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

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)

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 Overview

• Status: Unknown
• Conditions: Acute Myeloid Leukemia; Myelodysplastic Syndrome
• Intervention / Treatment: Drug: tranylcypromine; Drug: all-trans retinoic acid; Drug: cytarabine

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 Type: Interventional
• Enrollment (Anticipated): 60
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Michael Lübbert, MD, Prof.; Phone Number: 35340 +49 761 270; Email: michael.luebbert@uniklinik-freiburg.de
• Study Contact Backup: Name: Alexandra Schulz, MSc; Phone Number: 36710 +49 761 270; Email: alexandra.schulz@uniklinik-freiburg.de

Study Locations

• Germany
  • Düsseldorf, Germany, 40225
    • Recruiting
    • Universitätsklinik Düsseldorf, Medical School Duesseldorf
    • Contact: Andrea Kündgen, MD, PD Dr.; Phone Number: 6338 +49 211 811; Email: kuendgen@med.uni-duesseldorf.de
    • Contact: Ulrike Spiegelberg; Phone Number: 7714 +49 211 811; Email: spiegelberg@med.uni-duesseldorf.de
    • Principal Investigator: Andrea Kündgen, MD, PD Dr.
    • Sub-Investigator: Ulrich Germing, MD, Prof.
  • Frankfurt Main, Germany, 60590
    • Recruiting
    • Universitätsklinikum Frankfurt Main, Medical School Frankfurt
    • Contact: Tobias Berg, MD, Dr.; Phone Number: 84004 +49 69 6301; Email: tobias.berg@kgu.de
    • Contact: Gesine Bug, MD, PD Dr.; Phone Number: 7369 +49 69 6301; Email: gesine.bug@kgu.de
    • Principal Investigator: Tobias Berg, MD, Dr.
    • Sub-Investigator: Gesine Bug, MD, PD Dr.
  • Freiburg, Germany, 79106
    • Recruiting
    • Universitätsklinikum Freiburg, Medical School Freiburg
    • Contact: Michael Lübbert, MD, Prof.; Phone Number: 35340 +49 761 270; Email: michael.luebbert@uniklinik-freiburg.de
    • Contact: Alexandra Schulz, MSc; Phone Number: 36710 +49 761 270; Email: alexandra.schulz@uniklinik-freiburg.de
    • Sub-Investigator: Ralph Wäsch, MD, Prof.
  • München, Munich, Germany, 81675
    • Recruiting
    • Klinikum München rechts der Isar, Medical School Munich rechts der Isar
    • Contact: Katharina Götze, MD, Prof.; Phone Number: 5618 +49 89 4140; Email: katharina.goetze@mri.tum.de
    • Contact: Sandra Eckert; Phone Number: 5637 +49 89 4140; Email: sandra.eckert@mri.tum.de
    • Principal Investigator: Katharina Götze, MD, Prof.
    • Sub-Investigator: Mareike Verbeek, MD, Dr.
  • Tübingen, Tuebingen, Germany, 72076
    • Recruiting
    • Universitätsklinikum Tübingen, Medical School Tuebingen
    • Contact: Helmut R Salih, MD, Prof.; Phone Number: 83275 +49 7071 29; Email: helmut.salih@med.uni-tuebingen.de
    • Contact: Heinz Schwarz, SN; Phone Number: 82883 +49 7071 29; Email: heinz.schwarz@med.uni-tuebingen.de
    • Principal Investigator: Helmut R Salih, MD, Prof.
    • Sub-Investigator: Marcus M Schittenhelm, MD, Dr.
  • Baden-Wuerttemberg
    • Heidelberg, Baden-Wuerttemberg, Germany, 69120
      • Recruiting
      • Universitätsklinikum Heidelberg
      • Contact: Alwin Krämer, MD, Prof.; Phone Number: 5637750 +49 6221; Email: a.kraemer@Dkfz-Heidelberg.de
      • Contact: Anne-Marie Geueke; Phone Number: 568006 +49 6221; Email: anne-marie.geueke@med.uni-heidelberg.de
      • Principal Investigator: Alwin Krämer, MD,Prof.
      • Sub-Investigator: Tilmann Bochtler, MD,PD Dr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: TCP, ATRA, 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

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); Other Names: TCP; Jatrosom®; Drug: 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; Other Names: ATRA; Vesanoid®; Drug: cytarabine; 40mg s.c. (days 1-10); Other Names: AraC; Alexan®

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
Overall survival (OS)	Overall survival (OS)	12 months

Collaborators and Investigators

• Sponsor: Michael Luebbert
• Collaborators: University Hospital Freiburg
• Investigators: Principal Investigator: Michael Lübbert, MD, Prof., Medical Center - University Of Freiburg

Study record dates

Study Major Dates

• Study Start: May 1, 2015
• Primary Completion (Anticipated): December 1, 2020
• Study Completion (Anticipated): December 1, 2021

Study Registration Dates

• First Submitted: February 4, 2016
• First Submitted That Met QC Criteria: March 18, 2016
• First Posted (Estimate): March 24, 2016

Study Record Updates

• Last Update Posted (Actual): October 18, 2018
• Last Update Submitted That Met QC Criteria: October 16, 2018
• Last Verified: October 1, 2018

More Information

Terms related to this study

• Keywords: AML; MDS; relapsed; refractory; LSD1; epigenetic treatment; trans-retinoic acid ATRA; non-M3 AML blasts; tranylcypromine TCP
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Bone Marrow Diseases; Hematologic Diseases; Myelodysplastic Syndromes; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Central Nervous System Depressants; Antiviral Agents; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Dermatologic Agents; Tranquilizing Agents; Psychotropic Drugs; Antidepressive Agents; Anti-Anxiety Agents; Keratolytic Agents; Monoamine Oxidase Inhibitors; Cytarabine; Tretinoin; Tranylcypromine
• Other Study ID Numbers: 00806 UKF

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No