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Pilot Study of Autologous T Lymphocytes With ADCC in Patients With CD20-Positive B-Cell Malignancies

Primary Purpose

B-Cell Chronic Lymphocytic Leukemia, Non-Hodgkin's Lymphoma

Status
Unknown status
Phase
Phase 1
Locations
Singapore
Study Type
Interventional
Intervention
T-cell therapy + Rituximab + IL-2
Sponsored by
National University Hospital, Singapore
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for B-Cell Chronic Lymphocytic Leukemia

Eligibility Criteria

6 Months - 80 Years (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  1. Age: 6 months to 80 years old.

  2. 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.

  3. Shortening fraction greater than or equal to 25%.
  4. Glomerular filtration rate greater than or equal to 50 ml/min/1.73 m2.
  5. Pulse oximetry greater than or equal to 92% on room air.
  6. Direct bilirubin less than or equal to 3.0 mg/dL (50 mmol/L).
  7. Alanine aminotransferase (ALT) is no more than 2 times the upper limit of normal unless determined to be directly due to disease.
  8. Aspartate transaminases (AST) is no more than 2 times the upper limit of normal unless determined to be directly due to disease.
  9. Karnofsky or Lansky performance score of greater than or equal to 50.
  10. No clinical history of or overt autoimmune disease.
  11. No past history of previous severe adverse reactions to rituximab, eg. cytokine release syndrome
  12. 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.
  13. Is not receiving more than the equivalent of prednisone 10 mg daily.
  14. Not pregnant (negative serum or urine pregnancy test to be conducted within 7 days prior to enrollment).
  15. Not lactating.

Exclusion Criteria:

Failure to meet any of the inclusion criteria

Sites / Locations

  • National University HospitalRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

T-cell therapy + Rituximab + IL-2

Arm Description

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.

Outcomes

Primary Outcome Measures

Performance status assessed by age-dependent Performance Scores
Using KARNOFSKY PERFORMANCE STATUS SCALE (Recipient Age ≥ 16 years) and LANSKY PERFORMANCE STATUS SCALE (Recipient Age < 16 years)
Toxicity criteria
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: grades III-IV allergic reactions related to infusion; grade IV neutropenia lasting greater than 28 days; grade IV infection uncontrolled for greater than 7 days; grade IV other adverse events; treatment-related death (grade V).
Disease response criteria
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
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. 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

Full Information

First Posted
November 27, 2014
Last Updated
June 21, 2016
Sponsor
National University Hospital, Singapore
Collaborators
National University of Singapore
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1. Study Identification

Unique Protocol Identification Number
NCT02315118
Brief Title
Pilot Study of Autologous T Lymphocytes With ADCC in Patients With CD20-Positive B-Cell Malignancies
Official Title
Pilot Study of Autologous T Lymphocytes With Antibody-Dependent Cell Cytotoxicity in Patients With CD20-Positive B-Cell Malignancies
Study Type
Interventional

2. Study Status

Record Verification Date
June 2016
Overall Recruitment Status
Unknown status
Study Start Date
December 2014 (undefined)
Primary Completion Date
December 2017 (Anticipated)
Study Completion Date
December 2018 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
National University Hospital, Singapore
Collaborators
National University of Singapore

4. Oversight

Data Monitoring Committee
No

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
B-Cell Chronic Lymphocytic Leukemia, Non-Hodgkin's Lymphoma

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
18 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
T-cell therapy + Rituximab + IL-2
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
T-cell therapy + Rituximab + IL-2
Other Intervention Name(s)
T-cell therapy
Intervention Description
T cells collection T cells expansion and modification in the laboratory T cells infusion back to the patients
Primary Outcome Measure Information:
Title
Performance status assessed by age-dependent Performance Scores
Description
Using KARNOFSKY PERFORMANCE STATUS SCALE (Recipient Age ≥ 16 years) and LANSKY PERFORMANCE STATUS SCALE (Recipient Age < 16 years)
Time Frame
One-month (30 days) after the last T cell infusion
Title
Toxicity criteria
Description
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: grades III-IV allergic reactions related to infusion; grade IV neutropenia lasting greater than 28 days; grade IV infection uncontrolled for greater than 7 days; grade IV other adverse events; treatment-related death (grade V).
Time Frame
One-month (30 days) after the last T cell infusion
Title
Disease response criteria
Description
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.
Time Frame
One-month (30 days) after the last T cell infusion and at intervals thereafter till progression (approximately every 3 months for about a year)
Title
Persistence of CD16+ T cells and impact on B cell function
Description
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. Longer term impact on the suppression of B cell function will also be monitored by assaying B cell numbers and immunoglobulin levels.
Time Frame
Up to approximately month

10. Eligibility

Sex
All
Minimum Age & Unit of Time
6 Months
Maximum Age & Unit of Time
80 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Age: 6 months to 80 years old. 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. Shortening fraction greater than or equal to 25%. Glomerular filtration rate greater than or equal to 50 ml/min/1.73 m2. Pulse oximetry greater than or equal to 92% on room air. Direct bilirubin less than or equal to 3.0 mg/dL (50 mmol/L). Alanine aminotransferase (ALT) is no more than 2 times the upper limit of normal unless determined to be directly due to disease. Aspartate transaminases (AST) is no more than 2 times the upper limit of normal unless determined to be directly due to disease. Karnofsky or Lansky performance score of greater than or equal to 50. No clinical history of or overt autoimmune disease. No past history of previous severe adverse reactions to rituximab, eg. cytokine release syndrome 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. Is not receiving more than the equivalent of prednisone 10 mg daily. Not pregnant (negative serum or urine pregnancy test to be conducted within 7 days prior to enrollment). Not lactating. Exclusion Criteria: Failure to meet any of the inclusion criteria
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Michelle Poon, MBBS, MRCP
Phone
(65) 6779 5555
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Michelle Poon, MBBS, MRCP
Organizational Affiliation
National University Hospital, Singapore
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Yeh Ching Linn, MBBS, MRCP
Organizational Affiliation
Singapore General Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
National University Hospital
City
Singapore
ZIP/Postal Code
119228
Country
Singapore
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Michelle Poon, MBBS, MRCP
Phone
(65) 6779 5555
First Name & Middle Initial & Last Name & Degree
Michelle Poon, MBBS, MRCP
First Name & Middle Initial & Last Name & Degree
Yeh Ching Linn, MBBS, MRCP

12. IPD Sharing Statement

Citations:
PubMed Identifier
24197131
Citation
Kudo K, Imai C, Lorenzini P, Kamiya T, Kono K, Davidoff AM, Chng WJ, Campana D. T lymphocytes expressing a CD16 signaling receptor exert antibody-dependent cancer cell killing. Cancer Res. 2014 Jan 1;74(1):93-103. doi: 10.1158/0008-5472.CAN-13-1365. Epub 2013 Nov 6.
Results Reference
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Pilot Study of Autologous T Lymphocytes With ADCC in Patients With CD20-Positive B-Cell Malignancies

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