Phase I/II Trial of ATRA and TCP in Patients With Relapsed or Refractory AML and no Intensive Treatment is Possible

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Brief Title

Phase I/II Trial of ATRA and TCP in Patients With Relapsed or Refractory AML and no Intensive Treatment is Possible

Official Title

Phase I/II Pilot Trial of ATRA (Tretinoin) and TCP (Tranylcypromine) in Patients With Relapsed or Refractory Acute Myeloid Leukemia (AML) and no Intensive Treatment is Possible

Brief Summary

      Longterm disease-free survival (DFS) of older patients with acute myeloid leukemia (AML)
      remains poor. The vast majority of AML patients relapses within two years after start of
      therapy1,2. In Acute Promyelocytic Leukemia (APL, AML M3), all-trans-retinoic-acid (ATRA;
      Tretinoin) induces differentiation and subsequently clinical remission. So far effective
      differentiation therapy does not exist in other AML subtypes. Recent preclinical data suggest
      that the combinatorial use of ATRA and tranylcypromine (TCP), an irreversible
      Monoamine-Oxidase (MAO) and Lysin-specific demethylase (LSD) inhibitor that also inhibits
      LSD1 (a histone H3 Lysine 4 demethylase), induces leukemia cell differentiation and leukemic
      stem cell exhaustion in vitro and in vivo in non-APL AML subtypes.

      In this Phase I/II study the investigators will explore the feasibility, safety, as well as
      efficacy and of Tretinoin/TCP treatment in patients with relapsed or refractory AML or in
      patients with AML who are not eligible for intensive treatment. Patients will be treated with
      daily increasing doses of TCP (initially 10 mg/day, then +10 mg each day up to 80mg/d). After
      7 days, ATRA will be added at a fixed dose (45 mg/sqm/day). Overall, 16 evaluable patients
      are going to be treated. The primary endpoint is the fraction of patients that achieve CR,
      CRp( complete response with incomplete recovery of platelets), CRi (complete response with
      incomplete recovery of granulocytes) and PR. Secondary endpoints are tolerability, safety as
      well as progression-free survival and overall survival. Serum levels of TCP will be regularly
      analyzed. Pharmacodynamic analyses will be performed with analyses of the inhibition of LSD1
      by TCP. Further analyses will address the changes in Histone H3 lysine 4 tri demethylase
      (H3K4me3) levels in AML blasts and the differentiation status of AML blasts.

      Taken together, this Phase I/II study will analyze feasibility, pharmacodynamics and
      effectivity of ATRA and TCP as differentiation therapy in AML.
    


Study Phase

Phase 1/Phase 2

Study Type

Interventional


Primary Outcome

Analysis of the cumulative response rate (CR,CRp, CRi, PR)

Secondary Outcome

 number of participants with adverse events as a measure of safety and tolerability

Condition

AML

Intervention

Tranylcypromine

Study Arms / Comparison Groups

 Tretinoin & Tranylcypromine
Description:  Tretinoin started with 45mg/m2 on day 7 for one year, administered orally as soft capsules, Tranylcypromine started with 10mg/d up to a maximum dose of 60mg/d for on year, administered orally as tablets

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

16

Start Date

September 2014

Completion Date

September 2017

Primary Completion Date

September 2017

Eligibility Criteria

        Inclusion Criteria:

          1. Subjects must provide written informed consent prior to performance of study-specific
             procedures or assessments which are not routinely performed for diagnosis or
             monitoring of AML, and the subjects must be willing to comply with treatment and to
             follow up assessments and procedures

          2. Histologically or cytologically confirmed diagnosis of AML relapsed after or
             refractory to at least one induction regimen, or patients with AML at initial
             diagnosis who are not eligible for allogeneic transplant or intensive induction
             chemotherapy (investigator´s choice; for example reduced general state), except for
             AML M3 (acute promyelocytic leukemia).

          3. Age > 18 years

          4. Eastern Cooperative Oncology Group (ECOG) performance status of ≤3 (see Appendix, 3.2)

          5. Measurable disease burden (blasts in bonemarrow (BM) and/or peripheral blood (PB),
             extramedullary blasts [chloroma])

          6. Able to swallow and retain oral medication

          7. A life expectancy of at least 4 weeks

          8. Adequate contraception methods

          9. Adequate organ function

        Exclusion Criteria:

          1. Patients with more than 20.000/µl leukocytes in the peripheral blood that cannot be
             controlled by Hydroxyurea.

          2. Patients with a valid option for intensive chemotherapy and/ or stem cell
             transplantation. (Patients after allogeneic stem cell transplant must be off
             immunosuppressive agents for at least 2 weeks prior to study entry and Graft- versus
             host disease must have resolved to Grade <= 2)

          3. Patients with less than 30% blasts in the bone marrow at the time of diagnosis. They
             should receive Azacytidine monotherapy.

          4. History of cancer that according to the Investigator might confound the assessment of
             the endpoints of the study

          5. Uncontrolled peptic ulcer disease or clinically significant gastrointestinal
             abnormalities which interfere with oral dosing or any unstable or serious concurrent
             condition (e.g., active uncontrolled infection)

          6. Poorly controlled hypertension (defined as systolic blood pressure (SBP) of ≥170
             mmHg). Note: Initiation or adjustment of antihypertensive medication is permitted
             prior to study entry. BP must be re-assessed on two occasions that are separated by a
             minimum of 1 hour; on each of these occasions, the mean (of 3 readings) SBP/
             DBP(diastolic blood pressure) values from each BP assessment must be <140/90 mmHg in
             order for a subject to be eligible for he study.

          7. Prolongation of corrected QT interval (QTc) > 480 ms

          8. History of any one or more of the following cardiovascular conditions within the past
             6 months: cardiac angioplasty or stenting, myocardial infarction (MI), unstable
             angina, symptomatic peripheral vascular disease, class 3 or 4 congestive heart
             failure, as defined by the New York Heart Association (NYHA)

          9. Left ventricular ejection fraction (LVEF) at least 40% by multiple gated acquisition
             (MUGA) scan or echocardiogram (ECHO)

         10. History of cerebrovascular infarction or bleeding, pulmonary embolism (PE), or
             untreated deep venous thrombosis (DVT) within the past 6 months. Note: Subjects with
             recent DVT who have been treated with therapeutic anti- coagulant agents for at least
             6 weeks are eligible

         11. Evidence of serious active bleeding or bleeding diathesis (except for bleeding or
             petechiae due to AML- related thrombocytopenia which will be treated using platelet
             transfusions). Also, patients with known endobronchial lesions and/ or lesions
             infiltrating major pulmonary vessels will be excluded from the study due to excess
             risk of bleeding.

         12. Prior major surgery or trauma within 28 days prior to first dose of study drug

         13. Treatment with an investigational agent within 21 days or 5 half-life, whichever is
             longer prior to the first dose of study drug.

         14. Concurrent cytoreductive chemotherapy except hydroxyurea.

         15. Known immediate or delayed hypersensitivity reaction or idiosyncrasy to Tretinoin,
             Retinoids, soya, peanuts or Tranylcypromine.

         16. Patients with psychological, familial, sociological, or geographical conditions that
             do not permit compliance with the protocol

         17. Patients with known epilepsy or patients with known psychiatric affections (bipolar
             disorder, schizophrenia, suicidal patients)

         18. Pregnant or lactating and actively breastfeeding patients

         19. Patients who are indignant to comply with nutritional conditions (see Protocol)

         20. Poorly adjusted diabetes mellitus

         21. Patients with hereditary Galactose-Intolerance, Lactase-Intolerance or
             Glucose-Galactose-Malabsorption

         22. Known drug or alcohol abuse

         23. Phaeochromocytoma or carcinoid tumor

         24. Known cerebral vascular disease or other malformation of vessels (e.g. aneurysma)

         25. Diabetes insipidus

         26. Patients taking any of the following prohibited medication due to interaction with a)
             tretinoin and b) TCP.
      

Gender

All

Ages

18 Years - N/A

Accepts Healthy Volunteers

No

Contacts

Carsten Mueller-Tidow, Prof., +493455572924, [email protected]

Location Countries

Germany

Location Countries

Germany

Administrative Informations


NCT ID

NCT02261779

Organization ID

UKM_04_12_TCP_ATRA_AML

Secondary IDs

2012-002154-23

Responsible Party

Principal Investigator

Study Sponsor

Martin-Luther-Universität Halle-Wittenberg


Study Sponsor

Carsten Mueller-Tidow, Prof., Principal Investigator, Martin-Luther-Universität Halle-Wittenberg


Verification Date

July 2015