Clinical trial NCT01784068: Nilotinib Treatment-free Remission Study in CML (Chronic Myeloid Leukemia) Patients
Official title: A Single-arm, Multicenter, Nilotinib Treatment-free Remission Study in Patients With BCR-ABL1 Positive Chronic Myelogenous Leukemia in Chronic Phase Who Have Achieved Durable Minimal Residual Disease (MRD) Status on First Line Nilotinib Treatment.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Chronic Myelogenous Leukemia
Keywords: AMN107
Ph+ CML-CP
chronic phase
nilotinib treatment
2 years treatment
MR 4.5
Loss of MR 4
Loss of MMR
CML
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2013-02-05
Enrollment: 215
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: OTHER

Brief summary: The main purpose of the study was to investigate whether nilotinib treatment can be safely suspended with no recurrence of CML in selected patients who responded optimally on this treatment

Detailed description: The Primary objective of this study was to determine the percentage of patients who were in MMR at 48 weeks after starting the TFR phase (patients who required re-initiation of treatment were considered as non-responders).

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. All patients were treated with the planned nilotinib dose 300 mg BID (or at a reduced dose level of 400 mg QD if required from the perspective of toxicity). In order for patients to be eligible for the TFR phase, they had to fulfill the protocol specific definition of durable MRD. The four last quarterly performed PCR assessments must have fulfilled the following criteria:

* The last assessment was MR4.5 (BCR-ABL ≤ 0.0032% IS)
* No assessment worse than MR4.0 (BCR-ABL \>0.01% IS) and
* No more than two assessments between MR4.0 and MR4.5 (0.0032% IS\<BCR-ABL ≤ 0.01% IS)

Nilotinib TFR phase: Patients who were eligible to enter in the TFR phase after completing the 52 weeks consolidation phase, stopped taking nilotinib on the first day of the TFR phase. Duration of this phase was up to 10 years after the last patient enters in the TFR phase. BCR-ABL levels were monitored every four weeks during the first 48 weeks, every six weeks for the following 48 weeks and every 12 weeks during the last period.

Nilotinib treatment re-initiation (NTRI) phase: If a patient had a loss of MMR (BCR-ABL \>0.1% IS) in the TFR phase, the patient restarted nilotinib treatment. Patients were on nilotinib treatment for up to 10 years after the last patient entered the nilotinib TFR phase. Patients who required re-initiation of nilotinib treatment were monitored for the BCR-ABL level every four weeks for the first 24 weeks and then every 12 weeks thereafter in patients who regained MMR. The frequency of BCR-ABL monitoring in patients not regaining MMR within the first 24 weeks after re-initiation of treatment was at least every 12 weeks or more frequently as clinically indicated.

Eligibility criteria: Inclusion Criteria:

* Male or female patients ≥ 18 years of age
* Minimum of 2 calendar years of nilotinib treatment with at least the last 12 months of nilotinib treatment prior to pre-screening at approved total daily dose of 600 mg BID or at a reduced dose of 400 mg QD if required from the perspective of tolerance for BCR-ABL positive CML in documented chronic phase at the time of diagnosis
* Evidence of typical BCR-ABL transcripts (b3a2 and/or b2a2) at the time of CML-CP diagnosis i.e. prior to first start of TKI treatment which are amenable to standardized RT-PCR quantification"
* Patient in MR4.5 at prescreening at Novartis designated lab
* ECOG performance status of 0-2
* Adequate end organ function as defined by:

  * Direct bilirubin ≤ 1.5 x ULN except for i) patients 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 i.e. equivalent to ≤ Grade 1 NCI-CTCAE v.4.03
  * Serum lipase ≤ 2 x ULN i.e. equivalent to ≤ Grade 2 NCI-CTCAE v.4.03
  * Alkaline phosphatase ≤ 2.5 x ULN
  * Serum creatinine \< 1.5 x ULN
* Patients must have the following electrolyte values within normal limits or corrected to be within normal limits with supplements prior to first dose of study medication:

  * Potassium (suggested keep to prevent issues with QT and/or rhythm abnormalities)
  * Magnesium (suggested keep to prevent issues with QT and/or rhythm abnormalities)
  * Total calcium (corrected for serum albumin)
* Patients must have normal marrow function as defined:

  * Absolute Neutrophil Count (ANC) ≥ 1.5 x 10E9/L
  * Hemoglobin ≥ 9.0 g/dL
  * Platelets ≥ 100 x 10E9/L
* Documented chronic phase CML must meet all the criteria defined by:

  * \< 15% blasts in peripheral blood and bone marrow,
  * \< 30% blasts plus promyelocytes in peripheral blood and bone marrow,
  * \< 20% basophils in the peripheral blood,
  * ≥ 100 x 109/L (≥ 100,000/mm3) platelets,
  * No evidence of extramedullary leukemic involvement, with the exception of hepatosplenomegaly
* Patients must tolerate a minimum total daily dose of nilotinib of 400 mg

Exclusion Criteria:

* Previous treatment with BCR-ABL inhibitors other than nilotinib for more than a total cumulative duration of 4 weeks
* Previous treatment with alpha-interferon of any duration
* Previous anticancer agents for CML other than nilotinib except for cytoreduction after CML diagnosis until up to 4 weeks after first dose of nilotinib
* Known second chronic phase of CML after previous progression to AP/BC
* Poorly controlled diabetes mellitus (defined as HbA1c \> 9%)
* 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. (see http://www.torsades.org/medical-pros/drug-lists/printable-drug-list.cfm for a list of agents that prolong the QT interval)
* 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:

    1. 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.
    2. Placement of an intrauterine device (IUD) or intrauterine system (IUS)
    3. 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.

Primary outcomes:
measure: Percentage of Patients Who Are in MMR (Major Molecular Response) at 48 Weeks After Starting the Treatment-free Remission (TFR) Phase
timeFrame: 48 weeks
Secondary outcomes:
measure: Percentage of Patients Who Are in MR4.5 (BCR-ABL ≤ 0.0032% IS) at 48 Weeks After Starting the TFR Phase
timeFrame: 48 weeks
measure: Percentage of Patients Who Are in MMR at 96, 144,192, 264 Weeks and at the End of 6, 7, 8, 9 and 10 Years After Starting the TFR Phase
timeFrame: 96, 144, 192, 264 weeks, end of 6, 7, 8, 9 and 10 years
measure: Percentage of Patients Who Are in MR4.5 at 96, 144, 192, 264 Weeks and at the End of 6, 7, 8, 9 and 10 Years After Starting the TFR Phase
timeFrame: 96, 144, 192, 264 weeks, end of 6, 7, 8, 9 and 10 years
measure: Percentage of Patients in MMR at 48, 96, 144, 192, 264 Weeks and at the End of 6, 7, 8, 9 and 10 Years After Starting the TFR Phase of Nilotinib
timeFrame: 48, 96, 144, 192, 264 weeks and at the end of 6, 7, 8, 9 and 10 years
measure: Percentage of Patients in MR4.5 at 48, 96, 144, 192, 264 Weeks and at the End of 6, 7, 8, 9 and 10 Years After Starting the TFR Phase of Nilotinib
timeFrame: 48, 96, 144, 192, 264 weeks, end of 6, 7, 8, 9 and 10 years
measure: Percentage of Patients Who Achieve MMR Within 12 Weeks of Re-treatment With Nilotinib
timeFrame: 12 weeks
measure: Kinetics of BCR-ABL Transcript After Re-start of Nilotinib Therapy
timeFrame: Every 4 weeks up to week 24 and every 12 weeks thereafter up to 528 weeks after last patient has entered the TFR
measure: Duration of Re-initiated Treatment Required to Regain MMR After Loss of MMR
timeFrame: Every 4 weeks up to week 24 and every 12 weeks thereafter up to 528 weeks after the last patient has entered TFR
measure: Duration of Re-initiated Treatment Required to Regain MR4.5 After Loss of MMR
timeFrame: Every 4 weeks up to week 24 and every 12 weeks thereafter up to 528 weeks after the last patient has entered TFR
measure: Treatment-free Survival (TFS) After the Start of the TFR Phase
timeFrame: Every 4 weeks in the first period of 48 weeks of the TFR, every 6 weeks in the second period of 48 weeks in TFR and every 12 weeks in the last period of 432 weeks of the TFR
measure: Progression-free Survival (PFS) After the Start of the TFR Phase
timeFrame: Every 4 weeks in the first period of 48 weeks of the TFR, every 6 weeks in the second period of 48 weeks of TFR and every 12 weeks in the last period of 432 weeks of the TFR
measure: Overall Survival (OS) After the Start of the TFR Phase
timeFrame: Every 4 weeks in the first period of 48 weeks of the TFR, every 6 weeks in the second period of 48 weeks of TFR and every 12 weeks in the last period of 432 weeks of the TFR
measure: Safety Profile During the Nilotinib Treatment Consolidation Phase, During the TFR Phase and During Re-initiation Treatment With Nilotinib
timeFrame: Every 4 weeks in treatment consolidation and during the first 24 weeks of the re-initiation phase, every 12 weeks thereafter. Every 4, 6 and 12 weeks respectively in the first and second period of 48 weeks and in the last period of 432 weeks of the TFR
measure: Proportion of Patients Who Develop T3151, E255K/V, Y253H, F359V/C/I Mutations on Study or Any Other BCR-ABL Mutations in Patients Who Lost MMR After Nilotinib Suspension
timeFrame: Every 3 months in patients who lost MMR until the result is negative or up to 528 weeks after the last patient entered TFR. On average 3 analyses (every 3 months or up to 264 weeks after the last patient has entered TFR.)
measure: Percentage of Patients Who Are in Stable Response (MMR and MR4.5) After Achievement of That Response in Nilotinib Re-initiation Phase for 48, 96, 144, 192, 240, 288, 336, 384 and 432 Weeks, Based on Availability of Appropriate Data
timeFrame: 48, 96, 144, 192, 240, 288, 336, 384 and 432 weeks
Other outcomes:
Locations:
city: Fort Myers
country: United States
facility: Florida Cancer Specialists
state: Florida
city: Miami Lakes
country: United States
facility: Lakes Research
state: Florida
city: Tampa
country: United States
facility: H Lee Moffitt Cancer Center and Research Institute
state: Florida
city: Wichita
country: United States
facility: Cancer Center of Kansas
state: Kansas
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: New York
country: United States
facility: Memorial Sloan Kettering
state: New York
city: Portland
country: United States
facility: Oregon Health Sciences University
state: Oregon
city: Greenville
country: United States
facility: Cancer Centers of the Carolinas
state: South Carolina
city: Chattanooga
country: United States
facility: Tennessee Oncology PLLC
state: Tennessee
city: Ogden
country: United States
facility: Community Cancer Trials of Utah
state: Utah
city: Buenos Aires
country: Argentina
facility: Novartis Investigative Site
city: Graz
country: Austria
facility: Novartis Investigative Site
city: Rankweil
country: Austria
facility: Novartis Investigative Site
city: Salzburg
country: Austria
facility: Novartis Investigative Site
city: Vienna
country: Austria
facility: Novartis Investigative Site
city: Wien
country: Austria
facility: Novartis Investigative Site
city: Sint Niklaas
country: Belgium
facility: Novartis Investigative Site
state: Oost Vlaanderen
city: Brussel
country: Belgium
facility: Novartis Investigative Site
city: Bruxelles
country: Belgium
facility: Novartis Investigative Site
city: Charleroi
country: Belgium
facility: Novartis Investigative Site
city: Gent
country: Belgium
facility: Novartis Investigative Site
city: Kortrijk
country: Belgium
facility: Novartis Investigative Site
city: Liege
country: Belgium
facility: Novartis Investigative Site
city: Varna
country: Bulgaria
facility: Novartis Investigative Site
city: Bogota
country: Colombia
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state: Cundinamarca
city: Monteria
country: Colombia
facility: Novartis Investigative Site
city: Aarhus N
country: Denmark
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city: Bayonne
country: France
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state: Bayonne Cedex
city: Saint Priest en Jarez
country: France
facility: Novartis Investigative Site
state: Loire
city: Bordeaux
country: France
facility: Novartis Investigative Site
city: Brest
country: France
facility: Novartis Investigative Site
city: Corbeil Essonnes
country: France
facility: Novartis Investigative Site
city: Dunkerque
country: France
facility: Novartis Investigative Site
city: Grenoble
country: France
facility: Novartis Investigative Site
city: Nantes
country: France
facility: Novartis Investigative Site
city: Rouen
country: France
facility: Novartis Investigative Site
city: Strasbourg cedex
country: France
facility: Novartis Investigative Site
city: Strasbourg
country: France
facility: Novartis Investigative Site
city: Toulouse
country: France
facility: Novartis Investigative Site
city: Mannheim
country: Germany
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state: Baden Wuerttemberg
city: Frankfurt am Main
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state: Hessen
city: Leipzig
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state: Sachsen
city: Luebeck
country: Germany
facility: Novartis Investigative Site
state: Schleswig-Holstein
city: Aachen
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facility: Novartis Investigative Site
city: Bayreuth
country: Germany
facility: Novartis Investigative Site
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facility: Novartis Investigative Site
city: Bonn
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city: Bottrop
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city: Dresden
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city: Duesseldorf
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city: Duesseldorf
country: Germany
facility: Novartis Investigative Site
city: Freiburg
country: Germany
facility: Novartis Investigative Site
city: Goslar
country: Germany
facility: Novartis Investigative Site
city: Hamburg
country: Germany
facility: Novartis Investigative Site
city: Hamburg
country: Germany
facility: Novartis Investigative Site
city: Jena
country: Germany
facility: Novartis Investigative Site
city: Magdeburg
country: Germany
facility: Novartis Investigative Site
city: Mainz
country: Germany
facility: Novartis Investigative Site
city: Stuttgart
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: Athens
country: Greece
facility: Novartis Investigative Site
state: GR
city: Athens
country: Greece
facility: Novartis Investigative Site
city: Budapest
country: Hungary
facility: Novartis Investigative Site
city: Szeged
country: Hungary
facility: Novartis Investigative Site
city: Dublin
country: Ireland
facility: Novartis Investigative Site
city: Galway
country: Ireland
facility: Novartis Investigative Site
city: Ancona
country: Italy
facility: Novartis Investigative Site
state: AN
city: Brescia
country: Italy
facility: Novartis Investigative Site
state: BS
city: Cona
country: Italy
facility: Novartis Investigative Site
state: FE
city: Firenze
country: Italy
facility: Novartis Investigative Site
state: FI
city: Genova
country: Italy
facility: Novartis Investigative Site
state: GE
city: Nuoro
country: Italy
facility: Novartis Investigative Site
state: NU
city: Perugia
country: Italy
facility: Novartis Investigative Site
state: PG
city: Reggio Calabria
country: Italy
facility: Novartis Investigative Site
state: RC
city: Roma
country: Italy
facility: Novartis Investigative Site
state: RM
city: Orbassano
country: Italy
facility: Novartis Investigative Site
state: TO
city: Terni
country: Italy
facility: Novartis Investigative Site
state: TR
city: Napoli
country: Italy
facility: Novartis Investigative Site
city: Novara
country: Italy
facility: Novartis Investigative Site
city: Kashiwa-city
country: Japan
facility: Novartis Investigative Site
state: Chiba
city: Sapporo city
country: Japan
facility: Novartis Investigative Site
state: Hokkaido
city: Sagamihara
country: Japan
facility: Novartis Investigative Site
state: Kanagawa
city: Osaka Sayama
country: Japan
facility: Novartis Investigative Site
state: Osaka
city: Suita
country: Japan
facility: Novartis Investigative Site
state: Osaka
city: Saga-city
country: Japan
facility: Novartis Investigative Site
state: Saga
city: Kawagoe
country: Japan
facility: Novartis Investigative Site
state: Saitama
city: Shimotsuga Gun
country: Japan
facility: Novartis Investigative Site
state: Tochigi
city: Bunkyo-ku
country: Japan
facility: Novartis Investigative Site
state: Tokyo
city: Shinjuku Ku
country: Japan
facility: Novartis Investigative Site
state: Tokyo
city: Akita
country: Japan
facility: Novartis Investigative Site
city: Kumamoto
country: Japan
facility: Novartis Investigative Site
city: Groningen
country: Netherlands
facility: Novartis Investigative Site
city: Gdansk
country: Poland
facility: Novartis Investigative Site
city: Warszawa
country: Poland
facility: Novartis Investigative Site
city: Oviedo
country: Spain
facility: Novartis Investigative Site
state: Asturias
city: Tarragona
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: Terrassa
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: Orense
country: Spain
facility: Novartis Investigative Site
state: Galicia
city: Pamplona
country: Spain
facility: Novartis Investigative Site
state: Navarra
city: La Laguna
country: Spain
facility: Novartis Investigative Site
state: Santa Cruz De Tenerife
city: Baracaldo
country: Spain
facility: Novartis Investigative Site
state: Vizcaya
city: Barcelona
country: Spain
facility: Novartis Investigative Site
city: Las Palmas de Gran Canaria
country: Spain
facility: Novartis Investigative Site
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: Madrid
country: Spain
facility: Novartis Investigative Site
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Lund
country: Sweden
facility: Novartis Investigative Site
city: Stockholm
country: Sweden
facility: Novartis Investigative Site
city: Uppsala
country: Sweden
facility: Novartis Investigative Site
city: Cardiff
country: United Kingdom
facility: Novartis Investigative Site
city: Oxford
country: United Kingdom
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References: