AMG191 Conditioning/CD34+CD90 Stem Cell Transplant Study for SCID Patients

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Brief Title

AMG191 Conditioning/CD34+CD90 Stem Cell Transplant Study for SCID Patients

Official Title

A Phase 1 Study to Evaluate the Safety and Tolerability of Tandemly-purified Allogenic CD34+CD90+ HSC Administered Following Conditioning With AMG 191 to Achieve Engraftment and Immune Reconstitution in Patients With SCID

Brief Summary

      This is a single-arm, open label, Phase 1 study to assess the safety and tolerability of
      CD34+CD90+ hematopoietic stem cell (HSC) allografts infused into patients with SCID who are
      conditioned for transplantation with AMG 191, an antibody that targets CD117 present on
      endogenous HSC. The target dose of CD34+CD90+ HSC will be >1 x 10^6 cells/kg and the optimal
      conditioning dose of AMG 191 will be determined during dose escalation.

Detailed Description

      Hematopoietic stem cell transplantation (HCT) is the only proven cure for severe combined
      immunodeficiency (SCID), a rare disorder in which patients do not have functional
      lymphocytes. Unless treated, patients with SCID generally die from infections before age two.
      The success of HCT depends on the type of donor, and it is often not feasible to find a fully
      human leukocyte antigen (HLA)-matched unrelated donor due to the need to transplant early in
      life before infections develop. As a result, family members who are partially HLA-matched
      (haploidentical) often donate their blood stem cells for the transplant. There are three
      primary risks associated with poor HCT outcomes for SCID patients: 1) chemotherapeutic drugs
      are sometimes given to prepare the patient before HCT to improve the chance of successful
      engraftment; but these treatments (called "conditioning") can have deleterious short and
      long-term side effects to which SCID patients are especially vulnerable; 2) risk for
      developing graft-versus-host disease (GVHD) due to reaction by donor T cells contained in
      allografts against recipient tissues can cause serious, life-threatening complications,
      especially if the donor is only partially HLA-matched; and 3) if no conditioning is used true
      stem cells may not engraft, which prevents development of a long-term functioning immune
      system, especially B lymphocytes. As consequence many such patients need life-long
      gammaglobulin replacement therapy.

      This study will investigate a combined, two-step approach that is expected to improve the
      outcome of HCT for SCID: It is a phase 1 study. Hence, the study will test the safety of this
      two step approach.

      The first part of the study will test an experimental conditioning treatment that is expected
      to be less toxic to patients than standard chemotherapy. This treatment involves giving a one
      time intravenous dose of protein, called a monoclonal antibody, which binds to a specific
      molecule on the surface of cells, called c-kit or CD117. The antibody that will be used is
      called AMG 191. AMG 191 is expected to result in depletion of recipient bone marrow stem
      cells and thereby improve donor blood stem cell engraftment in the recipient's bone marrow
      and the development of an immune system from the donor. Patients followed for clearance of
      antibody from blood by pharmacokinetic (PK) studies.

      The second part will test if SCID patients who are conditioned for transplant with AMG 191
      will do better if they have more T-cells removed from the donor grafts. T-cells normally act
      to attack foreign pathogens such as viruses. However, when transplanted into a recipient as
      part of a blood stem cell graft, T-cells can cause harm by mistakenly attacking normal
      tissues, including the lymphoid organs of the recipient, resulting in GVHD or a more subtle
      form of GVHD called subclinical GVHD which is deleterious to immune function. While removal
      of T-cells from blood stem cell grafts is not novel, grafts in this study will under more
      stringent T-cell removal because patients with SCID are particularly prone to develop GVHD.
      Grafts will first undergo standard selection of CD34+ cells to reduce donor T-cells and
      enrich for blood stem cells. A second enrichment step will purify the blood stem cells away
      from remaining T-cells by staining the CD34-selected cells with another CD34 binding antibody
      plus an antibody that binds to CD90. CD34+CD90+ cells, represent a more purified stem cell
      fraction, and will be isolated using a cell sorter. This part of the study will determine if
      GVHD can be reduced and equivalent or improved immune function achieved compared to standard

Study Phase

Phase 1

Study Type


Primary Outcome

Emergent Adverse Events [Safety, and Tolerability of AMG 191 in patients with SCID]

Secondary Outcome

 Incidence and severity of acute and chronic GVHD




Humanized anti-CD117 Monoclonal Antibody

Study Arms / Comparison Groups

 Blood Stem Cell Transplant w/ anti-CD117 conditioning
Description:  The study will enroll three groups based on declining age (>/=12; >2 to <12; >/=3 months newly diagnosed SCID); groups will enroll in staggered order. There are three dose levels. Patients will receive a one time dose of intravenous anti-CD117 antibody (AMG 191), followed by monitoring for antibody clearance (PK). Once the antibody has cleared below a certain level, patients will receive the blood forming stem cell graft and be monitored for immune recovery. Initially, patients will be transplanted with standard-of-care CD34+ enriched grafts. Transplants of CD34+CD90+ graft can commence when the corresponding CD34+ cohort at a given dose AMG 191 level demonstrates adequate donor cell engraftment defined by > 5% myeloid chimerism at 6 months post-HCT.


* 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


Estimated Enrollment


Start Date

August 2016

Completion Date

August 2020

Primary Completion Date

August 2020

Eligibility Criteria

        Key Inclusion Criteria:

        All patient groups must have:

          1. Primary Immune Deficiency as defined by specific criteria, including but not limited
             to the following subtypes:

               1. T-, B+, NK-: IL-2Rcγ deficient, JAK3-deficient

               2. T-, B-, NK+: RAG1/2 deficient, Artemis-deficient

               3. T-, B+, NK+: IL7Rα deficient, CD3 subunit deficient, CD45 deficient

          2. Acceptable organ function as defined in study protocol

          3. Life expectancy of at least 8 weeks

          4. Female patients of childbearing potential willing to use an effective contraceptive
             method for the duration of study participation

        Key Inclusion Criteria for patients >/= two years of age who have had a prior allogeneic
        bone marrow transplant (BMT):

          1. Prior donor of appropriate age (≥ 5 years old) available for re-collection of stem
             cells by apheresis

          2. Previous allogeneic BMT (> 2 years prior) with poor graft function defined as one of
             the following:

               1. Inadequate B cell engraftment,

               2. Incomplete T cell reconstitution,

               3. Severe clinical symptoms explained by poor immunity

        Key Inclusion criteria specific for patients with newly diagnosed SCID:

        1. Haploidentical donor of appropriate age (> 5 years old) or HLA-matched unrelated donor
        available for apheresis

        Exclusion Criteria:

          1. Patients with any acute or uncontrolled infections

          2. Patients receiving any other investigational agents, or concurrent biological,
             chemotherapy, or radiation therapy

          3. Patients with active malignancies

          4. Pregnant women

          5. Women who are nursing and do not wish to discontinue breast feeding

          6. Lansky/Karnofsky performance score < 50%

          7. Patients with certain defined SCID subtypes, including:

               1. Omenn syndrome

               2. Leaky SCID

               3. Reticular dysgenesis

               4. Adenosine deaminase deficiency

               5. Purine nucleoside phosphorylase deficiency

          8. For patients who have had a prior HCT, any evidence of donor myeloid chimerism in
             peripheral blood by STR analysis.

          9. For patients with newly diagnosed SCID, an HLA-matched sibling eligible to donate
             hematopoietic cells

         10. Active GVHD within 6 months prior to enrollment, or on immunosuppressive therapy for




3 Months - N/A

Accepts Healthy Volunteers



Rajni A Agarwal, M.D., 650723083, [email protected]

Location Countries

United States

Location Countries

United States

Administrative Informations



Organization ID


Responsible Party

Principal Investigator

Study Sponsor

Stanford University


 California Institute for Regenerative Medicine (CIRM)

Study Sponsor

Rajni A Agarwal, M.D., Principal Investigator, Stanford University

Verification Date

November 2016