Pilot Study of Autologous T Lymphocytes With ADCC in Patients With CD20-Positive B-Cell Malignancies
- Conditions
- B-Cell Chronic Lymphocytic LeukemiaNon-Hodgkin's Lymphoma
- Interventions
- Drug: T-cell therapy + Rituximab + IL-2
- Registration Number
- NCT02315118
- Lead Sponsor
- National University Hospital, Singapore
- Brief Summary
Despite advancement in chemotherapy, radiotherapy and haematopoietic stem cell transplant (HSCT), and the recent introduction of more targeted therapies, a substantial proportion of patients with B-cell malignancies, such as B-cell chronic lymphocytic leukemia (CLL) and B-cell non-Hodgkin's lymphoma (NHL) still succumb to their malignancies. For CLL and low-grade NHL, cure is achievable only with HSCT but such aggressive approach is not justified as the initial therapy for most patients who have indolent disease; when disease has progressed, transplant is either not feasible or ineffective. For high-grade B-cell NHL, the availability of Rituximab has improved disease outcome but treatment failure portends nearly inevitable death from disease or treatment-related complications. Thus, newer, more effective therapies for patients with B-cell malignancies are urgently needed.
The present study translates recent laboratory findings into clinical application. In patients with B-cell malignancies receiving the anti-CD20 antibody Rituximab as standard therapy, the study aims to assess the feasibility and safety, as well as explore the efficacy, of infusing autologous T-lymphocytes engineered to express a CD16-41BB-CD3zeta chimeric receptor which mediates antibody-dependent cell cytotoxicity. Receptor expression is achieved by electroporation of mRNA.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- UNKNOWN
- Sex
- All
- Target Recruitment
- 18
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Age: 6 months to 80 years old.
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i) Diagnosis of aggressive CD20+ B-NHL with measurable tumor burden (by imaging, flow cytometry and/or PCR) post-treatment. This includes patients with persistent disease following more than 2 lines of chemotherapy, as well as patients who relapse following autologous transplantation, and in whom further salvage therapy has produced only a partial remission or where no effective salvage therapy available. Patients with bulky disease who require immediate salvage therapy will not be eligible.
OR ii) Diagnosis of poor risk indolent CD20+ B-NHL or Chronic Lymphocytic Leukemia. This includes high risk CLL cases with early relapse (<12 months following purine analog containing treatment or <24 months following autologous transplant), or with 17p deletion needing treatment, and who are not candidates (or refuses) allogeneic transplantation. Patients with advanced progressive indolent B-NHL with relapsed, refractory disease who have failed more than 2 lines of treatment (including autologous transplantation) may also be considered.
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Shortening fraction greater than or equal to 25%.
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Glomerular filtration rate greater than or equal to 50 ml/min/1.73 m2.
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Pulse oximetry greater than or equal to 92% on room air.
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Direct bilirubin less than or equal to 3.0 mg/dL (50 mmol/L).
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Alanine aminotransferase (ALT) is no more than 2 times the upper limit of normal unless determined to be directly due to disease.
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Aspartate transaminases (AST) is no more than 2 times the upper limit of normal unless determined to be directly due to disease.
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Karnofsky or Lansky performance score of greater than or equal to 50.
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No clinical history of or overt autoimmune disease.
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No past history of previous severe adverse reactions to rituximab, eg. cytokine release syndrome
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Has recovered from all acute NCI Common Toxicity Criteria grade II-IV non-hematologic acute toxicities resulting from prior therapy per the judgment of the PI.
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Is not receiving more than the equivalent of prednisone 10 mg daily.
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Not pregnant (negative serum or urine pregnancy test to be conducted within 7 days prior to enrollment).
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Not lactating.
Failure to meet any of the inclusion criteria
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description T-cell therapy + Rituximab + IL-2 T-cell therapy + Rituximab + IL-2 Patients will undergo apheresis procedure and T cell expansion will be done in the laboratory. All patients will receive Rituximab on day -2 and IL-2 three times per week for one week starting on day -1 (dose 1 of 3). IL-2 dosing will be continued 3 times per week for one week (3 doses total). On Day 0, T cell modification in the laboratory and T cell infusion in the patient will be done. A disease status evaluation will be conducted approximately 4 weeks post-T cell infusion.
- Primary Outcome Measures
Name Time Method Performance status assessed by age-dependent Performance Scores One-month (30 days) after the last T cell infusion Using KARNOFSKY PERFORMANCE STATUS SCALE (Recipient Age ≥ 16 years) and LANSKY PERFORMANCE STATUS SCALE (Recipient Age \< 16 years)
Toxicity criteria One-month (30 days) after the last T cell infusion Participants will be monitored for toxicity for a period of one-month (30 days) after the last T cell infusion. Monitored toxicities will include the following:
1. grades III-IV allergic reactions related to infusion;
2. grade IV neutropenia lasting greater than 28 days;
3. grade IV infection uncontrolled for greater than 7 days;
4. grade IV other adverse events;
5. treatment-related death (grade V).Disease response criteria One-month (30 days) after the last T cell infusion and at intervals thereafter till progression (approximately every 3 months for about a year) Response criteria follow those defined by NCCN Guidelines version 4.2011 for CLL and NHL.
For monitoring of treatment response, patients with CLL and NHL will have PET-CT scan at approximately 1 month before and after infusion and at intervals thereafter till progression. Peripheral blood and bone marrow studies (the latter only if bone marrow is involved pre-treatment) will be done to determine levels of residual disease by using established flow cytometric and molecular MRD assays.Persistence of CD16+ T cells and impact on B cell function Up to approximately month 1. The in vivo expression of anti-CD16V-BB-zeta on T cells will be monitored by flow cytometry. For this purpose, 10 ml of blood will be taken on Days 0, 1 and every other day after each infusion until infused T cells expressing the receptor become undetectable.
2. Longer term impact on the suppression of B cell function will also be monitored by assaying B cell numbers and immunoglobulin levels.
- Secondary Outcome Measures
Name Time Method
Trial Locations
- Locations (1)
National University Hospital
🇸🇬Singapore, Singapore