Clinical Trials /

Pilot Study of Leuprolide to Improve Immune Function After Allogeneic Bone Marrow Transplantation

NCT01338987

Description:

Background: - One way to treat certain cancers of the blood and immune system is to give a patient stem cells from the bone marrow of a donor whose genes are very similar but not identical to the patients. One problem with these transplants is that the new immune cells may not work as well in the recipient as they did in the donor. The result may be that the immune system will not work as well. This can increase the risk of severe infections and other complications. - Researchers are studying the use of drugs that lower hormone levels and may allow the immune system to recover in a way that improves white blood cell function. In this study they will be looking at the drug leuprolide, a drug that lowers estrogen or testosterone levels, to see if it might improve the function of the newly transplanted cells. Objectives: - To determine whether leuprolide improves immune system function after bone marrow transplant from a donor with similarities in their immune cells (matched to each other). - To evaluate the effectiveness of a nuclear medicine test with a radiotracer drug 3-deoxy-3 18F-fluorothymidine (FLT) in imaging studies. FLT will be used to image the immune system function in patients who have received bone marrow from the donor. Eligibility: - People between 15 (or as young as 9 in those who have gone through puberty) and 55 years of age. These patients must have acute myelogenous leukemia, acute lymphocytic leukemia, high-risk myelodysplastic syndrome, chronic myelomonocytic leukemia, or chronic myeloid leukemia. They must also be eligible for a bone marrow transplant. - Genetically similar donors for the patients who are eligible for a transplant. Design: - People taking part in the study will be screened with a physical examination, medical history, blood and urine tests, and imaging studies. Patients who are not in remission or who require a bone marrow donor search may receive chemotherapy first. - Donors will provide bone marrow for transplant according to standard bone marrow transplant (BMT) procedures. - All women and half of the men will receive regular leuprolide doses 2 weeks before BMT to suppress hormone function. - All recipients will receive 4 days of radiation followed by 2-4 days of chemotherapy before the bone marrow transplant (depending on age). Recipients will also receive other drugs to prevent transplant rejection and other complications of transplantation. - Recipients will be monitored in the hospital for 4 weeks after transplant with blood tests and other studies. - Some recipients will have an imaging study with FLT during the protocol. These imaging studies will take place before the transplant, on days 5 and 28 after transplant, and at a later time to be determined by the study researchers. - Following discharge, participants will be monitored closely for up to 6 months, with regular but less frequent followup visits for at least 5 years. Study-related medications, including vaccinations for the new immune system, will be provided by the National Institutes of Health during the hospital stay and after discharge.

Related Conditions:
  • Acute Lymphoblastic Leukemia
  • Acute Myeloid Leukemia
  • Myelodysplastic Syndromes
Recruiting Status:

Active, not recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Pilot Study of Lupron to Improve Immune Function After Allogeneic Bone Marrow Transplantation
  • Official Title: Multi-Institutional Prospective Pilot Study of Lupron to Enhance Lymphocyte Immune Reconstitution Following Allogeneic Bone Marrow Transplantation in Post-Pubertal Children and Adults With Molecular Imaging Evaluation

Clinical Trial IDs

  • ORG STUDY ID: 110136
  • SECONDARY ID: 11-C-0136
  • NCT ID: NCT01338987

Conditions

  • Myelodysplastic Syndrome RAEB 2
  • Acute Lymphocytic Leukemia
  • Acute Myelogenous Leukemia
  • Myelodysplastic Syndrome RAEB 1

Interventions

DrugSynonymsArms
LupronNIH Arm 1a
18F FLTNIH Arm 1a
CyclophosphamideNIH Arm 1b
MethotrexateNIH Arm 1b
TacrolimusNIH Arm 1b
BusulfanNIH Arm 2
FludarabineNIH Arm 2

Purpose

Background: - One way to treat certain cancers of the blood and immune system is to give a patient stem cells from the bone marrow of a donor whose genes are very similar but not identical to the patient s. One problem with these transplants is that the new immune cells may not work as well in the recipient as they did in the donor. The result may be that the immune system will not work as well. This can increase the risk of severe infections and other complications. - Researchers are studying the use of drugs that lower hormone levels and may allow the immune system to recover in a way that improves white blood cell function. In this study they will be looking at the drug lupron, a drug that lowers estrogen or testosterone levels, to see if it might improve the function of the newly transplanted cells. Objectives: - To determine whether lupron improves immune system function after bone marrow transplantation from a donor with similarities in their immune cells (matched to each other). - To evaluate the effectiveness of a nuclear medicine test with a radiotracer drug FLT in imaging studies. FLT will be used to image the immune system function in patients who have received bone marrow from the donor. Eligibility: - People between 15 (or as young as 9 in those who have gone through puberty) and 40 years of age. These patients must have acute myelogenous leukemia, acute lymphocytic leukemia, or high-risk myelodysplastic syndrome. They must also be eligible for a bone marrow transplant. - Genetically similar donors for the patients who are eligible for a transplant. Design: - People taking part in the study will be screened with a physical examination, medical history, blood and urine tests, and imaging studies. Patients who are not in remission or who require a bone marrow donor search may receive chemotherapy first. - Donors will provide bone marrow for transplant according to standard bone marrow transplant (BMT) procedures. - All women and half of the men will receive regular lupron doses 2 weeks before BMT to suppress hormone function. - All recipients will receive 4 days of radiation followed by 2-4 days of chemotherapy before the bone marrow transplant (depending on age). Recipients will also receive other drugs to prevent transplant rejection and other complications of transplantation. - Recipients will be monitored in the hospital for 4 weeks after transplant with blood tests and other studies. - Some recipients will have an imaging study with FLT during the protocol. These imaging studies will take place before the transplant, on days 5 and 28 after transplant, and at a later time to be determined by the study researchers. - Following discharge, participants will be monitored closely for up to 6 months, with regular but less frequent followup visits for at least 5 years. Study-related medications, including vaccinations for the new immune system, will be provided by the National Institutes of Health during the hospital stay and after discharge....

Detailed Description

      Background:

        -  Impaired lymphocyte immune reconstitution is associated with morbidity and mortality
           following allogeneic hematopoietic stem cell transplantation (HSCT).

        -  Data suggest that one of the limitations of immunity after HSCT is the lack of thymus
           recovery and proper B cell development.

        -  Androgen withdrawal has been shown to enhance T and B lymophopoiesis.

        -  Lupron is an approved, safe, gonadotropin releasing hormone (GnRH) agonist/antagonist.

        -  Noninvasive imaging modalities to study immune reconstitution would be invaluable to
           predict optimal or impaired immune recovery permitting early institution of therapies.

        -  FLT is 3 -deoxy-3 18F-fluorothymidine, a radiolabeled thymidine analogue that
           illustrates dividing hematopoietic cells and may predict immune recovery after
           allogeneic HSCT.

        -  FLT has been used safely in patients who have received intensive chemotherapy.

      Objectives:

        -  Primary: To determine if Lupron improves B lymphocyte reconstitution after HSCT.

        -  Primary: To assess whether 18F FLT PET/CT could predict early engraftment/immune
           reconstitution in marrow and thymus after allogeneic HSCT.

        -  Primary: To assess safety of Lupron after 2nd HSCT evaluated in a separate arm.

      Eligibility:

        -  Patients > 9 years old and pubertal and/or >15 year and less than or equal to 55 years,
           with aggressive leukemia (Acute Myelogenous Leukemia (AML), myelodysplastic syndromes
           (MDS) with high risk cytogenetics, Acute Lymphocytic Leukemia (ALL), CMML, certain CML)
           requiring HSCT will be enrolled at NCI.

        -  At University of Oklahoma, Age > 17 years old and less than or equal to 55 years for
           recipient.

        -  Patients > 4 and < 24 years with the above diseases will be enrolled at Children s
           National Medical Center.

      Design:

        -  This is a prospective pilot study, the primary aims of which are: 1) to assess whether
           Lupron enhances lymphocyte recovery after HSCT and 2) whether FLT imaging can be used to
           predict engraftment/immune reconstitution, and 3) whether Lupron and FLT are tolerable
           for second HSCT.

        -  At NCI and Univ of Oklahoma, post-pubertal pediatric male patients (<18 years) will be
           randomized to receive a 3 month (11.25 mg) injection and adult male patients will be
           randomized to receive 4-month preparation of Lupron (30 mg) or placebo two weeks before
           the preparative regimen for first BMT. Women and all individuals undergoing 2nd BMT will
           receive Lupron at these doses per age and be evaluated in the treated cohort. At
           Children s National Medical Center, the patients will not receive Lupron outside of the
           context of clinical care, and will receive myeloablative HSCT as per standard of care
           with FLT imaging for engraftment as the only primary endpoint.

        -  A target of 68 evaluable adult patients will be enrolled on this trial, which may
           necessitate up to 118 patients (118 donors) enrolled to reach this target at NCI and
           University of Oklahoma. A total of 10 pediatric patients will be enrolled at Children s
           National Medical Center for FLT imaging only. Sixteen of these patients will be enrolled
           to undergo second BMT.

        -  At NCI, adults greater than 18 years old both female and adult male patients undergoing
           2nd BMT will receive 4-month preparation of Lupron (30 mg) two weeks before the
           preparative regimen. All patients will undergo FLT imaging to evaluate whether this may
           predict HSCT response or failure (relapse). This will be a pilot arm of 16 patients
           total.

        -  The planned length of this trial is 7 years with interim analyses at day 100 and day
           365.

        -  Some of the patients are anticipated to be evaluated using FLT (to include only patients
           needed for the immunological primary endpoint, not increasing total patient numbers). 23
           adult NCI patients in total will undergo FLT PET/CT imaging on day -1, at day +5 or day
           +9, at 4 weeks, and at a future point to include evidence of GVHD relapse, or immune
           recovery. An estimated 50 patients (including subset of the 23 patients undergoing
           serial scanning) will be imaged approximately at 1 year for evaluation of thymus
           reconstitution. The total possible numbers will include no more than 118 patients to
           achieve the 68 evaluable adults for the immunological primary endpoint. However, all NCI
           patients will undergo a single 1 year FLT for evaluation of thymus reconstitution. 10
           pediatric patients at CNMC will undergo FLT PET/CT imaging on Day -1, day+9, and day +28
           (if possible). Initial images will be correlated with

      engraftment and other secondary endpoints.

      -Study endpoints to include: 1) safety of Lupron in the context of allogeneic BMT, 2)
      lymphocyte reconstitution after Lupron administration, 3) the incidence of acute and chronic
      GVHD and infectious complications, 4) remission rates after HSCT.
    

Trial Arms

NameTypeDescriptionInterventions
NIH Arm 1aActive ComparatorLupron and first transplant and FLT imaging at NIH
  • Lupron
  • 18F FLT
  • Cyclophosphamide
  • Methotrexate
  • Tacrolimus
NIH Arm 1bActive ComparatorNo lupron (men only are randomized) with first transplant and FLT imaging at NIH
  • 18F FLT
  • Cyclophosphamide
  • Methotrexate
  • Tacrolimus
CNMC armExperimentalFLT scan alone in children at CNMC only
  • 18F FLT
NIH Arm 2ExperimentalSecond transplant with lupron and FLT imaging
  • Lupron
  • 18F FLT
  • Cyclophosphamide
  • Busulfan
  • Fludarabine
UOK Arm 1aActive ComparatorLupron and first transplant at UOK
  • Lupron
  • Cyclophosphamide
  • Methotrexate
  • Tacrolimus
UOK Arm 1bActive ComparatorNo lupron (men only are randomized) with first transplant at UOK
  • Cyclophosphamide
  • Methotrexate
  • Tacrolimus
Arm 3ExperimentalHealthy Volunteer

    Eligibility Criteria

            -  ELIGIBILITY CRITERIA:
    
            INCLUSION CRITERIA: TRANSPLANT RECIPIENT
    
              1. At NIH : Age greater than or equal to 15 years old and/or greater than or equal to 9
                 years old and pubertal and less than or equal to 55 years for recipient. Pubertal is
                 defined by: prior menses at any time (females), documentation of clinical Tanner stage
                 greater than 2 at some point pre-chemotherapy or at the current visit. (At this point,
                 sex steroids have been produced for a few years which have driven initial pubertal
                 development). Tanner 2 is defined as: breast buds for females with coarse pubic hair,
                 and coarse pubic hair and testes > 2.5cm for males.
    
              2. At Children s National Medical Center only: age > 4 years old and < 24.
    
              3. At University of Oklahoma: Age greater than or equal to 17 years old and less than or
                 equal to 55 years for recipient.
    
              4. A diagnosis of a hematologic malignancy for which stem cell transplant is standard of
                 care:
    
            4.1. Acute Lymphocytic Leukemia
    
            Adult: (greater than or equal to 22 years) greater than or equal to CR2 OR CR1 with:
    
              -  Matched sibling donor for recipient treated on adult leukemia regimen
    
              -  t(9:22) or bcr-abl+; t(4:11), t(1:19), t(8:14), 11q23 (MLL rearrangements) complex
                 cytogenetics (5 or more chromosomal abnormalities), hypodiploidy (<44 chromosomes).
                 Note that patients with ALL blast crisis who emerge from CML are also eligible
    
              -  Primary induction failure, defined as failure to achieve CR with primary induction
                 chemotherapy
    
              -  High WBC (>30,000 for B-cell ALL and >100,000 for T-cell ALL) at diagnosis
    
              -  Persistence of minimal residual disease despite induction chemotherapy
    
            Pediatric (< 22 years): greater than or equal to CR2 OR CR1 with high risk features
    
              -  Matched sibling donor for recipient treated on adult leukemia regimen
    
              -  Primary induction failure (M3 (>25% with greater 200 cells counted) marrow at day 29),
                 M2 (5-25% blasts with greater than 200 cells counted) bone marrow or MRD > 1% at day
                 29 who then fail at day 43 with either an M2 or M3 BM or MRD > 1%
    
              -  Persistent leukemia and t(9;22) (MRD >1% day 29 or MRD > 0.01% endconsolidation)
    
              -  11q23 (MLL) rearrangements detected by cytogenetic or PCR at initial diagnosis who are
                 slow early responders (M2/M3 at day 14 or MRD> 0.01% at day 29)
    
              -  Extreme hypodiploidy (< 44 chromosomes or DNA index of <0.81) detected by
                 cytogenetic/ploidy analysis
    
            4.2 Acute Myelogenous Leukemia
    
            Adult: (greater than or equal to 22 years) greater than or equal to CR2 OR CR1 with high
            one of the following risk features
    
            -Adverse or intermediate-risk cytogenetics including:
    
              1. Normal cytogenetics
    
              2. complex karytoype (>2 abnormalities)
    
              3. inv (3) or t (3;3); t(11;19)(q23;p13.1); +13; -17/17p-; -18; -20; (t(6;9); t(6;11);
                 -7, 7q-; -5, 5q-; trisomy 8; t(3;5); t(9:11)(p22q23)
    
              4. monosomy karyotype (presence of an autosomal monosomy in conjunction with at least one
                 other autosomal monosomy or structural abnormality.
    
              5. Any other karyotype EXCEPT t(8;21), t(9;11), inv(16), or t (16;16), and M3 (17; 17)
                 unless ckit mutation present and then eligible.
    
              6. AML emerging from CML (blast crisis) are eligible
    
                 -Primary induction failure, defined as failure to achieve CR with primary induction
                 chemotherapy
    
                   -  Secondary AML, defined as AML related to antecedent MDS, MPN, or cytotoxic
                      chemotherapy
    
                   -  Hyperleukocytosis (WBC > 100,000 at diagnosis)
    
                   -  Mutations in the FMS-like tyrosine kinase 3 (FLT3) gene (FLT3-LM; FLT-ITDs)
    
                   -  Bilineage or biphenotypic leukemias are high risk features and eligible.
    
                 Pediatric (< 22 years): greater than or equal to CR2 OR CR1 with a high risk feature
                 including:
    
                 -Primary induction failure (greater than or equal to 5% blasts in marrow after
                 induction)
    
                   -  Persistent leukemia (>15% after first course of chemotherapy)
    
                   -  Complex karyoptype, monosomy 7, or -5/-5q, FLT3 ITD-AR (>0.4) EXCEPT if also
                      inv(16)/t(16;16), t(8,21)
    
                   -  Normal cytogenetics or abnormal cytogenetics EXCEPT if also inv(16)/t(16;16),
                      t(8,21) are eligible for SIBLING transplant only
    
                   -  Bilineage or biphenotypic leukemias are high risk features and eligible.
    
                 4.3. Myelodysplastic Syndrome RAEB 1 or 2; cytogenetics showing complex karyotype (3
                 or more abnormalities), monosomy 7/del(7q), or inv(3)/t(3q)/del(3q); or transfusion
                 dependent.
    
                 4.4. Chronic Myelomonocytic Leukemia
    
                 4.5. Chronic Myelogenous Leukemia who have failed 2G- tyrosine kinase inhibitors (TKI)
    
                 4.6. Standard pediatric indications for myeloablative transplantation for patients
                 undergoing HSCT at Children s National Medical Center per institutional guidelines
    
                 5. Disease status
    
                 If patients are found to not be in remission at screening, then the patient may be
                 returned to their primary hematologist/oncologist or may receive chemotherapy as per
                 standard of care for the malignant disease. Patients for whom this would be their
                 first allogeneic transplant must be in remission (< 5% malignant blasts in marrow and
                 peripheral blood and no evidence of extramedullary disease) for transplant. Patients
                 enrolled on this protocol for their second transplant do not need to have attained
                 remission prior to transplant.
    
                 6. Performance status: Karnofsky or Lansky performance status greater than or equal to
                 60% AND life expectance of greater than 3 months.
    
                 7. Ability to give informed consent. For recipients and donors < 18 years of age,
                 their legal guardian must give informed consent. Pediatric patients will be included
                 in an age appropriate discussion in accordance with institutional guidelines.
    
                 8 Hepatic function: Patients must have evidence of adequate liver function prior to
                 enrollment defined by total bilirubin < 2.5 mg/dL (unless documented Gilbert s
                 syndrome) AND transaminases less than or equal to 5 x the upper limit of normal for
                 age appropriate indices.
    
                 9. Renal function: Patients must have evidence of adequate renal function to proceed
                 with stem cell transplant, creatinine clearance > 60 ml/min/1.73 m2. GFR may also
                 demonstrate adequate renal function.
    
                 10. Left ventricular ejection fraction greater than or equal to 50% OR shortening
                 fraction of greater than or equal to 27% demonstrated on 2D echocardiogram or MUGA.
    
                 11. Pulmonary function of DLC0 adj/VA and FEV1 greater than or equal to 60% of normal
                 indices for age and height unless the patient has a likely acute reversible etiology
                 of decline and then DLCO adj/VA greater than or equal to 30% of normal. Pediatric
                 patients unable to complete PFTs may be enrolled as per enrolling institution SOP for
                 recipient guidelines.
    
                 12. Patients with prior autologous stem cell transplants will be included. Patients
                 with prior allogeneic stem cell transplants will be eligible for 2nd BMT if not
                 previously transplanted with FLT on 11-c-0136.
    
                 13. Prior experimental systemic therapies must have been completed greater than 2
                 weeks prior to study entry.
    
                 EXCLUSION CRITERIA: TRANSPLANT RECIPIENT
    
                   1. History of psychiatric disorder which may compromise compliance with transplant
                      protocol, or which does not allow for appropriate informed consent.
    
                   2. Active infections not responding to therapy. All efforts should be made to clear
                      the infection prior to enrollment.
    
                   3. Clinically significant systemic illness with manifestations of significant organ
                      dysfunction which in the judgment PI or AI would render the patient unlikely to
                      tolerate the protocol therapy or complete the study.
    
                   4. Presence of active malignancy from an organ system other than hematopoietic.
    
                   5. HIV infection.
    
                   6. Chronic active hepatitis B infection. Patients may be hepatitis B core antibody
                      positive but must be surface antigen negative and without active evidence of
                      disease.
    
                   7. Pregnant or lactating females will be excluded from this trial due to unknown
                      risks to the developing fetus. Patients of child-bearing potential must use an
                      effective form of contraception while on study.
    
                   8. Sexually active individuals capable of becoming pregnant who are unable or
                      unwilling to use effective form(s) of contraception during time enrolled on study
                      and for 1 year post-transplant.
    
                   9. History of prior Lupron intolerance. Note: patients ARE eligible if prior or
                      current lupron exposure.
    
                 INCLUSION CRITERIA: MATCHED RELATED TRANSPLANT DONOR
    
                   1. Age greater than or equal to 2 and less than or equal to 60 years old and able to
                      give consent or assent. For donors < 18 years old, the legal guardian must be
                      able to provide informed consent and an evaluation by a LSW or psychiatric
                      personnel will be needed to determine willingness to participate. Pediatric
                      patients will be included in an age appropriate discussion in accordance with
                      institutional guidelines.
    
                   2. HLA-matched related donor, excluding identical twins. Donors must be matched at
                      least 7 loci out of 8 at the allele or antigen level excluding antigen DRB1
                      mismatch.
    
                   3. Donor selection will be in accordance with NIH/CC Department of Transfusion
                      Medicine criteria and must be able to medically endure stem cell collection or as
                      per local institutional guidelines.
    
                   4. Donors must be HIV negative, HTLV negative, HBsA negative.
    
                   5. Donors must be physically able to and willing to tolerate marrow harvest
                      collection preferably, or in the absence of this option, able and willing to
                      donate via peripheral blood pheresis.
    
                 EXCLUSION CRITERIA: MATCHED RELATED TRANSPLANT DONOR
    
                   1. History of medical illness that in the estimation of the PI or DTM physician
                      precludes donation of marrow.
    
                   2. Anemia (Hb < 10 gm/dl) or thrombocytopenia (< 100,000/ ul).
    
                   3. Pregnant females (due to risk to fetus).
    
                   4. Current psychiatric diagnosis that would compromise compliance with transplant
                      protocol or precludes appropriate informed consent.
    
                   5. Presence of any blood transmissible infectious disease that cannot be cleared
                      prior to stem cell collection and poses an unacceptable risk for the recipient
                      (excludes CMV).
    
                   6. Active malignancy will exclude the donor. Any malignancy less than five years
                      postremission will exclude the donor. Non-hematologic malignancies greater than 5
                      years ago will not exclude the donor. Any history of hematologic malignancy will
                      be considered on a case by case basis.
    
                   7. Any medical contraindication to anesthesia or marrow donation will exclude the
                      donor.
    
                   8. Donors receiving experimental therapy or investigational agents.
    
                   9. Active autoimmune disease that in the opinion of the PI or AI would compromise
                      the success of the transplant.
    
                 INCLUSION CRITERIA- MATCHED UNRELATED DONOR
    
                   1. Unrelated donor matched at HLA-A, B, C, and DR loci by high resolution typing (at
                      8/8 or 7/8 antigen/allele match) are acceptable donors.
    
                   2. The evaluation of donors shall be in accordance with existing National Marrow
                      Donor Program (NMDP) Standard Policies and Procedures at all institutions.
    
                 INCLUSION CRITERIA- (18F) FLT CANDIDATE TRANSPLANT RECIPIENT
    
                   1. Meets criteria for Transplant Recipient
    
                   2. Age greater than or equal to 18 years old at NCI, and age > 4 years and < 24
                      years at Children s National Medical Center
    
                   3. Donor who is willing to undergo bone marrow or stem cell harvest.
    
                 EXCLUSION CRITERIA- (18F) FLT CANDIDATE TRANSPLANT RECIPIENT
    
                 1. History of prior fluorothymidine allergy or intolerance.
          
    Maximum Eligible Age:55 Years
    Minimum Eligible Age:2 Years
    Eligible Gender:All
    Healthy Volunteers:No

    Primary Outcome Measures

    Measure:To determine if Lupron improves B lymphocyte reconstitution after HSCT.
    Time Frame:12 months after first and second BMT
    Safety Issue:
    Description:Early engraftment/immune reconstitution in marrow after allogeneic HSCT

    Secondary Outcome Measures

    Measure:To investigate whether Lupron will decrease the incidence of acute or chronic GVHD without altering GVT after allogeneic HSCT.
    Time Frame:years
    Safety Issue:
    Description:
    Measure:To evaluate if Lupron decreases the incidence of infections after HSCT.
    Time Frame:2 years
    Safety Issue:
    Description:

    Details

    Phase:Phase 2
    Primary Purpose:Interventional
    Overall Status:Active, not recruiting
    Lead Sponsor:National Cancer Institute (NCI)

    Trial Keywords

    • FLT
    • Lupron
    • Thymic Renewal
    • Stem Cell Transplant
    • Acute Lymphocytic Leukemia
    • Acute Myelogenous Leukemia
    • Myelodyplastic Syndrome

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