Rituximab+mVPDL for CD20(+) Ph(-) Adult Acute Lymphoblastic Leukemia (RADICAL)

This study is currently recruiting participants.

Verified April 2013 by Asan Medical Center

Sponsor:

Information provided by (Responsible Party):

Dae-Young Kim, Asan Medical Center

ClinicalTrials.gov Identifier:

NCT01429610

First received: August 30, 2011

Last updated: April 9, 2013

Last verified: April 2013

History of Changes

Purpose

The investigators would like to propose a phase-2 prospective multicenter trial evaluating the efficacy of rituximab combination with our current chemotherapy strategy for adult Acute Lymphoblastic Leukemia (ALL), in order to prove out whether the addition of rituximab during induction, consolidation, and post-alloHCT status can improve the outcome in terms of relapse-free survival (RFS) when compared with our prior data as a historical control.

Condition	Intervention	Phase
Precursor Cell Lymphoblastic Leukemia-Lymphoma	Drug: Rituximab+mVPDL	Phase 2

Study Type:	Interventional
Study Design:	Endpoint Classification: Efficacy Study Intervention Model: Single Group Assignment Masking: Open Label Primary Purpose: Treatment
Official Title:	Phase 2 Study Evaluating the Efficacy of Rituximab Plus Modified VPDL for Newly Diagnosed CD20-Positive Philadelphia-Negative Adult Acute Lymphoblastic Leukemia

Resource links provided by NLM:

MedlinePlus related topics: Chronic Lymphocytic Leukemia Leukemia Lymphoma

Drug Information available for: Cytarabine Asparaginase Rituximab

U.S. FDA Resources

Further study details as provided by Asan Medical Center:

Primary Outcome Measures:

relapse-free survival (RFS) rate [ Time Frame: 2 years ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

complete remission (CR) rates [ Time Frame: 4 weeks (from the initiation of induction treatment) ] [ Designated as safety issue: No ]
among total patients / each subset of subsets A.

[Subset A]
1. Precursor B-cell vs. T-cell
2. Younger (age<60 years) vs. older (age≥60 years)
3. Risk group: standard vs. high
relapse-free survival rates [ Time Frame: 2 years ] [ Designated as safety issue: No ]
among patients in each subset of A & B.

[Subset A]
1. Precursor B-cell vs. T-cell
2. Younger (age<60 years) vs. older (age≥60 years)
3. Risk group: standard vs. high.
  
  [Subset B]
4. AlloHCT recipients vs. non-recipients.
overall survival rates [ Time Frame: 2 years ] [ Designated as safety issue: No ]
among total patients / each subset of A & B

[Subset A]
1. Precursor B-cell vs. T-cell
2. Younger (age<60 years) vs. older (age≥60 years)
3. Risk group: standard vs. high [Subset B]
4. AlloHCT recipients vs. non-recipients.
Cumulative incidence and maximal severity of acute / chronic graft-versus-host disease [ Time Frame: 2 years ] [ Designated as safety issue: No ]
among alloHCT recipients

Estimated Enrollment:	77
Study Start Date:	November 2011
Estimated Study Completion Date:	October 2015
Estimated Primary Completion Date:	October 2015 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: Rituximab+mVPDL Patients who were CD20(+), Philadelphia-negative, newly-diagnosed adult ALL and treated with rituximab + mVPDL treatment plan	Drug: Rituximab+mVPDL 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) L-asparaginase 4,000 units/m2/day im/sc (d17-28) Rituximab 375mg/m2/d (d8) 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) L-asparaginase 4,000 units/m2/day im/sc (d1-7) Rituximab 375mg/m2/d (d8) Consolidation B (cycles2&4) Cytarabine 2,000 mg/m2/day iv over 2 hours (d1-4) Etoposide 150 mg/m2/day iv over 3 hours (d1-4) Rituximab 375mg/m2/d days 8 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, Rituximab 375mg/m2/d (d8&22) Maintenance 6- Mercaptopurine 60 mg/m2 po (d1-28 ) Methotrexate 20 mg/m2 po (d1, 8, 15, 22) Consider alloHCT Other Names: Mabthera VCS Daunobrastina Solondo Leunase Cytarabine Efosin DBLMethotrexate

Arms

Assigned Interventions

Experimental: Rituximab+mVPDL

Patients who were CD20(+), Philadelphia-negative, newly-diagnosed adult ALL and treated with rituximab + mVPDL treatment plan

Drug: Rituximab+mVPDL

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)
- L-asparaginase 4,000 units/m2/day im/sc (d17-28)
- Rituximab 375mg/m2/d (d8)
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)
- L-asparaginase 4,000 units/m2/day im/sc (d1-7)
- Rituximab 375mg/m2/d (d8)
Consolidation B (cycles2&4)
- Cytarabine 2,000 mg/m2/day iv over 2 hours (d1-4)
- Etoposide 150 mg/m2/day iv over 3 hours (d1-4)
- Rituximab 375mg/m2/d days 8
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,
- Rituximab 375mg/m2/d (d8&22)
Maintenance
- 6- Mercaptopurine 60 mg/m2 po (d1-28 )
- Methotrexate 20 mg/m2 po (d1, 8, 15, 22)
Consider alloHCT

Other Names:

Mabthera
VCS
Daunobrastina
Solondo
Leunase
Cytarabine
Efosin
DBLMethotrexate

Detailed Description:

According to the recent results on the outcome of escalated daunorubicin-based protocol for adult ALL which has been performed by 'Adult ALL Working Party of the Korean Society of Hematology' (data were announced at 2010 Annual Meeting of ASCO, Chicago, IL), CR rate of 90.6% was satisfactory, but the 2-year / 3-year disease-free survival (DFS) were disappointing (43.6% and 39.9%, respectively), which means that the adequate post-remission therapy to control minimal residual disease after the achievement of CR is very important to improve the outcome of adult ALL.

Allogeneic hematopoietic cell transplantation (AlloHCT) is recommended as a post-remission therapy for patients with adult ALL, and reduced intensity conditioning has been tried to decrease TRM rate. However, many patients received consolidation chemotherapy rather than alloHCT owing to the absence of HLA-matched donor, limitation of age, and combined comorbidities (among 190 patients who have been included in our previously-mentioned study, only 52.3% received alloHCT).

Recently, stagnation in the treatment of adult ALL appears to be reached, maybe due to a borderline for further intensification of chemotherapeutic dose. Dose-escalation strategy has many difficulties in adoption for the treatment of adult ALL in terms of increased morbidity and mortality, not to mention the efficacy of such strategies. New, preferably non-chemotherapy approaches (maybe targeted therapy) are therefore urgently required.

For Ph(+) ALL, the introduction of BCR/ABL tyrosine kinase inhibitor has improved the treatment outcome with tolerable toxicities. Applying a similar strategy to Ph(-) ALL, targeting leukemia surface antigens with monoclonal antibodies is another promising strategy.

CD 20 expression of at least 20% has been known to be found in 22-48% of pre-B ALL, and appears to be associated with a poor prognosis, although there are controversies in pediatric patients. Based on the significant improvement of the outcome in B-cell NHL, preliminary data regarding the use of rituximab in frontline therapy for CD20-positive precursor B-cell ALL suggest its use may be beneficial. Especially, monoclonal antibodies are thought to be more effective when combined with chemotherapy and treated in the state of minimal residual disease, which suggests the interest of evaluating rituximab combined to current chemotherapy of adult ALL. Recent data on the efficacy of rituximab-combined chemotherapy showed that rates of CR and OS were superior with the modified hyperCVAD and rituximab regimens compared with standard hyper-CVAD (70% versus 38%, p<0.001) in younger (age < 60 years) CD20-positive subset, although it was an analysis of different patient groups who were treated with various regimen5.

Eligibility

Ages Eligible for Study:	15 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

Patients who were previously untreated and had either ALL or high-risk lymphoblastic lymphoma.
Ph(-) on chromosome analysis by conventional G-band technique and/or BCR-ABL(-) by PCR method
Patients whose leukemic blast cells express ≥20% of CD20 antigens at time of diagnosis
No prior chemotherapy for leukemia (use of hydroxyurea or leukapheresis are permitted.)
Estimated life expectancy of more than 3 months
ECOG performance status of 2 or lower, Karnofsky scale > 60
Adequate cardiac function (EF>45%) on echocardiogram or Heart scan (MUGA scan)
15 years of age and over.
Adequate renal function (creatinine<1.5 mg/dL)
Adequate hepatic function. (Bilirubin<1.5 mg/dL, transaminases levels<3 times the upper normal limit [5 times for patients with liver metastasis or hepatomegaly]). Even the initial level exceed the upper limits, patient will be acceptable when the levels on day 8 satisfies the inclusion criteria.
All patients gave written informed consent according to guidelines at each institution's committee on human research.

Exclusion Criteria:

Acute biphenotypic leukemia, acute biclonal leukemia, or acute mixed leukemia
Presence of significant uncontrolled active infection
Presence of uncontrolled bleeding
Any coexisting major illness or organ failure
Patients with psychiatric disorder or mental deficiency severe as to make compliance with the treatment unlike, and making informed consent impossible
Nursing women, pregnant women, women of childbearing potential who do not want adequate contraception
Patients with a diagnosis of prior malignancy unless disease-free for at least 5 years following therapy with curative intent (except curatively treated nonmelanoma skin cancer, in situ carcinoma, or cervical intraepithelial neoplasia)

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT01429610

Contacts

Contact: Seunghyun Baek, RN

82-2-3010-7289

bsh5932@naver.com

Locations

Korea, Republic of
Chonnam National University Hwasun Hospital	Recruiting
Hwasun, Chollanamdo, Korea, Republic of
Contact: Lee kaosin@naver.com
Sub-Investigator: Jae-Sook Ahn, MD
Sub-Investigator: Je-Jung Lee, MD, PhD
Sub-Investigator: Sung-Hoon Jung, MD
Principal Investigator: Deok-Hwan Yang, MD, PhD
Hematologic Oncology Clinic, National Cancer Center	Recruiting
Koyang, Kongki, Korea, Republic of
Contact: Yoon taikoo2@ncc.re.kr
Principal Investigator: Hyeon Seok Eom, MD, PhD
Sub-Investigator: Hyewon Lee, MD
Gyeonsang National University Hospital Gyeongsang National University School of Medicine	Withdrawn
Jinju, Kyongsangnam-do, Korea, Republic of
Kosin University College of Medicine, Kosin University Gospel Hospital	Recruiting
Busan, Korea, Republic of
Contact: Lim poya1949@paran.com
Principal Investigator: Yang Soo Kim, MD, PhD
Sub-Investigator: Ho-Sup Lee, MD, PhD
Inje University Haeundae-Paik Hospital	Recruiting
Busan, Korea, Republic of
Contact: Kwon rainbow325@nate.com
Principal Investigator: Young Don Joo, MD, PhD
Division of Hematology-Oncology, Dong-A University College of Medicine	Recruiting
Busan, Korea, Republic of
Contact: Lee 82-51-240-5044 br2916@hanmail.net
Principal Investigator: Sung-Hyun Kim, MD, PhD
Inje University Busan Paik Hospital	Recruiting
Busan, Korea, Republic of
Contact: Moon irein2000@nate.com
Principal Investigator: Won Sik Lee, MD, PhD
Sub-Investigator: Sang Min Lee, MD, PhD
Dong-A University College of Medicine	Recruiting
Busan, Korea, Republic of
Contact: Lee br2916@hanmail.net
Principal Investigator: Sung-Hyun Kim, MD, PhD
Chungbuk National University Hospital	Recruiting
Cheongju, Korea, Republic of
Contact: Park Helloparkbo@naver.com
Principal Investigator: Sung-Nam Lim, MD
Kyungpook National Unviersity Hospital	Not yet recruiting
Daegu, Korea, Republic of
Contact: Choi aimerchi@naver.com
Principal Investigator: Sang Kyun Sohn, MD, PhD
Sub-Investigator: Joon Ho Moon, MD.
Yeungnam University College of Medicine	Recruiting
Daegu, Korea, Republic of
Contact: Lee leehj0330@yahoo.co.kr
Principal Investigator: Min Kyoung Kim, MD, PhD
Sub-Investigator: Myung Soo Hyun, MD, PhD
Keimyung University Dongsan Medical Center	Recruiting
Daegu, Korea, Republic of
Contact: Park socool6014@naver.com
Principal Investigator: Young Rok Do, MD, PhD
Sub-Investigator: Ki Young Kwon, MD, PhD
Sub-Investigator: Jin Young Kim, MD
Catholic University of Daegu School of Medicine	Not yet recruiting
Daegu, Korea, Republic of
Contact: Shin EunjiShin@paran.com
Principal Investigator: Sung Hwa Bae, MD, PhD
Sub-Investigator: Hun Mo Ryoo, MD, PhD
Chungnam National University Hospital	Recruiting
Daejeon, Korea, Republic of
Contact: Lee ljy99@cnuh.co.kr
Principal Investigator: Deog-Yeon Jo, MD, PhD
Sub-Investigator: Ik-Chan Song, MD
Chung-Ang University Hospital	Recruiting
Seoul, Korea, Republic of
Contact: Park danapark2010@gmail.com
Principal Investigator: Eunkyung Park, MD, PhD
Sub-Investigator: Hee Jun Kim, MD, PhD
Seoul National University Hospital	Recruiting
Seoul, Korea, Republic of
Contact: Park keira79@paran.com
Principal Investigator: Inho Kim, MD, PhD
Sub-Investigator: Byoung Kook Kim, MD, PhD
Sub-Investigator: Seonyang Park, MD, PhD
Sub-Investigator: Sung-Soo Yoon, MD, PhD
Sub-Investigator: Ji Hyun Kwon, MD
Ewha Womans University Mokdong Hospital	Recruiting
Seoul, Korea, Republic of
Contact: Ryoo emhcrc@gmail.com
Principal Investigator: Yeung-Chul Mun, MD, PhD
Sub-Investigator: Hyun-Kyung Kim, MD, PhD
Soonchunhyang University Hospital	Recruiting
Seoul, Korea, Republic of
Contact: Lim s2916@schmc.ac.kr
Principal Investigator: Jong-Ho Won, MD, PhD
Sub-Investigator: Kyoung Ha Kim, MD, PhD
Samsung Medical Center	Recruiting
Seoul, Korea, Republic of
Contact: Shin hjds.shin@samsung.com
Principal Investigator: Jun Ho Jang, MD, PhD
Sub-Investigator: Chulwon Jung, MD, PhD
Sub-Investigator: Kihyun Kim, MD, PhD
Asan Medical Center, University of Ulsan College of Medicine	Recruiting
Seoul, Korea, Republic of
Contact: Paek bsh5932@naver.com
Principal Investigator: Dae-Young Kim, MD
Sub-Investigator: Kyoo-Hyung Lee, MD, PhD
Sub-Investigator: Je-Hwan Lee, MD, PhD
Sub-Investigator: Jung-Hee Lee, MD, PhD
Sub-Investigator: Yunsuk Choi, MD
Sub-Investigator: Young-Hun Park, MD
Korea University Anam Hospital	Recruiting
Seoul, Korea, Republic of
Contact: Song 82-2-920-5983 hema5983@kumc.or.kr
Principal Investigator: Yong Park, MD
Sub-Investigator: Byung Soo Kim, MD, PhD
Ulsan University Hospital, University of Ulsan College of Medicine	Recruiting
Ulsan, Korea, Republic of
Contact: Kim miyoung3798@yahoo.co.kr
Principal Investigator: Hawk Kim, MD, PhD
Sub-Investigator: Jae Hoo Park, MD, PhD

Sponsors and Collaborators

Asan Medical Center

Investigators

Principal Investigator:	Young Don Joo, MD, PhD	Inje University
Study Director:	Dae-Young Kim, MD	Asan Medical Center

More Information

Publications:

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Okamoto M, Okano A, Akamatsu S, Ashihara E, Inaba T, Takenaka H, Katoh N, Kishimoto S, Shimazaki C. Rituximab is effective for steroid-refractory sclerodermatous chronic graft-versus-host disease. Leukemia. 2006 Jan;20(1):172-3. No abstract available.

Zaja F, Bacigalupo A, Patriarca F, Stanzani M, Van Lint MT, Filì C, Scimè R, Milone G, Falda M, Vener C, Laszlo D, Alessandrino PE, Narni F, Sica S, Olivieri A, Sperotto A, Bosi A, Bonifazi F, Fanin R; GITMO (Gruppo Italiano Trapianto Midollo Osseo). Treatment of refractory chronic GVHD with rituximab: a GITMO study. Bone Marrow Transplant. 2007 Aug;40(3):273-7. Epub 2007 Jun 4.

Kebriaei P, Saliba RM, Ma C, Ippoliti C, Couriel DR, de Lima M, Giralt S, Qazilbash MH, Gajewski JL, Ha CS, Champlin RE, Khouri IF. Allogeneic hematopoietic stem cell transplantation after rituximab-containing myeloablative preparative regimen for acute lymphoblastic leukemia. Bone Marrow Transplant. 2006 Aug;38(3):203-9. Epub 2006 Jun 26.

Responsible Party:	Dae-Young Kim, Assistant Professor, Asan Medical Center
ClinicalTrials.gov Identifier:	NCT01429610 History of Changes
Other Study ID Numbers:	KAALL-004
Study First Received:	August 30, 2011
Last Updated:	April 9, 2013
Health Authority:	South Korea: Korea Food and Drug Administration (KFDA)

Keywords provided by Asan Medical Center:

acute lymphoblastic leukemia
rituximab
VPDL
CD20

Additional relevant MeSH terms:

Leukemia
Leukemia, Lymphoid
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Lymphoma
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Cytarabine
Rituximab

Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antineoplastic Agents
Therapeutic Uses
Antiviral Agents
Anti-Infective Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents

ClinicalTrials.gov processed this record on May 16, 2013

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