Rapamycin for Immunosuppression and B Cell Modulation Post Stem Cell Transplant for Acute Lymphoblastic Leukemia (ALL)

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Brief Title

Rapamycin for Immunosuppression and B Cell Modulation Post Stem Cell Transplant for Acute Lymphoblastic Leukemia (ALL)

Official Title

CHP-753, Rapamycin for Immunosuppression and B Cell Modulation Post Stem Cell Transplant for Acute Lymphoblastic Leukemia (ALL)

Brief Summary

      Objectives:

      Primary objective: Evaluate toxicity of rapamycin when used for post-bone marrow transplant
      graft vs. host disease prophylaxis in children with acute lymphoblastic leukemia (ALL).

      Investigator initiated; four participating institutions; Phase II pilot study
    

Detailed Description

      Objectives:

      Primary objective: Evaluate toxicity of rapamycin when used for post-bone marrow transplant
      graft vs. host disease prophylaxis in children with acute lymphoblastic leukemia (ALL).

      Rapamycin Rapamycin (RAPA, RapamuneR) (sirolimus) is an immunosuppressive agent that was
      approved by the FDA in 1999. It is a macrocyclic lactone that is structurally similar to
      Tacrolimus (FK506) and binds to the same intracellular protein as FK506, FKBP1,2,3, but it
      has an entirely different mechanism of action and a different principal target protein. The
      target of the RAPA: FKBP complex is the mammalian target of rapamycin (mTOR). Unlike the
      calcineurin inhibitors cyclosporine (CSA) and - FK506, RAPA exerts its effects by inhibiting
      growth factor-driven transduction signals in the T-cell response to alloantigen, thus
      preventing proliferation among T and B lymphocytes3,4. This action is at a later stage in T
      cell mediated response than that of CSA or FK506. Important cyclin-dependent signaling
      kinases are blocked, which results in cell cycle arrest between G1 and S phase. RAPA prevents
      factor dependent growth of activated T cells, but does not prevent the autocrine production
      or release of growth factors from activated T cells. Rapamycin has been studied in clinical
      trials of solid organ allografts, and have been shown to prolong allograft survival by
      inhibiting host CD4+ and CD8+ T cell expansion5, 6. RAPA has synergistic immunosuppressive
      properties when used with CSA or FK506, and its use allows lower doses of the more
      nephrotoxic calcineurin inhibitors to accomplish decreased rejection. The use of full dose
      calcineurin inhibitors with RAPA can result in nephrotoxicity, but these agents can be safely
      used at a reduced dose with RAPA.

      Our goal with Rapamycin is to achieve two necessary ends with one medication: a leukemic
      precursor effect (see above), and prevention of graft vs. host disease (GVHD). With CSA OR
      FK506, acute GVHD develops in approximately 40% of pediatric matched related donor
      recipients, and the majority is mild and easily controllable by the addition of
      methylprednisolone or prednisone. At Children's hospital of Philadelphia (CHOP), "short
      course" methotrexate in addition to CSA OR FK506 is given only to patients >14 years, or
      those with older donors. Chronic GVHD occurs in approximately 20% of pediatric matched
      related donor recipients, and 75% of this is limited to skin. Therefore, the use of RAPA in
      this group may accomplish adequate immunosuppression so as to prevent GVHD, as well as
      provide anti- B and anti-T cell malignancy effect. RAPA may also prove less toxic than the
      calcineurin inhibitors as well, in which both nephrotoxicity and neurotoxicity remain serious
      side effects.

      Allogeneic bone marrow transplantation for children with ALL Children who have very high-risk
      features, such as t(4;11) or t(9;22), or those who relapse while on chemotherapy are rarely
      cured by chemotherapy alone. These patients, as well as those beyond second remission, are
      generally referred for allogeneic stem cell transplantation. Approximately 25-30% of these
      patients will have a matched sibling donor. Matched sibling, matched unrelated, and cord
      blood donor bone marrow transplant results in approximately 40-60% of patients surviving
      disease free, but relapse remains the largest obstacle to cure. Rapamycin, with its apoptotic
      effects upon B cell precursor malignancies, may prove effective in decreasing the incidence
      of relapse in these patients, particularly when used in a state of minimal residual disease
      post transplant. We expect to treat approximately 10 patients with ALL yearly with matched
      related donor BMT between the four centers involved in this study.

      Rapamycin studies in conjunction with a calcineurin inhibitor (CSA or FK506) At the Dana
      Farber Cancer Institute (DFCI), 50 patients with related, human leukocyte antigen (HLA)
      matched peripheral stem cell transplants were studied using the combination of FK506 and
      repaying. The hypothesis tested was that the omission of methotrexate would not increase the
      rate of GVHD, and would reduce toxicity. The rate of grade II-IV acute GVHD was 16%, and
      III-IV 5%, which is extremely favorable for adults. Transplant related mortality at 100 days
      was 5%.

      This study was done following an earlier study of low dose methotrexate in the higher risk
      unrelated donor transplant patient. This study showed that rapamycin provided excellent GVHD
      prevention in the high-risk cohort.

      We will substitute FK506 for cyclosporine as per the Boston experience. This will be
      considered a standard practice within our division to increase patient compliance and
      comfort. This does not increase risk to patients, as oral FK506 is better tolerated RAPA and
      FK506 appear to be synergistic which may result in better GVHD prophylaxis.

      Study Procedures:

      Conditioning:

        1. Thiotepa 5 mg/kg days -7, -6. Given IV over 4 hours. Cyclophosphamide 60 mg/kg days -5,
           -4. Given over 1 hour IV with routine supportive care.

        2. Total body irradiation (TBI) 200 cGy/fraction x 6 fractions given over 3 days*.
           Testicular boost 400 cGy may be given for males. Patients with prior CNS disease and no
           prior central nervous system (CNS) irradiation: 600 cGy prior to starting conditioning.
           *TBI may be given before or after Thiotepa and cyclophosphamide. If given before Stem
           cells are to be given 48 hours after the end of cyclosphosphamide.

      Graft vs. Host Disease Prophylaxis:

        1. Tacrolimus IV by continuous infusion .03mg/kg per day beginning day -3. Target serum
           levels between 5-10 patients will switch to oral form when tolerating PO's ("Per Os" or
           "By mouth".

        2. Methotrexate 5mg/m2 will be given IV on days 1, 3, and 6 for all patients and on day 11
           for patients receiving unrelated donor marrow.

        3. Rapamycin day 0 with dosing as follows: 2.5 mg/m2/d (4mg/d max) PO daily.

      Absent GVHD Immune Suppression Weaning:

        1. Tacrolimus: Matched sibling donor allograft taper at day +42 over 6-8wks. Mismatched or
           unrelated allograft or cord blood taper at day +100 to be off by day +180.

        2. Sirolimus: At day + 180 wean over 4 weeks.
    

Study Phase

Phase 2

Study Type

Interventional


Primary Outcome

Number of Participants With Transplant-related Mortality

Secondary Outcome

 Percentage of Patients Developing Acute Graft vs. Host Disease (GVHD)

Condition

Acute Lymphoblastic Leukemia

Intervention

RAPAMYCIN

Study Arms / Comparison Groups

 All participants
Description:  

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

63

Start Date

August 2005

Completion Date

March 2010

Primary Completion Date

March 2010

Eligibility Criteria

        Inclusion Criteria:

          1. Pediatric patients' ages (0 - 21 years) with lymphoid malignancies considered for
             allogeneic bone marrow transplant from HLA-identical sibling donor, single antigen
             mismatched related or unrelated donor marrow /peripheral blood stem cell (PBSC) or
             cord blood available for marrow donation.

             First remission:

               -  if remission not achieved by day28

               -  high risk cytogenetic features, including t(9;22) or t(4;11) Second or third
                  remission

          2. Signed informed consent.

        Exclusion Criteria:

        1. Organ criteria:

          1. Cardiac: ECHO shortening fraction <27%

          2. Renal: Creatinine clearance <60 ml/min/1.73 m2

          3. Hepatic: Bilirubin >1.5 mg/dl, transaminases <3x normal

          4. Infection: active viral, fungal or bacterial infection including HIV.
      

Gender

All

Ages

N/A - 21 Years

Accepts Healthy Volunteers

No

Contacts

Michael Pulsipher, MD, , 

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT00795886

Organization ID

HCI14044


Responsible Party

Sponsor

Study Sponsor

University of Utah

Collaborators

 Children's Hospital of Philadelphia

Study Sponsor

Michael Pulsipher, MD, Principal Investigator, Primary Children's Hospital


Verification Date

July 2013