| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Chronic Myelogenous Leukemia in chronic phase (CML-CP), previously treated with imatinib and have not achieved deep molecular response |
|
| E.1.1.1 | Medical condition in easily understood language |
| Chronic Myelogenous Leukemia is a cancer of the blood characterized by a gene mutation (Philadelphia chromosome) which causes proliferation of white blood cells in the bone marrow |
|
| 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 | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10009012 |
| E.1.2 | Term | Chronic myelogenous leukemia |
| 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 | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To assess whether asciminib 40 mg QD + imatinib or asciminib 60 mg QD + imatinib is more effective than continued imatinib |
|
| E.2.2 | Secondary objectives of the trial |
• - To estimate efficacy of switch to nilotinib
- To estimate difference in efficacy between asciminib 60 mg + imatinib and switch to nilotinib
- To estimate difference in efficacy between asciminib 40 mg + imatinib and 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 60 mg or 40 mg and imatinib when administered in combination
•To estimate efficacy of asciminib 80 mg QD
•To characterize the safety and tolerability profile of asciminib 80 mg QD
•To assess the pharmacokinetic profile of asciminib 80 mg QD. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subjects eligible for inclusion in this study must meet all of the following
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 one year (12 calendar months) treatment with imatinib
first line for CML-CP (patients have to be on imatinib 300 mg QD or higher).
4. BCR-ABL1 levels > 0.01% IS and ≤ 1% IS at the time of
randomisation as confirmed with a central assessment at screening;
patients must not have achieved deep molecular response (MR4 IS)
confirmed by 2 consecutive tests at any time during prior imatinib
treatment. An isolated, single test result with BCR-ABL1 levels < 0.01 %
(MR4 IS) is allowed, however it should not have been observed within
the 9 months prior to randomization .
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
• 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
6. Patients must have the following laboratory values (≥ LLN) or
corrected to within normal limits with supplements prior to
randomization:
- Potassium (potassium increase of up to 6.0 mmol/L is acceptable if
associated with creatinine clearance* within normal limits)
- 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 creatinine
clearance* within normal limits)
- Magnesium (magnesium increase of up to 3.0 mg/dL or 1.23 mmol/L if
associated with creatinine clearance* within normal limits)
*Creatinine clearance as calculated using Cockcroft-Gault formula |
|
| E.4 | Principal exclusion criteria |
Subjects meeting any of the following criteria are not eligible for
inclusion in this study.
1. Treatment failure according to European Leukemia Network criteria
(Baccarani et al 2013) 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+)
*In 2 consecutive tests, of which one with a BCR-ABL level ≥1%.
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:
• History of myocardial infarction (MI), angina pectoris, coronary artery bypass graft (CABG) within 6 months prior to randomization
• Concomitant clinically significant arrhythmias, e.g. sustained
ventricular tachycardia, and clinically significant second or third degree
AV block without a pacemaker
• Resting QTcF ≥ 450 msec (male) or ≥ 460 msec (female) prior to
randomization
• Long QT syndrome, family history of idiopathic sudden death or
congenital long QT syndrome, or any of the following:
• Risk factors for Torsades de Pointes including uncorrected
hypokalemia or hypomagnesemia, history of cardiac failure, or history of
clinically significant/symptomatic bradycardia
• Concomitant medications with a "known" risk of Torsades de Pointes
per crediblemeds.org that cannot be discontinued or replaced by safe
alternative medication
• 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 chronic liver disease or ongoing acute 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), chronic
Hepatitis B (HBV), or chronic Hepatitis C (HCV) infection. Testing for
Hepatitis B surface antigen (HBsAg) and Hepatitis B core antibody (anti-
HBc) will be performed at study entry. If HBsAg or anti-HBc is positive,
Hepatitis B surface antibody (anti-HBs) and/or HBVDNA measurement is
recommended to confirm negative viral status.
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 strong inducers or inhibitors of CYP3A 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.
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.
Women of child-bearing potential, defined as all women physiologically
capable of becoming pregnant, unless they are using highly effective
methods of contraception while taking study treatment and for 14 days
after stopping study medication in treatment arms 1- 4, or for 3 days
after stopping asciminib single agent treatment. If local regulations or locally approved prescribing information are more stringent than the protocol required duration of contraception, the longer duration must be
followed. Highly effective contraception methods include: - see more
details in section 5.2 of the protocol.
16. Patients who have achieved deep molecular response (MR4 IS),
confirmed by 2 consecutive tests at any time during prior imatinib
treatment. |
|
| 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
•Molecular Response (MR)4.5 rate at 48 weeks
-Time to MR4.5
-Duration of MR4.5
•Incidence and severity of adverse events, changes in laboratory values,
clinically notable ECG abnormalities and vital signs
•Plasma concentrations of asciminib. 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 | 5 |
| 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 | 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 |
| Chile |
| Hong Kong |
| Taiwan |
| Australia |
| Canada |
| Japan |
| Korea, Republic of |
| Russian Federation |
| United Kingdom |
| United States |
| Austria |
| Czechia |
| Denmark |
| France |
| Germany |
| Italy |
| Poland |
| Portugal |
| Spain |
|
| 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 end of study treatment period for patients in Treatment arms 1-4
will be at 96 weeks (plus
30 days for the safety follow up) after the last randomized subject
received the first dose of
study treatment.
The end of study treatment period for patients in the asciminib single
agent cohort will be at
48 weeks (plus 30 days for the safety follow up) after the last enrolled
subject in that cohort
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 | 4 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
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