VARIANT: Venetoclax After TKI to Target Persisting Stem Cells in CML
Study Details
Study Description
Brief Summary
There is currently no available treatment, capable to increase the rate of sustained deep molecular remissions after TKI discontinuation in CML. Venetoclax could be such a drug. The study will provide unprecedented biological insights on the effects of venetoclax in controlling minimal residual stem cell disease induced by long-term prior TKI therapy. If the study would be positive, the findings could become practice changing for patients in deep molecular remission under TKI and willing to tolerate a temporary additional treatment.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 2 |
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Venetoclax Venetoclax will be taken orally once daily (400 mg) for 12 months after stop of TKI |
Drug: Venetoclax
Venetoclax will be taken orally once daily (400 mg) for 12 months
|
Outcome Measures
Primary Outcome Measures
- stem cell change [at 6 months and 12 months after start of Venetoclax]
Reduction of BCR::ABL1 stem cells measured by quantitative genomic PCR in bone marrow after venetoclax administration.
Secondary Outcome Measures
- European Organisation for Research and Treatment of Cancer - Quality of Life C30 - Questionnaire [at 6 months and 12 months after start of Venetoclax]
compared to baseline with EORTC-QLQ C30 - Questionnaire (Score from 1 to 4; 1 better, 4 worse)
- Kinetics of BCR::ABL1-transcript expression [monthly after start of Venetoclax until month 12]
Kinetics of typical BCR::ABL1 transcript level over time after Tyrosine kinase stop
- Overall survival (OS) [monthly after start of Venetoclax until month 12]
defined as the time between the date of enrollment and the date of death from any cause.
Eligibility Criteria
Criteria
Inclusion Criteria:
-
Patients with diagnosis of chronic phase CML with cytogenetic confirmation of Philadelphia (Ph) chromosome
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Ph negative cases or patients with variant translocations who are BCR::ABL1 positive in multiplex PCR are also eligible
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Typical b2a2 and/or b3a2 BCR::ABL1 transcripts
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Subject must be ≥ 18 years of age
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Stored DNA from initial diagnosis (prior TKI treatment) for BCR::ABL1 breakpoint analysis
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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
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At least 3 years of TKI therapy
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Patients who failed to discontinue TKI in a prior discontinuation attempt are still eligible if they fulfill criteria 6. after retreatment with TKI
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WHO performance status 0-2
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Laboratory assessments within normal limits
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Aspartate transaminase (AST) and alanine transaminase (ALT) < 3.0X ULN
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Bilirubin ≤1.5 x ULN (unless bilirubin rise is due to Gilbert's syndrome or of non-hepatic origin)
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Subject must have adequate renal function as demonstrated by a creatinine clearance ≥ 30 mL/min; calculated by the Cockcroft Gault formula or measured by 24 hours urine collection
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Patients with reproductive potential agree to use effective contraceptive measures throughout the study
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Negative pregnancy test in women of childbearing potential
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Subject must voluntarily sign and date an informed consent
Exclusion Criteria:
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Concomitant use of strong CYP3A-Inhibtors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, clarithromycin, ritonavir) is contraindicated 7 days prior to venetoclax.
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Concomitant use of moderate CYP3A-Inhibitors (e.g., ciprofloxacin, diltiazem, erythromycin, fluconazole, verapamil) should be avoided.
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Grapefruit products, Seville oranges, and starfruit (carambola) should be avoided during treatment with venetoclax as they contain inhibitors of CYP3A
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Concomitant use of venetoclax with P-gp and BCRP inhibitors
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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
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Patients with severe renal impairment (Crea-Clearance < 30 ml/min) or on dialysis
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Patients with severe hepatic impairment
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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
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Known impaired cardiac function
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Impaired gastrointestinal function or disease that may alter the absorption of study drug
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Patients who have undergone major surgery ≤ 2 weeks prior to starting study drug or who have not recovered from side effects of such therapy
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Active or uncontrolled infections at the time of enrolment
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Known HIV sero-positivity or known active hepatitis B or C infection (HIV testing is not required)
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Participation in another clinical study with other investigational drugs within 14 days prior to enrolment
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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
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Subject has acute leukemia
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Subject has known active CNS involvement
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Universitätsklinikum Jena | Jena | Germany | 07747 |
Sponsors and Collaborators
- Thomas Ernst, PD Dr. med.
- Ludwig-Maximilians - University of Munich
- AbbVie
Investigators
- Principal Investigator: Thomas Ernst, Prof. Dr., University Hospital Jena
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- VARIANT
- 2022-003069-39