Clinical trial NCT03874858: De-escalation and TFR Study in CML Patients Treated With Nilotinib Followed by a Second Attempt After Nilotinib and Asciminib Combination
Official title: A Phase II, Single-arm Study of De-escalation and Treatment-free Remission in Patients With Chronic Myeloid Leukemia Treated With Nilotinib in First-line Therapy Followed by a Second Attempt After Nilotinib and Asciminib Combination: DANTE Study
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Chronic Myeloid Leukemia
Keywords: CML
CML-CP
TFR
nilotinib
AMN107
Tasigna
DMR
sustained deep molecular response
full treatment-free remission
TKI
qPCR
adult
ddPCR
asciminib
TFR failure
ABL001
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2019-03-14
Enrollment: 124
Sex: ALL
Minimum age (years): 18
Maximum age (years): 99
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This study is constituted of two stage: Treatment-Free Remission 1 (TFR1) stage and Treatment-Free Remission 2 (TFR2) stage.

The purpose of the TFR1 stage is to assess the effect of nilotinib reduced to half the standard dose for 12 months on treatment-free remission in patients with Chronic Myeloid Leukemia - Chronic Phase (CML-CP) treated with first-line nilotinib who reached a sustained deep molecular response before entering the study.

The purpose of the TFR2 stage is to evaluate whether the use of asciminib in combination with nilotinib after failure of a first attempt at TFR can lead to higher and more durable TFR rates after a second attempt at TKI discontinuation than those reported in other studies.

Detailed description: This is a prospective, single arm, phase II study constituted of two stage: Treatment-Free Remission 1 (TFR1) stage and Treatment-Free Remission 2 (TFR2) stage.

The TFR1 stage is made up of 4 periods:

1. Screening (week -4 - week 0)
2. Nilotinib consolidation (week 0 - week 48): Patients will be treated with nilotinib 300 mg QD. At the end or during the consolidation period, patients will proceed as follows:

   * Patients with sustained DMR at the end of the consolidation phase will enter the treatment-free remission (TFR1) and nilotinib will be discontinued. If two or more consecutive quarterly BCR-ABL RQ-PCR assessments are not performed or results are not available, the patient will not be eligible for TFR1 period and will be treated with nilotinib 300 mg QD until the end of the TFR1 stage (week 144).
   * Patients with loss of major molecular response (MMR) at any time during the consolidation phase will enter the follow-up period and will return to the standard nilotinib administration regimen (nilotinib 300 mg BID) until the end of the TFR1 stage (week 144).
   * Patients with more than MMR, but without meeting the definition of sustained DMR, will remain in the consolidation phase and will be treated with nilotinib 300 mg QD until the end of the TFR1 stage (week 144).
3. Nilotinib treatment-free remission (TFR1) (week 48 - week 144): During the TFR1 period, BCR-ABL levels will be monitored until the end of the TFR1 stage (week 144)
4. Follow up: Patients who remain on half-dose nilotinib after week 48 and patients with loss of MMR at any time during the study will enter follow-up until week 144.

Patients discontinued from the treatment for any reason will be followed for survival information until week 144. All patients still on study treatment at the end of the study will be transitioned to prescription nilotinib.

The TFR2 stage will include two cohorts; an internal cohort made up of patients who participated in the TFR1 stage of this study, and an external cohort of patients who failed a first attempt at TFR with nilotinib outside of this study. The TFR2 stage is made up of 4 periods:

1. Screening for reinduction
2. Reinduction (week 0-96): Patients will be treated with asciminib 40 mg BID + nilotinib 300 mg BID for 96 weeks. Patients will proceed as follows:

   * Patients with sustained DMR at the end of reinduction will enter TFR2 and asciminib + nilotinib will be discontinued. If two or more consecutive quarterly BCR-ABL RQ-PCR assessments are not performed or results are not available, the patient will not be eligible for TFR2
   * Patients not eligible for TFR2 but with more than an MMR continue treatment with asciminib + nilotinib until the end of reinduction (week 96) and then continue nilotinib monotherapy at 300 mg BID until the end of the TFR2 stage (week 144).
   * Patients with loss of MMR at any time during reinduction or during nilotinib monotherapy will be discontinued from the study.
3. Asciminib+nilotinib treatment-free remission (TFR2) (week 96-week 144): During the TFR2 period, BCR-ABL levels will be monitored every month for one year
4. Follow up: Patients with loss of MMR during TFR2 and patients not eligible for TFR2 but with more than an MMR will be treated with nilotinib 300 mg BID and monitored until week 144. If MMR loss occurs during reinduction or during nilotinib monotherapy, patients will be discontinued from the study and treated according to clinical practice.

Eligibility criteria: Inclusion Criteria TFR1 stage:

1. 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.

Exclusion Criteria TFR1 stage:

1. 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

Highly effective contraception methods include:

* Total abstinence (when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.
* Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy), total hysterectomy, or tubal ligation at least six weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment.
* Male sterilization (at least 6 months prior to screening). The vasectomized male partner should be the sole partner for that subject.
* Use of oral, injected or implanted hormonal methods of contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS), or other forms of hormonal contraception that have comparable efficacy (failure rate \<1%), for example hormone vaginal ring or transdermal hormone contraception.

In case of use of oral contraception, women should have been stable on the same pill for a minimum of 3 months before starting the study.

Women are considered post-menopausal and not of childbearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (i.e. age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy), total hysterectomy, or tubal ligation at least six weeks ago. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of childbearing potential.

Inclusion Criteria TFR2 stage:

1. Signed informed consent to the TFR2 stage from the patient or from his/her legal representative.
2. Male and female patients 18 years or older.
3. Diagnosis of CP-CML according to the WHO and no previous history of progression to AP/BP CML.
4. First-line treatment with nilotinib for at least 3 calendar years, followed by first TFR attempt.
5. Failed first TFR attempt followed by at least 1 year of nilotinib retreatment before enrollment in TFR2 stage.
6. MR4 or better (BCR-ABL ≤ 0.01% IS) assessed at screening.
7. Patient must meet the following laboratory values at the reinduction screening visit:

   1. Absolute neutrophil count ≥1.0 x 109/L
   2. Platelets ≥75 x 109/L
   3. Hemoglobin (Hgb) ≥ 9 g/dL
   4. Serum creatinine \< 1.5 mg/dL
   5. 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
   6. AST ≤ 3.0 x ULN
   7. ALT ≤ 3.0 x ULN
   8. Alkaline phosphatase ≤ 2.5 x ULN
   9. 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
   10. Serum levels of potassium, magnesium, total calcium within the normal limits. Correction of electrolytes levels with supplements to fulfil enrolment criteria is allowed.
8. ECOG performance status 0-2.
9. Study subjects must be able to comply with study procedures and follow-up examinations.

Exclusion Criteria TFR2 stage:

1. 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. 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)
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.
6. History of acute pancreatitis within 1 year prior to study entry or past medical history of chronic pancreatitis.
7. Known presence of a significant congenital or acquired bleeding disorder unrelated to cancer.
8. 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.
9. Patients who have not recovered from prior surgery.
10. Treatment with other investigational agents (defined as not used in accordance with the approved indication) within 4 weeks.
11. 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).
12. 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.
13. 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.
14. Pregnant or nursing (lactating) women.
15. 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

Highly effective contraception methods include:

* Total abstinence (when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.
* Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy), total hysterectomy, or tubal ligation at least six weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment.
* Male sterilization (at least 6 months prior to screening). The vasectomized male partner should be the sole partner for that subject.
* Use of oral, injected or implanted hormonal methods of contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS), or other forms of hormonal contraception that have comparable efficacy (failure rate \<1%), for example hormone vaginal ring or transdermal hormone contraception.

In case of use of oral contraception, women should have been stable on the same pill for a minimum of 3 months before starting the study.

Women are considered post-menopausal and not of childbearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (i.e. age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy), total hysterectomy, or tubal ligation at least six weeks ago. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of childbearing potential.

Primary outcomes:
measure: Percentage of patients in full treatment-free remission 96 weeks after the start of the consolidation period of TFR1 stage
timeFrame: Baseline of consolidation phase up to 96 weeks of TFR1 stage
measure: Percentage of patients in treatment-free remission 48 weeks after starting a second attempt at treatment-free remission during TFR2 stage.
timeFrame: Baseline TFR2 phase (week 96 of TFR2 stage) up to week 144 of TFR2 stage
Secondary outcomes:
measure: Percentage of patients who remain in sustained Deep Molecular Response (DMR) at the end of the consolidation period (week 48 TFR1 stage).
timeFrame: Baseline of consolidation period up to 48 weeks (TFR1 stage)
measure: Percentage of patients who remain in DMR at the end of the consolidation period (week 48 of TFR1 stage), at 96 weeks and at 144 weeks after the start of the consolidation period of TFR1 stage.
timeFrame: Baseline of consolidation period, week 48, week 96 and week 144 (TFR1 stage)
measure: Percentage of patients in full treatment-free remission 144 weeks after the start of consolidation ( end of the TFR1 stage.)
timeFrame: Baseline of consolidation period, week 144 of TFR1 stage
measure: Percentage of patients with MMR or better at 48, 96, 144 weeks after starting the consolidation period of TFR1 stage
timeFrame: Baseline of consolidation period, week 48, 96 and 144 of TFR1 stage
measure: Change in BCR-ABL transcript levels after re-start of nilotinib therapy in patients who failed Treatment Free Remission Phase during TFR1 stage.
timeFrame: Restart of nilotinib therapy up to 144 weeks of TFR1 stage
measure: Change in BCR-ABL transcript levels after discontinuation of nilotinib therapy in TFR1 period in TFR1 stage.
timeFrame: Discontinuation of nilotinib therapy in patients in TFR phase up to 144 weeks of TFR1 stage
measure: Change in BCR-ABL transcript levels during the consolidation period of TFR1 stage.
timeFrame: Baseline of consolidation period up to 48 weeks of TFR1 stage
measure: Full Treatment-Free Survival (FTFS) in TFR1 stage
timeFrame: Baseline of consolidation period up to 144 weeks of TFR1 stage
measure: Treatment-Free Remission rate (TFR rate) after the start of consolidation of TFR1 stage
timeFrame: Baseline of consolidation, week 96 and week 144 of TFR1 stage
measure: Treatment-free survival (TFS) in TFS1 stage
timeFrame: From the start of the TFR phase up to 144 weeks of TFR1 stage.
measure: Progression-free survival (PFS) after the start of the consolidation period of TFR1 stage
timeFrame: Baseline of consolidation up to 144 weeks of TFR1 stage
measure: Progression Free Survival (PFS) after the start of TFR1 period of TFR1 stage
timeFrame: From the start of the TFR1 period up to week 144 of TFR1 stage.
measure: Overall Survival (OS) in TFR1 stage
timeFrame: Baseline of consolidation up to 144 weeks of TFR1 stage
measure: Correlation between clinical and laboratory factors and clinical outcome
timeFrame: Baseline of consolidation phase up to 96 weeks of TFR1 stage
measure: Number of patients stratified by risk of cardiovascular disease through the Framingham risk score (TFR1 stage)
timeFrame: Baseline of TFR1 stage
measure: Number of patients stratified by risk of cardiovascular disease through the Systemic Coronary Risk Evaluation (SCORE) (TFR1 stage)
timeFrame: Baseline of TFR1 stage
measure: Percentage of patients eligible for the TFR2 period among patients entering reinduction with asciminib + nilotinib in TFR2 stage
timeFrame: Baseline of TFR2 stage up to week 96 of TFR2 stage
measure: Number of patients with loss of MMR in TFR2 who regain MMR/DMR by the end of the TFR2 stage
timeFrame: Baseline TFR2 phase (week 96 of TFR2 stage) up to week 144 of TFR2 stage
measure: Change in BCR-ABL transcript levels during reinduction of TFR2 stage.
timeFrame: Baseline of TFR2 stage up to week 96 of TFR2 stage
measure: Change in BCR-ABL transcript levels after restart of nilotinib therapy in patients who failed TFR2 period in TFR2 stage.
timeFrame: Restart of nilotinib therapy up to week 144 of TFR2 stage
measure: Change in BCR-ABL transcript levels after restart of nilotinib therapy in patients who were not eligible for entering the TFR2 period in TFR2 stage.
timeFrame: Restart of nilotinib therapy up to week 144 of TFR2 stage
measure: Change in BCR-ABL transcript levels after discontinuation of asciminib + nilotinib therapy in TFR2 stage.
timeFrame: Discontinuation of asciminib + nilotinib (week 96 of TFR2 stage) up to week 144 of TFR2 stage
measure: Treatment-free survival (TFS) in TFR2 stage
timeFrame: From the start of the TFR period of TFR2 stage up to Week 144 of TFR2 stage.
measure: Progression Free Survival (PFS) after the start of TFR2 period of TFR2 stage
timeFrame: From the start of the TFR2 period of TFR2 stage up to week 144 of TFR2 stage.
measure: Overall Survival (OS) in TFR2 stage
timeFrame: Baseline of reinduction period up to week 144 of TFR2 stage
measure: Correlation between clinical and laboratory factors and clinical outcome
timeFrame: Baseline of reinduction up to 144 weeks of TFR2 stage
measure: Number of patients stratified by risk of cardiovascular disease through the Framingham risk score (TFR2 stage)
timeFrame: Baseline of TFR2 stage
measure: Number of patients stratified by risk of cardiovascular disease through the Systemic Coronary Risk Evaluation (SCORE) (TFR2 stage)
timeFrame: Baseline of TFR2 stage
Other outcomes:
Locations:
city: Bari
country: Italy
facility: Novartis Investigative Site
state: BA
city: Bologna
country: Italy
facility: Novartis Investigative Site
state: BO
city: Cagliari
country: Italy
facility: Novartis Investigative Site
state: CA
city: Catania
country: Italy
facility: Novartis Investigative Site
state: CT
city: Catanzaro
country: Italy
facility: Novartis Investigative Site
state: CZ
city: Firenze
country: Italy
facility: Novartis Investigative Site
state: FI
city: Genova
country: Italy
facility: Novartis Investigative Site
state: GE
city: Milano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Milano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Palermo
country: Italy
facility: Novartis Investigative Site
state: PA
city: Palermo
country: Italy
facility: Novartis Investigative Site
state: PA
city: Pescara
country: Italy
facility: Novartis Investigative Site
state: PE
city: Perugia
country: Italy
facility: Novartis Investigative Site
state: PG
city: Pisa
country: Italy
facility: Novartis Investigative Site
state: PI
city: Reggio Emilia
country: Italy
facility: Novartis Investigative Site
state: RE
city: Roma
country: Italy
facility: Novartis Investigative Site
state: RM
city: Roma
country: Italy
facility: Novartis Investigative Site
state: RM
city: Roma
country: Italy
facility: Novartis Investigative Site
state: RM
city: Salerno
country: Italy
facility: Novartis Investigative Site
state: SA
city: Siena
country: Italy
facility: Novartis Investigative Site
state: SI
city: Orbassano
country: Italy
facility: Novartis Investigative Site
state: TO
city: Torino
country: Italy
facility: Novartis Investigative Site
state: TO
city: Torino
country: Italy
facility: Novartis Investigative Site
state: TO
city: Verona
country: Italy
facility: Novartis Investigative Site
state: VR
city: Napoli
country: Italy
facility: Novartis Investigative Site
city: Napoli
country: Italy
facility: Novartis Investigative Site
city: Novara
country: Italy
facility: Novartis Investigative Site
Study officials:
References: