E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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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 | 21.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10009700 |
E.1.2 | Term | CML |
E.1.2 | System Organ Class | 100000004864 |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
Reduction of BCR::ABL1 stem cells measured by quantitative genomic PCR in bone marrow after venetoclax administration. |
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E.2.2 | Secondary objectives of the trial |
• Molecular relapse free survival (RFS) with relapse defined as loss of major molecular remission (MMR), that is, an increase of the BCR::ABL1 level (IS) to > 0.1%. • Incidence of adverse events grade 1-5. • Quality of life. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Patients with diagnosis of chronic phase CML with cytogenetic confirmation of Philadelphia (Ph) chromosome 2. Ph negative cases or patients with variant translocations who are BCR::ABL1 positive in multiplex PCR are also eligible 3. Typical b2a2 and/or b3a2 BCR::ABL1 transcripts 4. Subject must be ≥ 18 years of age 5. Stored DNA from initial diagnosis (prior TKI treatment) for BCR::ABL1 breakpoint analysis 6. BCR::ABL1 transcript level according to the international scale (IS) of MR4 or better which has been confirmed three times within the past 13 months and was assessed by an IS-certified reference laboratory, such as of the University Jena , the University Mannheim, or another MR4-certified laboratory in Germany 7. At least 3 years of TKI therapy 8. Patients who failed to discontinue TKI in a prior discontinuation attempt are still eligible if they fulfill criteria 6. after retreatment with TKI 9. WHO performance status 0-2 10. Adequate end organ function as defined by: • Total bilirubin (TBL) < 3 x Upper Limit of Normal (ULN); patients with Gilbert’s syndrome may only be included if TBL ≤ 3.0 x ULN or direct bilirubin ≤ 1.5 x ULN, • Creatinine Clearance (CrCl) ≥ 30 millilitres per minute (mL/min) as calculated using Cockcroft-Gault formula, Serum lipase ≤ 1.5 x ULN. For serum lipase > ULN 1.5 x ULN, value must be considered not clinically significant and not associated with risk factors for acute pancreatitis. 11. Patients must have the following laboratory values within normal limits or corrected to within normal limits with supplements: • Potassium (potassium increase of up to 6.0 mmol/L is acceptable if associated with CrCl ≥ 90 mL/min), • Total calcium (corrected for serum albumin); (calcium increase of up to 12.5 mg/dl or 3.1 mmol/L is acceptable if associated with CrCl ≥ 90 mL/min), • Magnesium (magnesium increase of up to 3.0 mg/dL or 1.23 mmol/L if associated with CrCl ≥ 90 mL/min), • For patients with mild to moderate renal impairment (CrCl ≥ 30 mL/min and <90 mL/min) - potassium, total calcium (corrected for serum albumin) and magnesium should be within normal limits or corrected to within normal limits with supplements. 12. Women of childbearing age must use a highly effective method of contraception while using venetoclax. Women using hormonal contraceptives should also use a barrier method. 13. Negative pregnancy test in women of childbearing potential 14. Subject must voluntarily sign and date an informed consent |
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E.4 | Principal exclusion criteria |
1. Concomitant use of strong CYP3A-Inhibtors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, clarithromycin, ritonavir) is contraindicated 7 days prior to venetoclax. 2. Concomitant use of moderate CYP3A-Inhibitors (e.g., ciprofloxacin, diltiazem, erythromycin, fluconazole, verapamil) should be avoided. 3. Grapefruit products, Seville oranges, and starfruit (carambola) should be avoided during treatment with venetoclax as they contain inhibitors of CYP3A 4. Concomitant use of venetoclax with P-gp and BCRP inhibitors 5. Concomitant use of venetoclax with strong CYP3A inducers (e.g., carbamazepine, phenytoin, rifampin) or moderate CYP3A inducers (e.g., bosentan, efavirenz, etravirine, modafinil, nafcillin) should be avoided 6. Concomitant use of preparations containing St. John´s wort 7. Patients with severe renal impairment (Crea-Clearance < 30 ml/min) or on dialysis 8. Patients with severe hepatic impairment 9. Patients who are pregnant or breast feeding, or females of reproductive potential not employing an effective method of birth control. Female patients must agree to employ an effective barrier method of birth control throughout the study and for and for at least 30 days after ending venetoclax treatment 10. Known impaired cardiac function 11. Impaired gastrointestinal function or disease that may alter the absorption of study drug 12. Patients who have undergone major surgery ≤ 2 weeks prior to starting study drug or who have not recovered from side effects of such therapy 13. Active or uncontrolled infections at the time of enrolment 14. Known HIV sero-positivity or known active hepatitis B or C infection (HIV testing is not required) 15. Participation in another clinical study with other investigational drugs within 14 days prior to enrolment 16. Any medical, mental, psychological or psychiatric condition that in the opinion of the investigator would not permit the patient to complete the study or understand the patient information 17. Subject has acute leukemia 18. Subject has known active CNS involvement 19. Hypersensitivity to venetoclax or any component of the formulation |
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E.5 End points |
E.5.1 | Primary end point(s) |
Reduction of BCR::ABL1 stem cells measured by quantitative genomic PCR in bone marrow after venetoclax administration. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
month 6 and month 12 after start of Venetoclax |
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E.5.2 | Secondary end point(s) |
• Molecular relapse free survival (RFS) with relapse defined as loss of major molecular remission (MMR), that is, an increase of the BCR::ABL1 level (IS) to > 0.1%. • Incidence of adverse events grade 1-5. • Quality of life. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
• Molecular relapse free survival (RFS) with relapse defined as loss of major molecular remission (MMR), that is, an increase of the BCR::ABL1 level (IS) to > 0.1%: monthly until month 15 • Incidence of adverse events grade 1-5: monthly until month 15 • Quality of life: month 6 and 12 |
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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 | No |
E.6.7 | Pharmacodynamic | No |
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) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
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 | 2 |
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 | No |
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
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Last Visit Last Subject (at latest 15 months after start of Venetoclax-Therapy of the last recruited subject) |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 0 |
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 |