that is
likely to cause interactions;
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.

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Addresses

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    • Universitätsklinikum Freiburg
    • Hugstetter Strasse 49
    • 79095  Freiburg
    • Germany
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    • Uniklinkum FreiburgMedizinische Klinik 1
    • Mr.  Prof. Dr. med.  Michael  Lübbert 
    • Hugstetterstr. 55
    • 79106  Freiburg
    • Germany
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    • Universitätsklinikum Freiburg, Dept. Innere Medizin, Klinik für Innere Medizin I, Schwerpunkt Hämatologie, Onkologie und Stammzelltransplantation
    • Ms.  Dr.   Ulrike   Kohlweyer 
    • Hugstetter Str. 55
    • 79106  Freiburg
    • Germany
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Sources of Monetary or Material Support

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    • DKTK
    • Im Neuenheimer Feld 280
    • 69120  Heidelberg
    • Germany
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    • Universtitätsklinikum FreiburgCCCF Grant
    • CCCF Grant 
    • Hugstetterstr.55
    • 79106  Freiburg
    • Germany
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Status

  •   Recruiting ongoing
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Trial Publications, Results and other Documents

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