Brief Title
Reactivating NK Cells in Treating Refractory Head and Neck Cancer
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
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).
.
Study Phase
Phase 1/Phase 2
Study Type
Interventional
Primary Outcome
Safety as measured by clinical examination including hematology, renal and liver function tests, adverse events and any significant biochemical abnormalities or toxicities
Condition
Nasopharyngeal Cancer
Intervention
Cetuximab + NK cells
Study Arms / Comparison Groups
Cetuximab + NK cells
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).
Publications
* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.
Recruitment Information
Recruitment Status
Drug
Estimated Enrollment
31
Start Date
July 2015
Completion Date
August 2019
Primary Completion Date
August 2019
Eligibility Criteria
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
Gender
All
Ages
21 Years - N/A
Accepts Healthy Volunteers
No
Contacts
, 6772 2631, [email protected]
Location Countries
Singapore
Location Countries
Singapore
Administrative Informations
NCT ID
NCT02507154
Organization ID
NK0906
Responsible Party
Sponsor
Study Sponsor
National University Hospital, Singapore
Study Sponsor
, ,
Verification Date
August 2018