Nilotinib and Combination Chemotherapy in Treating Patients With Newly Diagnosed Acute Lymphoblastic Leukemia

NCT ID: NCT00844298

Last Updated: 2015-09-07

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 91 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2009-01-31
• Study Completion Date: 2014-07-31

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.

Conditions

Leukemia

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Nilotinib+mVPD

Patients who were Philadelphia-positive, newly-diagnosed adult ALL and treated with nilotinib + mVPD treatment plan

Group Type: EXPERIMENTAL

Nilotinib+mVPD

Intervention Type: DRUG

1. Induction:

• Daunorubicin 90 mg/m2/day by continuous iv infusion (d1-3)
• Vincristine 2 mg iv push (d1, 8, 15, 22)
• Prednisolone 60 mg/m2/day po (d1-28)
• Nilotinib 400mg bid/d (d8-)

2. Consolidation A (cycle1)

• Daunorubicin 45 mg/m2/day by continuous iv (d1, 2)
• Vincristine 2 mg iv (d1, 8)
• Prednisolone 60 mg/m2/day po (d1-14)
• Nilotinib 400mg bid/d

3. Consolidation B (cycles 2&4)

• Cytarabine 2,000 mg/m2/day iv over 2 hours (d1-4)
• Etoposide 150 mg/m2/day iv over 3 hours (d1-4)
• Nilotinib 400mg bid/d

4. Consolidation C (cycles 3&5)

• Methotrexate 220 mg/m2 iv bolus, then 60mg/m2/h for 36 hours (d1-2, 15-16)
• Leucovorin followed immediately by 50 mg/m2 iv every 6hrs for three doses,
• Nilotinib 400mg bid/d

5. Maintenance

◦Nilotinib 400mg bid/d (during 2 years, for patients without alloHCT)

6. Consider alloHCT

Interventions

Nilotinib+mVPD

1. Induction:

• Daunorubicin 90 mg/m2/day by continuous iv infusion (d1-3)
• Vincristine 2 mg iv push (d1, 8, 15, 22)
• Prednisolone 60 mg/m2/day po (d1-28)
• Nilotinib 400mg bid/d (d8-)

2. Consolidation A (cycle1)

• Daunorubicin 45 mg/m2/day by continuous iv (d1, 2)
• Vincristine 2 mg iv (d1, 8)
• Prednisolone 60 mg/m2/day po (d1-14)
• Nilotinib 400mg bid/d

3. Consolidation B (cycles 2&4)

• Cytarabine 2,000 mg/m2/day iv over 2 hours (d1-4)
• Etoposide 150 mg/m2/day iv over 3 hours (d1-4)
• Nilotinib 400mg bid/d

4. Consolidation C (cycles 3&5)

• Methotrexate 220 mg/m2 iv bolus, then 60mg/m2/h for 36 hours (d1-2, 15-16)
• Leucovorin followed immediately by 50 mg/m2 iv every 6hrs for three doses,
• Nilotinib 400mg bid/d

5. Maintenance

◦Nilotinib 400mg bid/d (during 2 years, for patients without alloHCT)

6. Consider alloHCT

Intervention Type: DRUG

Other Intervention Names

Mabthera; VCS; Daunobrastina; Solondo; Leunase; Cytarabine; Efosin; DBLMethotrexate

Eligibility Criteria

Inclusion 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

• Minimum Eligible Age: 15 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Asan Medical Center

OTHER

Sponsor Role: lead

Responsible Party

Kyoo-Hyung Lee

Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Kyoo H. Lee, MD

Role: PRINCIPAL_INVESTIGATOR

Asan Medical Center

Locations

Daegu Fatima Hospital

Daegu, , South Korea

Kyungpook National University Hospital

Daegu, , South Korea

Yeungnam University Medical Center

Daegu, , South Korea

Daegu Catholic University Hospital

Daegu, , South Korea

National Cancer Center - Korea

Goyang, , South Korea

Chonnam National University Hwasun Hospital

Jeollanam-do, , South Korea

Gyeongsang National University Hospital

Jinju, , South Korea

Pusan National University Hospital

Pusan, , South Korea

Inje University Seoul Paik Hospital

Seoul, , South Korea

Seoul National University Hospital

Seoul, , South Korea

Kyung Hee University Hospital

Seoul, , South Korea

Samsung Medical Center

Seoul, , South Korea

Asan Medical Center - University of Ulsan College of Medicine

Seoul, , South Korea

Konkuk University Medical Center

Seoul, , South Korea

Ajou University Hospital

Suwon, , South Korea

Ulsan University Hospital

Ulsan, , South Korea

Countries

South Korea

References

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.

Reference Type: DERIVED

PMID: 26065651 (View on PubMed)

Other Identifiers

AMC-UUCM-2008-0310

Identifier Type: -

Identifier Source: secondary_id

NOVARTIS-AMC-UUCM-2008-0310

Identifier Type: -

Identifier Source: secondary_id

CDR0000632225

Identifier Type: -

Identifier Source: org_study_id