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

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ClinicalTrials.gov Identifier: NCT02507154
Recruitment Status : Unknown
Verified August 2018 by National University Hospital, Singapore.
Recruitment status was:  Recruiting
First Posted : July 23, 2015
Last Update Posted : August 21, 2018
Information provided by (Responsible Party):
National University Hospital, Singapore

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.

Condition or disease Intervention/treatment Phase
Nasopharyngeal Cancer Head and Neck Squamous Cell Carcinoma Drug: Cetuximab + NK cells Phase 1 Phase 2

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).


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 31 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : July 2015
Estimated Primary Completion Date : August 2019
Estimated Study Completion Date : August 2019

Arm Intervention/treatment
Experimental: Cetuximab + NK cells
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).
Drug: Cetuximab + NK cells
Other Name: Erbitux

Primary Outcome Measures :
  1. Safety as measured by clinical examination including hematology, renal and liver function tests, adverse events and any significant biochemical abnormalities or toxicities [ Time Frame: 12- 18 weeks ]

    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).

  2. Objective tumor response [ Time Frame: Up to 24 months ]
    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.

Information from the National Library of Medicine

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Ages Eligible for Study:   21 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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

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): NCT02507154

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Contact: Chwee Ming Lim, MBBS 6772 2631 chwee_ming_lim@nuhs.edu.sg

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National University Hospital Recruiting
Singapore, Singapore, 119228
Contact: Chwee Ming Lim, MBBS    6772 2631    chwee_ming_lim@nuhs.edu.sg   
Contact: Serene CH Siow    6772 3850    chor_hiang_siow@nuhs.edu.sg   
Principal Investigator: Chwee Ming Lim, MBBS         
Sponsors and Collaborators
National University Hospital, Singapore
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: National University Hospital, Singapore
ClinicalTrials.gov Identifier: NCT02507154    
Other Study ID Numbers: NK0906
First Posted: July 23, 2015    Key Record Dates
Last Update Posted: August 21, 2018
Last Verified: August 2018
Keywords provided by National University Hospital, Singapore:
NK cells
nasopharyngeal cancer
head and neck squamous cell cancer
Additional relevant MeSH terms:
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Carcinoma, Squamous Cell
Squamous Cell Carcinoma of Head and Neck
Nasopharyngeal Neoplasms
Nasopharyngeal Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms, Squamous Cell
Head and Neck Neoplasms
Neoplasms by Site
Pharyngeal Neoplasms
Otorhinolaryngologic Neoplasms
Nasopharyngeal Diseases
Pharyngeal Diseases
Stomatognathic Diseases
Otorhinolaryngologic Diseases
Antineoplastic Agents, Immunological
Antineoplastic Agents