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

NCT02717884 | Unknown Phase 1 DMC

• 1 other identifier: 00806 UKF
• Study Type: interventional
• Target: 60
• Locations: 1 country
• Sites: 6

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

Conditions

Acute Myeloid Leukemia; Myelodysplastic Syndrome

Keywords

AML; MDS; relapsed; trans-retinoic acid ATRA; epigenetic treatment; non-M3 AML blasts; tranylcypromine TCP; LSD1; refractory

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (2)

• Objective best response

  through study completion, an average of one year

• Overall survival (OS)

  12 months

Study Arms (1)

TCP, ATRA, Cytarabine

EXPERIMENTAL

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; Drug: all-trans retinoic acid; Drug: cytarabine

Interventions

tranylcypromine DRUG

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)

Also known as: TCP, Jatrosom®

TCP, ATRA, Cytarabine

all-trans retinoic acid DRUG

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

Also known as: ATRA, Vesanoid®

TCP, ATRA, Cytarabine

cytarabine DRUG

40mg s.c. (days 1-10)

Also known as: Alexan®, AraC

TCP, ATRA, Cytarabine

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients \>18 years (no upper age limit);
• AML (WHO) or intermediate or higher risk MDS/ Chronic Myelomonocytic Leukemia (CMML) (IPSS-R \>3.0);
• No standard treatment available (comorbidities, higher age, refractoriness to standard or salvage chemotherapy and allografting, azanucleosides failure\*);
• Patients with \< 30.000 leukocytes/µl;
• Eastern Cooperative Oncology Group (ECOG) 0,1,2;
• Written informed consent obtained according to international guidelines and local laws;
• 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.

You may not qualify if:

• Patients eligible for this trial must not meet any of the following criteria:
• Acute promyelocytic leukemia (APL, French-American-British classification system (FAB) M3);
• Eligibility for standard induction or consolidation chemotherapy, immediate allografting, or a hypomethylating agent;
• AML with central nervous system (CNS) involvement;
• AraC treatment within one month prior to registration;
• Prior exposure to histone deacetylase inhibitors, including sodium valproate within one month prior to registration;
• Stem cell transplant patient with graft-versus-host disease (GvHD) or under systemic immunosuppression;
• Previous gastrointestinal surgery that might interfere with drug absorption;
• Pheochromocytoma;
• Carcinoid tumor;
• Confirmed or suspected cerebrovascular disease;
• Vascular malformations including aneurysm;
• Severe renal insufficiency;
• Severe or poorly controlled hypertension;
• Severe cardiovascular disease;

Sponsors & Collaborators

• Michael Luebbert: lead
• University Hospital Freiburg: collaborator

Study Sites (6)

Universitätsklinikum Heidelberg

Heidelberg, Baden-Wurttemberg, 69120, Germany

RECRUITING

Universitätsklinik Düsseldorf, Medical School Duesseldorf

Düsseldorf, 40225, Germany

RECRUITING

Universitätsklinikum Frankfurt Main, Medical School Frankfurt

Frankfurt am Main, 60590, Germany

RECRUITING

Universitätsklinikum Freiburg, Medical School Freiburg

Freiburg im Breisgau, 79106, Germany

RECRUITING

Klinikum München rechts der Isar, Medical School Munich rechts der Isar

München, Munich, 81675, Germany

RECRUITING

Universitätsklinikum Tübingen, Medical School Tuebingen

Tübingen, Tuebingen, 72076, Germany

RECRUITING

MeSH Terms

Conditions

Leukemia, Myeloid, Acute; Myelodysplastic Syndromes; Recurrence

Interventions

Tranylcypromine; Tretinoin; Cytarabine

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Bone Marrow Diseases; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Propylamines; Amines; Organic Chemicals; Vitamin A; Retinoids; Carotenoids; Polyenes; Alkenes; Hydrocarbons, Acyclic; Hydrocarbons; Cyclohexenes; Cyclohexanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Terpenes; Diterpenes; Pigments, Biological; Biological Factors; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Arabinonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides

Study Officials

• Michael Lübbert, MD, Prof.

  Medical Center - University of Freiburg

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Michael Lübbert, MD, Prof.

CONTACT

+49 761 270; michael.luebbert@uniklinik-freiburg.de

Alexandra Schulz, MSc

CONTACT

+49 761 270; alexandra.schulz@uniklinik-freiburg.de

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Prof. Dr. med.

Study Record Dates

• First Submitted: February 4, 2016
• First Posted: March 24, 2016
• Study Start: May 1, 2015
• Primary Completion: December 1, 2020
• Study Completion: December 1, 2021
• Last Updated: October 18, 2018

Record last verified: 2018-10

Data Sharing

• IPD Sharing: Will not share

Locations

DE (6)