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A Study of Full Treatment-free Remission in Patients With Chronic Myeloid Leukemia Treated With Nilotinib (DANTE)

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ClinicalTrials.gov Identifier: NCT03874858
Recruitment Status : Recruiting
First Posted : March 14, 2019
Last Update Posted : May 3, 2021
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Brief Summary:
This is a prospective, single arm, phase II study 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.

Condition or disease Intervention/treatment Phase
Chronic Myeloid Leukemia Drug: Nilotinib Phase 2

Detailed Description:

The purpose of the present study is to evaluate the rate of full treatment-free molecular remission in a selected population of CML-CP patients treated with nilotinib at half the standard dose during a consolidation period of 12 months, followed by complete therapy cessation.

The study is made up of 4 phases:

  • Screening (week -4 - week 0)
  • Nilotinib consolidation (week 0 - week 48)
  • Nilotinib treatment-free remission (TFR) phase (week 48 - week 144)
  • Follow up phase Patients fulfilling this protocol-specific definition of sustained deep molecular response (DMR) and all other inclusion/exclusion criteria will start the consolidation phase of the study.

During Nilotinib consolidation (week 0 - week 48) period, 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 tretament-free remission (TFR) phase and nilotinib will be discontinued.
  • Patients with loss of major molecular response (MMR) at any time during the consolidation phase will enter the follow-up phase and will return to the standard nilotinib administration regimen (nilotinib 300 mg BID) until the end of the trial (week 144). Loss of MMR is defined as breakpoint cluster region--c-abl oncogene 1 (BCR-ABL) >0.1% international scale assessed in a single blood sample and will mandate reinitiation of nilotinib treatment at 300 mg BID within 5 weeks after the collection of the blood sample demonstrating loss of MMR.
  • 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 trial (week 144).

During the TFR phase, BCR-ABL levels will be monitored every month for the first year at weeks 52, 56, 60, 64, 68, 72, 76, 80, 84, 88, 92, 96 and then every three months until the end of the study at weeks 108, 120, 132 and 144 (end of study) or whenever clinically indicated at the discretion of the investigator. The primary objective will be evaluated at week 96. During the TFR phase, loss of MMR will cause reinitiation of nilotinib treatment at 300 mg BID.

Follow up phase for patients who were discontinued from the trial, starting from the date of trial discontinuation up to the end of the trial (144 week), and for patients with loss of MMR at any time during the study.

Patients discontinued from the treatment for any reason will be followed for survival information every 3 months until week 144.

All patients still on study treatment at the end of the study will be transitioned to prescription nilotinib.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 103 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase II, Single-arm, Multicenter Study of Full Treatment-free Remission in Patients With Chronic Myeloid Leukemia in Chronic Phase Treated With Nilotinib in First-line Therapy Who Have Achieved a Sustained, Deep Molecular Response for at Least 1 Year
Actual Study Start Date : April 1, 2019
Estimated Primary Completion Date : August 31, 2022
Estimated Study Completion Date : February 1, 2024


Arm Intervention/treatment
Experimental: Nilotinib
Oral 300 mg hard capsules taken once a day
Drug: Nilotinib
Nilotinib oral 300 mg QD hard capsules
Other Name: AMN107




Primary Outcome Measures :
  1. Percentage of patients in full treatment-free remission 96 weeks after the start of the consolidation phase. [ Time Frame: Baseline of consolidation phase up to 96 weeks ]

    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.

    Percentage of patients in full treatment-free remission 96 weeks after the start of the consolidation phase is calculated by dividing the number of patients with no loss of MMR-Major Molecular Response (BCR-ABL ≤ 0.1% (IS) after 96 weeks by the number of patients who entered the consolidation phase.



Secondary Outcome Measures :
  1. Percentage of patients who remain in sustained Deep Molecular Response (DMR) at the end of the consolidation phase (week 48). [ Time Frame: Baseline of consolidation phase up to 48 weeks ]
    The percentage of patients in sustained DMR at the end of the consolidation phase (week 48). Sustained DMR: ≥ MR 4.0 (BCR-ABL level ≤0.01% IS) in all of the last 4 BCR-ABL RQ-PCR assessments. The proportion of patients in sustained DMR at the end of the consolidation phase (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 phase.

  2. Percentage of patients who remain in DMR at the end of the consolidation phase (week 48), at 96 weeks and at 144 weeks after the start of the consolidation phase. [ Time Frame: Baseline of consolidation phase, week 48, 96 and 144 ]
    The percentage of patients in deep molecular response is calculated by dividing the number of patients in DMR (≥ MR 4.0 (BCR-ABL level ≤0.01% IS in all of the last 4 BCR-ABL RQ-PCR assessments) 48, 96 and 144 weeks after the start of the consolidation phase by the number of patients who entered the consolidation phase.

  3. Percentage of patients in full treatment-free remission 144 weeks after the start of the consolidation phase. [ Time Frame: Baseline of consolidation phase, week 144 ]
    The percentage of patients in full treatment-free remission at week 144 is calculated by dividing the number of patients with no loss of MMR (BCR-ABL ≤ 0.1% (IS)) 144 weeks after the start of the consolidation phase by the number of patients who entered the consolidation phase.

  4. Percentage of patients with MMR or better at 48, 96, 144 weeks after starting the consolidation phase [ Time Frame: Baseline of consolidation phase, week 48, 96 and 144 ]
    The percentage 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 phase.

  5. Change in Polymerase Chain Reaction (PCR) of BCR-ABL transcript after re-start of nilotinib therapy in patients who failed Treatment Free Remission Phase. [ Time Frame: Restart of nilotinib therapy up to approximately 144 weeks ]
    Descriptive statistics of BCR-ABL levels (International scale), measured by quantitative Polymerase Chain Reaction (PCR), over time after re-start of nilotinib therapy up to 144 weeks in patient who failed Treatment Free Remission Phase.

  6. Change in Polymerase Chain Reaction (PCR) of BCR-ABL transcript after discontinuation of nilotinib therapy in Treatment Free Remission Phase. [ Time Frame: Discontinuation of nilotinib therapy in patients in TFR phase up to approximately 144 weeks ]
    Descriptive statistics of BCR-ABL levels (IS), measured by quantitative PCR, over time after discontinuation of nilotinib therapy in Treatment Free Remission Phase up to 144 weeks.

  7. Change in Polymerase Chain Reaction (PCR) of BCR-ABL transcript during the consolidation period. [ Time Frame: Baseline of consolidation phase up to 48 weeks ]
    Descriptive statistics of BCR-ABL levels (IS), measured by quantitative PCR, over time during the consolidation period to 48 weeks.

  8. Full Treatment-Free Survival (FTFS) [ Time Frame: Baseline of consolidation phase up to 144 weeks ]
    FTFS: time from the start of the consolidation phase 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. Proportion of patients among those who entered the TFR phase with no loss of MMR and no reinitiation of nilotinib after drug discontinuation [ Time Frame: Baseline of consolidation up to 96 and 144 weeks ]
    Percentage of patients in TFR 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 the TFR phase.

  10. Treatment-free survival (TFS) [ Time Frame: From the start of the TFR phase up to Week 144. ]
    TFS: time from the start of the TFR phase 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. Progression-free survival (PFS) after the start of consolidation phase [ Time Frame: Baseline of consolidation phase up to 144 weeks ]
    PFS: time from the start of the consolidation phase to progression to AP/BC or death due to any cause, whichever occurs first.

  12. Progression Free Survival (PFS) after the start of TFR phase [ Time Frame: From the start of the TFR phase up to week 144. ]
    PFS: time from the start of the TFR phase to progression to AP/BC or death due to any cause, whichever occurs first.

  13. Overall Survival (OS) [ Time Frame: Baseline of consolidation phase up to 144 weeks ]
    OS: time from start of the study to death due to any cause.

  14. The number of patients with Adverse Events as measure of safety and tolerability [ Time Frame: From screening up to approximately week 144 ]
    To assess safety during the nilotinib treatment consolidation phase, TFR phase and during reinitiation of treatment with nilotinib.

  15. Correlation between clinical and laboratory factors and clinical outcome [ Time Frame: Baseline of consolidation phase up to 96 weeks ]
    Statistical correlation between clinical and laboratory correlates at diagnosis (e.g. Sokal Risk scale, demography, type of BCR-ABL transcript) or during previous treatment (e.g. Early Molecular Response=BCR-ABL transcript measured by quantitative PCR <10% after 3 months of first-line treatment with nilotinib at the dose of 300 mg BID) and the achievement of Full Treatment Free Remission and Treatment Free Remission at 96 weeks



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  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:

  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.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03874858


Contacts
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Contact: Novartis Pharmaceuticals +41613241111 novartis.email@novartis.com
Contact: Novartis Pharmaceuticals

Locations
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Italy
Novartis Investigative Site Recruiting
Bari, BA, Italy, 70124
Novartis Investigative Site Recruiting
Bologna, BO, Italy, 40138
Novartis Investigative Site Recruiting
Cagliari, CA, Italy, 09126
Novartis Investigative Site Recruiting
Catania, CT, Italy, 95123
Novartis Investigative Site Recruiting
Catanzaro, CZ, Italy, 88100
Novartis Investigative Site Recruiting
Firenze, FI, Italy, 50134
Novartis Investigative Site Recruiting
Genova, GE, Italy, 16132
Novartis Investigative Site Recruiting
Milano, MI, Italy, 20122
Novartis Investigative Site Recruiting
Milano, MI, Italy, 20162
Novartis Investigative Site Recruiting
Palermo, PA, Italy, 90127
Novartis Investigative Site Recruiting
Palermo, PA, Italy, 90146
Novartis Investigative Site Recruiting
Pescara, PE, Italy, 65124
Novartis Investigative Site Recruiting
Perugia, PG, Italy, 06100
Novartis Investigative Site Recruiting
Pisa, PI, Italy, 56126
Novartis Investigative Site Withdrawn
Ravenna, RA, Italy, 48100
Novartis Investigative Site Recruiting
Reggio Emilia, RE, Italy, 42123
Novartis Investigative Site Recruiting
Roma, RM, Italy, 00144
Novartis Investigative Site Recruiting
Roma, RM, Italy, 00161
Novartis Investigative Site Recruiting
Roma, RM, Italy, 00168
Novartis Investigative Site Recruiting
Salerno, SA, Italy, 84131
Novartis Investigative Site Recruiting
Siena, SI, Italy, 53100
Novartis Investigative Site Recruiting
Orbassano, TO, Italy, 10043
Novartis Investigative Site Recruiting
Torino, TO, Italy, 10126
Novartis Investigative Site Recruiting
Torino, TO, Italy, 10128
Novartis Investigative Site Withdrawn
Udine, UD, Italy, 33100
Novartis Investigative Site Recruiting
Verona, VR, Italy, 37126
Novartis Investigative Site Recruiting
Napoli, Italy, 80131
Novartis Investigative Site Recruiting
Napoli, Italy, 80132
Novartis Investigative Site Recruiting
Novara, Italy, 28100
Sponsors and Collaborators
Novartis Pharmaceuticals
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Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT03874858    
Other Study ID Numbers: CAMN107AIT15
2018-002898-21 ( EudraCT Number )
First Posted: March 14, 2019    Key Record Dates
Last Update Posted: May 3, 2021
Last Verified: April 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description:

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com


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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Novartis ( Novartis Pharmaceuticals ):
CML
CML-CP
TFR
nilotinib
AMN107
Tasigna
DMR
sustained deep molecular response
full treatment-free remission
TKI
qPCR
adult
ddPCR
Additional relevant MeSH terms:
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Leukemia
Leukemia, Myeloid
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Neoplasms by Histologic Type
Neoplasms
Myeloproliferative Disorders
Bone Marrow Diseases
Hematologic Diseases