TRANSATRA: Study of Sensitization of Non-M3 AML Blasts to ATRA by Epigenetic Treatment With Tranylcypromine (TCP)
Study Details
Study Description
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
Condition or Disease | Intervention/Treatment | Phase |
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Phase 1/Phase 2 |
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 Design
Arms and Interventions
Arm | Intervention/Treatment |
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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:
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:
Drug: cytarabine
40mg s.c. (days 1-10)
Other Names:
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Outcome Measures
Primary Outcome Measures
- 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
- 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)
Eligibility Criteria
Criteria
Inclusion Criteria:
Patients eligible for inclusion in this trial must meet all of the following criteria:
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Patients >18 years (no upper age limit);
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AML (WHO) or intermediate or higher risk MDS/ Chronic Myelomonocytic Leukemia (CMML) (IPSS-R >3.0);
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No standard treatment available (comorbidities, higher age, refractoriness to standard or salvage chemotherapy and allografting, azanucleosides failure*);
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Patients with < 30.000 leukocytes/µl;
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Eastern Cooperative Oncology Group (ECOG) 0,1,2;
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Written informed consent obtained according to international guidelines and local laws;
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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:
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Acute promyelocytic leukemia (APL, French-American-British classification system (FAB) M3);
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Eligibility for standard induction or consolidation chemotherapy, immediate allografting, or a hypomethylating agent;
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AML with central nervous system (CNS) involvement;
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AraC treatment within one month prior to registration;
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Prior exposure to histone deacetylase inhibitors, including sodium valproate within one month prior to registration;
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Stem cell transplant patient with graft-versus-host disease (GvHD) or under systemic immunosuppression;
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Previous gastrointestinal surgery that might interfere with drug absorption;
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Pheochromocytoma;
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Carcinoid tumor;
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Confirmed or suspected cerebrovascular disease;
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Vascular malformations including aneurysm;
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Severe renal insufficiency;
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Severe or poorly controlled hypertension;
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Severe cardiovascular disease;
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Hepatic insufficiency/liver disease;
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Porphyria;
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Diabetes insipidus;
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History or presence of malignant hyperthermia;
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Known psychiatric disorders;
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Known allergy against soy beans or peanuts;
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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));
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Simultaneous intake of the prohibited medication, incl. linezolid, that is likely to cause interactions (see detailed list study protocol);
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Patients who refuse to follow study-specific dietary guidelines;
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Known or persistent abuse of medication, drugs or alcohol;
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Current or planned pregnancy, nursing period;
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Failure to use safe methods of contraception;
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Simultaneous participation in other interventional trials which could interfere with this trial and/or participation before the end of a required restriction period;
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Participation in a clinical trial within the last 30 days before the start of this trial
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Persons who are in a relationship of dependence/employment with the sponsor or the investigator;
Contacts and Locations
Locations
Site | City | State | Country | Postal Code | |
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1 | Universitätsklinikum Heidelberg | Heidelberg | Baden-Wuerttemberg | Germany | 69120 |
2 | Universitätsklinik Düsseldorf, Medical School Duesseldorf | Düsseldorf | Germany | 40225 | |
3 | Universitätsklinikum Frankfurt Main, Medical School Frankfurt | Frankfurt Main | Germany | 60590 | |
4 | Universitätsklinikum Freiburg, Medical School Freiburg | Freiburg | Germany | 79106 | |
5 | Klinikum München rechts der Isar, Medical School Munich rechts der Isar | München, Munich | Germany | 81675 | |
6 | Universitätsklinikum Tübingen, Medical School Tuebingen | Tübingen, Tuebingen | Germany | 72076 |
Sponsors and Collaborators
- Michael Luebbert
- University Hospital Freiburg
Investigators
- Principal Investigator: Michael Lübbert, MD, Prof., Medical Center - University of Freiburg
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- 00806 UKF