Chronic myeloid leukaemia Cancer Chronic myeloid leukaemia [CML], BCR/ABL-positive
Conditions
Interventions
The trial will commence initially with a control arm (TKI) and 2 experimental arms (TKI + EZH2i [Tazemetostat-EPZ-6438], TKI + MDM2i [Idasanutlin –RO5503781]). The number of experimental arms will cha
Sponsors
NHS Greater Glasgow and Clyde
University of Glasgow
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Inclusion Criteria – Chronic Phase Patients: 1. Patient aged >18 years 2. Patient has given written informed consent to participate in the trial 3. Patients with Ph+, BCR ABL + Chronic Phase CML 4. Prior treatment with at least two 2nd (nilotinib, dasatinib or bosutinib) or 3rd generation (ponatinib) TKI, or imatinib after failure or intolerance to 2nd/3rd generation TKI, on same TKI for period of > 6 months 5. No switch between TKIs within the last 6 months 6. ELN failure defined as BCR-ABL level on IS of >10% and/or Ph >35% at > 6 months of taking 2nd or subsequent line of TKI therapy or >1% and/or Ph >0% by 12 months of taking 2nd or subsequent line of TKI therapy. Patients entering TASTER on imatinib need to meet the above definition for failure of 2nd or subsequent line of TKI therapy and/or be intolerant to 2nd or subsequent line of TKI therapy, and have ELN failure on imatinib 7. Patients with ECOG grade 0 to 2 8. Patients require tohave adequate renal function defined as calculated creatinine clearance > 40ml/min per the Cockcroft and Gault formula (appendix 5) or local institutional standard formula 9. Adequate haematological and biochemical function as indicated below. These measurements must be performed within 7 days prior to randomisation: 9.1. ALT or AST 1.5 x ULN, they will require to have conjugated and unconjugated bilirubin checked, if conjugated bilirubin 1.0 x 109/l 9.5. Platelets > 100 x 109/l 9.6. WBC 18 years 2. Patient has given written informed consent to participate in the trial. 3. Patients with Ph+, BCR-ABL + Accelerated Phase CML defined as presence of one of the following: 3.1. Blasts in blood or marrow 15-29%, or blasts plus promyelocytes in blood or marrow >30%, with blasts <30% 3.2. Basophils in
Exclusion criteria
Exclusion criteria: Exclusion Criteria – Chronic Phase Patients: 1. Pregnant or lactating women 2. Females of child bearing potential or males not willing to use a highly effective method of contraception 3. Patient in planning for allogeneic SCT within 6 months 4. Patients with cardiovascular disease defined as: 4.1. QTc > 450 (males), >470 (females) 4.2. Stage II to IV congestive heart failure (CHF) as determined by the New York Heart Association (NYHA) classification system for heart failure within the previous 6 months 4.3. Myocardial infarction within the previous 6 months 4.4. Symptomatic cardiac arrhythmia requiring treatment within the previous 6 months 4.5. Grade III or IV fluid retention within the previous 6 months 5. Known BCR-ABL kinase domain mutation expected to be sensitive to an alternative TKI 6. Patients with a history of another malignancy other than non-metastatic basal cell or squamous cell carcinoma of the skin or in-situ carcinoma of the cervix; the exception is if patients have been disease-free for at least 5 years, and are deemed by the investigator to be low risk for recurrence of that malignancy. Patients with a history of breast cancer continuing on tamoxifen or an aromatase inhibitor are eligible for the study if they have been disease free for at least 5 years 7. Patients with history of T-cell lymphoblastic lymphoma (T-LBL) or T-cell acute lymphoblastic leukaemia (T –ALL) 8. Patients with thrombocytopenia, neutropenia or anaemia of grade > 3 (per CTCAE version 5.0 criteria) or any prior history of other myeloid malignancies including myelodysplastic syndrome (MDS) 9. Patients taking medications that are known strong CYP3A4 inducers (including St John’s Wort) and strong CYP3A4 inhibitors unless stopped at least 14 days before commencing trial medication. Moderate CYP3A4 inducers and inhibitors should be used with caution 10. Patients taking medications that are known strong CYP2C8 inhibitors and inducers or CYP2C8 substrates unless stopped at least 14 days before commencing trial medications. Moderate CYP2C8 inducers and inhibitors may be used with caution 11. Patients taking medications that are known UGT inhibitors and inducers unless stopped at least 14 days before commencing trial medications 12. Patients taking medications that are OATP1B1 and OATP1B3 substrates with a narrow safety window (or safety concerns) should be stopped at least 14 days before commencing trial medications. Others should be used with caution 13. Patients taking concomitant treatment with medicines listed as prohibited in section 5.3.9 for imatinib, section 5.4.8 nilotinib, section 5.5.8 dasatinib, section 5.6.8 bosutinib or section 5.7.8 ponatinib (as applicable to patient) 14. Patients unable to temporarily interrupt treatment with oral or parental anticoagulants/anti platelet agents (e.g. warfarin, chronic daily treatment with aspirin [>325 mg/day], clopidrogel, dabigatran, apixiban, rivaroxaban, or subcutaneous [SC] anticoagulant prophylaxis) during treatment phase. These agents must be stopped at least 7 days (or 5 half lifes) before commencing trial medications 15. Patients unwilling to remove Seville orang
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| The proportion of treatment ‘responders’ defined as patients who achieve a > 0.5 log reduction in BCR-ABL1 mRNA levels at any time during 32 weeks of treatment (by 33 weeks from baseline) | — |
Secondary
| Measure | Time frame |
|---|---|
| 1. Toxicities assessed according to NCI CTCAE V5.0 2. Durability of improvement in BCR-ABL1 mRNA level in responding chronic and accelerated phase CML patients, measured by levels of BCR ABL1 every 3 months from baseline until end of study 3. Rate of haematological improvement measured by standard FBC and manual differential WBC assessed monthly from baseline to 32 weeks 4. Rate of CyR improvement by 32 weeks, measured by standard cytogenetics - metaphase cytogenetics on >20 metaphases obtained from WBC in bone marrow 5. Rate of molecular improvement by 32 weeks (BCR-ABL 20.0 x 109/L, platelet count that rises to = 600 x 109/L, appearance of blasts in the peripheral blood 7.4. Increasing WBC count: for patients not achieving a CHR, haematological progression will be defined as a doubling of WBC count at least one month apart with at least the second value >20.0 x 109/L 7.5. Loss of major cytogenetic response (MCR): for patients that were in MCR at study entry; loss of MCR will be defined as an increase in the Ph+ bone marrow cells by at least 30 percentage points (e.g., from 20% to 50%, or from 30% to 60%) confirmed by a second cytogenetic analysis =1 month later 8. Time to haematological, cytogenetic and molecular response will be determined by the time from baseline (randomisation) to each of haematological, cytogenetic and molecular response. 9. Time to molecular, cytogenetic or haematological relapse and to progression to accelerated or blast phase and to progression to accelerated or blast phase will be determined by the time from baseline (randomisation) to each of molecular, cytogenetic or haematological relapse, and progression. 10. Quality of life measured using MDASI-CML and EQ5D at baseline, C9 D1, C16 D1 and C20 D1 | — |
Countries
England, Scotland, United Kingdom
Contacts
Public ContactKaren Carty
Outcome results
None listed