Clinical trial NCT02315118: 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
Overall status: UNKNOWN
Phase: PHASE1
PHASE2
Conditions: B-Cell Chronic Lymphocytic Leukemia
Non-Hodgkin's Lymphoma
Lead sponsor: National University Hospital, Singapore
Sponsor class: OTHER
Collaborators: name: National University of Singapore
First posted: 2014-12-11
Enrollment: 18
Sex: ALL
Minimum age (years): 6
Maximum age (years): 80
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.


Eligibility criteria: 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

Primary outcomes:
measure: Performance status assessed by age-dependent Performance Scores
timeFrame: One-month (30 days) after the last T cell infusion
measure: Toxicity criteria
timeFrame: One-month (30 days) after the last T cell infusion
measure: Disease response criteria
timeFrame: One-month (30 days) after the last T cell infusion and at intervals thereafter till progression (approximately every 3 months for about a year)
measure: Persistence of CD16+ T cells and impact on B cell function
timeFrame: Up to approximately month
Secondary outcomes:
Other outcomes:
Locations:
city: Singapore
country: Singapore
facility: National University Hospital
Study officials:
affiliation: National University Hospital, Singapore
name: Michelle Poon, MBBS, MRCP
role: PRINCIPAL_INVESTIGATOR
affiliation: Singapore General Hospital
name: Yeh Ching Linn, MBBS, MRCP
role: PRINCIPAL_INVESTIGATOR
References:
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.