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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT02963064
Recruitment Status : Recruiting
First Posted : November 15, 2016
Last Update Posted : November 15, 2016
California Institute for Regenerative Medicine (CIRM)
Information provided by (Responsible Party):
Judith Anne Shizuru, Stanford University

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.

Condition or disease Intervention/treatment Phase
SCID Biological: Humanized anti-CD117 Monoclonal Antibody Procedure: Blood Forming Stem Cell Transplant (CD34+CD90+) Phase 1

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 grafts.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 90 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Study Start Date : August 2016
Estimated Primary Completion Date : August 2020
Estimated Study Completion Date : August 2020

Arm Intervention/treatment
Experimental: Blood Stem Cell Transplant w/ anti-CD117 conditioning
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.
Biological: Humanized anti-CD117 Monoclonal Antibody
Procedure: one time intravenous infusion of anti-CD117 antibody

Procedure: Blood Forming Stem Cell Transplant (CD34+CD90+)
Procedure: one time intravenous infusion of donor blood forming stem cells

Primary Outcome Measures :
  1. Emergent Adverse Events [Safety, and Tolerability of AMG 191 in patients with SCID] [ Time Frame: 104 weeks ]
    Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) will be assessed. Patient assessments will include alterations in vital signs, changes in physical exam, and clinical laboratory studies. Patients will be monitored for myelosuppression and anti-AMG 191 antibodies.

Secondary Outcome Measures :
  1. Incidence and severity of acute and chronic GVHD [ Time Frame: Through study completion, about 104 weeks ]
    Evaluation of clinical symptoms, patient questionnaire, Lansky/Karnofsky scale, and clinician assessment.

  2. Hematopoietic recovery following HSC transplantation [ Time Frame: Through study completion, about 104 weeks ]
    Hematopoietic recovery will be evaluated by measurement of blood parameters including total WBC, hemoglobin, hematocrit, and platelet count.

  3. Dose of AMG 191 that achieves adequate donor HSC engraftment at 24 weeks [ Time Frame: Through study completion, about 104 weeks ]
    Myeloid chimerism is measured by isolation of CD15+ from peripheral blood mononuclear cells (PBMC) and STR analysis of the CD15+ cells.

  4. AMG 191 Pharmacokinetic Outcome [ Time Frame: Depending on dose received, up to 20 days ]
    Parameters will be estimated using standard population methodologies and non-linear mixed effect modeling. The influence of patient-specific clinical covariates on drug clearance will be investigated, including patient demographics and laboratory biochemistries.

  5. AMG 191 Pharmacodynamic Outcome [ Time Frame: Depending on dose received, up to 20 days ]
    Exploratory PK-PD analyses to investigate and identify the relationship between drug exposure and clinical endpoints for both safety and efficacy will be performed.

  6. Evaluation of quantitative immune recovery follow CD34 CD90 transplantation [ Time Frame: Through study completion, about 104 weeks ]
    T, B, and NK cell will be measured by CBC differential studies and flow cytometry and values will be compared to CD34 enriched HSPC.

Other Outcome Measures:
  1. Determine if donor myeloid chimerism at 4 weeks predicts donor HSC engraftment at 24 weeks post-transplant [ Time Frame: Through study completion, about 104 weeks ]
    Blood myeloid chimerism measured by STR analysis of CD15+ at 4 weeks post-transplant will be compared to values obtained from the same patient at 24 weeks post-transplant.

  2. Determine if SCID phenotype influences response to conditioning with AMG 191 and resultant donor HSC engraftment [ Time Frame: Through study completion, about 104 weeks ]
    Blood myeloid chimerism at 24 weeks will be compared across the different SCID phenotypes.

  3. Compare B and T cell repertoires in SCID patients transplanted with CD34 enriched HSC versus CD34+CD90+ HSC [ Time Frame: Through study completion, about 104 weeks ]
    Diversity of the T and B cell repertoire will be assessed by parallel high throughput sequencing of the TCR beta chain and immunoglobulin heavy chain gene, respectively.

  4. Determine if HSC engraftment is associated with improved quality of life in patients of prior HSC transplantation. [ Time Frame: Through study completion, about 104 weeks ]
    Patients or patient surrogates in Groups A and B will be asked to complete QoL surveys in the pre- and post-transplant setting and results will be compared.

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   3 Months and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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 GVHD.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT02963064

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Contact: Judith A Shizuru, M.D, PhD 650723083
Contact: Anne T Le, B.S. 6507697987

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United States, California
Lucile Packard Children's Hospital Recruiting
Palo Alto, California, United States, 94304
Contact: Kirstin F Dougall    650-721-8389   
UCSF Benioff's Children's Hospital Not yet recruiting
San Francisco, California, United States, 94158
Contact: Carol Fraser-Browne    415-476-2188   
Sponsors and Collaborators
Stanford University
California Institute for Regenerative Medicine (CIRM)
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Principal Investigator: Rajni A Agarwal, M.D. Stanford University
Principal Investigator: Christopher C Dvorak, M.D. University of California, San Francisco

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Responsible Party: Judith Anne Shizuru, Professor of Medicine (Blood and Marrow Transplantation), Stanford University Identifier: NCT02963064    
Other Study ID Numbers: JAS-BMT-CP-001
First Posted: November 15, 2016    Key Record Dates
Last Update Posted: November 15, 2016
Last Verified: November 2016
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
Keywords provided by Judith Anne Shizuru, Stanford University:
Bone Marrow Transplantation
Stem Cells
Additional relevant MeSH terms:
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Severe Combined Immunodeficiency
Infant, Newborn, Diseases
DNA Repair-Deficiency Disorders
Metabolic Diseases
Immunologic Deficiency Syndromes
Immune System Diseases
Antibodies, Monoclonal
Immunologic Factors
Physiological Effects of Drugs