| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Chronic Myeloid Leukaemia - Chronic Phase |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 | 20.1 |
| 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) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 |
| 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) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10009014 |
| E.1.2 | Term | Chronic myeloid leukaemia (in remission) |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10009014 |
| E.1.2 | Term | Chronic myeloid leukaemia (in remission) |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10060369 |
| E.1.2 | Term | Chronic myeloid leukaemia without mention of remission |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10052065 |
| E.1.2 | Term | Chronic phase chronic myeloid leukaemia |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 |
| To assess whether asciminib (40mg, 4 times a day) plus imatinib or asciminib (60mg, 4 times a day) plus imatinib is more effective than continued treatment with imatinib in CML patients that have not achieved a Deep Molecular Response. |
|
| E.2.2 | Secondary objectives of the trial |
To estimate the efficacy of a switch to nilotinib:
To estimate the difference in efficacy betwen asciminib 60mg plus imatinib and a switch to nilotinib
To estimate the difference in efficacy between asciminib 40mg plus imatinib and a switch to nilotinib
To assess additional parameters of the efficacy of:
- asciminib 60 mg added to imatinib vs continued imatinib or switch to nilotinib
- asciminib 40 mg added to imatinib vs continued imatinib or switch to nilotinib
To characterize the safety and tolerability profile of asciminib 60 mg or 40 mg + imatinib vs continued imatinib or switch to nilotinib
To assess the pharmacokinetic profile of asciminib 60mg or 40 mg and imatinib when administered in combination
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Signed informed consent must be obtained prior to participation in the study.
2. Male or female patients ≥ 18 years of age with a confirmed diagnosis of CML-CP defined as:
- < 15% blasts in peripheral blood and bone marrow
- < 30% blasts plus promyelocytes in peripheral blood and bone marrow
- < 20% basophils in the peripheral blood
- ≥ 100 x 109/L (≥ 100 000/mm3) platelets
- No evidence of extramedullary leukemic involvement, with the exception of hepatosplenomegaly
3. Minimum of two years (24 calendar months) treatment with imatinib first line for CMLCP (patients have to be on imatinib 400 mg QD at randomization and had no dose change in the past three months).
4. BCR-ABL1 levels > 0.01% IS and ≤ 1% IS at the time of study entry as confirmed with a central assessment at screening; patients must not have achieved deep molecular response (MRe4 IS) at any time during prior imatinib treatment.
5. Patient must meet the following laboratory values before randomization:
- Absolute Neutrophil Count ≥ 1.5 x 109/L
- Platelets ≥ 75 x 109/L
- Hemoglobin (Hgb) ≥ 9 g/dL
- Serum creatinine < 1.5 mg/dL
- Total bilirubin ≤ 1.5 x ULN except for patients with Gilbert’s syndrome who may only be included with total bilirubin ≤ 3.0 x ULN
- Aspartate transaminase (AST) ≤ 3.0 x ULN
- Alanine transaminase (ALT) ≤ 3.0 x ULN
- Alkaline phosphatase ≤ 2.5 x ULN
6. Patients must have the following laboratory values (≥ LLN) or corrected to within normal limits with supplements prior to randomization: potassium, magnesium, phosphorus, total calcium (corrected for serum albumin).
|
|
| E.4 | Principal exclusion criteria |
1. Treatment failure according to European Leukemia Network criteria during imatinib treatment.
- after 3 months of treatment no Complete Hematologic Response (CHR) and/or Ph+ > 95%
- after 6 months of treatment BCR-ABL1 > 10% and/or Ph+ > 35%
- after 12 months of treatment BCR-ABL1 > 1% and/or Ph+ > 0
- at any time loss of CHR, loss of CCyR, confirmed loss of MMR, mutations, clonal chromosomal abnormalities in Ph+ cells (CCA/Ph+)
2. Known second chronic phase of CML after previous progression to AP/BC.
3. Previous treatment with any TKIs other than imatinib.
4. History or current diagnosis of ECG abnormalities indicating significant risk or safety for subjects participating in the study such as:
a. History of myocardial infarction (MI), angina pectoris, coronary artery bypass graft (CABG) within 6 months prior to randomization
b. Concomitant clinically significant arrhythmias, e.g. sustained ventricular tachycardia, and clinically significant second or third degree AV block without a pacemaker
c. Resting QTcF ≥ 450 msec (male) or ≥ 460 msec (female) prior to randomization
d. Long QT syndrome, family history of idiopathic sudden death or congenital long QT syndrome, or any of the following:
i. Risk factors for Torsades de Pointes including uncorrected hypokalemia or hypomagnesemia, history of cardiac failure, or history of clinically significant/symptomatic bradycardia
ii. Concomitant medications with a "known" risk of Torsades de Pointes per qtdrugs.org that cannot be discontinued or replaced by safe alternative medication
iii. inability to determine the QTcF interval
5. Severe and/or uncontrolled concurrent medical disease that in the opinion of the investigator could cause unacceptable safety risks or compromise compliance with the protocol (e.g. uncontrolled diabetes, active or uncontrolled infection, uncontrolled clinically significant hyperlipidemia and high serum amylase).
6. History of acute pancreatitis within 1 year prior to randomization or past medical history of chronic pancreatitis.
7. History of acute or chronic liver disease.
8. History of other active malignancy within 3 years prior to randomization with the exception of basal cell skin cancer, indolent prostate cancer and carcinoma in situ treated curatively.
9. Known history of Human Immunodeficiency Virus (HIV), Hepatitis B (HBV), or Hepatitis C (HCV) infection. Testing for Hepatitis B surface antigen (HBsAg) and Hepatitis B core antibody (HBcAb) will be performed at study entry.
10. Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of study drug (e.g. ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection, or gastric bypass surgery).
11. Treatment with medications that meet one of the following criteria and that cannot be discontinued or switched to a different medication at least one week prior to the start of treatment and for the duration of the study:
a. Strong inducers or inhibitors of CYP3A
b. Substrates of CYP3A4/5 with narrow therapeutic index
12. Patients must avoid consumption of grapefruit, Seville oranges or products containing the juice of each during the entire study and preferably 7 days before the first dose of study medications, due to potential CYP3A4 interaction with the study medications. Orange juice is allowed.
13. History of hypersensitivity to any of the study treatments or its excipients or to drugs of similar chemical classes.
14. Participation in a prior investigational study within 30 days prior to randomization or within 5 half- lives of the investigational product, whichever is longer.
15. Pregnant or nursing (lactating) women.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Molecular Response (MR)4.5 rate at 48 weeks |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
• - Molecular Response (MR)4.5 rate at 48 weeks
- Difference in rate of MR4.5 at 48 weeks
• - Rate of MR4.5 at 96 weeks
- Rate of MR4.5 by 48 and 96 weeks
- Sustained MR4.5 at 96 weeks
- Time to MR4.5
• Incidence and severity of adverse events, changes in laboratory
• Plasma concentrations of asciminib and imatinib when administered in
combination. PK parameters include but are not limited to Cmax, Tmax,
Cmin, AUClast and AUCtau |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
The assessments are done for each parameter according to visits
indicated in the Visit Schedule. For more details please refer to Visit
Evaluation Schedule table 8-1 and 8-2 of the protocol |
|
| 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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| 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 | 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 | Yes |
| 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 | 4 |
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 24 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Austria |
| Canada |
| Chile |
| Czech Republic |
| Denmark |
| France |
| Germany |
| Hong Kong |
| Italy |
| Japan |
| Korea, Republic of |
| Poland |
| Portugal |
| Russian Federation |
| Spain |
| Taiwan |
| United Kingdom |
| United States |
|
| 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
|
The study will end at 96 weeks (plus 30 days for the safety follow up) after the last
randomized subject received the first dose of study treatment. |
|
| 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 | 10 |
| E.8.9.1 | In the Member State concerned days | 3 |
| 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 | 10 |
| E.8.9.2 | In all countries concerned by the trial days | 26 |
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