Gastrointestinal Metastatic Cancer Clinical Trial
Official title:
Allogenic Immunotherapy Based on Natural Killer Cell Adoptive Transfer in Metastatic Gastrointestinal Carcinoma Treated With Cetuximab : a Phase I Trial
Gastrointestinal (GI) cancers account for the most common cancers. Despite recent advances
in GI cancer treatments, the 5-year overall survival rate for these patients remain
unacceptable, except for patients who are candidates for metastasis surgical resection.
Strategies leading to a decrease of metastatic number and size will contribute to improve
the probability to undergo a curative surgical procedure.
Haploidentical Natural Killer (NK) cells can persist and expand in vivo following adoptive
transfer and may have a role in the treatment of selected malignancies, since the failure to
recognize the appropriate KIR ligand on a mismatched tumor cell can trigger NK cell
elimination of that target cell. NK also express an activating Fc receptor that mediates
antibody-dependent cellular cytotoxicity (ADCC) and production of immune modulatory
cytokines in response to antibody-coated targets. Cetuximab, an IgG1 chimeric monoclonal
antibody against colorectal cancers that expressed EGFR (epidermal growth factor receptor),
improves overall survival and progression-free survival and preserves quality-of-life
measures in patients with colorectal cancer in whom other treatments have failed.
In an attempt to improve the outcome in GI cancers, we will conduct a phase I/II clinical
trial assessing NK cell based immunotherapy. Patients with liver metastases related to a
EGFR+ GI cancer, previously treated by a standard chemotherapy that did not achieve a
complete response or a curative resection of residual metastases will be included in this
phase I/II trial supported by the French National Institute of Cancer (INCA, PHRC 2005).
This phase I/II study will involve 22 patients. The main objective of this study will be to
demonstrate the safety of NK hepatic intraarterial infusion in association with cetuximab.
Secondary objectives will include the assessment of the clinical efficacity of this
strategy.
Patients will be treated with a conditioning chemotherapy including 60 mg/kg intravenous
cyclophosphamide, 25 mg/m2 intravenous fludarabine for 5 consecutive days and cetuximab. A
lymphapheresis from an haploidentical related donor will be performed and T cells will be
depleted . Allogenic NK cells will then be adoptively transferred by hepatic intraarterial
infusion according to a dose escalation protocol (three doses with at least three patients
per cohort)to define the dose-limiting toxicity (DLT). Then 10 more patients will receive
the recommended NK cell dose.
Dose escalation protocol : 3.10^6 ; 8.10^6 and 12.10^6 cells/kg of recipient body weight.
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Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment