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

Acute Myeloid Leukemia Clinical Trial

— TRANSATRA  

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)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT02717884
• Other study ID #: 00806 UKF
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: May 2015
• Est. completion date: December 2021

Study information

• Verified date: October 2018
• Source: University Hospital Freiburg
• Contact: Michael Lübbert, MD, Prof.
• Phone: +49 761 270
• Email: michael.luebbert[@]uniklinik-freiburg.de
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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

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

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 60
• Est. completion date: December 2021
• Est. primary completion date: December 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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;

Related Conditions & MeSH terms

• Acute Myeloid Leukemia
• Leukemia
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute
• Myelodysplastic Syndrome
• Myelodysplastic Syndromes
• Preleukemia

Intervention

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)
• 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
• cytarabine
40mg s.c. (days 1-10)

Locations

Country	Name	City	State
Germany	Universitätsklinik Düsseldorf, Medical School Duesseldorf	Düsseldorf
Germany	Universitätsklinikum Frankfurt Main, Medical School Frankfurt	Frankfurt Main
Germany	Universitätsklinikum Freiburg, Medical School Freiburg	Freiburg
Germany	Universitätsklinikum Heidelberg	Heidelberg	Baden-Wuerttemberg
Germany	Klinikum München rechts der Isar, Medical School Munich rechts der Isar	München, Munich
Germany	Universitätsklinikum Tübingen, Medical School Tuebingen	Tübingen, Tuebingen

Sponsors (2)

Lead Sponsor	Collaborator
Michael Luebbert	University Hospital Freiburg

Country where clinical trial is conducted

Germany, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	MTD determination of TCP in combination with fixed-dose of ATRA and with fixed-dose Cytarabine;	MTD determination of TCP in combination with fixed-dose of ATRA and with fixed-dose Cytarabine;	first 28 days of treatment
Secondary	Objective best response	(CR complete remission, CRi complete remission with incomplete blood count recovery, PR partial remission)	through study completion, an average of one year
Secondary	Overall survival (OS)	Overall survival (OS)	12 months