Clinical trial NCT01698905: Treatment-free Remission After Achieving Sustained MR4.5 on Nilotinib (ENESTop)
Official title: A Phase II, Single Arm, Open Label Study of Treatment-free Remission in Chronic Myeloid Leukemia (CML) Chronic Phase (CP) Patients After Achieving Sustained MR4.5 on Nilotinib
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Chronic Myeloid Leukemia
Keywords: AMN107
CML
Phase II
single arm
open label
nilotinib
treatment-free remission
MR4.5
confirmed loss of MR4
loss of MMR
Ph+ CML-CP
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2012-10-03
Enrollment: 163
Sex: ALL
Minimum age (years): 18
Maximum age (years): 100
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: A clinical research study to find out if it is safe to stop the drug nilotinib (Tasigna) in chronic myeloid leukemia (CML) patients. Patients who started treatment with imatinib (Gleevec) when they were first diagnosed with CML, then switched to nilotinib (Tasigna) for at least 2 years with the combined time on imatinib (Gleevec) and nilotinib (Tasigna) for at least 3 years and have very small amount of leukemia cells remaining after the nilotinib (Tasigna) treatment will qualify for the study.

Detailed description: The Primary objective was to evaluate the proportion of patients in TFR within 48 weeks following nilotinib cessation.

This study originally consisted of seven phases (five treatment phases and two treatment-free phases) from which two were the focus of this primary analysis report (consolidation, TFR and treatment re-initiation) The study consisted of 2 main phases: Consolidation and TFR

Nilotinib treatment consolidation phase (NTCS): Patients who satisfied all inclusion/exclusion criteria were enrolled in the consolidation phase and continued to receive nilotinib for 52 weeks at the dose which the patient was receiving prior to study entry. If a patient maintained MR4.5 throughout the consolidation phase, he/she was eligible to enter in the TFR phase. If a patient had confirmed loss of MR4.5 during the consolidation phase, he/she was not eligible to enter in the TFR phase and continued nilotinib treatment.

Nilotinib TFR phase: Patients who were eligible to enter in the TFR phase after completing the 52 week consolidation phase stopped taking nilotinib on the first day of the TFR phase. Duration of this phase was up to 520 weeks after the last patient enters in the TFR phase.

Nilotinib treatment re-initiation phase (NTRI): If a patient had a confirmed loss of MR4 (two consecutive BCR-ABL \>0.01% IS) or loss of MMR (BCR-ABL \>0.1% IS) in the TFR phase, the patient restarted nilotinib treatment. Patients will be on nilotinib treatment for up to 520 weeks after the last patient entered the nilotinib TFR phase, or until a patient experience unacceptable toxicity, disease progression and/or treatment discontinued at the discretion of the Investigator or if the patient withdrew consent. Nilotinib cessation was not attempted for a second time in the patient who reinitiated treatment or discontinued following the TFR phase.

Nilotinib treatment continuation phase (NTCT) and Nilotinib treatment prolonged continuation phase (NTCT-P): Patients who were not eligible to enter into the TFR phase after completing the 52-week NTCS phase entered the nilotinib treatment continuation (NTCT) phase and would continue treatment with nilotinib for another 52 weeks (a total of 104 weeks of treatment). Patients who were not able to maintain MR4.5 and had a confirmed loss of MR4.5 during the NTCT phase were not eligible to enter the TFR-2 phase. These patients entered into the nilotinib prolonged treatment continuation phase (NTCT-P) and continued nilotinib treatment until 520 weeks after the last patient entered the nilotinib TFR phase, or until the patients experience unacceptable toxicity, disease progression and/or treatment would be discontinued at the discretion of the Investigator or withdrawal of consent.

Nilotinib TFR-2 phase: Patients who maintained MR4.5 during the NTCT phase were eligible to cease nilotinib treatment and enter the TFR-2 phase. The duration of the nilotinib TFR-2 phase is up to 520 weeks after the last patient entered the TFR phase. Patients stopped taking nilotinib therapy on the day they entered the TFR-2 phase.

Nilotinib treatment re-initiation-2 (NTRI-2): If a patient had a loss of MMR or a confirmed loss of MR4 during the TFR-2 phase, he/she entered the nilotinib treatment re-initiation-2 (NTRI-2) phase and resumed nilotinib treatment at a dose of either 300 mg or 400 mg bid.

Safety follow-up was performed within 30 days after the last dose of study treatment or the last day in TFR/TFR-2.

Post-treatment follow-up visits were performed every 12 weeks up to 520 weeks after the last patient entered the nilotinib TFR phase.

Eligibility criteria: Inclusion Criteria:

1. Male or female patients \>= 18 years of age
2. ECOG Performance Status of 0, 1, or 2
3. Patient with diagnosis of BCR-ABL positive CML CP
4. Patient has received a minimum of 3 years of tyrosine kinase inhibitor treatment (first with imatinib (\> 4 weeks) and then switched to nilotinib) since initial diagnosis
5. Patient has at least 2 years of nilotinib treatment prior to study entry.
6. Patient has achieved MR4.5 (local laboratory assessment) during nilotinib treatment, and determined by a Novartis designated central PCR lab assessment at screening
7. Adequate end organ function as defined by:

   * Direct bilirubin ≤ 1.5 x ULN except for i) patient with documented Gilbert's syndrome for whom any bilirubin value is allowed and ii) for patients with asymptomatic hyperbilirubinemia (liver transaminases and alkaline phosphatase within normal range)
   * SGOT(AST) and SGPT(ALT) \< 3 x ULN (upper limit of normal)
   * Serum lipase ≤ 2 x ULN
   * Alkaline phosphatase ≤ 2.5 x ULN
   * Serum creatinine \< 1.5 x ULN
8. Patients must have the following electrolyte values ≥ LLN (lower limit of normal) limits or corrected to within normal limits with supplements prior to the first dose of study medication:

   * Potassium
   * Magnesium
   * Total calcium (corrected for serum albumin)
9. Patients must have normal marrow function as defined below:

   * Absolute Neutrophil Count (ANC) ≥ 1.5 x 109/L
   * Platelets ≥ 100 x 109/L
   * Hemoglobin ≥ 9.0 g/dL
10. Written informed consent obtained prior to any screening procedures

Exclusion Criteria:

1. Prior AP, BC or allo-transplant
2. Patient has documented MR4.5 at the time when switched from imatinib to nilotinib
3. Patients with known atypical transcript
4. CML treatment resistant mutation(s) (T315I, E255K/V, Y253H, F359C/V) detected if a 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)
5. Dose reductions due to neutropenia or thrombocytopenia in the past 6 months
6. Patient ever attempted to permanently discontinue imatinib or nilotinib treatment
7. Known impaired cardiac function including any one of the following:

   * Inability to determine the 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)
8. 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 (defined as HbA1c \> 9%), uncontrolled infection)
9. History of acute pancreatitis within 1 year prior to study entry or past medical history of chronic pancreatitis
10. Known presence of a significant congenital or acquired bleeding disorder unrelated to cancer
11. History of other active malignancy within 5 years prior to study entry with the exception of previous or concomitant basal cell skin cancer, previous cervical carcinoma in situ treated curatively
12. Patients who have not recovered from prior surgery
13. Treatment with other investigational agents (defined as not used in accordance with the approved indication) within 4 weeks of Day 1
14. 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. See Appendix 14.1 for a list of these medications. This list may not be comprehensive.
15. 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.
16. 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 study entry. (Please see www.azcert.org/medical-pros/drug-lists/printable-drug-list.cfm for a list of agents that prolong the QT interval.)
17. 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)
18. 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.
19. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, must have a negative serum pregnancy test before initiation of study treatment and must also use highly effective methods of contraception while enrolled in the study. The use of highly effective contraception should continue for at least 14 days after the last dose of study treatment or until the last day of TFR/TFR-2, or for the duration of a monthly cycle of oral contraception, whichever is longer. Acceptable forms of highly effective contraception methods include:

    * 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), 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 be 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), total 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 is suspected of being pregnant during the study or within 30 days as part of safety evaluations after the final dose of nilotinib, the Study Doctor needs to be informed immediately and any ongoing study treatment with nilotinib has to be stopped immediately.

Primary outcomes:
measure: Percentage of Patients in Treatment Free Remission (TFR) Within 48 Weeks
timeFrame: First 48 weeks following nilotinib cessation.
Secondary outcomes:
measure: Percentage of Patients in Treatment Free Remission (TFR) Within 96, 144, 192, 264 Weeks and Within 6,7,8,9 and 10 Years
timeFrame: 96, 144, 192, 264 weeks and within 6,7,8,9 and 10 years following nilotinib cessation
measure: Progression Free Survival (PFS) to Accelerated Phase/Blast Crisis (AP/BC) or Death
timeFrame: nilotinib cessation up to approximately 580 weeks
measure: Treatment Free Survival (TFS)
timeFrame: nilotinib cessation up to approximately 580 weeks
measure: Overall Survival (OS)
timeFrame: nilotinib cessation up to approximately 580 weeks
measure: Change in BCR-ABL (Oncoprotein Product of BCR-ABL Fusion Gene) Transcripts After Re-start of Nilotinib Therapy
timeFrame: re-start of nilotinib up to approximately 48 weeks
measure: Percentage of Patients With Stable MMR in Nilotinib Re-initiation Phase
timeFrame: start of nilotinib in re-initiation phase up to approximately 432 weeks
measure: Percentage of Patients With Stable MR4 in Nilotinib Re-initiation Phase
timeFrame: start of nilotinib in re-initiation phase up to approximately 432 weeks
measure: Percentage of Patients With Stable MR4.5 in Nilotinib Re-initiation Phase
timeFrame: start of nilotinib in re-initiation phase up to approximately 432 weeks
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: USC Kenneth Norris Comprehensive Cancer Center
state: California
city: Beech Grove
country: United States
facility: Indiana Blood and Marrow Institute
state: Indiana
city: Baltimore
country: United States
facility: St Agnes Hospital
state: Maryland
city: Galveston
country: United States
facility: University of Texas Medical Branch
state: Texas
city: Vancouver
country: United States
facility: Compass Oncology
state: Washington
city: Caba
country: Argentina
facility: Novartis Investigative Site
state: Buenos Aires
city: Buenos Aires
country: Argentina
facility: Novartis Investigative Site
city: Adelaide
country: Australia
facility: Novartis Investigative Site
state: South Australia
city: Box Hill
country: Australia
facility: Novartis Investigative Site
state: Victoria
city: Antwerp
country: Belgium
facility: Novartis Investigative Site
city: Goiania
country: Brazil
facility: Novartis Investigative Site
state: GO
city: Belo Horizonte
country: Brazil
facility: Novartis Investigative Site
state: MG
city: Rio de Janeiro
country: Brazil
facility: Novartis Investigative Site
state: RJ
city: Rio De Janiero
country: Brazil
facility: Novartis Investigative Site
state: RJ
city: Porto Alegre
country: Brazil
facility: Novartis Investigative Site
state: RS
city: Campinas
country: Brazil
facility: Novartis Investigative Site
state: SP
city: Hamilton
country: Canada
facility: Novartis Investigative Site
state: Ontario
city: Toronto
country: Canada
facility: Novartis Investigative Site
state: Ontario
city: Montreal
country: Canada
facility: Novartis Investigative Site
state: Quebec
city: Quebec
country: Canada
facility: Novartis Investigative Site
city: Bordeaux
country: France
facility: Novartis Investigative Site
city: Grenoble
country: France
facility: Novartis Investigative Site
city: Lyon
country: France
facility: Novartis Investigative Site
city: Strasbourg cedex
country: France
facility: Novartis Investigative Site
city: Vandoeuvre Les Nancy
country: France
facility: Novartis Investigative Site
city: Mannheim
country: Germany
facility: Novartis Investigative Site
state: Baden Wuerttemberg
city: Berlin
country: Germany
facility: Novartis Investigative Site
city: Heilbronn
country: Germany
facility: Novartis Investigative Site
city: Potsdam
country: Germany
facility: Novartis Investigative Site
city: Ulm
country: Germany
facility: Novartis Investigative Site
city: Athens
country: Greece
facility: Novartis Investigative Site
state: Attiki
city: Larissa
country: Greece
facility: Novartis Investigative Site
state: GR
city: Athens
country: Greece
facility: Novartis Investigative Site
city: Haifa
country: Israel
facility: Novartis Investigative Site
city: Petach Tikva
country: Israel
facility: Novartis Investigative Site
city: Ramat Gan
country: Israel
facility: Novartis Investigative Site
city: Nagoya
country: Japan
facility: Novartis Investigative Site
state: Aichi
city: Narita
country: Japan
facility: Novartis Investigative Site
state: Chiba
city: Fukuoka city
country: Japan
facility: Novartis Investigative Site
state: Fukuoka
city: Kurume city
country: Japan
facility: Novartis Investigative Site
state: Fukuoka
city: Akita
country: Japan
facility: Novartis Investigative Site
city: Aomori
country: Japan
facility: Novartis Investigative Site
city: Chiba
country: Japan
facility: Novartis Investigative Site
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
state: Seocho Gu
city: Monterrey
country: Mexico
facility: Novartis Investigative Site
state: Nuevo Leon
city: Krakow
country: Poland
facility: Novartis Investigative Site
state: Malopolskie
city: Gdansk
country: Poland
facility: Novartis Investigative Site
city: Warszawa
country: Poland
facility: Novartis Investigative Site
city: Moscow
country: Russian Federation
facility: Novartis Investigative Site
city: Saint Petersburg
country: Russian Federation
facility: Novartis Investigative Site
city: Saint Petersburg
country: Russian Federation
facility: Novartis Investigative Site
city: Singapore
country: Singapore
facility: Novartis Investigative Site
city: Sevilla
country: Spain
facility: Novartis Investigative Site
state: Andalucia
city: Santander
country: Spain
facility: Novartis Investigative Site
state: Cantabria
city: Badalona
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: Alicante
country: Spain
facility: Novartis Investigative Site
state: Comunidad Valenciana
city: La Laguna
country: Spain
facility: Novartis Investigative Site
state: Santa Cruz De Tenerife
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Liverpool
country: United Kingdom
facility: Novartis Investigative Site
city: Nottingham
country: United Kingdom
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References:
citation: Mahon FX, Boquimpani C, Kim DW, Benyamini N, Clementino NCD, Shuvaev V, Ailawadhi S, Lipton JH, Turkina AG, De Paz R, Moiraghi B, Nicolini FE, Dengler J, Sacha T, Takahashi N, Fellague-Chebra R, Acharya S, Wong S, Jin Y, Hughes TP. Treatment-Free Remission After Second-Line Nilotinib Treatment in Patients With Chronic Myeloid Leukemia in Chronic Phase: Results From a Single-Group, Phase 2, Open-Label Study. Ann Intern Med. 2018 Apr 3;168(7):461-470. doi: 10.7326/M17-1094. Epub 2018 Feb 20.