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

• Status: Recruiting
• Trial end date: 2021-12-01
• Target enrollment: 0
• Participant gender: All

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

• Phase: Phase 1/Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Michael Luebbert; Ulrike Kohlweyer
• Collaborator: University Hospital Freiburg
• Treatments: Cytarabine; Tranylcypromine; Tretinoin

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;