| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Chronic myeloid leukaemia |
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| E.1.1.1 | Medical condition in easily understood language |
| Chronic myeloid leukaemia |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10009013 |
| E.1.2 | Term | Chronic myeloid leukaemia |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| 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 |
The trial will investigate whether a novel agent can be combined with TKI to improve treatment response, as measured by BCR-ABL1 transcript levels (the abnormal gene which causes CML) on the International Scale (IS) in chronic and accelerated phase chronic myeloid leukaemia.
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| E.2.2 | Secondary objectives of the trial |
-To determine the toxicity, safety and tolerability of the combination of TKI plus a novel agent in the experimental arms
- To determine durability of improvement in BCR-ABL1 mRNA level in responding patients in chronic and accelerated phase CML.
-To determine the rate of haematological improvement by 32 weeks.
- To determine the rate of (CyR) improvement by 32 weeks.
- To determine the rate of molecular improvement by 32 weeks (BCR-ABL <10%, < 1%, <0.1% and < 0.01%)
- To investigate drug-drug interactions by measuring levels of TKI and novel agents (i.e. PK).
-To estimate overall patient survival,event-free survival and relapse free survival.
- To estimate time to haematological, cytogenetic and molecular response.
- To estimate the time to molecular, cytogenetic or haematological relapse and to progression to accelerated or blast phase.
- To evaluate quality of life using MDASI-CML and EQ5D.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
There are separate inclusion criteria's for each phase of disease. The principal inclusion criteria are noted below:
Chronic Phase
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 stable 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/3rd generation TKI or >1% and/or Ph >0% by 12 months of taking 2nd/3rd generation TKI. Patients entering TASTER on imatinib need to meet the above definition for failure of 2nd/3rd generation TKI and/or be intolerant to 2nd/3rd generation TKI, and have ELN failure on imatinib.
7.Patients with ECOG grade 0 to 2.
8.Patients require to have adequate renal function defined as calculated creatinine clearance > 40ml/min.
9.Adequate haematological and biochemical function
10.Willingness to comply with scheduled visits, treatment plans and laboratory tests and other trial procedures.
11.Ability to swallow oral medications
12.Females of childbearing potential must have a negative pregnancy test within 7 days prior to randomisation and agree to use highly effective contraceptive measures from the time of negative pregnancy test up to 90 days after the last dose of study drug.
13.Male patients with partners of child-bearing potential must agree to use highly effective contraceptive measures for the duration of the study and up to 90 days after the last dose of study drug.
Accelerated Phase
1.Patient aged >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:
•Blasts in blood or marrow 15-29%, or blasts plus promyelocytes in blood or
marrow >30%, with blasts <30%
•Basophils in blood ≥20%
•Persistent thrombocytopenia (<100x109/L) unrelated to therapy
•Clonal chromosome abnormalities in Ph+ cells (CCA/Ph+), major route, on
treatment
4.Treatment with > one 2nd (nilotinib, dasatinib or bosutinib) or 3rd generation (ponatinib) TKI, or imatinib after failure or intolerance to 2nd/3rd generation TKI, on stable TKI for period of > 3 months.
5.No switch between TKIs within the last 3 months.
6.Failure in accelerated phase defined as BCR-ABL level on IS of >10% and/or Ph>65% at 3 months, >10% or Ph >35% at > 6 months or >1% and/or Ph >0% by 12 months of taking 2nd/3rd generation TKI. Patients entering TASTER on imatinib need to meet the above definition for failure of 2nd/3rd generation TKI and/or be intolerant to 2nd/3rd generation TKI, and have ELN failure on imatinib
7.Patients with ECOG grade 0 to 2.
8.Patients require to have adequate renal function defined as calculated creatinine clearance > 40ml/min.
9.Adequate haematological and biochemical function
10.Willingness to comply with scheduled visits, treatment plans and laboratory tests and other trial procedures.
11.Ability to swallow oral medications
12.Females of childbearing potential must have a negative pregnancy test within 7 days prior to randomisation and agree to use highly effective contraceptive measures from the time of negative pregnancy test up to 90 days after the last dose of study drug.
13.Male patients with partners of child-bearing potential must agree to use highly effective contraceptive measures for the duration of the study and up to 90 days after the last dose of study drug.
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| E.4 | Principal exclusion criteria |
There are separate exclusion criteria's for each phase of disease. The principal exclusion criteria are noted below:
Chronic Phase
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:
•QTc > 450 (males), 470 (females);
•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;
•Myocardial infarction within the previous 6 months;
•Symptomatic cardiac arrhythmia requiring treatment within the previous 6 months;
•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.
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 and inhibitors (including St. John’s Wort) unless stopped at least 14 days before commencing trial medication.
10.Patients unwilling to remove Seville oranges, grapefruit juice and grapefruits from their diet.
Accelerated Phase Patients
Exclusion Criteria – Accelerated 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:
•QTc > 450 (males), 470 (females);
•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;
•Myocardial infarction within the previous 6 months;
•Symptomatic cardiac arrhythmia requiring treatment within the previous 6 months;
•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.
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 and inhibitors (including St. Johns Wort) unless stopped at least 14 days before commencing trial medication
10.Patients unwilling to remove Seville oranges, grapefruit juice and grapefruits from their diet.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary outcome measure is the proportion of treatment "responders" defined as patients who achieve a ≥ 0.5 log reduction in after 32 weeks of treatment BCR-ABL1 mRNA levels at any time during 32 weeks of treatment (by 33 weeks from baseline). |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
For all patients (chronic and accelerated phase) response is defined ≥ 0.5 log reduction in BCR-ABL1 mRNA levels at any time during 32 weeks of treatment (by 33 weeks from baseline).
All patients will have BCR-ABL1 mRNA levels measured at following time-points to measure response: Baseline, C4 WK13 (D1), C7 WK 25(D1), C9 WK 33 (D1) thereafter 12 weekly |
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| E.5.2 | Secondary end point(s) |
Secondary endpoints
- To determine the safety of a novel agent given in combination with TKI.
- Durability of improvement in BCR-ABL1 mRNA level in responding chronic and accelerated phase CML patients, assessed every 3 months until end of study.
- Rate of haematological improvement by 32 weeks.
- Rate of CyR improvement by 32 weeks.
- Rate of molecular improvement by 32 weeks (BCR-ABL <10%, <1%, <0.1%, and <0.01%).
- Drug-drug interactions by measuring levels of TKI and novel agents (i.e. PK).
- Overall patient survival, event-free survival and relapse-free survival.
- Time to haematological, cytogenetic and molecular response.
- Time to molecular, cytogenetic or haematological relapse and to progression to accelerated or blast phase .
- Evaluation of quality of life using MDASI-CML and EQ5D.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
- Safety of novel agent in combination with TKI, toxicity assessed at time-points specified in protocol using NCI CTCAE V5
-Durability of improvement in BCR-ABL1 mRNA levels assessed every 3 months from baseline.
- Overall patient survival, event-free survival and relapse free survival will be determined by time from baseline (randomisation) to each of these.
- Time to haematological, cytogenetic and molecular response will be determined by the time from baseline to each of these.
- Time to molecular, cytogenetic or haematological relapse and to progression to accelerated or blast phase will be determined by the time from baseline (randomisation) to each of these.
- Quality of life (QOL) as measured at baseline, C9 Wk33 (D1), C15 Wk61 (D1) C20 Wk81 D1 |
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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 | 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) | 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 | Yes |
| E.8.1.1 | Randomised | Yes |
| 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 | Yes |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 23 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.5.1 | Number of sites anticipated in the EEA | 23 |
| 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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| For the purpose of complying with UK Clinical Trial Regulations the trial will be considered ‘closed’ when the endpoint for the primary analysis of the final experimental arm has been reached. Follow-up of all patients will continue for a minimum of 81 weeks for the patients who respond at week 33 and continue on their study agent and for a minimum of 93 weeks for the patients who switch. |
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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 | 5 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | 28 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
| E.8.9.2 | In all countries concerned by the trial days | 28 |
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