Clinical trial NCT01429610: Rituximab+mVPDL for CD20(+) Adult Acute Lymphoblastic Leukemia
Official title: Phase 2 Study Evaluating the Efficacy of Rituximab Plus Modified VPDL for Newly Diagnosed CD20-Positive Adult Acute Lymphoblastic Leukemia
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
Conditions: Precursor Cell Lymphoblastic Leukemia-Lymphoma
Keywords: acute lymphoblastic leukemia
rituximab
VPDL
CD20
Lead sponsor: Asan Medical Center
Sponsor class: OTHER
First posted: 2011-09-07
Enrollment: 78
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: 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.

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 criteria: Inclusion Criteria:

* Patients who were previously untreated and had either ALL or high-risk lymphoblastic lymphoma.
* 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)

Primary outcomes:
measure: relapse-free survival (RFS) rate
timeFrame: 2 years
Secondary outcomes:
measure: complete remission (CR) rates
timeFrame: 4 weeks (from the initiation of induction treatment)
measure: relapse-free survival rates
timeFrame: 2 years
measure: overall survival rates
timeFrame: 2 years
measure: Cumulative incidence and maximal severity of acute / chronic graft-versus-host disease
timeFrame: 2 years
Other outcomes:
Locations:
city: Hwasun
country: Korea, Republic of
facility: Chonnam National University Hwasun Hospital
state: Chollanamdo
city: Ilsan
country: Korea, Republic of
facility: Hematologic Oncology Clinic, National Cancer Center
state: Kongki
city: Busan
country: Korea, Republic of
facility: Division of Hematology-Oncology, Dong-A University College of Medicine
city: Busan
country: Korea, Republic of
facility: Dong-A University College of Medicine
city: Busan
country: Korea, Republic of
facility: Inje University Busan Paik Hospital
city: Busan
country: Korea, Republic of
facility: Inje University Haeundae-Paik Hospital
city: Busan
country: Korea, Republic of
facility: Kosin University College of Medicine, Kosin University Gospel Hospital
city: Daegu
country: Korea, Republic of
facility: Catholic University of Daegu School of Medicine
city: Daegu
country: Korea, Republic of
facility: Keimyung University Dongsan Medical Center
city: Daegu
country: Korea, Republic of
facility: Kyungpook National Unviersity Hospital
city: Daegu
country: Korea, Republic of
facility: Yeungnam University College of Medicine
city: Daejeon
country: Korea, Republic of
facility: Chungnam National University Hospital
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center, University of Ulsan College of Medicine
city: Seoul
country: Korea, Republic of
facility: Chung-Ang University Hospital
city: Seoul
country: Korea, Republic of
facility: Ewha Womans University Mokdong Hospital
city: Seoul
country: Korea, Republic of
facility: Korea University Anam Hospital
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Seoul
country: Korea, Republic of
facility: Soonchunhyang University Hospital
city: Ulsan
country: Korea, Republic of
facility: Ulsan University Hospital, University of Ulsan College of Medicine
Study officials:
affiliation: Inje University Haeundae Paik Hospital
name: Young Don Joo, MD, PhD
role: PRINCIPAL_INVESTIGATOR
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