Clinical trial NCT00844298: Nilotinib and Combination Chemotherapy in Treating Patients With Newly Diagnosed Acute Lymphoblastic Leukemia
Official title: Tasigna® (Nilotinib) Plus Multi-Agent Chemotherapy for Newly-Diagnosed Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Leukemia
Keywords: Philadelphia chromosome positive adult precursor acute lymphoblastic leukemia
untreated adult acute lymphoblastic leukemia
Lead sponsor: Asan Medical Center
Sponsor class: OTHER
First posted: 2009-02-16
Enrollment: 91
Sex: ALL
Minimum age (years): 15
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: RATIONALE: Nilotinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving nilotinib together with combination chemotherapy may kill more cancer cells.

PURPOSE: This phase II trial is studying how well giving nilotinib together with combination chemotherapy works in treating patients with newly diagnosed acute lymphoblastic leukemia.

Detailed description: OBJECTIVES:

Primary

* To determine the clinical efficacy of nilotinib and combination chemotherapy, in terms of hematologic and molecular complete remission (CR) rates, in patients with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia or acute mixed lineage leukemia.

Secondary

* To establish the prognostic factors for patients treated with this regimen.
* To determine the duration of CR in patients treated with this regimen.
* To determine the duration of progression-free and overall survival of these patients.
* To determine the toxicity of this regimen in these patients.

OUTLINE: This is a multicenter study. Patients are stratified according to age (15 to 64 years vs ≥ 65 years).

* Induction therapy: Patients receive daunorubicin hydrochloride IV continuously over 24 hours on days 1-3, vincristine sulfate IV on days 1 and 8, and oral prednisolone on days 1-14. Patients undergo bone marrow examination on day 14. Patients in hematologic remission proceed to consolidation therapy. Patients with residual leukemic cells \> 5% receive an additional dose of daunorubicin hydrochloride IV continuously over 24 hours on day 15 before proceeding to consolidation therapy.
* Consolidation therapy: For course 1, patients receive daunorubicin hydrochloride IV continuously over 24 hours on days 1 and 2, vincristine sulfate IV on days 1 and 8, and oral prednisolone on days 1-14. For courses 2 and 4, patients receive cytarabine IV over 2 hours and etoposide IV over 3 hours on days 1-4. For courses 3 and 5, patients receive methotrexate IV continuously over 36 hours on days 1, 2, 15, and 16 and leucovorin calcium IV every 6 hours for 3 doses and then orally until blood methotrexate levels are in a safe range.

Patients also receive oral nilotinib twice daily beginning on day 8 of induction therapy and continuing until the completion of consolidation therapy.

After completion of consolidation therapy, patients with a hematopoietic stem cell donor proceed to allogeneic hematopoietic stem cell transplantation (HSCT). Patients who do not undergo HSCT continue to receive oral nilotinib twice daily for up to 2 years after completion of consolidation therapy.

After completion of study therapy, patients are followed periodically for up to 1 year.

Eligibility criteria: DISEASE CHARACTERISTICS:

* Newly diagnosed acute lymphoblastic leukemia or acute mixed lineage leukemia

  * Positive for Bcr-Abl fusion transcript (Philadelphia chromosome-positive disease) by RT-PCR

PATIENT CHARACTERISTICS:

* ECOG performance status 0-2
* Total bilirubin \< 2 mg/dL
* SGOT \< 3 times upper limit of normal (ULN)
* Alkaline phosphatase ≤ 2.5 times ULN (unless considered tumor-related)
* Creatinine \< 2.0 mg/dL ULN
* Serum amylase and lipase ≤ 1.5 times ULN
* Potassium, magnesium, and phosphorus normal (supplementation allowed)
* Not pregnant or nursing
* Negative pregnancy test
* Fertile patients must use effective contraception
* No rare hereditary problems with galactose intolerance, severe lactase deficiency, or glucose-galactose malabsorption
* No known sensitivity to any of the study drugs
* No severe medical condition that, in the opinion of the investigator, would preclude study participation
* No impaired cardiac function, including any of the following:

  * LVEF \< 45% or below the lower limit of normal by ECHO
  * Long QT syndrome or known family history of long QT syndrome
  * Clinically significant resting bradycardia (\< 50 beats per minute)
  * QTc \> 450 msec on baseline ECG (using the QTcF formula)
  * Myocardial infarction within the past 12 months
  * Other clinically significant heart disease, including any of the following:

    * Unstable angina
    * Congestive heart failure
    * Uncontrolled hypertension
    * Uncontrolled arrhythmias
* No other primary malignant disease requiring systemic treatment
* No acute or chronic liver, pancreatic, or severe renal disease
* No other severe and/or life-threatening medical disease
* No history of significant congenital or acquired bleeding disorder unrelated to cancer
* No impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of study drug
* No history of non-compliance

PRIOR CONCURRENT THERAPY:

* More than 30 days since prior investigational agents
* No concurrent medications that have the potential to prolong the QTc interval
* No concurrent strong CYP3A4 inhibitors
* No concurrent therapeutic coumarin derivatives

Primary outcomes:
measure: Proportion of Patients Achieving Hematologic and Molecular Complete Remission (CR) After Induction Therapy
timeFrame: 1 month
Secondary outcomes:
measure: Disease(Relapse)-Free Survival
timeFrame: 2 years
measure: Overall Survival
timeFrame: 2 years
Other outcomes:
Locations:
city: Daegu
country: Korea, Republic of
facility: Daegu Fatima Hospital
city: Daegu
country: Korea, Republic of
facility: Kyungpook National University Hospital
city: Daegu
country: Korea, Republic of
facility: Yeungnam University Medical Center
city: Daegu
country: Korea, Republic of
facility: Daegu Catholic University Hospital
city: Goyang
country: Korea, Republic of
facility: National Cancer Center - Korea
city: Jeollanam-do
country: Korea, Republic of
facility: Chonnam National University Hwasun Hospital
city: Jinju
country: Korea, Republic of
facility: Gyeongsang National University Hospital
city: Pusan
country: Korea, Republic of
facility: Pusan National University Hospital
city: Seoul
country: Korea, Republic of
facility: Inje University Seoul Paik Hospital
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Seoul
country: Korea, Republic of
facility: Kyung Hee University Hospital
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center - University of Ulsan College of Medicine
city: Seoul
country: Korea, Republic of
facility: Konkuk University Medical Center
city: Suwon
country: Korea, Republic of
facility: Ajou University Hospital
city: Ulsan
country: Korea, Republic of
facility: Ulsan University Hospital
Study officials:
affiliation: Asan Medical Center
name: Kyoo H. Lee, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Kim DY, Joo YD, Lim SN, Kim SD, Lee JH, Lee JH, Kim DH, Kim K, Jung CW, Kim I, Yoon SS, Park S, Ahn JS, Yang DH, Lee JJ, Lee HS, Kim YS, Mun YC, Kim H, Park JH, Moon JH, Sohn SK, Lee SM, Lee WS, Kim KH, Won JH, Hyun MS, Park J, Lee JH, Shin HJ, Chung JS, Lee H, Eom HS, Lee GW, Cho YU, Jang S, Park CJ, Chi HS, Lee KH; Adult Acute Lymphoblastic Leukemia Working Party of the Korean Society of Hematology. Nilotinib combined with multiagent chemotherapy for newly diagnosed Philadelphia-positive acute lymphoblastic leukemia. Blood. 2015 Aug 6;126(6):746-56. doi: 10.1182/blood-2015-03-636548. Epub 2015 Jun 11.