Details

Details

Title A Phase 1b, Multicenter, Open-Label, Safety, Tolerability, and Activity Study of SYNT001 in Subjects with Chronic, Stable Warm Autoimmune Hemolytic Anemia (WAIHA)

IRB SYNT 1Z17

CC 17-995

Hospital Main Campus

Phase Phase 1

Disease Anemia

Drug SYNT001

Description

Description

Primary Objective
  • To evaluate the safety and tolerability of 5 once-weekly IV infusions of SYNT001 at different dose levels in subjects with chronic active, but stable, WAIHA.
Secondary Objectives
  • To determine the PK of SYNT001 following 5 once-weekly 1-hour IV infusions at different dose levels
  • To assess the effect of 5 once-weekly doses of SYNT001 at different dose levels on the following PD biomarkers:
    • Immunoglobulins: IgG, IgG subtypes (IgG1-4), IgA, IgM
    • Albumin
  • To assess the effect of 5 once-weekly doses of SYNT001 at different dose levels on the following disease activity markers:
    • Hematocrit
    • o Hemoglobin
    • Platelet count
    • Reticulocyte count
    • Lactate dehydrogenase (LDH)
    • Haptoglobin
    • Direct Coombs test
    • Total and Indirect bilirubin
  • To assess immunogenicity (anti-SYNT001 antibodies)
Exploratory Objectives
  • To assess the effect of 5 once-weekly doses of SYNT001 at different dose levels on the following biomarkers, including:
    • D-dimer
    • Antiphospholipid antibodies:
      • Lupus anticoagulant
      • Anti-cardiolipin antibody
      • Anti-beta-2-GP1 antibody
    • Antinuclear antibody (ANA) titer
    • Anti-dsDNA antibody titer
    • Circulating immune complexes (CIC)
    • Complement component 3 (C3)
    • Cold agglutinins (titer and thermal amplitude)
    • Quantitative Coombs assay
    • Exploratory biomarkers (FCGR2A single nucleotide polymorphism-SNP, RNAseq, urine IgG)
    • Immune phenotyping by flow cytometry for measurement of CD3+CD4+ T, CD3+CD8+ T, monocytes, NK cells and B cells
  • To characterize blood transfusions during the study
  • To characterize corticosteroid use during the study
Inclusion Criteria

Inclusion Criteria

  1. Willing and able to read, understand and sign an informed consent form;
  2. Male or female ≥ 18 years of age;
  3. Confirmed diagnosis by enrolling physician of WAIHA, including positive direct Coombs test;
  4. Evidence of active hemolysis including all the below:
    • Hemoglobin < 10 g/dL and
    • LDH > ULN or Haptoglobin < LLN or Indirect Bilirubin >ULN;
  5. Other treatments for WAIHA:
    • If treated with rituximab or other anti-CD20 antibodies, last dose > 3 months prior to screening;
    • If being treated with other immunosuppressants (i.e., azathioprine, mycophenolate mofetil or cyclosporine), dose must be stable (< 10% change in dose) for 6 weeks prior to screening
    • If being treated with corticosteroids, dose must ≤ 1mg/kg/day of prednisone or equivalent and stable (< 10% change in dose) for 2 weeks prior to screening
  6. Treatment of CLL or NHL
    • If being treated with an oral FDA-approved therapy for CLL or NHL, dose must be stable (< 10% change in dose) for 6 weeks prior to screening; Bruton's tyrosine kinase inhibitor dose must be stable (<10% change in dose) for 8 weeks prior to screening
  7. Body mass index (BMI) 18.5 - 39.9 kg/m2;
  8. Has a negative pregnancy test (for women of childbearing potential) documented prior to the first dose of study drug;
  9. Females of childbearing potential must agree to be abstinent or else use any two of the following medically acceptable forms of contraception (<1% per year failure rate) from the Screening Period through the final study visit: oral contraceptive, condom with or without spermicidal jelly, diaphragm or cervical cap with spermicidal jelly, or intrauterine device (IUD). A female whose male partner has had a vasectomy must agree to use one additional form of medically acceptable contraception.
  10. Females of non-childbearing potential, defined as surgically sterile (status post hysterectomy, bilateral oophorectomy, or bilateral tubal ligation) or post-menopausal for at least 12 months do not require contraception during the study.
  11. Males with female partners of childbearing potential, including males who are surgically sterile (post vasectomy), must agree to be abstinent or else use a medically acceptable form of contraception from the screening period through the final study visit.
Exclusion Criteria

Exclusion Criteria

  1. Unable or unwilling to comply with the protocol;
  2. Active non-hematologic malignancy or history of non-hematologic malignancy in the 3 years prior to screening (exclusive of non-melanoma skin cancer and cervical cancer in situ);
  3. Karnofsky Performance Scale ≤ 50
  4. History of blood transfusions more frequently than once per week over the 4 weeks prior to screening;
  5. Estimated glomerular filtration rate (eGFR) < 60 mL/minute/1.73m2
  6. Platelet count < 30 x 109/L;
  7. Positive for HIV or hepatitis C antibody;
  8. Positive for hepatitis B surface antigen;
  9. Splenectomy within 3 months of screening;
  10. Any T-cell or NK-cell non-Hodgkin lymphoma (NHL), and any moderate- or high-grade B-cell lymphoma, including Burkitt lymphoma, lymphoblastic B-cell lymphoma, diffuse large B-cell lymphoma, mantle cell lymphoma, small non-cleaved cell non-Burkitt lymphoma;
  11. Received any cytotoxic (other than azathioprine and chlorambucil) or mAb therapy in the 3 months prior to screening;
  12. Any exposure to an investigational drug or device within 30 days prior to screening;
  13. IVIG treatment within 60 days of screening;
  14. Plasmapheresis or immunoadsorption within 60 days of screening
  15. Cellular therapy, including CAR-T, at any time prior to screening
  16. Use of any immunosuppressive drugs apart from corticosteroids, azathioprine, mycophenolate mofetil, or cyclosporine within 3 months of screening;
  17. Active infection or history of recurrent infections;
  18. Serum total IgG < 600 mg/dL;
  19. Subject has any current medical condition that, in the opinion of the Investigator, may compromise their safety or compliance, preclude successful conduct of the study, or interfere with interpretation of the results (e.g., a significant pre-existing illness or other major comorbidity that the Investigator considers may confound the interpretation of the study results);
  20. Any vaccination within 2 weeks of screening