Ofatumumab as Part of Reduced Intensity Conditioning (RIC) Regimen for Patients With High Risk Chronic Lymphocytic Leukemia (CLL) Undergoing Allogeneic Hematopoietic Cell Transplantation

This study is currently recruiting participants. (see Contacts and Locations)
Verified January 2012 by Grupo Espanol de trasplantes hematopoyeticos y terapia celular
Sponsor:
Collaborator:
GlaxoSmithKline
Information provided by (Responsible Party):
Grupo Espanol de trasplantes hematopoyeticos y terapia celular
ClinicalTrials.gov Identifier:
NCT01455051
First received: October 17, 2011
Last updated: January 10, 2012
Last verified: January 2012
  Purpose

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.


Condition Intervention Phase
Chronic Lymphocytic Leukemia
Drug: Ofatumumab
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by Grupo Espanol de trasplantes hematopoyeticos y terapia celular:

Primary Outcome Measures:
  • CPFS at 3y [ Time Frame: At 3 years ] [ Designated as safety issue: Yes ]
    Current progression-free survival (CPFS) at 3 years.


Secondary Outcome Measures:
  • CPFS at 5y [ Time Frame: At 5 years ] [ Designated as safety issue: Yes ]
    Current progression-free survival (CPFS) at 5 years

  • NRM at 1/5 years [ Time Frame: At 1 and 5 years ] [ Designated as safety issue: Yes ]
    Non-relapse mortality at 1 and 5 years

  • Acute GVHD at 3mo [ Time Frame: At 3 months ] [ Designated as safety issue: Yes ]
    Incidence of acute graft-versus-host disease, grade II-IV, at 3 months

  • Chronic GVHD at 1/5y [ Time Frame: At 1 and 5 years ] [ Designated as safety issue: Yes ]
    Incidence of extensive chronic graft-versus-host disease at 1 and 5 years

  • Toxicity [ Time Frame: During all 3 years ] [ Designated as safety issue: Yes ]
    Evaluation of toxicity following common toxicity criteria, release 3.0

  • OS at 3/5y [ Time Frame: At 3 and 5 years ] [ Designated as safety issue: Yes ]
    Overall survival at 3 and 5 years


Estimated Enrollment: 25
Study Start Date: October 2011
Estimated Study Completion Date: October 2017
Estimated Primary Completion Date: October 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Ofatumumab
We plan to add five doses of ofatumumab to the standard conditioning regimen (fludarabine + melphalan). Ofatumumab will be administered on days -20 (300 mg), -13 (2000 mg), -6 (2000 mg), +1 (1000 mg) and +8 (1000 mg) of the transplantation (day 0 being the day of the hematopoietic cell infusion). If the patient requires donor lymphocyte infusions within 3 years after the procedure, these infusions will also include one administration of 300 mg of ofatumumab, followed by a 1000 mg dose, 7 days later).
Drug: Ofatumumab
We plan to add five doses of ofatumumab to the standard conditioning regimen (fludarabine + melphalan). Ofatumumab will be administered on days -20 (300 mg), -13 (2000 mg), -6 (2000 mg), +1 (1000 mg) and +8 (1000 mg) of the transplantation (day 0 being the day of the hematopoietic cell infusion). If the patient requires donor lymphocyte infusions within 3 years after the procedure, these infusions will also include one administration of 300 mg of ofatumumab, followed by a 1000 mg dose, 7 days later).
Other Name: Arzerra

  Eligibility

Ages Eligible for Study:   18 Years to 70 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01455051

Contacts
Contact: Olga Cabrerizo +34 917541925 olga.cabrerizo@meditrial.es
Contact: Jose Luis Martinez +34 917541925 jose.martinez@meditrial.es

Locations
Spain
Hospital Germans Trias i Pujol Recruiting
Badalona, Spain
Contact: Christelle Ferra, MD       CHRISTELLE.FERRA@telefonica.net   
Principal Investigator: Christelle Ferra, MD, PhD         
Hospital Vall d'Hebron Recruiting
Barcelona, Spain
Contact: Francesc Bosch, MD, PhD       fbosch@vhebron.net   
Principal Investigator: Francesc Bosch, MD, PhD         
Hospital de la Santa Creu Sant Pau Recruiting
Barcelona, Spain, 08025
Contact: Carolina Moreno, MD, PhD       cmorenoa@santpau.cat   
Principal Investigator: Carolina Moreno, MD, PhD         
Institut Catala d'Oncologia Recruiting
Hospitalet de Llobregat, Spain
Contact: Rafael Duarte, MD, PhD       rduarte@iconcologia.net   
Principal Investigator: Rafael Duarte, MD, PhD         
Hospital La Princesa Recruiting
Madrid, Spain
Contact: Javier Loscertales, MD       javlos@yahoo.com   
Principal Investigator: Javier Loscertales, MD         
Hospital Puerta de Hierro Recruiting
Madrid, Spain
Contact: Jose Angel Garcia-Marco, MD, PhD       jagarciam@medynet.com   
Principal Investigator: Jose Angel Garcia-Marco, MD, PhD         
Hospital Central de Asturias Recruiting
Oviedo, Spain
Contact: Carlos Vallejo, MD         
Principal Investigator: Carlos Vallejo         
Hospital La Fe Recruiting
Valencia, Spain
Contact: Jaime Sanz         
Principal Investigator: Jaime Sanz         
Hospital Clinico Recruiting
Valencia, Spain
Contact: Maria Jose Terol       terol39@ono.com   
Principal Investigator: Maria Jose Terol, MD, PhD         
Sponsors and Collaborators
Grupo Espanol de trasplantes hematopoyeticos y terapia celular
GlaxoSmithKline
Investigators
Principal Investigator: Julio Delgado, MD, PhD Hospital Clinic of Barcelona
  More Information

No publications provided

Responsible Party: Grupo Espanol de trasplantes hematopoyeticos y terapia celular
ClinicalTrials.gov Identifier: NCT01455051     History of Changes
Other Study ID Numbers: GETH-CLL4, 2010-024467-40
Study First Received: October 17, 2011
Last Updated: January 10, 2012
Health Authority: United States: Institutional Review Board
Spain: Spanish Agency of Medicines

Additional relevant MeSH terms:
Leukemia
Leukemia, Lymphocytic, Chronic, B-Cell
Leukemia, Lymphoid
Immune System Diseases
Immunoproliferative Disorders
Leukemia, B-Cell
Lymphatic Diseases
Lymphoproliferative Disorders
Neoplasms
Neoplasms by Histologic Type

ClinicalTrials.gov processed this record on October 23, 2014