| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| relapse or refractory AML in patients unfit for an intensive treatment |
|
| E.1.1.1 | Medical condition in easily understood language |
| refrctory acute myeloid leukemia or relapse of AML in patients who cannot tolerate an intensive chemotherapy |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 17.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10000886 |
| E.1.2 | Term | Acute myeloid leukemia |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| Analysis of the cumulative response rate (CR, CRp, CRi, PR) of all AML patients |
|
| E.2.2 | Secondary objectives of the trial |
• To assess the safety and tolerability of repeated oral administration of Tretinoin and Tranylcypromin to patients with AML.
• To assess the cumulative incidence and degree of histone methylation of promotor genes in AML blasts after treatment with Tretinoin and tranylcylpromine, and correlation with clinical reponse.
• To compare in vivo treatment effects onto histone methylation levels and differentiation with TCP/ATRA effects in AML blasts exposed in vitro.
• To assess overall survival (OS) in relationship to historical control patients
• To determine the duration of response
• Identification of molecular biomarkers that determine response to TCP/ATRA
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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. Patients can be included with histologically or cytologically confirmed diagnosis of AML (except AML M3/ APL) in presence of relapsed after or refractory disease after at least one therapy regimen. Relapsed or refractory patients can be included into the clinical trial when no response to other therapy options can be expected or when intensive therapy in these patients cannot be administered. ,
3. Age ≥ 18 years
4. Eastern Cooperative Oncology Group (ECOG) performance status of ≤3 (see Appendix, 3.2)
5. Measurable disease burden (blasts in BM and/or 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
ATRA has teratogenic potential if taken during therapy with ATRA and one months after end of treatment. Therefore an effective contraception is necessary to prevent teratology. Pregnancy tests will performed at screening and every 28 days. Only female are eligible to enter and participate in this study if she is of a) non-childbearing potential (i.e., physiologically incapable of becoming pregnant), including any female who has had a hysterectomy, a bilateral oophorectomy (ovariectomy), a bilateral tubal ligation, or who is post-menopausal. Subjects not using hormone replacement therapy (HRT) must have experienced total cessation of menses for ≥1 year and be greater than 45 years in age, OR, in questionable cases, have a follicle stimulating hormone (FSH) value >40 mIU/mL and an estradiol value <40 pg/mL (<140 pmol/L). For most forms of HRT, at least 2 to 4 weeks must elapse between the cessation of HRT and determination of menopausal status; length of this interval depends on the type and dosage of HRT. If a female subject is determined not to be post-menopausal, she must use adequate contraception, as defined immediately below. A female is also eligible to enter and participate in this study if she is of b) childbearing potential, including any female who has had a negative serum pregnancy test within one week prior to the first dose of study treatment, preferably as close to the first dose as possible and agrees to use adequate contraception. Acceptable contraceptive methods, when used consistently and in accordance with both the product label and the instructions of the physician, are an intrauterine device with a documented failure rate of less than 1% per year, vasectomised partner who is sterile prior to the female subject’s entry and is the sole sexual partner for that female, complete abstinence from sexual intercourse for 14 days before exposure to study medication through the dosing period and for at least 28 days after the last dose of study medication, barrier contraception (condom with spermicidal jelly, foam suppository, or film; diaphragm with spermicide; or male condom and diaphragm with spermicide),or oral contraceptives ((mini-pill is not a save contraception method and should be avoid). .
Female subjects who are lactating must discontinue nursing prior to the first dose of study drug and should refrain from nursing throughout the treatment period and for 28 days following the last dose of study drug.
A male with a female partner of childbearing potential is eligible to enter and participate in the study if he uses a barrier method of contraception (condom with spermicidal jelly, foam suppository, or film; diaphragm with spermicide; or male condom and diaphragm with spermicide) or abstinence during the study.
Patients who reject contraceptive methods are not allowed to take part in this study.
9. Adequate organ function |
|
| E.4 | Principal 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 immunsuppressive agents for at least 2 weeks prior to study entry and Graft- versus host disease must have resolved to Grade <= 2)
3. Patients with other available therapy options that are likely to induce remission or to prolong patients´ lives.
4. Acute promyelocytic leukemia (APL)
5. History of cancer that according to the Investigator might confound the assessment of the endpoints of the study
6. 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)
7. Poorly controlled hypertension (defined as systolic blood pressure (SBP) of ≥140 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 values from each BP asessment must be <140/90 mmHg in order for a subject to be eligible for he study.
8. Prolongation of corrected QT interval (QTc) > 480 ms
9. 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 III or IV congestive heart failure, as defined by the New York Heart Association (NYHA)
10. Left ventricular ejection fraction (LVEF) at least 40% by multiple gated acquisition (MUGA) scan or echocardiogram (ECHO)
11. 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
12. 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.
13. Prior major surgery or trauma within 28 days prior to first dose of study drug
14. Treatment with an investigational agent within 21 days or 5 half-lifes, whichever is longer prior to the first dose of study drug.
15. Concurrent cytoreductive chemotherapy except hydroxyurea.
16. Known immediate or delayed hypertensitivity reaction or idiosyncrasy to Tretinoin, Retinoide, vitamin A, soya, peanuts or Tranylcypromine.
17. Patients with psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol
18. Patients with known epilepsy or patients with known psychiatric affections (bipolar disorder, schizophrenia, suicidal patients)
19. Pregnant or lactating and actively breastfeeding patients. Patients unwilling to use effective contraception methods (s. 5.2.1; 8.) cannot take part in this study.
20. Patients who are indignant to comply with nutritional conditions (see Protocol)
21. Poorly adjusted diabetes mellitus
22. Patients with hereditary Galaktose-Intolerance, Lactase-Intolerance or Glucose-Galactose-Malabsorption, Fructose- Intolerance
23. Known drug or alcohol abuse
24. Phaeochromocytoma or carcinoid tumor
25. Known cerebral vascular disease or other malformation of vessels (e.g. aneurysma)
26. Diabetes insipidus
27. hyperthyreodism or other diseases with risk for hypertensive crisis
28. Patients taking any of the following prohibited medication due to interaction with a) tretinoin and b) TCP.
a) Tretinoin Vitamine A,
Tetracycline,
Medication inducing P450 enzymes: rifampicine, glucocorticoid, Phenobarbital
Medication inhibiting P450 enzymes: Ketoconazol, erythromycine, azole, cimetidine, verapamil, diltiazem, ciclosporine, all-trans-retinoic acid
Antifibrinolytics (Tranexamacid, Aminocapronacid or Aprotinin)
b) TCP Concurrent medication with serotonin reuptake inhibitors SSRI is prohibited regarding the risk of serotonin syndrome (10 days up to after TCP treatment):
• Fluoxetin
• Paroxetin
• Fluvoxamin
• Clomipramin
• Venlafaxin
Concurrent medication with other serotoninerg is prohibited (risk of hypertensive crisis and serotonin syndrome):
• Sumatriptane and other triptanes
• Buspirone
• Imipramine
• Amphetamine
• Indirect Sympathomimetc drugs drugs
Further concurrent drugs are prohibited:
• L-Tryptophane (risk of delirium)
• Disulfiram (unknown interaction)
• Pethidine, Tramadol, Dextromorphane (risk of circulatory and respiratory instability)
• ether
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Analysis of the cumulative response rate (CR, CRp, CRi, PR) of all AML patients. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| after each cycle, each cycle consists of 28 days |
|
| E.5.2 | Secondary end point(s) |
• To assess the safety and tolerability of repeated oral administration of Tretinoin and Tranylcypromin to patients with AML.
• To assess the cumulative incidence and degree of histone methylation of promotor genes in AML blasts after treatment with Tretinoin and tranylcylpromine, and correlation with clinical reponse.
• To compare in vivo treatment effects onto histone methylation levels and differentiation with TCP/ATRA effects in AML blasts exposed in vitro.
• To assess overall survival (OS) in relationship to historical control patients
• To determine the duration of response
• Identification of molecular biomarkers that determine response to TCP/ATRA
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| after each cycle, each cycle consists of 28 days |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| first administration of tranylcypromine in AML |
|
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
end of the trial is defindes as the time point the data bank is locked.
Justification for this definition: study- specific documentation has to be completed until this time- point. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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