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

Phase 1

• Conditions: Acute Myeloid Leukemia; Myelodysplastic Syndrome
• Interventions: Drug: tranylcypromine; Drug: all-trans retinoic acid; Drug: cytarabine

• Registration Number: NCT02717884
• Lead Sponsor: Michael Luebbert

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 Timeline

• Study Start: 2015-05
• Study First Submitted: 2016-02-04
• Study First Submitted QC: 2016-03-18
• Study First Posted: 2016-03-24
• Status Verified: 2018-10
• Last Update Submitted: 2018-10-16
• Last Update Posted: 2018-10-18
• Primary Completion: 2020-12
• Study Completion: 2021-12

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 60

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;

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
TCP, ATRA, Cytarabine	tranylcypromine	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
TCP, ATRA, Cytarabine	all-trans retinoic acid	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
TCP, ATRA, Cytarabine	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

Primary Outcome Measures

Name	Time	Method
MTD determination of TCP in combination with fixed-dose of ATRA and with fixed-dose Cytarabine;	first 28 days of treatment	MTD determination of TCP in combination with fixed-dose of ATRA and with fixed-dose Cytarabine;

Secondary Outcome Measures

Name	Time	Method
Objective best response	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)	12 months	Overall survival (OS)

Trial Locations

Locations (6)

Universitätsklinikum Freiburg, Medical School Freiburg; 🇩🇪 Freiburg, Germany

Universitätsklinikum Tübingen, Medical School Tuebingen; 🇩🇪 Tübingen, Tuebingen, Germany

Universitätsklinikum Heidelberg; 🇩🇪 Heidelberg, Baden-Wuerttemberg, Germany

Klinikum München rechts der Isar, Medical School Munich rechts der Isar; 🇩🇪 München, Munich, Germany

Universitätsklinik Düsseldorf, Medical School Duesseldorf; 🇩🇪 Düsseldorf, Germany

Universitätsklinikum Frankfurt Main, Medical School Frankfurt; 🇩🇪 Frankfurt Main, Germany