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

Recruitment & Eligibility

Status: Recruiting

Sex: All

Target Recruitment: 60

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.

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.

Study & Design

Study Type: interventional

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
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).

Secondary Outcome Measures

Name	Time	Method
Safety:<br>- Adverse events and serious adverse events<br>- Vital signs (pulse rate and blood pressure)<br>- Laboratory data including hematologic parameters<br><br>Efficacy (phase II part):<br>- Overall survival<br>- EORTC QLQ C30<br>- HADS-D<br><br>Translational endpoints:<br>- in vivo target validation and functional evaluation of LSD1 inhibition