Clinical Trials /

Therapy for Progressive and/or Refractory Hematologic Malignancies

NCT02223312

Description:

The purpose of this study is to evaluate the safety and effectiveness of Tumor Associated Peptide Antigen (TAPA) pulsed dendritic cell (DC) vaccines in the treatment of progressive and/or refractory hematologic malignancies (HM). We hypothesize that treatment of patients with relapsed and/or refractory HM, without available potentially curative treatment options, and whose neoplastic cells express at least one (1) TAPA of a defined panel of TAPAs, using low-dose cyclophosphamide (CYP) followed by an autologous, monocyte-derived, TAPA-pulsed DC vaccine and low-dose granulocyte macrophage colony stimulating factor (GM-CSF), will result in TAPA-specific T-cell responses without significant toxicities. We also hypothesize CD4+ T-cell and CD8+ T-cell responses generated against specific TAPAs may translate into clinical antitumor activity.

Related Conditions:
  • Chronic Lymphocytic Leukemia
  • Hodgkin Lymphoma
  • Multiple Myeloma
  • Non-Hodgkin Lymphoma
Recruiting Status:

Withdrawn

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Therapy for Progressive and/or Refractory Hematologic Malignancies
  • Official Title: Phase I/II Study of Low-Dose Cyclophosphamide, Tumor Associated Peptide Antigen-Pulsed Dendritic Cell Therapy and Low Dose GM-CSF, in Patients With Progressive and/or Refractory Hematologic Malignancies

Clinical Trial IDs

  • ORG STUDY ID: KiroVAX002.2
  • SECONDARY ID: BSK01 Dendritic cell vaccine
  • NCT ID: NCT02223312

Conditions

  • Cancer
  • Hematologic Malignancies

Interventions

DrugSynonymsArms
TAPA-pulsed DC vaccineTAPA-pulsed DC vaccine

Purpose

The purpose of this study is to evaluate the safety and effectiveness of Tumor Associated Peptide Antigen (TAPA) pulsed dendritic cell (DC) vaccines in the treatment of progressive and/or refractory hematologic malignancies (HM). We hypothesize that treatment of patients with relapsed and/or refractory HM, without available potentially curative treatment options, and whose neoplastic cells express at least one (1) TAPA of a defined panel of TAPAs, using low-dose cyclophosphamide (CYP) followed by an autologous, monocyte-derived, TAPA-pulsed DC vaccine and low-dose granulocyte macrophage colony stimulating factor (GM-CSF), will result in TAPA-specific T-cell responses without significant toxicities. We also hypothesize CD4+ T-cell and CD8+ T-cell responses generated against specific TAPAs may translate into clinical antitumor activity.

Detailed Description

      Patients diagnosed with progressive and/or refractory hematologic malignancies, who have
      failed conventional therapy and have no potentially curative therapeutic options available,
      will be candidates for this Phase I/II study. Following confirmation of disease progression
      and/or refractoriness, eligible patients who agree to participate and sign a consent form
      will have their neoplastic cells and/or blood analyzed for the expression of a specific panel
      of Tumor Associated Peptide Antigens (TAPAs), including SP17, Ropporin, AKAP4, PTTG1 and
      Span-xb. Patients whose tumors express one (1) or more of these TAPAs will receive three (3)
      days of subcutaneous Granulocyte Macrophage Colony Stimulating Factor (GM-CSF) to increase
      bone marrow production of monocytes and dendritic cell (DC) precursors, and peripheral blood
      mononuclear cells will be obtained by phlebotomy and/or leukapheresis for generation of
      autologous DCs. Patient's DCs will be generated at Kiromic's Cell Processing GMP facility,
      according to established Standard Operating Procedures, and activated by pulsing/loading them
      with the TAPA(s) relevant for each particular patient. Patients will receive five (5) days of
      low-dose cyclophosphamide prior to each vaccination with TAPA-pulsed DCs to decrease Treg
      activity. TAPA-pulsed DCs will be administered at a fixed dose of up to 1 x 107 DCs at least
      two (2) days following cyclophosphamide administration. DC vaccination schedule will be once
      every fourteen (14) days via subcutaneous (SC) and intradermal (ID) injections for a total of
      6 vaccinations. Low dose GM-CSF will also be administered SC for five (5) consecutive days,
      starting three (3) to six (6) hours after each TAPA-pulsed DC treatment, to optimize immune
      response and DC viability in vivo. Patients will be followed on a weekly basis (or more
      frequently if required) to evaluate treatment-related toxicity. Immune responses and
      anti-tumor responses will be evaluated per protocol specifications. Continuation and stopping
      rules for the study will be defined based on toxicity/tolerability (Phase I) and/or immune
      efficacy (Phase II).
    

Trial Arms

NameTypeDescriptionInterventions
TAPA-pulsed DC vaccineExperimentalThe subject will take low-dose cyclophosphamide by mouth for 5 days starting 7 days prior to the vaccine cycle. The vaccine contains 1 x 10^7 TAPA-pulsed dendritic cells and is administered SQ with low-dose GM-CSF following the low-dose cyclophosphamide cycle. A total of six (6) cycles of cyclophosphamide and six (6) DC vaccines cycles will be administered alternating every 14 days.
  • TAPA-pulsed DC vaccine

Eligibility Criteria

        Inclusion Criteria:

          1. Ability to provide informed consent.

          2. Patients at least eighteen (18) years of age diagnosed with the following
             histologically proven, progressive and/or refractory HM following standard therapy:
             Multiple Myeloma (MM), Hodgkins Disease (HD), Non-Hodgkins Lymphoma (NHL) and Chronic
             Lymphocytic Leukemia (CLL), and without potentially curative therapeutic options, will
             be eligible.

          3. Expression of one (1) or more of the following TAPAs: SP17, AKAP4, Ropporin, PTTG1 and
             Span-xb, by either RT-PCR and/or immunocytochemistry, Western blotting or ELISA, in
             neoplastic cells and/or blood.

          4. Presence of measurable or evaluable disease.

          5. Patients must not have any active infectious process.

          6. Patients must have a negative test for HIV, Hepatitis A, B, and C.

          7. Patients must not be receiving active immunosuppressive therapy.

          8. Patients must have discontinued systemic antineoplastic therapy (including systemic
             corticosteroids) at least four (4) weeks prior to enrollment.

          9. Patients may not have any known allergy to GM-CSF.

         10. Patients must be willing to provide at least 250 mL, and up to 500 mL, of whole blood
             obtained by phlebotomy and/or consent to leukapheresis for DC generation.

         11. Adequate renal and hepatic function (creatinine ≤ 2.0 mg/dl, bilirubin ≤ 2.0 mg/dl,
             AST and ALT ≤ 4X upper limit of normal range).

         12. Adequate hematologic function (Platelets ≥ 60,000/mm3, lymphocytes ≥ 1,000/mm3,
             neutrophils ≥ 750/mm3, hemoglobin ≥ 10 g/dl).

         13. Karnofsky performance status ≥ 70%.

         14. Expected survival ≥ 6 months.

         15. Patient Human Leucocyte Antigen (HLA) typing should demonstrate HLA-A*01, and/or
             HLA-A-*02, and/or HLA-A*24 restriction.

         16. Either a female or male of reproductive capacity wishing to participate in this study
             must be using, or agree to use, one or more types of birth control during the entire
             study and for 3 months after completing the study. Birth control methods may include
             condoms, diaphragms, birth control pills, spermicidal gels or foams, anti-gonadotropin
             injections, intrauterine devices (IUD), surgical sterilization, or subcutaneous
             implants. Another choice is for a subject's sexual partner to use one of these birth
             control methods. Women of reproductive capacity will be required to undergo a urine
             pregnancy test before completion of the post-screening informed consent process.

        Exclusion Criteria:

          1. Patients without confirmed progressive and/or refractory MM, HD, NHL and CLL, or those
             with confirmed progressive and/or refractory MM, HD, NHL and CLL but who have a
             potentially curative therapeutic intervention available, are excluded from the study.

          2. Patients without measurable or evaluable disease.

          3. Patients receiving cytotoxic therapy, radiation therapy, immunotherapy or non-topical
             steroids for HM within four (4) weeks of enrollment.

          4. Active immunosuppressive or cytotoxic therapy (excluding topical steroids) for any
             other condition.

          5. Persistent fever (>24 hours) documented by repeated measurement or active,
             uncontrolled infection within 4 weeks of enrollment.

          6. Active ischemic heart disease or history of myocardial infarction within six months.

          7. Active autoimmune disease, including, but not limited to, Systemic Lupus Erythematosus
             (SLE), Multiple Sclerosis (MS), Ankylosing Spondylitis (AS), and Rheumatoid Arthritis
             (RA).

          8. Pregnancy or breast feeding.

          9. Active second invasive malignancy, other than basal cell carcinoma of the skin.

         10. Life expectancy of less than 6 months.

         11. Patients with contraindications to CYP and/or GM-CSF.

         12. Patients who have received organ transplantations.

         13. Patients with psychological or geographic conditions that prevent adequate follow-up
             or compliance with the study protocol.

         14. Patients with documented primary or secondary central nervous system (CNS) involvement
             at any time during disease course are excluded from the study.

         15. Patient with HLA-A alleles not belonging to any of the following subtypes: HLA-A*01,
             or HLA-A*02, or HLA-A*24.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Number of adverse events that occur due to toxicity of low-dose CYP followed by TAPA-pulsed DC therapy and low-dose GM-CSF administration
Time Frame:Every 7 days
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Immunological efficacy as indicated by T-cell cytokine levels
Time Frame:up to 5 months
Safety Issue:
Description:
Measure:Immunological efficacy as determined by a positive delayed type hypersensitivity (DTH) skin test
Time Frame:up to 5 months
Safety Issue:
Description:DTH skin test will be performed 8-10 days before vaccine administration. DTH response will be evaluated again at days 28 and 70 of the trial as well as 14 and 60 days after the trial has ended.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Withdrawn
Lead Sponsor:Kiromic, Inc.

Last Updated