Trial Title:
Neoadjuvant and Adjuvant Toripalimab and Cetuximab in Patients With Recurrent, Resectable Squamous Cell Carcinoma of Head and Neck: a Prospective, Single-arm,Phase II Study
NCT ID:
NCT05586100
Condition:
Patients With Locally Recurrent Resectable Head and Neck Squamous Cell Carcinoma
Conditions: Official terms:
Carcinoma
Carcinoma, Squamous Cell
Squamous Cell Carcinoma of Head and Neck
Recurrence
Cetuximab
Study type:
Interventional
Study phase:
Phase 2
Overall status:
Recruiting
Study design:
Allocation:
N/A
Intervention model:
Single Group Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
Toripalimab+cetuximab
Description:
Toripalimab administered by intravenous drip at a fixed dose of 240 mg for subjects
weighing <50 kg at baseline, using 3 mg/kg. administered every 3 weeks, 2 preoperative
and 6 postoperative doses.
The starting dose of cetuximab is 400 mg/m2, with a titration time of 120 min, and the
titration rate should be controlled within 5 ml/min. The maintenance dose is 250 mg/m2
administered weekly for a total of 6 preoperative doses; patients with positive
intraoperative pathological margins/extra lymph node envelope invasion are treated with
an additional 6 cycles of postoperative cetuximab adjuvant therapy.
Arm group label:
cetuximab in combination with toripalimab
Summary:
This study is the first clinical study of Neoadjuvant and Adjuvant treatment of head and
neck squamous cell carcinoma with drugs targeting EGFR signaling pathway combined with
PD-1 inhibitors, which explores the new combination therapies urgently needed in clinical
practice and lays a foundation for subsequent studies, with important scientific research
significance and clinical value.
Detailed description:
Head and neck cancer is the sixth most common cancer in the world, with more than 550,000
incidences and 300,000 deaths worldwide each year. more than 95% of head and neck cancers
are squamous cell carcinomas, and head and neck squamous cell carcinoma (HNSCC) damages
and affects patients' appearance and basic physiological, sensory and speech functions,
thereby affecting their quality of life. This affects the quality of life of patients.
Due to the difficulty of early detection, more than 60% of head and neck squamous cell
carcinoma patients are found to be locally advanced, and the prognosis of locally
advanced head and neck cancer is poor, with up to 60% of patients experiencing local
recurrence and distant metastasis.
Currently, the preferred treatment option for patients with locally recurrent resectable
HNSCC is to undergo salvage surgery with or without postoperative local radiotherapy
based on pathology, staging, and history of prior radiotherapy. However, even after
receiving aggressive treatment, at least 20% of patients with HNSCC still develop local
recurrence or distant metastases. In previous studies, the five-year survival rates of
patients with locally recurrent, resectable head and neck squamous carcinoma who
underwent salvage surgery ranged from 11% to 40%. How to improve the prognosis of
patients with locally recurrent, resectable HNSCC is an urgent clinical problem.
The epidermal growth factor receptor (EGFR) is highly expressed in 90% of HNSCC, and high
expression of EGFR protein and high copy number of its gene are significantly associated
with poor prognosis, short survival, and increased risk of metastasis in HNSCC. The
chimeric EGFR-blocking monoclonal antibody cetuximab is approved by the FDA for the
first/second-line treatment of recurrent/metastatic, unresectable HNSCC and significantly
improves long-term survival in recurrent/metastatic, unresectable HNSCC compared with
chemotherapy alone. In the 2021 edition of the CSCO guidelines, cetuximab is recommended
as a Class I expert in combination with chemotherapy for the first-line treatment of
recurrent/metastatic HNSCC without indications for surgery and radiotherapy (Class 1A
evidence), and as a Class II expert in single-agent use for the second-line or salvage
treatment of recurrent/metastatic HNSCC without indications for surgery and radiotherapy
(Class 2A evidence). Meanwhile, it was approved by the CFDA in February 2020 in
combination with platinum and fluorouracil chemotherapy for the first-line treatment of
recurrent/metastatic HNSCC, and was successfully covered by Medicare in November 2021.
However, whether cetuximab provides a survival benefit in patients with locally
recurrent, resectable HNSCC has not been reported in studies.
The successful development of programmed death receptor 1 (PD-1) immune checkpoint
inhibitors has significantly impacted the treatment of HNSCC. In patients with
unresectable recurrent or metastatic HNSCC resistant to platinum-based therapy,
KEYNOTE-040 compared pembrolizumab with the investigator's choice of treatment regimen
(docetaxel, methotrexate, or cetuximab), and this trial was just short of the primary
endpoint (improved overall survival with pembrolizumab) in the intention-to-treat
population (8.4 months in the pembrolizumab group [95% CI, 6.4 to 9.4] vs. 6.9 months
[95% CI, 5.9 to 8.0] in the standard treatment group; hazard ratio for death, 0.80; 95%
CI, 0.65 to 0.98; P=0.02). In the CheckMate 141 trial, which randomized patients who had
received prior platinum-based therapy in a 2:1 ratio to receive either nivolumab or a
regimen of the investigator's choice, respectively. Nivolumab improved overall survival
(7.5 months [95% CI, 5.5 to 9.1] vs. 5.1 months [95% CI, 4.0 to 6.0]; hazard ratio for
death, 0.70; 97.73% CI, 0.51 to 0.96; P=0.01), remission rate (13.3% vs. 5.8%) and
6-month progression-free survival (19.7% vs. 9.9%), and reduced the incidence of serious
adverse events (13.1% vs. 35.1%). After more than 2 years of follow-up, a survival
benefit of nivolumab treatment remained for patients (hazard ratio for death, 0.68; 95%
CI, 0.54 to 0.86; 24-month overall survival, 16.9% vs. 6.0%). The U.S. Food and Drug
Administration (FDA) approved both pembrolizumab and nivolumab in 2016 for second-line
treatment of advanced HNSCC because they enabled patients to achieve durable remissions
and improved survival. In the KEYNOTE-048 study, 882 patients with previously untreated
recurrent or metastatic HNSCC were randomized to receive either pembrolizumab
monotherapy, Pembrolizumab + chemotherapy (fluorouracil and platinum-based agents) or the
standard treatment regimen of fluorouracil and platinum-based agents + cetuximab (the
regimen in the EXTREME trial), which confirmed that In the first-line treatment of
patients with unresectable recurrent or metastatic HNSCC, pembrolizumab combined with
chemotherapy significantly improved overall survival in the total population, and
pembrolizumab alone in those with CPS ≥ 1, compared with the traditional EXTREME regimen
of targeted chemotherapy, and the FDA approved pembrolizumab for the first-line treatment
of advanced HNSCC in 2019.
Currently, immunotherapy and EGFR-targeted therapy for combination therapy have been
explored in several studies. The basic rationale supporting these combination therapies
is that the two therapies combine different immunological and tumor biological mechanisms
that enhance antitumor activity; it is well known that anti-PD-1 therapy enhances
cytotoxic T lymphocytes and promotes tumor regression and immune rejection. In contrast,
anti-EGFR antibodies induce antibody-dependent cytotoxicity and lead to interactions
between immune cells (including natural killer cells and dendritic cells). This
interaction can stimulate tumor antigen-specific cellular immunity and generate
antigen-specific T-lymphocyte responses [12]. Thus, the two classes of drugs may produce
antitumor synergistic effects. In an open-label, multicenter, multicohort phase II
clinical trial, the application of pembrolizumab in combination with cetuximab in 33
patients with unresectable recurrent/metastatic HNSCC not previously treated with
pembrolizumab and cetuximab showed an overall response rate of 45% at 6 months, while the
median duration of remission in patients with effective treatment reached 13.3 months,
and two other cohorts are currently recruiting and results have not yet been published,
initially showing that the combination of immunotherapy and EGFR-targeted therapy holds
promise in patients with relapsed/metastatic HNSCC. However, this treatment modality has
not been explored in patients with relapsed resectable HNSCC.
In an open-label, multicenter, single-arm phase II clinical trial, patients with locally
relapsed resectable HNSCC were treated with the PD-1 inhibitor nivolumab and the NK cell
surface molecule KIR inhibitor Lirilumab in a double-exemption study that was expected to
enroll 54 patients, but only 28 subjects were ultimately enrolled due to discontinuation
of Lirilumab supply. The study found that the enrolled patients achieved a pathological
remission rate of 43%, a one-year DFS of 55.2%, and a 2-year DFS rate of 64% and a 2-year
OS rate of 80% in subjects who achieved pathological remission, possibly limited by study
discontinuation of enrollment, which has shown good long-term efficacy although the
primary study endpoint was not met.
JS001 or toripalimab, the most leading investigational drug of Juniper Biologics against
various malignancies, is a recombinant humanized anti-PD-1 injectable monoclonal antibody
that was approved for marketing by the State Drug Administration (NMPA) of China on
December 17, 2018.JS001 has a high binding affinity and can better compete with PD-L1 and
PD-L2 binding competition on tumor cells, while inducing endocytosis of PD-1 receptors
and reducing PD-1 expression on the cell membrane surface. Results from completed
clinical trials of toripalimab in a variety of cancers, including malignant melanoma,
nasopharyngeal carcinoma, and esophageal squamous cell carcinoma, showed that
immune-related adverse events were rare and received the first global conditional
approval in China on December 17, 2018, for the treatment of unresectable or metastatic
melanoma that was previously unavailable for systemic therapy. Individual cases have
shown excellent responsiveness and good tolerability of the combination of toripalimab
and single-agent chemotherapy in the first-line treatment of elderly R/M HNSCC, while its
therapeutic role in R/M HNSCC remains to be investigated.
Therefore, based on the data of previously reported studies of EGFR-targeted therapy
combined with immunotherapy in patients with unresectable recurrent/metastatic HNSCC and
the preliminary results of PD-1 combined with KIR inhibitors in patients with locally
recurrent resectable HNSCC treated with double-free neoadjuvant therapy, we hypothesized
that cetuximab in combination with toripalimab prior to salvage surgery could benefit to
this high-risk population of patients with locally recurrent resectable HNSCC. This study
is the first clinical study of EGFR-targeted therapy combined with PD-1 inhibitor for the
neoadjuvant treatment of locally recurrent resectable HNSCC in China, which is of great
scientific significance and clinical value in exploring the urgent need for new
combination therapies and new treatment options for this high-risk group of patients with
locally recurrent resectable HNSCC, and laying the foundation for subsequent studies.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
1. age 18-75 years old, regardless of gender
2. histologically or cytologically confirmed and surgically curable recurrent localized
squamous carcinoma of the head and neck (tumor primary sites are oropharynx, oral
cavity, hypopharynx, and larynx) without any antitumor systemic therapy during the
recurrent stage (allowed as part of treatment for locally advanced tumors and
requiring more than 6 months between the end of treatment and the signing of the
informed consent)
3. an ECOG score of 0 or 1.
4. an expected survival of ≥ 12 weeks.
5. have at least one measurable lesion according to RECIST 1.1 criteria, and a
previously treated lesion with radiation therapy, if disease progression has
occurred, may also be a measurable lesion.
6. availability of tumor tissue for PD-L1 detection (paraffin specimens less than 2
years old or fresh tumor tissue)
7. patients with oropharyngeal carcinoma provide a test status for P16, using the IHC
method.
8. Organ function levels must meet the following requirements (14 days prior to the
first dose of study drug):
Bone marrow:absolute neutrophil count (ANC) ≥ 1.5×109/L, platelets (PLT) ≥
100×109/L, hemoglobin (HB) ≥ 9g/dL (not transfused or receiving component blood
within 14 days prior to testing); Liver: serum total bilirubin (TBIL) ≤ 1.5 times
the upper limit of normal value, aspartate aminotransferase (AST) and alanine
aminotransferase (ALT) ≤ 2.5 times the upper limit of normal value (in case of liver
metastases, AST and ALT ≤ 5 times the upper limit of normal value are allowed);
serum creatinine ≤ 1.5 times the upper limit of normal value and endogenous
creatinine clearance ≥ 50 mL/min (Cockcroft-Gault formula) Gault formula);
International normalized ratio (INR), activated partial thromboplastin time (APTT) ≤
1.5 times the upper limit of normal (only for patients not receiving
anticoagulation; patients receiving anticoagulation should keep anticoagulants
within the therapeutically required range); Thyroid stimulating hormone (TSH) ≤ 1 x
ULN (if abnormal FT3 and FT4 levels should be examined at the same time; if FT3 and
FT4 levels are normal, the patient can be enrolled) Urine protein ≤ 1+, if urine
protein > 1+, 24-hour urine protein measurement should be collected, and its total
amount should be ≤ 1 gram; Normal cardiac function, i.e. normal or abnormal ECG
examination without clinical significance and cardiac ultrasound showing left
ventricular ejection fraction (LVEF) >50%.
9. female subjects of reproductive potential must have a negative serum pregnancy test
prior to the first dose of the trial drug; 10. male or female subjects of
reproductive potential must be using a highly effective method of contraception
(e.g., oral contraceptive pills, intrauterine device, abstinence from sexual
intercourse, or barrier method of contraception in combination with spermicide)
throughout the trial and continue to use contraception for 90 days after the end of
treatment.
11. Subjects voluntarily enrolled in the study, signed an informed consent form, were
compliant and cooperative with follow-up.
Exclusion Criteria:
1. with distant metastatic lesions or localized lesions not indicated for surgery
(patients with stage IVb or IVc)
2. have progressed within 6 months after systemic therapy directed at locally advanced
squamous head and neck cancer.
3. a prior history of primary nasopharyngeal cancer tumor.
4. patients who have participated or are participating in a clinical trial of another
drug/therapy within 4 weeks prior to the first dose of the study drug.
5. underwent/received major surgery or have not recovered from the side effects of such
surgery, live vaccination, immunotherapy within 4 weeks prior to the first dosing of
the study drug, and radiation therapy within 2 weeks.
6. receiving any other concurrent antitumor therapy.
7. the patient has any active autoimmune disease or a history of autoimmune disease
(e.g., the following, but not limited to: autoimmune hepatitis, interstitial
pneumonia, uveitis, enterocolitis, hepatitis, pituitary inflammation, vasculitis,
nephritis, hyperthyroidism; vitiligo that does not require systemic therapy may be
included; asthma that has completely resolved in childhood and does not require any
intervention in adulthood may be included; patients requiring bronchial (asthma that
requires medical intervention with bronchodilators cannot be included).
8. patients who are on immunosuppressive, or systemic hormone therapy for
immunosuppressive purposes (doses >10 mg/day of prednisone or other equipotent
hormones) and continue to use them within 2 weeks prior to enrollment
9. a history of other malignancies within the past 5 years, with the exception of cured
basal cell carcinoma of the skin, squamous cell carcinoma of the skin, early stage
prostate cancer and carcinoma in situ of the cervix
10. patients who have received hematopoietic stimulating factors, such as granulocyte
colony-stimulating factor (G-CSF), erythropoietin, etc., within 1 week prior to the
first dose of the study drug
11. prior treatment with PD-1/PD-L1/PD-L2/CTLA-4 antibodies or activating or inhibitory
agents targeting T-cell receptors (e.g., OX40, CD137)
12. prior drug treatment with cetuximab.
13. positive test results for HIV antibodies or syphilis spirochete antibodies
14. Patients with active hepatitis B or C:
If HBsAg or HBcAb is positive, add HBV DNA test (the result is higher than the upper
limit of the normal range).
If HCV antibody test result is positive, add HCV RNA test (the result is higher than
the upper limit of the normal range).
15. known to be allergic to recombinant humanized PD-1 monoclonal antibody drug and its
components;
16. known to be allergic to EGFR monoclonal antibody drugs and their components;
17. have active lung disease (interstitial pneumonia, pneumonia, obstructive lung
disease, asthma) or a history of active tuberculosis
18. have any uncontrollable clinical problem, including but not limited to: Persistent
or active (severe) infection; Poorly medically controlled hypertension (blood
pressure greater than 150/90 mmHg persistently).
Poorly controlled diabetes mellitus; Cardiac disease (Class III/IV congestive heart
failure or heart block as defined by the New York Heart Association);
19. the following conditions within 6 months prior to the first dose: deep vein
thrombosis or pulmonary embolism; myocardial infarction; severe or unstable
arrhythmia or angina; percutaneous coronary intervention, acute coronary syndrome,
coronary artery bypass graft; cerebrovascular accident, transient ischemic attack,
cerebral embolism
20. having undergone stem cell transplantation or organ transplantation
21. persons with a history of psychotropic substance abuse that they are unable to
abstain from or a history of psychiatric disorders
22. other serious, acute or chronic medical conditions or abnormalities in laboratory
tests that, in the judgment of the investigator, may increase the risk associated
with participation in the study, or may interfere with the interpretation of study
results
23. Patients who, in the judgment of the investigator, have poor compliance or have
other conditions that make them unsuitable for participation in the trial.
Gender:
All
Minimum age:
18 Years
Maximum age:
75 Years
Healthy volunteers:
No
Locations:
Facility:
Name:
the Ninth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
Address:
City:
Shanghai
Zip:
200011
Country:
China
Status:
Recruiting
Contact:
Last name:
Guoxin Ren, M.D.
Phone:
13916948812
Email:
renguoxincn@sina.com
Investigator:
Last name:
Guoxin Ren, M.D.
Email:
Principal Investigator
Investigator:
Last name:
Houyu Ju, M.D.
Email:
Sub-Investigator
Investigator:
Last name:
Min Ruan, M.D.
Email:
Principal Investigator
Start date:
January 1, 2023
Completion date:
December 31, 2026
Lead sponsor:
Agency:
Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University
Agency class:
Other
Source:
Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05586100
