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Allogenic Immunotherapy Based on Natural Killer (NK) Cell Adoptive Transfer in Metastatic Gastrointestinal Carcinoma Treated With Cetuximab (NK-EGFR01)

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ClinicalTrials.gov Identifier: NCT02845999
Recruitment Status : Completed
First Posted : July 27, 2016
Last Update Posted : July 27, 2016
Sponsor:
Collaborator:
National Cancer Institute, France
Information provided by (Responsible Party):
Centre Hospitalier Universitaire de Besancon

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Gastrointestinal Metastatic Cancer Biological: allogenic immunotherapy based on Natural Killer cells adoptive transfer Biological: cetuximab Drug: Cyclophosphamide Drug: fludarabine Drug: interleukin-2 Phase 1

Detailed Description:

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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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 9 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Allogenic Immunotherapy Based on Natural Killer Cell Adoptive Transfer in Metastatic Gastrointestinal Carcinoma Treated With Cetuximab : a Phase I Trial
Study Start Date : November 2009
Actual Primary Completion Date : January 2013

Resource links provided by the National Library of Medicine

Drug Information available for: Cetuximab

Arm Intervention/treatment
Experimental: Allogenic NK cells transfer
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). T
Biological: allogenic immunotherapy based on Natural Killer cells adoptive transfer
day -1 : donor NK cell purification ; day 0 : adoptive transfer (according to a dose escalation) ; Dose escalation protocol : 3.10^6 ; 8.10^6 and 12.10^6 cells/kg of recipient body weight

Biological: cetuximab
day -8 : cetuximab 400 mg/m2 ; day -1 and every week (for 7 weeks) : cetuximab 250 mg/m2

Drug: Cyclophosphamide
day -6 : cyclophosphamide 60 mg/Kg

Drug: fludarabine
day -6 to day -2 : fludarabine 25 mg/m2

Drug: interleukin-2
day -1 : addition of 1000 UI/ml of interleukin 2 to NK cells and overnight culture at 37°C, 5%CO2 ; day 0, hour +12 : 10 MUI of interleukin 2 injection, 2 times a week during 3 weeks.




Primary Outcome Measures :
  1. number of patients with clinical or biological grade 3 or 4 treatment-related adverse events as assessed by CTCAE v4.0 [ Time Frame: 6 weeks ]


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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • metastatic gastrointestinal cancer (colorectal, pancreas, small intestine, bile ducts), gastrointestinal stromal tumor or digestive neuroendocrine tumor.
  • presence of liver metastases
  • Age > 18 and < 65 (male and female)
  • ECOG performances status 0 or 1
  • EGFR expression confirmed by immunohistochemistry
  • allogenic donor with one or more KIR/MHC class I mismatch
  • absence of alternative treatment available
  • evidence of progressive disease
  • written informed consent

Exclusion Criteria:

  • malignant secondary disease dated backed < 2 years (exception : in situ carcinoma of the cervix uteri, adequately treated skin basal cell carcinoma)
  • hypersensitivity against one of the treatment of this study
  • history of cardiac or respiratory failure
  • history of auto-immune disease
  • renal or hepatic failure
  • pregnancy or lactation
  • patient with any medical or psychiatric condition or disease which would makes the patient inappropriate for entry into this study.
  • EBV serology negative in recipient and positive in donor
  • bilirubin greater than 1,5 times upper limit of normal
  • ASAT and/or alkaline phosphatase greater than 5 times upper limit of normal in presence of liver metastases.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02845999


Locations
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France
University hospital of Besançon
Besançon, France, 25000
Sponsors and Collaborators
Centre Hospitalier Universitaire de Besancon
National Cancer Institute, France

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Responsible Party: Centre Hospitalier Universitaire de Besancon
ClinicalTrials.gov Identifier: NCT02845999     History of Changes
Other Study ID Numbers: N2005/48-A
First Posted: July 27, 2016    Key Record Dates
Last Update Posted: July 27, 2016
Last Verified: March 2016
Keywords provided by Centre Hospitalier Universitaire de Besancon:
natural killer cells
adoptive transfer
allogenic immunotherapy
gastrointestinal cancer EGFR+
Additional relevant MeSH terms:
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Neoplasm Metastasis
Neoplasms
Neoplastic Processes
Pathologic Processes
Cyclophosphamide
Cetuximab
Fludarabine
Fludarabine phosphate
Interleukin-2
Immunologic Factors
Immunosuppressive Agents
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Antineoplastic Agents, Immunological
Antimetabolites, Antineoplastic
Antimetabolites
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents