Nilotinib Treatment-Free Remission for Chronic Myeloid Leukemia

(ENESTfreedom Trial)

No longer recruiting at 156 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Novartis Pharmaceuticals

Must be taking: Nilotinib

Must not be taking: CYP3A4 inhibitors, QT prolonging

Disqualifiers: Diabetes, Cardiac issues, Pregnancy, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 5 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 12

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if individuals with chronic myeloid leukemia (CML) can safely discontinue the drug nilotinib (Tasigna) without experiencing a cancer recurrence. Initially, patients continue with nilotinib to ensure their cancer remains controlled, followed by a treatment-free phase to monitor for any recurrence. Those who have taken nilotinib for at least two years and have shown an excellent response to the treatment may be suitable candidates for this trial. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group, allowing participants to contribute to significant findings.

Do I need to stop my current medications to join the trial?

The trial requires that you stop taking certain medications, especially those that affect the liver enzyme CYP3A4 or prolong the QT interval (a heart rhythm measure). If you are on these medications, you may need to switch to different ones before starting the trial.

Is there any evidence suggesting that nilotinib treatment is likely to be safe for humans?

Research has shown that nilotinib is generally safe for patients with chronic myeloid leukemia (CML). In one study, patients who took nilotinib for two years did not experience any new or severe side effects. Another study found that adults with CML worldwide tolerated nilotinib well.

While side effects can occur, they are usually manageable. For those considering joining a trial with nilotinib, previous research suggests that the treatment has a good safety record for similar patients. ^{1 2 3 4 5}

Why are researchers excited about this study treatment for CML?

Nilotinib is unique because it offers a potential treatment-free remission option for chronic myeloid leukemia (CML) patients who have achieved deep molecular response. Most treatments for CML require continuous medication to maintain remission, but nilotinib allows patients to potentially pause treatment while still keeping the disease under control. Researchers are excited about this approach as it could improve quality of life by reducing the long-term side effects and costs associated with continuous therapy.

What evidence suggests that nilotinib might be an effective treatment for chronic myeloid leukemia?

Research has shown that nilotinib can effectively treat chronic myeloid leukemia (CML). In this trial, participants will initially receive nilotinib treatment. Studies indicate that patients who achieve a deep molecular response, characterized by a very low level of cancer cells, have about an 80% chance of remaining in remission without ongoing treatment. This trial will assess the potential for patients to enter a treatment-free remission phase after achieving such a response. Nilotinib has proven more effective than some other treatments, like imatinib, and can lead to more years of good-quality life. These findings suggest that nilotinib could be a strong option for people with CML who wish to manage their condition without constant medication. ^{6 7 8 9 10}

Who Is on the Research Team?

Novartis Pharmaceuticals

Principal Investigator

Novartis Pharmaceuticals

Are You a Good Fit for This Trial?

Adults diagnosed with chronic phase Chronic Myeloid Leukemia (CML) who have been treated with nilotinib for at least two years and are in deep molecular response. They must have normal organ and marrow function, no history of pancreatitis or uncontrolled diabetes, not be pregnant or breastfeeding, and cannot be on certain medications that affect liver enzymes or prolong the QT interval.

Inclusion Criteria

I have been treated with nilotinib for my CML for at least 2 years, including the last 12 months.

My CML was confirmed with specific genetic markers before starting TKI treatment.

I am able to get out of my bed or chair and move around.

Exclusion Criteria

Impaired cardiac function including any one of the following: LVEF < 45% or below the institutional lower limit of the normal range (whichever is higher), Inability to determine the QT interval on ECG, except for patients with evidence of measurable QT interval at the time of CML diagnosis (e.g. prior to first start of TKI treatment) and who have no documented clinical signs of cardiovascular disease and/or clinical signs of conduction abnormality, Complete left bundle branch block, Right bundle branch block plus left anterior or posterior hemiblock, Use of a ventricular-paced pacemaker, Congenital 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, QTc > 450 msec on the average of three serial baseline ECG (using the QTcF formula). If QTcF > 450 msec and electrolytes are not within normal ranges, electrolytes should be corrected and then the patient re-tested for QTc. This exclusion criterion is not applicable for patients with non-measurable QT interval who have evidence of measurable QT interval at the time of CML diagnosis (e.g. prior to first start of TKI treatment) and who have no documented clinical signs of cardiovascular disease and/or clinical signs of conduction abnormality, History or clinical signs of myocardial infarction within 1 year of study entry, History of unstable angina within 1 year of study entry, Other clinically significant heart disease (e.g. congestive heart failure, cardiomyopathy or uncontrolled hypertension), History of acute pancreatitis within 1 year of study entry or past medical history of chronic pancreatitis, Known presence of significant congenital or acquired bleeding disorder unrelated to cancer, 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, uncontrolled infection), History of another active malignancy within 5 years prior to study entry with the exception of previous or concomitant basal cell skin cancer and previous carcinoma in situ treated curatively, Treatment with other investigational agents (defined as not used in accordance with the approved indication) within 4 weeks of Day 1, Patients who have not recovered from prior surgery, 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 starting study drug, 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 starting study drug. These herbal medicines may include Echinacea, (including E. purpurea, E. angustifolia and E. pallida), Piperine, Artemisinin, St. John's Wort, and Ginkgo, Patients who are currently receiving treatment with any medications that have the potential to prolong the QT interval and the treatment cannot be either safely discontinued or switched to a different medication prior to starting study drug, 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), Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test, Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during the study and for 14 days after the final dose of nilotinib. Highly effective contraception is defined as either: Total abstinence (when this is in line with the preferred and usual lifestyle of the patient. 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) 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 enrolling). For female patients on the study the vasectomized male partner should be the sole partner for that patient, Use of a combination of any two of the following: Use of oral, injected or implanted hormonal methods of contraception or other forms of hormonal contraception that have comparable efficacy (failure rate <1%), for example hormone vaginal ring or transdermal hormone contraception, Placement of an intrauterine device (IUD) or intrauterine system (IUS), Barrier methods of contraception: Condom or Occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository, In case of use of oral contraception women should have been stable on the same pill for a minimum of 3 months before taking study treatment Women are considered post-menopausal and not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks prior to enrolling. 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 child bearing potential, If a study patient becomes pregnant or suspects being pregnant during the study or within 30 days after the final dose of nilotinib, the Study Doctor needs to be informed immediately and ongoing study treatment with nilotinib has to be stopped immediately.

I have been treated with BCR-ABL inhibitors, other than nilotinib, for over 4 weeks.

I have taken cancer drugs for CML, but not nilotinib, except for initial treatment.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

Nilotinib Treatment Consolidation Phase

Patients receive nilotinib for 52 weeks to achieve durable MRD status

52 weeks

Every 4 weeks

Treatment-Free Remission (TFR) Phase

Patients stop nilotinib treatment and are monitored for recurrence of CML

Up to 10 years

Every 4 weeks for the first 48 weeks, every 6 weeks for the next 48 weeks, every 12 weeks thereafter

Nilotinib Treatment Re-initiation Phase

Patients who lose MMR restart nilotinib treatment and are monitored for BCR-ABL levels

Up to 10 years

Every 4 weeks for the first 24 weeks, every 12 weeks thereafter

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Nilotinib
• Treatment-free

Trial Overview The trial is testing if patients with CML who respond well to nilotinib can safely stop treatment without the disease coming back. Participants will first receive nilotinib until they achieve a specific level of response before attempting a treatment-free period.

How Is the Trial Designed?

Group I: Nilotinib followed by treatment-free Experimental Treatment 1 Intervention

Patients who received a minimum of 2 years of first line nilotinib treatment and with pre-screen PCR results in ≥ MR4.5 entered the consolidation phase of the study (52 weeks - nilotinib 300 mg BID). Patients with Minimal Residual Disease (MRD) at the end of this phase entered the Treatment-Free Remission (TFR) phase where no treatment was given. Non eligible patients will enter the continuation phase of the study. Patients with MRD at the end of the continuation phase will enter the TFR-2 phase of the study where no treatment is given. Non eligible patients will enter the prolonged continuation phase of the study. If at any time during TFR or TFR-2 the patient loses MMR, nilotinib treatment will be immediately re-initiated (nilotinib 300 mg BID).

Nilotinib is already approved in European Union, United States, Canada, Japan, Switzerland for the following indications:

Approved in European Union as Tasigna for:

• Chronic myeloid leukemia (CML) in adult patients resistant to or intolerant of at least one prior therapy including imatinib

Approved in United States as Tasigna for:

• Chronic phase (CP) and accelerated phase (AP) Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) in adult patients resistant to or intolerant to prior therapy that included imatinib

Approved in Canada as Tasigna for:

• Chronic myeloid leukemia (CML) in adult patients resistant to or intolerant of at least one prior therapy including imatinib

Approved in Japan as Tasigna for:

• Chronic myeloid leukemia (CML) in adult patients resistant to or intolerant of at least one prior therapy including imatinib

Approved in Switzerland as Tasigna for:

• Chronic myeloid leukemia (CML) in adult patients resistant to or intolerant of at least one prior therapy including imatinib

Who Is Running the Clinical Trial?

Novartis Pharmaceuticals

Lead Sponsor

Trials

2,963

Recruited

4,275,000+

Founded

1996

Headquarters

Basel, Switzerland

Known For

Precision medicine

Top Products

Gleevec, Cosentyx, Entresto, Kisqali

Dr. Vas Narasimhan

Novartis Pharmaceuticals

Chief Executive Officer since 2018

MD from Harvard Medical School

Dr. Shreeram Aradhye

Novartis Pharmaceuticals

Chief Medical Officer since 2021

MD

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12248582/

Real-World Evidence of Treatment-Free Remission ... Historically, CML has had a poor prognosis with an 8-year overall survival rate of <20% [2,3,4]. In 2001, the United States Food and Drug ...

2. onlinelibrary.wiley.com onlinelibrary.wiley.com/doi/10.1002/hon.70126

Treatment‐Free Remission in Chronic Phase ... This phase II study evaluated nilotinib de-escalation outcomes in adults with CML in chronic phase (CP) treated with first-line nilotinib ...

3. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.6566

Long-term follow-up of treatment-free remission in chronic ... The long-term follow-up results continue to demonstrate improved TFR rates of approximately 80% in patients who achieve a deep molecular response (MR4 or ...

4. valueinhealthjournal.com valueinhealthjournal.com/article/S1098-3015(24)06796-2/fulltext

The Cost-Effectiveness of Frontline Tyrosine Kinase ... Nilotinib is most effective (20.13 quality-adjusted life-years [QALYs]) and imatinib is least effective (17.25 QALYs) for the model including ...

5. ashpublications.org ashpublications.org/blood/article-abstract/doi/10.1182/blood.2024026310/534929/The-Evolution-of-Treatment-Free-Remission?redirectedFrom=fulltext

The evolution of treatment-free remission - ASH Publications , et al. Full treatment-free remission outcome in patients with chronic myeloid leukemia in chronic phase following one year of nilotinib de-escalation: 96-week ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4916554/

Nilotinib is effective in patients with chronic myeloid leukemia ... Nilotinib therapy remained well tolerated after 24 months, and no changes were observed in the overall safety profile with longer follow-up. Severe ...

7. scientificarchives.com scientificarchives.com/article/safety-and-tolerability-of-nilotinib-in-patients-with-chronic-myeloid-leukemia-during-routine-clinical-practice-results-from-the-eraser-study-from-greece

Safety and Tolerability of Nilotinib in Patients with Chronic ... The ERASER study demonstrated that nilotinib was well tolerated in adult patients with BCR/ABL+ CML-CP from a wide geographical area of Greece. High rates of ...

8. bloodresearch.or.kr bloodresearch.or.kr/journal/view.html?doi=10.5045/br.2022.2021137

Safety and efficacy of nilotinib in adult patients with chronic ... As for the efficacy results, CHR was achieved in 89.5% (442/494 patients), and minor cytogenetic response or major cytogenetic response was ...

9. clinicaltrials.gov clinicaltrials.gov/study/NCT02086487

Efficacy and Safety Assessment of NIlotinib in CML ... Patients diagnosed with chronic myeloid leukemia receiving treatment of Imatinib 400 mg but show sub-optimal response on Imatinib therapy as per the ELN 2013 ...

10. ashpublications.org ashpublications.org/bloodadvances/article/7/23/7279/497976/The-long-term-efficacy-and-safety-of-nilotinib-in

The long-term efficacy and safety of nilotinib in pediatric ... Nilotinib treatment demonstrated sustained long-term efficacy in pediatric patients with CML-CP. The overall benefit-risk assessment of ...