Clinical trial NCT01455051: Ofatumumab as Part of Reduced Intensity Conditioning (RIC) Regimen for Patients With High Risk Chronic Lymphocytic Leukemia (CLL) Undergoing Allogeneic Hematopoietic Cell Transplantation
Official title: Ofatumumab as Part of the Reduced Intensity Conditioning Regimen for Patients With High Risk Chronic Lymphocytic Leukemia Undergoing Allogeneic Hematopoietic Cell Transplantation: a Pilot Study by GETH and GELLC
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Chronic Lymphocytic Leukemia
Lead sponsor: Grupo Espanol de trasplantes hematopoyeticos y terapia celular
Sponsor class: OTHER
Collaborators: name: GlaxoSmithKline
First posted: 2011-10-19
Enrollment: 25
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: A good proportion of patients with chronic lymphocytic leukemia (CLL) can be managed effectively with palliative chemotherapy. However, there is a group of younger patients with poor risk disease whose life expectancy is significantly reduced. As a result, reduced intensity conditioning (RIC) allogeneic hematopoietic cell transplantation (allo-HCT) has been investigated as a potentially curative procedure.

Recently, the European Group for Blood and Marrow Transplantation (EBMT) published a set of guidelines suggesting situations where allo-HCT might be considered a therapeutic option for CLL patients. Their conclusions were that allo-HCT was reasonable for younger CLL patients refractory to fludarabine, relapsing within two years of intensive treatment, or with p53 abnormalities requiring treatment.

However, the results with RIC allo-HCT are not entirely satisfactory, and progression-free survival after allo-HCT revolves around 35-40% at 3-5 years following allo-HCT. This is due to non-relapse mortality, which is significantly associated with the development of graft-versus-host disease (GVHD), but also due to disease relapse. These relapses may occur early in the course of the transplantation, like any other hematological malignancy, but late relapses have also been reported.

Several strategies have been tested in order to improve these results. The anti-CD20 monoclonal antibody rituximab, given concomitantly with allo-HCT or donor lymphocyte infusions, may reduce graft-versus-host disease and facilitate disease control. This may be due, not only to direct cytotoxicity, but also to modulation of GVHD and the graft-versus CLL effect (GVCLL). Interestingly, rituximab has been shown to promote the cross-presentation of tumor-derived peptides by antigen-presenting cells, thus enhancing the formation of cytotoxic T-cell clones and a GVCLL effect. With the addition of rituximab to the conditioning regimen, rates at 4 years for current progression-free survival (CPFS) and overall survival were 44% and 48%.

The investigators hypothesize that ofatumumab, having a more potent anti-CLL activity and complement-dependent cytoxicity than rituximab, could improve disease control and modulate the GVCLL effect more effectively, thus reducing the GVHD rate and subsequently improving the non-relapse mortality and progression-free survival in the long term.


Eligibility criteria: Inclusion Criteria:

1. Patients diagnosed with CD20+ chronic lymphocytic leukemia according to the World Health Organization.
2. Patients older than 18 and younger than 70 years old.
3. Patients who failed to meet NCI Working Group criteria for complete or partial response after therapy with regimens containing fludarabine or with disease relapse within 12 months after completing therapy with fludarabine containing regimen. Patients not eligible for fludarabine treatment, could also be included provided the disease remains unresponsive or relapses with 12 months after completing alternative salvage regimens (i.e. autologous HCT, bendamustine, gemcitabine, alemtuzumab or high-dose methyl-prednisolone), OR Patients with novo or acquired "17p deletion" cytogenetic abnormality. These patients must have received induction chemotherapy but could be transplanted in first complete or partial response.
4. Patients must have achieved a complete or partial response after the last therapy given prior to transplantation. Patients with clinically suspected or histologically confirmed Richter's transformation could be included if they are in complete response at the time of transplantation.
5. Patients who have not received more than four lines of therapy prior to transplantation.
6. Patients who have suitable HLA-matched related or unrelated donors willing to receive G-CSF, undergo apheresis to collect PBMC, and to donate stem cells. Patients with a single-locus mismatched donor available are also eligible.
7. ECOG functional status of 0 to 2.
8. Life expectancy of at least 6 months.
9. Signed informed consent.

Exclusion Criteria:

* Intolerance to rituximab or any other anti-CD20 monoclonal antibody.
* Diagnosis of CNS involvement with CLL.
* Prior allogeneic HCT.
* Subjects who have current active hepatic or biliary disease (with exception of patients with Gilbert's syndrome, asymptomatic gallstones, liver metastases or stable chronic liver disease per investigator assessment).
* Treatment with any known non-marketed drug substance or experimental therapy within 5 terminal half lives or 4 weeks prior to enrollment, whichever is longer, or currently participating in any other interventional clinical study.
* Other past or current malignancy. Subjects who have been free of malignancy for at least 5 years, or have a history of completely resected non-melanoma skin cancer, or successfully treated in situ carcinoma are eligible.
* Active infection unresponsive to medical therapy such as, but not limited to, chronic renal infection, chronic chest infection, tuberculosis and active hepatitis C.
* History of significant cerebrovascular disease in the past 6 months or ongoing event with active symptoms or sequelae.
* Known HIV positive.
* Clinically significant cardiac disease including unstable angina, acute myocardial infarction within six months prior to randomization, congestive heart failure (NYHA III-IV), and arrhythmia unless controlled by therapy, with the exception of extra systoles or minor conduction abnormalities.
* Significant concurrent, uncontrolled medical condition including, but not limited to, renal, hepatic, gastrointestinal, endocrine, pulmonary, neurological, cerebral or psychiatric disease which in the opinion of the investigator may represent a risk for the patient.
* Positive serology for Hepatitis B (HB) defined as a positive test for HBsAg. In addition, if negative for HBsAg but HBcAb positive (regardless of HBsAb status), a HB DNA test will be performed and if positive the subject will be excluded.
* Positive serology for hepatitis C (HC) defined as a positive test for HCAb, in which case reflexively perform a HC RIBA immunoblot assay on the same sample to confirm the result.
* Severe organ dysfunction as defined by: cardiac ejection fraction \<40%; DLCO \<40%; calculated GFR \< 30 ml/min; or bilirubin \> 3 times the upper normal limit (unless due to CLL or Gilbert syndrome).
* Pregnant or lactating women. Women of childbearing potential must have a negative pregnancy test at screening.
* Women of childbearing potential, including women whose last menstrual period was less than one year prior to screening, unable or unwilling to use adequate contraception from study start to one year after the last dose of protocol therapy. Adequate contraception is defined as hormonal birth control, intrauterine device, double barrier method or total abstinence.
* Male subjects unable or unwilling to use adequate contraception methods from study start to one year after the last dose of protocol therapy.

Primary outcomes:
measure: CPFS at 3y
timeFrame: At 3 years
Secondary outcomes:
measure: CPFS at 5y
timeFrame: At 5 years
measure: NRM at 1/5 years
timeFrame: At 1 and 5 years
measure: Acute GVHD at 3mo
timeFrame: At 3 months
measure: Chronic GVHD at 1/5y
timeFrame: At 1 and 5 years
measure: Toxicity criteria
timeFrame: During all 3 years
measure: OS at 3/5y
timeFrame: At 3 and 5 years
Other outcomes:
Locations:
city: Badalona
country: Spain
facility: Hospital Germans Trias i Pujol
city: Barcelona
country: Spain
facility: Hospital de la Santa Creu Sant Pau
city: Barcelona
country: Spain
facility: Hospital Vall d'Hebron
city: Hospitalet de Llobregat
country: Spain
facility: Institut Catala d'Oncologia
city: Madrid
country: Spain
facility: Hospital La Princesa
city: Madrid
country: Spain
facility: Hospital Puerta de Hierro
city: Oviedo
country: Spain
facility: Hospital Central de Asturias
city: Valencia
country: Spain
facility: Hospital Clinico
city: Valencia
country: Spain
facility: Hospital La Fe
Study officials:
affiliation: Hospital Clinic of Barcelona
name: Julio Delgado, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Montesinos P, Cabrero M, Valcarcel D, Rovira M, Garcia-Marco JA, Loscertales J, Moreno C, Duarte R, Terol MJ, Villamor N, Abrisqueta P, Caballero D, Sanz J, Delgado J. The addition of ofatumumab to the conditioning regimen does not improve the outcome of patients with high-risk CLL undergoing reduced intensity allogeneic haematopoietic cell transplantation: a pilot trial from the GETH and GELLC (CLL4 trial). Bone Marrow Transplant. 2016 Oct;51(10):1404-1407. doi: 10.1038/bmt.2016.145. Epub 2016 May 23. No abstract available.