A study of full treatment-free remission in patients with chronic myeloid leukemia

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Novartis Farma S.p.A.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

18 Jan 2019 → 15 Oct 2025

Decision date (initial)

2024-09-09

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

External identifiers

EU CT number

2024-516122-66-00

EudraCT number

2018-002898-21

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety

TFR1 stage: To determine the percentage of patients in full treatment-free remission 96 weeks after the start of consolidation.
Full Treatment-Free Remission (FTFR) is defined as patients with Major Molecular Response (MMR) or better, including those who have totally discontinued treatment during the Treatment-Free Remission (TFR) phase and those who are treated with half the standard dosage.
TFR2 stage: To estimate the percentage of patients in treatment-free remission 48 weeks after starting a second attempt at treatment-free remission (TFR2).
Treatment-Free Remission (TFR) is defined as patients with Major Molecular Response (MMR) or better.

Secondary objectives 28

1. TFR1 stage: To determine the percentage of patients who remain in sustained Deep Molecular Response (DMR) at the end of consolidation (week 48).
2. To determine the percentage of patients who remain in DMR at the end of consolidation (week 48), at 96 weeks after the start of consolidation and at 144 weeks after the start of consolidation (end of study).
3. To determine the percentage of patients in full treatment-free remission 144 weeks after the start of consolidation (end of the TFR1 stage).
4. To determine the percentage of patients with MMR or better at the end of consolidation (week 48), 96 weeks after the start of consolidation, and 144 weeks after starting consolidation (end of study) regardless of whether they required reinitiation of treatment.
5. To characterize the kinetics of BCR-ABL transcripts after restart of nilotinib therapy in patients who failed TFR1.
6. To characterize the kinetics of BCR-ABL transcripts after discontinuation of nilotinib therapy.
7. To characterize the kinetics of BCR-ABL transcripts during consolidation.
8. To estimate Full Treatment-Free Survival (FTFS) after the start of consolidation
9. To estimate the Treatment-Free-Remission rate (TFR rate) at week 96 and week 144 after the start of consolidation.
10. To estimate treatment-free survival (TFS).
11. To estimate progression-free survival (PFS) after the start of consolidation.
12. To estimate PFS after the start of TFR1.
13. To estimate overall survival (OS) after the start of the study.
14. To assess safety during nilotinib treatment consolidation, TFR1 and during reinitiation of treatment with nilotinib.
15. To identify factors (e.g., patient demography, Sokal risk category, Early Molecular Response (EMR), type of transcript, ELTS at diagnosis) associated with full-treatment-free remission and treatment-free remission related to nilotinib.
16. To evaluate the risk of cardiovascular disease in CML patients through the Framingham risk score and Systemic Coronary Risk Evaluation (SCORE).
17. TFR2 stage: To estimate the percentage of patients eligible for TFR2 among patients entering reinduction with asciminib + nilotinib.
18. To estimate the number of patients with loss of MMR in TFR2 who regain MMR/DMR by the end of the TFR2 stage.
19. To characterize the kinetics of BCR-ABL transcripts during reinduction.
20. To characterize the kinetics of BCR-ABL transcript after restart of nilotinib therapy in patients who failed TFR2 period.
21. To characterize the kinetics of BCR-ABL transcript after restart of nilotinib therapy in patients who were not eligible for entering the TFR2 period.
22. To characterize the kinetics of BCR-ABL transcripts after discontinuation of asciminib + nilotinib therapy.
23. To estimate treatment-free survival (TFS).
24. To estimate progression free survival (PFS) after the start of TFR2.
25. To estimate overall survival (OS) after the start of reinduction.
26. To assess safety after the start of reinduction.
27. To identify factors (e.g., demography, Sokal risk category, Early Molecular Response (EMR), type of transcript) associated with asciminib + nilotinib TFR.
28. To evaluate the risk of cardiovascular disease in CML patients through the Framingham risk score and SCORE

Conditions and MedDRA coding

Chronic myeloid leukemia

Study design 2 periods

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 17

1. TFR1 stage: Male and female patients 18 years or older.
2. Diagnosis of CML-CP according to the World Health Organization.
3. Patients with CML-CP under first-line treatment with nilotinib at the approved daily dose of 300 mg BID mg for at least 3 calendar years. Note: At study entry, an ongoing treatment at a dose ≥400 mg per day is allowed.
4. Sustained DMR defined as ≥ MR 4.0 (BCR-ABL level ≤0.01% IS) in all of the last 4 BCR-ABL RQ-PCR assessments with a minimum interval between each assessment of 3 months and a maximum interval of 6 months.
5. Patient must meet the following laboratory values at the screening visit: • Absolute Neutrophil Count ≥1.0 x 109/L • Platelets ≥75 x 109/L • Hemoglobin (Hgb) ≥ 9 g/dL • Serum creatinine < 1.5 mg/dL • Aspartate transaminase (AST) ≤ 3.0 x Upper Limit of Normal (ULN) • Alanine transaminase (ALT) ≤ 3.0 x ULN • Serum lipase ≤ 2 x ULN
6. Patient has an Eastern Cooperative Oncology Group (ECOG) performance status 0-2.
7. Study subjects must be able to comply with study procedures and follow-up examinations.
8. Signed informed consent to the TFR1 stage from the patient or from his/her legal representative.
9. TFR2 stage: Signed informed consent to the TFR2 stage from the patient or from his/her legal representative.
10. Male and female patients 18 years or older.
11. Diagnosis of CP-CML according to the WHO and no previous history of progression to AP/BP CML.
12. First-line treatment with nilotinib for at least 3 calendar years, followed by first TFR attempt.
13. Failed first TFR attempt followed by at least 1 year of nilotinib retreatment before enrollment in TFR2 stage.
14. MR4 or better (BCR-ABL ≤ 0.01% IS) assessed at screening.
15. Patient must meet the following laboratory values at the reinduction screening visit: a. Absolute neutrophil count ≥1.0 x 109/L b. Platelets ≥75 x 109/L c. Hemoglobin (Hgb) ≥ 9 g/dL d. Serum creatinine < 1.5 mg/dL e. Total bilirubin ≤ 2 x ULN except for patients with Gilbert’s syndrome who may only be included if total bilirubin ≤ 3.0 x ULN or direct bilirubin ≤ 1.5 x ULN f. AST ≤ 3.0 x ULN g. ALT ≤ 3.0 x ULN h. Alkaline phosphatase ≤ 2.5 x ULN i. 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 j. Serum levels of potassium, magnesium, total calcium within the normal limits. Correction of electrolytes levels with supplements to fulfil enrolment criteria is allowed.
16. ECOG performance status 0-2.
17. Study subjects must be able to comply with study procedures and follow-up examinations.

Exclusion criteria 31

1. TFR1 stage: Patients with known atypical transcript.
2. CML treatment resistant mutation(s) (T315I, E255K/V, Y253H, F359C/V) detected if testing was done in the past (there is no requirement to perform mutation testing at study entry if it was not done in the past).
3. Dose reductions/interruptions due to neutropenia or thrombocytopenia in the past 6 months.
4. Patient ever attempted to permanently discontinue nilotinib treatment.
5. Known impaired cardiac function including any one of the following: • Inability to determine QT interval on ECG • Complete left bundle branch block • Long QT syndrome or a known family history of long QT syndrome • History of or presence of clinically significant ventricular or atrial tachyarrhythmias • Clinically significant resting bradycardia • QTcF > 480 msec • History or clinical signs of myocardial infarction within 1 year prior to study entry • History of unstable angina within 1 year prior to study entry • Other clinically significant heart disease (e.g. uncontrolled congestive heart failure or uncontrolled hypertension)
6. 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.
7. History of acute pancreatitis within 1 year prior to study entry or past medical history of chronic pancreatitis.
8. Known presence of a significant congenital or acquired bleeding disorder unrelated to cancer.
9. History of other active malignancy within 5 years prior to study entry except for previous or concomitant basal cell skin cancer, previous cervical carcinoma in situ treated curatively.
10. Patients who have not recovered from prior surgery.
11. Treatment with other investigational agents (defined as not used in accordance with the approved indication) within 4 weeks of Day 1.
12. 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).
13. Patients actively receiving therapy with strong CYP3A4 inhibitors and/or inducers, and the treatment cannot be either discontinued or switched to a different medication prior to study entry.
14. Patients actively receiving therapy with herbal medicines that are strong CYP3A4 inhibitors and/or inducers, and the treatment cannot be either discontinued or switched to a different medication prior to study entry. These herbal medicines may include Echinacea, (including E. purpurea, E. angustifolia and E. pallida), Piperine, Artemisinin, St. John's Wort, and Ginkgo.
15. Pregnant or nursing (lactating) women.
16. Women of childbearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing and for at least 14 days after stopping medication. There is a limited amount of data on pregnancies in patients while attempting treatment-free remission (TFR). If pregnancy is planned during the TFR phase, the patient must be informed of a potential need to re-initiate treatment with nilotinib during pregnancy.
17. TFR2 stage: Patients with known atypical transcript.
18. CML treatment resistant mutation(s) (T315I, E255K/V, Y253H, F359C/V) detected if testing was done in the past (there is no requirement to perform mutation testing at study entry if it was not done in the past).
19. Dose reductions/interruptions due to neutropenia or thrombocytopenia in the past 6 months.
20. Known impaired cardiac function including any one of the following: • Inability to determine QT interval on ECG • Complete left bundle branch block • Long QT syndrome or a known family history of long QT syndrome • History of or presence of clinically significant ventricular or atrial tachyarrhythmias • Clinically significant resting bradycardia • QTcF > 450 msec (male) or > 460 msec (female) • History or clinical signs of myocardial infarction within 1 year prior to study entry • History of unstable angina within 1 year prior to study entry • Other clinically significant heart disease (e.g. uncontrolled congestive heart failure or uncontrolled hypertension)
21. 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.
22. History of acute pancreatitis within 1 year prior to study entry or past medical history of chronic pancreatitis.
23. Known presence of a significant congenital or acquired bleeding disorder unrelated to cancer.
24. History of other active malignancy within 5 years prior to study entry except for previous or concomitant basal cell skin cancer, previous cervical carcinoma in situ treated curatively.
25. Patients who have not recovered from prior surgery.
26. Treatment with other investigational agents (defined as not used in accordance with the approved indication) within 4 weeks.
27. 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).
28. Patients actively receiving therapy with strong CYP3A4 inhibitors and/or inducers, and the treatment cannot be either discontinued or switched to a different medication prior to study entry.
29. Patients actively receiving therapy with herbal medicines that are strong CYP3A4 inhibitors and/or inducers, and the treatment cannot be either discontinued or switched to a different medication prior to study entry. These herbal medicines may include Echinacea, (including E. purpurea, E. angustifolia and E. pallida), Piperine, Artemisinin, St. John's Wort, and Ginkgo.
30. Pregnant or nursing (lactating) women.
31. Women of childbearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing and for at least 14 days after stopping medication. There is a limited amount of data on pregnancies in patients while attempting treatment-free remission (TFR). If pregnancy is planned during the TFR phase, the patient must be informed of a potential need to re-initiate treatment with nilotinib during pregnancy

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. TFR1 stage: BCR-ABL ≤ 0.1% (IS) 96 weeks after the start of consolidation. TFR2 stage: BCR-ABL ≤ 0.1% (IS) 48 weeks after the start of TFR2.

Secondary endpoints 28

1. TFR1 stage: Sustained DMR is defined as no loss of MR4.0 (BCR-ABL level ≤ 0.01% IS) in any BCR-ABL RQ-PCR assessment. The proportion of patients in sustained DMR at the end of consolidation (week 48) is calculated by dividing the number of patients in sustained DMR at week 48 by the number of patients who entered the consolidation period.
2. DMR: ≥ MR 4.0 (BCR-ABL level ≤0.01% IS) at week 48, 96 and 144 after the start of the consolidation period. The proportion of patients in deep molecular response is calculated by dividing the number of patients in DMR 48, 96 and 144 weeks after the start of consolidation by the number of patients who entered the consolidation period.
3. BCR-ABL ≤ 0.1% (IS) 144 weeks after consolidation. The proportion of patients in full treatment-free remission at week 144 is calculated by dividing the number of patients with no loss of MMR 144 weeks after the start of consolidation by the number of patients who entered the consolidation period.
4. BCR-ABL ≤ 0.1% (IS) 48, 96, 144 weeks after the start of the consolidation. The proportion of patients with MMR at week 48, 96 and 144 is calculated by dividing the number of patients with MMR at week 48, 96 and 144, regardless of whether they required re-initiation of treatment after the start the study, by the number of patients who entered the consolidation.
5. BCR-ABL transcript levels (IS) after restart of nilotinib therapy in patients who failed TFR1.
6. BCR-ABL transcript levels (IS) after discontinuation of nilotinib therapy in patients in TFR1.
7. BCR-ABL transcript levels (IS) during consolidation.
8. FTFS: time from the start of consolidation to the earliest occurrence of any of the following events: loss of MMR, reinitiation of treatment due to any cause, progression to accelerated phase (AP)/blast crisis (BC), or death due to any cause.
9. TFR rate: proportion of patients among those who entered TFR1 with no loss of MMR and no reinitiation of nilotinib after drug discontinuation at weeks 96 and 144 after the start of consolidation. The proportion of patients in TFR1 at weeks 96 and week 144 is calculated by dividing the number of patients with no loss of MMR and no reinitiation of nilotinib after drug discontinuation at weeks 96 and week 144 by the number of patients who entered TFR1.
10. TFS: time from the start of TFR1 to the earliest occurrence of any of the following events: loss of MMR, reinitiation of treatment due to any cause, progression to AP/BC or death due to any cause.
11. PFS: time from the start of consolidation to progression to AP/BC or death due to any cause, whichever occurs first.
12. PFS: time from the start of TFR1 to progression to AP/BC or death due to any cause, whichever occurs first.
13. OS: time from start of the study to death due to any cause.
14. Type, frequency and severity of adverse events, laboratory values that fall outside of the pre-determined ranges and clinically notable ECG and other safety data during nilotinib treatment consolidation, TFR1, and during reinitiation of treatment with nilotinib.
15. Successful FTFR and TFR - no loss of MMR and no reinitiation of nilotinib therapy in the first 96 weeks following the study start.
16. Framingham risk score and SCORE at baseline
17. TFR2 stage: Eligibility is defined as sustained DMR, defined as no loss of MR4.0 (BCR-ABL level ≤ 0.01% IS) in any BCR-ABL RQ-PCR assessment. The proportion of eligible patients is calculated by dividing the number of eligible patients by the number of patients who entered reinduction.
18. DMR: ≥ MR 4.0 (BCR-ABL level ≤0.01% IS); MMR: (BCR-ABL level ≤0.1% IS). The proportion of patients who regain MMR/DMR is calculated by dividing the number of patients in MMR/DMR 48 weeks after the start of TFR2 by the number of patients with loss of MMR in TFR2.
19. BCR-ABL transcript levels (IS) during reinduction.
20. BCR-ABL transcript levels (IS) after restart of nilotinib therapy in patients who failed TFR2 period.
21. BCR-ABL transcript levels (IS) after restart of nilotinib therapy in patients who were not eligible for entering the TFR2 period.
22. BCR-ABL transcript levels (IS) after discontinuation of asciminib + nilotinib therapy in patients in TFR2.
23. TFS: time from the start of TFR2 stage to the earliest occurrence of any of the following events: loss of MMR, reinitiation of treatment due to any cause, progression to AP/BC or death due to any cause.
24. PFS: time from the start of TFR2 stage to progression to AP/BC or death due to any cause, whichever occurs first.
25. OS: time from start of reinduction to death due to any cause.
26. Type, frequency and severity of adverse events, laboratory values that fall outside of the pre-determined ranges and clinically notable ECG and other safety data after the start of reinduction.
27. Successful TFR2 - no loss of MMR and no reinitiation of nilotinib therapy starting from reinduction for TFR2.
28. Framingham risk score and SCORE at the start of reinduction.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 4

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Novartis Farma S.p.A.

Sponsor organisation

Novartis Farma S.p.A.

Address

Viale Luigi Sturzo 43

City

Milan

Postcode

20154

Country

Italy

Scientific contact point

Organisation

Novartis Farma S.p.A.

Contact name

Alessandra Misto

Public contact point

Organisation

Novartis Farma S.p.A.

Contact name

Federica Ventura

Third parties 5

Locations

1 EU/EEA country · 12 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 17 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

4 submissions — initial application plus substantial / non-substantial modifications