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Combined Bone Marrow and Renal Transplantation for Hematologic Disorders With End Stage Renal Disease

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ClinicalTrials.gov Identifier: NCT02158052
Recruitment Status : Recruiting
First Posted : June 6, 2014
Last Update Posted : March 26, 2019
Sponsor:
Information provided by (Responsible Party):
Thomas Spitzer, Massachusetts General Hospital

Tracking Information
First Submitted Date  ICMJE May 30, 2014
First Posted Date  ICMJE June 6, 2014
Last Update Posted Date March 26, 2019
Study Start Date  ICMJE February 2015
Estimated Primary Completion Date February 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 5, 2014)
The primary endpoint is the renal allograft rejection rate at 6 months post-transplant. [ Time Frame: Participants will be followed on an intention-to-treat basis, and data from all enrolled participants will be collected, irrespective of outcome, for the scheduled minimum follow-up period of 3 years. ]
BUN and creatinine will be measured daily while hospitalized, then weekly up to 100 days, then at month 6, and years 1, 1.5, 2, 3. Renal biopsies will be performed as clinically indicated for suspected rejection
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT02158052 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: June 5, 2014)
Assess anti-tumor response rates in patients with hematologic malignancies [ Time Frame: Participants will be followed on an intention-to-treat basis, and data from all enrolled participants will be collected, irrespective of outcome, for the scheduled minimum follow-up period of 3 years. ]
  • Bone marrow biopsy and aspirate for patients with hematologic malignancy and prior bone marrow involvement (pre-transplant, Day 100, 6 months, year 1, year 2).
  • Quantification of serum and urine M protein and serum free light chain analyses for patients with myeloma (Days 35, 70, 100, month 6, year 1, year 1.5, year 2, year 3).
  • Quantitative immunoglobulin analysis (Days 7, 14, 21, 28, 42, 56, 70, 84, 100, month 6, year 1, year 1.5, year 2, year 3).
  • Additional disease staging procedures and studies for other hematologic malignancies as clinically indicated.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Combined Bone Marrow and Renal Transplantation for Hematologic Disorders With End Stage Renal Disease
Official Title  ICMJE Combined HLA-Matched Bone Marrow and Kidney Transplantation for Multiple Myeloma or Other Hematologic Disorders With End Stage Renal Disease
Brief Summary This pilot trial offers the unique opportunity for both the treatment of multiple myeloma or systemic AL amyloidosis for which hematopoietic stem cell transplantation would be ordinarily indicated and the reversal of end-stage renal failure, while avoiding the risks associated with long-term standard anti-rejection therapy used in renal transplantation. The primary objectives of this study are to assess renal allograft tolerance (that is, the acceptance of the kidney without the need for anti-rejection therapy), assess anti-tumor response rates in multiple myeloma and AL amyloidosis, and assess complication rates for genetically (HLA) matched related donor combined bone marrow and kidney transplantation using a low dose total body irradiation based preparative regimen.
Detailed Description The induction of transplantation tolerance involves the specific elimination of the immune response to the transplant but not to other antigens. In the realm of kidney transplantation, tolerance means that the recipient is unable to detect the donor transplant kidney as foreign, and therefore the recipient is unable to reject the kidney. Donor bone marrow engraftment leads to kidney graft tolerance in animal models. Renal failure is a major complication of multiple myeloma and AL amyloidosis for which the only known cure is allogeneic bone marrow transplantation. Standard bone marrow transplantation is associated with prohibitive toxicities in patients with end stage renal disease, and is generally not considered an option for those patients. Patients with multiple myeloma and AL amyloidosis are excluded from conventional renal transplantation protocols because of their underlying malignancy. A less toxic bone marrow transplantation protocol, utilizing low dose total body irradiation and anti-thymocyte globulin, combined with renal transplantation, could provide an opportunity for cure of the myeloma or amyloidosis and correction of end stage renal disease. In addition, successful marrow engraftment may be expected to lead to a state of tolerance. Successful implementation of tolerance would be a major benefit to transplant recipients. The significance of developing tolerance is that the patient could be spared the disabling complications of indefinite immunosuppression, which include infections, cataracts, osteoporosis, diabetes, atherosclerosis, hypertension, and malignancy.
Study Type  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Multiple Myeloma
  • Amyloidosis
Intervention  ICMJE
  • Drug: Tacrolimus
    Tacrolimus starting on Day -1
  • Drug: Anti-thymocyte globulin
    20 mg/kg IV on Days -3, -1, +1, +3
  • Procedure: Kidney transplant
    On Day 0 the renal transplant is performed according to standard surgical techniques.
  • Drug: Bone marrow transplant from a related donor
    Donor bone marrow (> 2 x 10e8 nucleated cells/kg of recipient body weight) is prepared for infusion according to the standard procedure. The infusion begins in the operating room as soon as the vascular anastomosis of the renal allograft has been completed.
  • Radiation: Total body irradiation 400 centigray (200 cGy X 2)
    On transplant day -1
Study Arms  ICMJE Experimental: Transplantation
Single arm combined bone marrow and kidney transplantation
Interventions:
  • Drug: Tacrolimus
  • Drug: Anti-thymocyte globulin
  • Procedure: Kidney transplant
  • Drug: Bone marrow transplant from a related donor
  • Radiation: Total body irradiation 400 centigray (200 cGy X 2)
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: June 5, 2014)
10
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE February 2021
Estimated Primary Completion Date February 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Participant Inclusion Criteria

  • Participants with end-stage renal failure due to or in association with multiple myeloma or systemic AL amyloidosis which hematopoietic cell transplantation is appropriate and a ≥ 50% five-year survival probability with transplantation is expected. This includes, but is not limited to:
  • Multiple myeloma (MM), ISS stage II or III in complete or very good partial remission
  • AL amyloidosis without significant cardiac disease
  • Males or females 18 - 65 years of age.
  • Participants must have an HLA-matched or one of six HLA A, B, or DR antigen-mismatched related donor, with high resolution molecular class I and II allele typing.
  • Men and women of reproductive potential must agree to use a reliable method of birth control during the treatment, and women should do so for a period of 2 years following the transplant.
  • Participants should be on dialysis or have a CrCl <20 ml/min.
  • Patients should not have evidence of renal recovery of their renal failure over a 90 day period of therapy for their underlying malignancy or other blood disorder.
  • Patients with a history of other malignancies excluding basal cell carcinoma of the skin and carcinoma in situ of the cervix with a disease-free survival interval of >2 years. Patients with the following malignancies must demonstrate a 5 year disease-free survival:

    • Breast cancer with positive nodes
    • Malignant melanoma (other than in situ)
    • Colorectal cancer (other than Dukes Stage A or B1)
  • Patients with multiple myeloma must have received previous treatment with a bortezomib-based regimen.

Patients with AL amyloidosis must have received previous treatment with a bortezomib-based regimen and/or autologous stem cell transplantation

  • Patients with a history of malignant melanoma must be reviewed by an independent oncologist prior to enrollment.
  • Recipient ability to understand and provide informed consent.

Participant Exclusion Criteria

  • Evidence of active infection as defined by: a) clinical syndrome consistent with viral or bacterial infection (e.g., influenza, URI, UTI) or b) fever with a clinical site of infection identified, or c) microbiologically documented infection, including, but not limited to, bacteremia or septicemia.
  • Participation in other investigational drug use at the time of enrollment.
  • Contraindication to therapy with any one of the proposed agents (e.g., history of allergy to horse serum in ATG).
  • Serologic positivity to HIV or HCV.
  • Women of childbearing age in whom adequate contraception cannot be maintained.
  • AST/ALT > 3 x normal or bilirubin > 1.5 x normal (unless due to Gilbert's syndrome).
  • Pregnancy or uncontrolled serious medical illness not related to underlying myeloma.
  • Cardiac ejection fraction < 40% by echocardiogram.
  • FEV1 < 50% predicted or corrected DLCO < 50% predicted.
  • ABO blood group incompatibility in the host-vs-graft direction.

    • Diagnosis of myelodysplastic syndrome

Donor Inclusion Criteria

  • HLA-matched or one of six HLA A, B, or DR antigen-mismatched related male or female donor 18-65 years of age.
  • ECOG performance status 0 or 1.
  • Excellent health per conventional pre-donor history (medical and psychosocial evaluation).
  • Acceptable laboratory parameters (hematology in normal or near-normal range; liver function < 2 times the upper limit of normal and normal creatinine).
  • Compatible ABO blood group.
  • Negative donor lymphocyte crossmatch.
  • No positive testing for viral infection (HbsAg, HIV, HCV, HTLV-1).
  • Cardiac/Pulmonary evaluation within normal limits (CXR, EKG).
  • Donor ability to understand and provide informed consent.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 65 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Thomas R Spitzer, MD 617-724-1124 tspitzer@partners.org
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02158052
Other Study ID Numbers  ICMJE KdBMT-2
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Plan Description:

There is no plan to share IPD, including the study protocol and consent form with other researchers.

Any publication that results from this trial will not include any patient identifiers.

Responsible Party Thomas Spitzer, Massachusetts General Hospital
Study Sponsor  ICMJE Massachusetts General Hospital
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Thomas R Spitzer, MD Massachusetts General Hospital
PRS Account Massachusetts General Hospital
Verification Date March 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP