study of sensitization of non-m3 aml blasts to atra by epigenetic treatment with tranylcypromine (tcp)

Conditions: Acute Myeloid Leukemia; Myelodysplastic Syndrome

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

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

Eligibility 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;

Keywords: aml mds relapsed trans-retinoic acid atra epigenetic treatment non-m3 aml blasts tranylcypromine tcp lsd1 refractory