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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

Tracking Information
First Submitted Date  ICMJE February 4, 2016
First Posted Date  ICMJE March 24, 2016
Last Update Posted Date October 18, 2018
Study Start Date  ICMJE May 2015
Estimated Primary Completion Date December 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 16, 2018)
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;
Original Primary Outcome Measures  ICMJE
 (submitted: March 18, 2016)
MTD determination of TCP in combination with fixed-dose of ATRA and with fixed-dose Cytarabine; [ Time Frame: first 28 days of treatment ]
Change History Complete list of historical versions of study NCT02717884 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: October 16, 2018)
  • 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)
  • Overall survival (OS) [ Time Frame: 12 months ]
    Overall survival (OS)
Original Secondary Outcome Measures  ICMJE
 (submitted: March 18, 2016)
  • objective best response (CR complete remission, CRi complete remission with incomplete blood count recovery, PR partial remission) [ Time Frame: through study completion, an average of one year ]
  • Overall survival (OS) [ Time Frame: 12 months ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Study of Sensitization of Non-M3 AML Blasts to ATRA by Epigenetic Treatment With Tranylcypromine (TCP)
Official Title  ICMJE 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)
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

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  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Acute Myeloid Leukemia
  • Myelodysplastic Syndrome
Intervention  ICMJE
  • 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
Study Arms  ICMJE 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

Interventions:
  • Drug: tranylcypromine
  • Drug: all-trans retinoic acid
  • Drug: cytarabine
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 Recruiting
Estimated Enrollment  ICMJE
 (submitted: March 18, 2016)
60
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 2021
Estimated Primary Completion Date December 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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;
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: 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
Listed Location Countries  ICMJE Germany
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02717884
Other Study ID Numbers  ICMJE 00806 UKF
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Michael Luebbert, University Hospital Freiburg
Study Sponsor  ICMJE Michael Luebbert
Collaborators  ICMJE University Hospital Freiburg
Investigators  ICMJE
Principal Investigator: Michael Lübbert, MD, Prof. Medical Center - University of Freiburg
PRS Account University Hospital Freiburg
Verification Date October 2018

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