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Reactivating NK Cells in Treating Refractory Head and Neck Cancer (NKEXPHNC)

Primary Purpose

Nasopharyngeal Cancer, Head and Neck Squamous Cell Carcinoma

Status
Unknown status
Phase
Phase 1
Locations
Singapore
Study Type
Interventional
Intervention
Cetuximab + NK cells
Sponsored by
National University Hospital, Singapore
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Nasopharyngeal Cancer focused on measuring cetuximab, NK cells, nasopharyngeal cancer, head and neck squamous cell cancer

Eligibility Criteria

21 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria

  1. Age >21
  2. Histologically confirmed diagnosis of EGFR-positive nasopharyngeal carcinoma or EGFR positive HNSCC (based on >80% immunohistochemistry of biopsy of recurrent tumor Ventana (Roche) clone 3C6
  3. Recurrent cancer that is not surgically salvageable
  4. Metastatic disease (after one course of palliative chemotherapy has been completed)
  5. Presence of measurable tumor by RECIST 1.1 criteria
  6. At least two weeks since receipt of any biological therapy, chemotherapy, and/or radiation
  7. Adequate organ function
  8. Haemoglobin ≥ 9g/dL ANC ≥ 1500/µL Platelet count ≥ 100,000/µL Creatinine clearance ≥60ml/minute Total bilirubin ≤ 1.5 x upper limit normal (ULN) AST ≤ 5 x upper limit normal ALT ≤ 2 x upper limit normal INR and PTT <1.5 x upper limit normal (ULN)
  9. ECOG performance status of 0-2
  10. Life expectancy of at least 60 days
  11. Localized radiotherapy for palliative pain management is permissible
  12. Written consent to participate on study
  13. Physiological dose of steroid replacement is permissible

Exclusion Criteria

  1. Treatment within the last 30 days with any investigational drug
  2. Hypersensitivity to cetuximab or any excipients of the NK cell product
  3. Concurrent administration of any other tumor therapy, including cytotoxic chemotherapy, hormonal therapy, and immunotherapy
  4. Major surgery within 28 days of study drug administration
  5. Radiotherapy to the target lesions during study or within 3 weeks prior to study treatment.
  6. Autologous bone marrow transplant
  7. Active infection that in the opinion of the investigator would compromise the patient's ability to tolerate therapy
  8. Lactating or pregnant
  9. Unwilling to use adequate barrier contraception measures during study period.
  10. Second primary malignancy that is clinically detectable at the time of consideration for study enrolment
  11. Receipt of immunosuppressives or steroids (=1mg/kg) during time period of 3 days prior to expanded NK cell infusion to 30 days after infusion (i.e. day -3 to day +30).
  12. Symptomatic brain metastases
  13. Electrocardiogram with clinically significant findings.
  14. Serious concomitant disorders that would compromise the safety of the patient or compromise the patient's ability to complete the study, at the discretion of the investigator; serious cardiac illness or medical conditions including but not limited to:

    • Patients with dyspnea at rest.
    • History of documented congestive heart failure
    • High risk uncontrolled arrhythmias
    • Angina pectoris requiring a medicinal product
    • Clinically significant valvular disease
    • Poorly controlled hypertension

Sites / Locations

  • National University HospitalRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Cetuximab + NK cells

Arm Description

During cycle 1, patient will receive intravenous cetuximab and subcutaneous IL-2 on day 1, followed by NK cell infusion on day 2, with subcutaneous IL-2 for an additional 5 doses three times a week to support NK cell viability and expansion in vivo. Following NK cell infusion, cetuximab will be administered weekly for another 2 weeks. During cycle 2 and 3, one cycle of cetuximab monotherapy will be administered 3 weeks apart. Patients who demonstrate objective tumor response or stable disease after cycle 3 will receive a second infusion of NK cells along with cetuximab during cycle 4 therapy at the same dose and schedule as in cycle 1. This will be followed by 2 additional cycles of cetuximab monotherapy (3 weeks apart).

Outcomes

Primary Outcome Measures

Safety as measured by clinical examination including hematology, renal and liver function tests, adverse events and any significant biochemical abnormalities or toxicities
During cycle 1 (21 days) and for at least 21 days following a second NK cell infusion if administered, patients will be reviewed twice a week. Clinical examination including hematology, renal and liver function tests will be performed. Any adverse events (using NCI CTC grading) and concomitant medications notation will be recorded. Any significant biochemical abnormalities or toxicities will be monitored till resolution of these findings or 30 days after patient withdraws from this study, whichever occurs later. During cycles with cetuximab monotherapy, patients with be reviewed once every cycle (21 days).
Objective tumor response
In this study, treatment response will be determined using RECIST 1.1 criteria, after two and four cycles of therapy. The endpoints of the study are objective tumor response including overall response rate (ORR), partial response (PR), duration of complete response (DCR) and duration of partial response (DPR). Complete response is defined by complete resolution of target lesion while partial response is defined by reduction of the target lesion by at least 20% from its baseline. Duration of tumor response will be censored at the date of the last follow-up visit for tumor responders who are still alive and who have not progressed.

Secondary Outcome Measures

Full Information

First Posted
July 22, 2015
Last Updated
August 20, 2018
Sponsor
National University Hospital, Singapore
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1. Study Identification

Unique Protocol Identification Number
NCT02507154
Brief Title
Reactivating NK Cells in Treating Refractory Head and Neck Cancer
Acronym
NKEXPHNC
Official Title
Phase I/II Study of Expanded, Activated Autologous Natural Killer Cell Infusions With Cetuximab for Patients With EGFR-Positive Nasopharyngeal Carcinoma or Head and Neck Squamous Cell Carcinoma
Study Type
Interventional

2. Study Status

Record Verification Date
August 2018
Overall Recruitment Status
Unknown status
Study Start Date
July 2015 (Actual)
Primary Completion Date
August 2019 (Anticipated)
Study Completion Date
August 2019 (Anticipated)

3. Sponsor/Collaborators

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

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This study aims to determine the safety and efficacy of expanded activated autologous NK cells administered after cetuximab in patients with EGFR-positive nasopharyngeal carcinoma or head and neck squamous cell carcinoma.
Detailed Description
Natural killer (NK) cells are cytotoxic lymphocytes of the innate immune system that are responsible for direct and indirect cytolytic killing of virally-transformed and/or cancer cells. Harnessing NK cells in cancer immunotherapy therefore, provides a direct cytotoxic effect on cancer cells which further stimulates further downstream adaptive anti-tumor immune responses against the cancer. In order to effect a more targeted killing of these tumor cells, using a monoclonal antibody (mAb) to direct these NK cells to the target site is feasible, provided a specific tumor antigen can be identified. In nasopharyngeal Carcinoma (NPC) and head and neck squamous cell carcinoma (HNSCC) where epidermal growth factor receptor (EGFR) is ubiquitously expressed, combining NK cell therapy with cetuximab (a chimeric mouse/human anti-EGFR monoclonal antibody) to direct these NK cells against these EGFR tumor targets is possible. In this study, we seek to enhance the antitumor activity of cetuximab to treat EGFR-positive head and neck cancers by combing infusion of activated expanded autologous NK cells with cetuximab. Patients selected for this trial are those with refractory NPC and HNSCC where no feasible therapeutic options are available. This is a lead-in phase I followed by a phase II study. The phase I study will enroll 9 patients and will test the feasibility and safety of this combination strategy and determine the tolerated dose of NK cell infusion (1x1^06/kg or 1x10^7/kg NK cells) in adult EGFR positive NPC and HNSCC patients. For the first 3 patients, each new patient will only be enrolled at least 3 weeks after treatment of the preceding patient to allow sufficient time to monitor toxicities. Initial phase of treatment consists of 7 weeks of cetuximab monotherapy. At week 8, clinical evaluation will be done to determine patients who are suitable to continue this study with NK cell therapy, based on the severity of toxicities encountered. Eligible patients will undergo apheresis (Day -10) to harvest NK cells. The collected NK cells will be expanded and activated in the laboratory. During cycle 1, cetuximab will be given on day 1 with subcutaneous IL-2 (three times per week for 2 weeks); followed by expanded NK cells on day 2. The purpose of IL-2 is to sustain activity of these NK cells in-vivo. Cetuximab will be administered weekly for additional 2 weeks following the NK cell infusion during cycle 1. For cycle 2 and 3, cetuximab monotherapy will be administered every 21 days. Clinical evaluation will be performed upon completion of cycle 3. Patients with stable disease or with partial response will be allowed to continue with a second NK infusion dose as per cycle 1, followed by additional 2 more cycles of cetuximab monotherapy (every 21 days). .

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Nasopharyngeal Cancer, Head and Neck Squamous Cell Carcinoma
Keywords
cetuximab, NK cells, nasopharyngeal cancer, head and neck squamous cell cancer

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
31 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Cetuximab + NK cells
Arm Type
Experimental
Arm Description
During cycle 1, patient will receive intravenous cetuximab and subcutaneous IL-2 on day 1, followed by NK cell infusion on day 2, with subcutaneous IL-2 for an additional 5 doses three times a week to support NK cell viability and expansion in vivo. Following NK cell infusion, cetuximab will be administered weekly for another 2 weeks. During cycle 2 and 3, one cycle of cetuximab monotherapy will be administered 3 weeks apart. Patients who demonstrate objective tumor response or stable disease after cycle 3 will receive a second infusion of NK cells along with cetuximab during cycle 4 therapy at the same dose and schedule as in cycle 1. This will be followed by 2 additional cycles of cetuximab monotherapy (3 weeks apart).
Intervention Type
Drug
Intervention Name(s)
Cetuximab + NK cells
Other Intervention Name(s)
Erbitux
Primary Outcome Measure Information:
Title
Safety as measured by clinical examination including hematology, renal and liver function tests, adverse events and any significant biochemical abnormalities or toxicities
Description
During cycle 1 (21 days) and for at least 21 days following a second NK cell infusion if administered, patients will be reviewed twice a week. Clinical examination including hematology, renal and liver function tests will be performed. Any adverse events (using NCI CTC grading) and concomitant medications notation will be recorded. Any significant biochemical abnormalities or toxicities will be monitored till resolution of these findings or 30 days after patient withdraws from this study, whichever occurs later. During cycles with cetuximab monotherapy, patients with be reviewed once every cycle (21 days).
Time Frame
12- 18 weeks
Title
Objective tumor response
Description
In this study, treatment response will be determined using RECIST 1.1 criteria, after two and four cycles of therapy. The endpoints of the study are objective tumor response including overall response rate (ORR), partial response (PR), duration of complete response (DCR) and duration of partial response (DPR). Complete response is defined by complete resolution of target lesion while partial response is defined by reduction of the target lesion by at least 20% from its baseline. Duration of tumor response will be censored at the date of the last follow-up visit for tumor responders who are still alive and who have not progressed.
Time Frame
Up to 24 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
21 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria Age >21 Histologically confirmed diagnosis of EGFR-positive nasopharyngeal carcinoma or EGFR positive HNSCC (based on >80% immunohistochemistry of biopsy of recurrent tumor Ventana (Roche) clone 3C6 Recurrent cancer that is not surgically salvageable Metastatic disease (after one course of palliative chemotherapy has been completed) Presence of measurable tumor by RECIST 1.1 criteria At least two weeks since receipt of any biological therapy, chemotherapy, and/or radiation Adequate organ function Haemoglobin ≥ 9g/dL ANC ≥ 1500/µL Platelet count ≥ 100,000/µL Creatinine clearance ≥60ml/minute Total bilirubin ≤ 1.5 x upper limit normal (ULN) AST ≤ 5 x upper limit normal ALT ≤ 2 x upper limit normal INR and PTT <1.5 x upper limit normal (ULN) ECOG performance status of 0-2 Life expectancy of at least 60 days Localized radiotherapy for palliative pain management is permissible Written consent to participate on study Physiological dose of steroid replacement is permissible Exclusion Criteria Treatment within the last 30 days with any investigational drug Hypersensitivity to cetuximab or any excipients of the NK cell product Concurrent administration of any other tumor therapy, including cytotoxic chemotherapy, hormonal therapy, and immunotherapy Major surgery within 28 days of study drug administration Radiotherapy to the target lesions during study or within 3 weeks prior to study treatment. Autologous bone marrow transplant Active infection that in the opinion of the investigator would compromise the patient's ability to tolerate therapy Lactating or pregnant Unwilling to use adequate barrier contraception measures during study period. Second primary malignancy that is clinically detectable at the time of consideration for study enrolment Receipt of immunosuppressives or steroids (=1mg/kg) during time period of 3 days prior to expanded NK cell infusion to 30 days after infusion (i.e. day -3 to day +30). Symptomatic brain metastases Electrocardiogram with clinically significant findings. Serious concomitant disorders that would compromise the safety of the patient or compromise the patient's ability to complete the study, at the discretion of the investigator; serious cardiac illness or medical conditions including but not limited to: Patients with dyspnea at rest. History of documented congestive heart failure High risk uncontrolled arrhythmias Angina pectoris requiring a medicinal product Clinically significant valvular disease Poorly controlled hypertension
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Chwee Ming Lim, MBBS
Phone
6772 2631
Email
chwee_ming_lim@nuhs.edu.sg
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
Chwee Ming Lim, MBBS
Phone
6772 2631
Email
chwee_ming_lim@nuhs.edu.sg
First Name & Middle Initial & Last Name & Degree
Serene CH Siow
Phone
6772 3850
Email
chor_hiang_siow@nuhs.edu.sg
First Name & Middle Initial & Last Name & Degree
Chwee Ming Lim, MBBS

12. IPD Sharing Statement

Citations:
PubMed Identifier
35098345
Citation
Lim CM, Liou A, Poon M, Koh LP, Tan LK, Loh KS, Petersson BF, Ting E, Campana D, Goh BC, Shimasaki N. Phase I study of expanded natural killer cells in combination with cetuximab for recurrent/metastatic nasopharyngeal carcinoma. Cancer Immunol Immunother. 2022 Sep;71(9):2277-2286. doi: 10.1007/s00262-022-03158-9. Epub 2022 Jan 30.
Results Reference
derived

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Reactivating NK Cells in Treating Refractory Head and Neck Cancer

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