Nonmyeloablative Conditioning and Transplantation for Patients With Refractory Systemic Lupus Erythematosus (SLE)

• ClinicalTrials.gov Identifier: NCT02080195
• Recruitment Status: Terminated
• First Posted: March 6, 2014
• Results First Posted: October 2, 2018
• Last Update Posted: October 2, 2019
• Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• Collaborator: Maryland Stem Cell Research Fund
• Information provided by (Responsible Party): Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Tracking Information

• First Submitted Date: February 28, 2014
• First Posted Date: March 6, 2014
• Results First Submitted Date: September 6, 2018
• Results First Posted Date: October 2, 2018
• Last Update Posted Date: October 2, 2019
• Actual Study Start Date: September 13, 2016
• Actual Primary Completion Date: March 28, 2017 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: September 6, 2018)

The Feasibility of the Conditioning Regimen and Post Transplantation Cyclophosphamide in Refractory SLE Patients With Donors Having Various Degrees of Matching [ Time Frame: 1 year ]

Number of participants who were alive at 1 year after transplant and who had not suffered graft rejection, acute or chronic GVHD, or Grade 3 or higher (CTCAE V4.0) adverse events.

• Original Primary Outcome Measures (submitted: March 4, 2014): The feasibility of the conditioning regimen and post transplantation cyclophosphamide in refractory SLE patients with donors having various degrees of matching [ Time Frame: 60 days ]

Current Secondary Outcome Measures (submitted: September 19, 2019)

• RIFLE Score [ Time Frame: 1 year ]
  Change in Responder Index for Systemic Lupus Erythematosis (RIFLE) assessment. This is a qualitative assessment of organ function. The 12 month response will be assessed as: complete= complete or partial resolution in more than one organ, partial= complete or partial resolution in at least one organ, the same= no change or no worsening in any organ, worse= worsening in any organ
• Survival [ Time Frame: 1 year ]
  Number of patients alive and alive without relapse, respectively.
• Graft Failure [ Time Frame: 60 days ]
  Number of participants with primary and/or secondary graft failure.
• Acute Graft Versus Host Disease (GVHD) [ Time Frame: Up to 2 years ]
  Percentage of participants who developed grades II-IV and grades III-IV acute GVHD. Acute GVHD is defined by the Przepiorka criteria, which stages the degree of organ involvement in the skin, liver, and gastrointestinal (GI) tract, based on severity, with Stage 1+ being least severe and stage 4+ being the most severe. Grading of acute GVHD is as follows: Grade I (skin involvement stages 1+ to 2+, with no liver or GI involvement), Grade II (skin involvement stages 1+ to 3+, liver 1+, GI tract 1+), Grade III (skin involvement stages 2+ to 3+, liver 1+, GI tract 2+ to 4+), Grade IV (skin involvement stages 4+, Liver 4+).
• Chronic Graft Versus Host Disease (GVHD) [ Time Frame: Up to 2 years ]
  Percentage of participants who developed chronic GVHD as defined by the NIH consensus criteria. This system gives scores from 0 to 3 for Karnofsky performance score, skin, mouth, eyes, gastrointestinal, liver, lungs, joints, and genitals, as well as an overall severity (mild, moderate, or severe). Mild chronic GVHD involves only 1 or 2 organs or sites (except the lung), with no clinically significant functional impairment (maximum of score 1 in all affected organs or sites). Moderate chronic GVHD involves 1) at least 1 organ or site with clinically significant but no major disability (maximum score of 2 in any affected organ or site) OR 2) 3 or more organs or sites with no clinically significant functional impairment (maximum score of 1 in all affected organs or sites). Severe chronic GVHD indicates major disability caused by chronic GVHD (score of 3 in any organ or site).

Original Secondary Outcome Measures (submitted: March 4, 2014)

• Evaluation of the improvement in the RIFLE score with the goal as target organ complete response with no worsening in any other organ [ Time Frame: 1 year ]
• The overall survival (OS) and event-free survival (EFS) [ Time Frame: 1 year ]
• The incidences of primary and secondary graft failure [ Time Frame: 60 days ]
• The cumulative incidence of acute and chronic graft versus-host disease (GVHD) [ Time Frame: 100 days to 2 years ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Nonmyeloablative Conditioning and Transplantation for Patients With Refractory Systemic Lupus Erythematosus (SLE)
• Official Title: A Phase I/II Study of Nonmyeloablative Conditioning and Transplantation of Human Leukocyte Antigen (HLA)-Matched, Partially HLA-mismatched, HLA-haploidentical or Matched Unrelated Bone Marrow for Patients With Refractory SLE
• Brief Summary: The main goal of the study is to determine if bone marrow transplant (BMT) from a less specific pool of donors in combination with high dose cyclophosphamide can induce remission of refractory systemic lupus erythematosus.

Detailed Description

Systemic lupus erythematosus (SLE) is a devastating systemic autoimmune disease that predominantly affects young women, is more common in African-Americans than in whites, and results in poor quality of life. Lupus has no cure, and up to 90% of patients require corticosteroids for disease control. More than half of patients with lupus have permanent organ damage, much of which is either directly due to or increased by corticosteroids. To satisfactorily manage moderate-to-severe SLE, the investigators need effective treatments that will allow corticosteroid-sparing.

High-dose chemotherapy followed by autologous BMT or peripheral blood progenitor transplantation (PBSCT) has been proposed as a novel approach to treat severe autoimmune diseases. Allogeneic BMT is not currently utilized for the routine treatment of SLE because of the significant morbidity (GVHD) and mortality associated with the procedure.

The investigators have recently developed an approach to BMT using post-transplant cyclophosphamide that allows us to safely perform allogeneic BMT from matched, mismatched, unrelated or haploidentical donors. Transplant-related mortality, graft-failure and risk of GVHD have been very low with this approach. Furthermore, this approach allows us to greatly expand the donor pool since any patient shares exactly one HLA haplotype with each biological parent or child and half of siblings, an eligible haploidentical donor can be identified rapidly in nearly all cases.

This trial will employ a fludarabine + cyclophosphamide conditioning along with posttransplantation cyclophosphamide on for patients with refractory SLE. The purpose of this trial is to improve the salvage rate for patients with refractory SLE through a reformatting of the immune system.

• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Lupus Erythematosus
• Graft-versus-host Disease

Intervention

• Drug: Cyclophosphamide
  14.5 mg/kg/day on Days -6 and -5. 50 mg/kg/day on Days 3 and 4.
  Other Names:

  • Cytoxan
  • Cy
• Drug: Fludarabine
  30 mg/m^2/day on Days -6 through -2.
  Other Name: Fludara
• Drug: Tacrolimus
  Starting on Day 5. Dose will be adjusted according to blood levels.
  Other Names:

  • FK-506
  • Prograf
• Drug: Mycophenolate Mofetil
  15 mg/kg three times per day from Day 5 to Day 35.
  Other Names:

  • Cellcept
  • MMF
• Drug: Rabbit antithymocyte globulin
  0.5 mg/kg on Day -9. 2 mg/kg/day on Days -8 and -7.
  Other Name: Thymoglobulin
• Radiation: Total body irradiation
  200 centigray on Day -1.
• Biological: Allogeneic bone marrow transplant
  Infusion on Day 0.
  Other Name: BMT

Study Arms

Experimental: Nonmyeloablative Conditioning and BMT

Nonmyeloablative conditioning with rabbit antithymocyte globulin, cyclophosphamide, fludarabine, and total body irradiation. Allogeneic bone marrow transplant on Day 0. Graft versus host disease (GVHD) prophylaxis with cyclophosphamide, mycophenolate mofetil, and tacrolimus.

Interventions:

• Drug: Cyclophosphamide
• Drug: Fludarabine
• Drug: Tacrolimus
• Drug: Mycophenolate Mofetil
• Drug: Rabbit antithymocyte globulin
• Radiation: Total body irradiation
• Biological: Allogeneic bone marrow transplant

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Terminated
• Actual Enrollment (submitted: July 19, 2017): 1
• Original Estimated Enrollment (submitted: March 4, 2014): 25
• Actual Study Completion Date: March 29, 2017
• Actual Primary Completion Date: March 28, 2017 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Four or more American College of Rheumatology (ACR) criteria for the classification of SLE or 4 or more of the SLICE criteria
• Involvement of one or more of the following organ systems: renal, neurologic, hematologic, cardiac, pulmonary, gastrointestinal
• A lack of response to corticosteroids in moderate-to-high doses, and to either an equivalent degree of immunosuppression with azathioprine, methotrexate, cyclosporin, tacrolimus, belimumab, rituximab, mycophenolate mofetil, and/or appropriate other treatment
• Patients should be eligible for transplantation according to the BMT Policy Manual

Exclusion Criteria:

• Age less than 18 years and over 75 years
• Any risk of pregnancy
• Patients who are preterminal or moribund

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 75 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT02080195
• Other Study ID Numbers: J13134; NA_00082453 ( Other Identifier: Johns Hopkins IRB )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• Original Responsible Party: Same as current
• Current Study Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• Original Study Sponsor: Same as current
• Collaborators: Maryland Stem Cell Research Fund

Investigators

• Principal Investigator: Javier Bolaños-Meade, MD; The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

• PRS Account: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• Verification Date: September 2019