Reducing Excision Margins After Neoadjuvant Chemoimmunotherapy for HPV Negative Resectable Locally Advanced Head and Neck Squamous Cell Carcinoma (REMATCH)
Phase: NA
Conditions: Squamous Cell Carcinoma of Head and Neck, Neoadjuvant Therapy, Resection Margin
Sponsor: Union Hospital, Tongji Medical College, Huazhong University of Science and Technology

Reducing Excision Margins After Neoadjuvant Chemoimmunotherapy
for HPV Negative Resectable Locally Advanced HNSCC（REMATCH）
Date：2022.6.26
1. Study purpose / endpoint

purpose of research
To
observe
and
evaluate
the
safety
and
efficacy
of
neoadjuvant
chemotherapy combined with anti-PD-1 antibody for negative HPV therapy and
for surgical reduction after operable locally advanced head and neck squamous
cell carcinoma.

Primary study endpoint
(1) D FS (disease-free survival) rate of tumors at 2 years
(2) Organ retention rate.

Secondary study endpoints
(1) ORR, pCR rate, 2y-OS;
(2) Quality of life: EORTC-QLQ-H & N35, EORTC-QLQ-C30 quality of life scale
(3) Safety assessment: treatment-related toxicity, using the CTCAE 4.0
standard.
2. research design
2.1 system design
This study is a prospective, single-arm, multicenter exploratory study designed to
evaluate the safety and efficacy of reduced surgical coverage following neoadjuvant
chemotherapy combined with anti-PD-1 antibody against HPV-negative surgically
locally advanced head and neck SCC.
2.2 sample capacity
With the single group target value method, the expected 2-year DFS of this trial
is 80.0%, the target value is 60%, take a=0.025 (unilateral), power=0.80, and the
statistical sample size is 45 cases.Considering factors such as shedding, increasing the

number of enrolled cases by 20%, and 54 patients enrolled in this trial were
proposed.When the lower limit of 95%CI of DFS in this trial is greater than 60% of
the target value, "neoadjuvant chemotherapy + immunity + reduced range surgery"
can be considered effective for head and neck squamous cell carcinoma and meet the
requirements.
3. study population
3.1 DC
HPV negative operable locally advanced head and neck squamous cell
carcinoma (oral, oropharyngeal, hypoopharyngeal, or laryngeal squamous cell
carcinoma).
3.2 Selection criteria
Patients must meet all of the following conditions to be enrolled in this study:
1. Age 18-70 years, no gender;
2. Histological diagnosis of oral cavity, oropharyngeal, hypoopharyngeal or
laryngeal
squamous
cell
carcinoma;
surgical
resection
after
preoperative
evaluation;
3. Evaluation criteria for negative H P V: negative P16 immunohistochemistry,
that is, the negative result of p16 is less than 70%, if there is any doubt, the
negative HPV FISH test shall prevail;
Local advanced, as defined by the American Joint Committee on
Cancer [AJCC] Guide 8, as follows:
- -HPV-negative disease, stage III, IVa, and IVb; she has received
no previous specialist oncology treatment for head and neck
squamous cell carcinoma;
4. With at least one evaluable target lesion according to the RECIST version 1.1
criteria;
5.ECOG physical status is 0-1 points;
6. Main organs have normal function, that is, they meet the following standards:
(1) Routine blood examination standards shall meet: (no blood transfusion
within 14 days)

a．Hb≥90g/L:
b．ANC≥1.5x109/L;
c．PLT≥80x109／L；
(2) The biochemical inspection shall meet the following standards
A. B I L <1.25 times the upper normal value (ULN);
b.ALT and AST<2.5xULN; in case of liver metastases, ALT and AST
<5x ULN:
c. Serum Cr ULN, endophytic creatinine clearance of> 50ml / min
(Cockcroft-Gaut formula);
7. Sign a written informed consent prior to any trial-related activities;
8. The investigator judged able to comply with the study protocol;
9. Pregnancy test (for fertile female patients) was negative at screening;
1. Fertility male patients and women at risk of fertility and pregnancy must agree
to the use of two contraceptive methods (at least one is considered highly
effective contraception) throughout the study period.
Unfertile women (i. e. meeting at least one of the following criteria):
-A
hysterectomy
and
/
or
bilateral
oophorectomy
with
documented records;
- -The medically confirmed decline of ovarian function;
-Postmenopausal status is defined as at least 12 consecutive
months in the absence of other pathologic or physiological
reasons, and the status confirmed by serum follicle-stimulating
hormone (FSH) level is consistent with the postmenopausal
status.
2. Patients who are willing and able to follow visit arrangements, treatment plans,
laboratory tests, and other research procedures.
3. Signed and dated informed consent indicating that the patient (or legal
representative, if permitted by local guidelines / practice practices) has been
informed of all relevant aspects of the study.

3.3 Exclusion criteria
Subjects will not be enrolled in this study if they meet any of the following
conditions:
1. Previous immunotherapy with anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137
or anti-CTLA-4 antibodies (including ipilimumab) or any other antibodies or
drugs specifically targeted to the T cell co-stimulation or immune checkpoint
pathway.
2. Major surgery for the first 4 weeks prior to enrollment;
3. Those who have proven allergies to PD-1 antibody or its excipients;
4. Any active autoimmune disease or a history of autoimmune disease (such as
interstitial
pneumonia,
uveitis,
enteritis,
hepatitis,
hypopusitis,
vasculitis,
myocarditis, nephritis, hyperthyroidism, reduced thyroid function (hormone
replacement therapy can be included): vitiligo or asthma in childhood, adults
without any intervention, need bronchodilator medical intervention asthma
patients can be included);
5. Other malignant tumors that have suffered previously or at the same time
(except for malignant tumors that have been cured and have survived without
cancer for more than 5 years, such as skin basal cell carcinoma, cervical
carcinoma in situ, and papillary thyroid carcinoma, etc.);
6. Heart clinical symptoms or diseases that fail to be controlled, such as: (1) heart
failure of grade NYHAII or above (2) unstable heart pattern pain (3) patients who
have ever had myocardial infarction within 1 year (4) patients with clinically
meaningful supraventricular or ventricular arrhythmias who require clinical
intervention;
7. Subjects requiring systemic treatment with corticosteroids (> 10mg / day of
prednisone efficacy dose) or other immunosuppressive agents within 14 days
before administering the study drug, allowing inhaled or topical use of steroids
and efficacy doses of prednisone in the absence of active autoimmune disease;
8. Active infections requiring treatment;
9. Patients with congenital or acquired immune function defects (e. g.,
HIV-infected persons), active hepatitis B (HBV-DNA 104 copy number / ml or
2000IU / ml), or hepatitis C (hepatitis C antibody is positive, and HCV-RNA is
above the lower limit of detection of the analytical method);

10. The patient has received other oncology specialties before the visit;
11. Live vaccine was received within 4 weeks of starting study treatment;
12. Known history of psychotropic substance abuse, alcohol abuse, or drug use;
13. Pregnant or lactating women;
14. From the judgment of the investigator, the subject has other factors that may
cause him to terminate the study, such as other serious diseases (including mental
illness) requiring combined treatment, seriously abnormal laboratory tests, family
or social factors that may affect the safety of the subject or the collection of trial
data;
15. Patients that the surgeon believes cannot be radically removed;
16. Active pulmonary tuberculosis;
17. Severe infections occurring within 4 weeks prior to starting the study
treatment (including, but not limited to, hospitalization due to infection,
bacteremia, or complications of severe pneumonia);
18 Received systemic immunostimulatory drugs (including but not limited to
interferon or interleukin-2 [IL-2]) or remained in the half-life of five drugs (older
of both).
3.4 Subjects' exit criteria
The ①developed a treatment failure as prescribed by the protocol.
The ②presents with unacceptable therapeutic toxicity.
③with development may significantly affect clinical status assessment or
diseases that require interrupted treatment.
④patients may be withdrawn from this study at any time for any reason.
Exit procedure: Patients should be asked about the cause of their withdrawal and
any adverse events that have occurred, and, if possible, they should be observed and
evaluated by the investigator.Serious or unexpected adverse reactions should be
followed-up.Once the patient exits or stops the trial, the investigator should try to
obtain information about the patient.The researchers should do their best to complete
the final evaluation and record their efforts.The results of these evaluations and
observations, together with a description of the reasons for patient withdrawal, must
be recorded in the original data.The main reasons for withdrawal or suspension must

be recorded in the case report form (CRF), and the relevant follow-up study steps
(discharge visit) must be completed where possible.
4. Research intervention
4.1 Study intervention description
The study protocol intervention is: the second cycle of chemotherapy, a
week after the third cycle of chemotherapy imaging and endoscopic tumor
evaluation, according to the RECIST1.1 standard, tumor withdrawal more than
50% of patients, lymph node type positive lymph node area selective regional
lymph node dissection, primary area according to the original imaging scope and
endoscopic scope, combined with intraoperative pathological quick examination,
narrow the surgical scope under the premise of R0.
5. stages of research

Screening period
The screening period begins with the signing of the informed consent form
to enrollment or screening failure.Subjects must sign the informed consent form
before performing the screening procedure specified in this study.For the
presigned laboratory tests and imaging assessments done prior to routine clinical
care, the relevant data can be used during the prescribed window period.
Informed consent was signed 28 days before treatment, collected baseline
questionnaire, demographic data, previous disease history and treatment history,
combined medication and concomitant diseases, physical examination, imaging
examination of tumor lesions (CT, E US or MRI), KPSGPA score, quality of life
scale, hematuria routine liver and renal function test, electrocardiogram, adverse
events and combined medication, and check the entry criteria; and collected
tumor tissue specimens.

stage of therapy
Combined medication and concomitant diseases, physical examination, KPS
score, quality of life scale, hematuria and routine urinary liver and renal function

tests,
electrocardiogram,
and
adverse
events
were
recorded
during
the
neoadjuvant therapy and during each preoperative cycle;
Combined medication and concomitant diseases, physical examination,
KPSGPA score, quality of life scale, hematuria routine liver and kidney function
testing, electrocardiogram, and adverse events before postoperative adjuvant
therapy;

Safety follow-up period
During the neoadjuvant treatment period and in each preoperative cycle, the
patients recorded the combined medication and concomitant diseases, physical
examination, KPS, GPA score, quality of life scale, routine liver and renal
function testing of hematuria, electrocardiogram, and adverse events;
Combined medication and concomitant diseases, physical examination, KPS,
GPA score, quality of life scale, hematuria routine liver and kidney function
testing, electrocardiogram, and adverse events before postoperative adjuvant
therapy;
6. appraise
6.1 Primary and secondary endpoints / outcome evaluation

Main evaluation indicators
(1) Tumor D FS (disease-free survival) rate at 2 years
(2) Organ retention rate

Secondary study evaluation indicators
(1) ORR, pCR rate, 2y-OS;
(2) Quality of life: EORTC-QLQ-H & N35, EORTC-QLQ-C30 quality of life scale
6.2 safety evaluation

Safety assessment: Treatment-related toxicities, using the CTCAE4.0 criteria
7. Adverse events and serious adverse events
7.1 Follow-up of the AE / SAE
All AE / SAE should be reported regardless (from ICF signing until 4 weeks after
the last study drug administration).Four weeks after the last medication, only

considering the SAE associated with the study drug was reported.All should be
followed up to disappearance, remission to baseline level or level 1, reached a stable
state, or reasonably explained (e. g. loss to follow-up, death), and timely and
accurately recorded in the CRF table.
7.2 Adverse events were reported
Collection of adverse event information should be started from the subject
signing the informed consent until the first visit after the last medication (within 4
weeks).For each visit, the investigator should inquire about the adverse events
occurring after the last visit.The investigator shall follow up until the end of the
adverse events, have a stable status, make remission to the baseline level or level 1,
receive reasonable explanation, be lost to follow-up, and die; and timely and
accurately record them in the CRF table.
7.3 Reporting of serious adverse events
The collection period for serious adverse events (SAE) shall start since the
subject signed the informed consent form until 4 weeks after the last use of the
study drug (including the last day of 4 weeks).In case of SAE, the investigator must
immediately fill in the Serious Adverse Event Report Form, within 24 hours of
notification, sign and date, and immediately submit it to the ethics committee office
and the project leader of Zhengda Tianqing Pharmaceutical Group Co., Ltd.
SAE occurring 90 days after the last use of the study drug is generally not
reported unless suspected as related to the study drug.The SAE should document in
detail the symptoms, severity, correlation with the test drug, time of the drug,
occurrence, treatment, measures taken, time and manner of follow-up, and
outcome.If the investigator considers that a C. SAE is not related to the test drug and
potentially related to the study condition (e. g., termination of original therapy, or
comorbidities in the course of the trial), this relationship should be detailed in the
narrative section of the SAE report form.If the intensity of an occurring SAE or its
relationship with the subject drug changes, a follow-up report should be submitted
immediately.If
the
investigator
considers
that
the
previously
reported
SAE
information is misreported, it can make the correct, cancel or downgrade

instructions in the follow-up report and report them according to the SAE reporting
procedure.
7.4 Adverse event reporting of special concern
If it is also a serious adverse event, please fill in the CFDA Serious Adverse Event
Report Form simultaneously, and report it to the relevant units according to the SAE
procedure.
7.5 Pregnancy report
If a female subject is pregnant during the clinical trial, the subject will
immediately terminate the study medication and fill in the Pregnancy Report /
Follow-up Form within 24 hours of the investigator's knowledge of the pregnancy.
If the male subject's partner is pregnant during the clinical trial, the subject will
continue the clinical trial and complete the Pregnancy Report / Follow-up Form
within 24 hours after the investigator learns that the subject's partner is pregnant.
The investigators will follow up the pregnancy results until 1 month after the
mother delivers them.
If
the
pregnancy
result
is
stillbirth,
spontaneous
abortion,
and
fetal
malformation, it is considered as SAE, and it needs to be reported according to the
time limit requirements of SAE.
8. Statistical analysis and statistical methods
After receiving the CRF, the data administrator will check the data and feedback
the possible questions to the researcher, who should verify and reply as soon as
possible.The data administrator establishes the database in time and enters the data
twice.After the database is reviewed, the main researchers, data administrators and
statisticians will lock the data.In order to ensure data security, irrelevant personnel
can not approach and modify the data, and the data must be backed up.Any data
change must be signed by a consent form from the principal investigator, the
statistician and the data administrator.
8.1 Selection of the data for the statistical analysis
●
Full Analysis set (Full Analysis Set): Efficacy of all cases on medication

and taken at least once according to the Intituality analysis (ITT) principle.For case
data that failed to observe the full course of treatment, the last observation data
was carried forward to the study final result (LOCF).
●Compliance protocol set (Per-protocol Set): all cases that met the study
protocol, had good compliance, took no medication ban during the study period,
and completed the contents specified in the case report form.No fill-in was made
for the missing data.Statistical analysis of drug efficacy was performed for both
FAS and PPS.
●
Safety Analysis Set (Safety Analysis Set): All patients with all enrolled
cases, who have used the study medication at least once, and who have had
post-medication safety records, belong to the safety analysis set.This dataset was
used for the security analysis.
8.2 Statistical analysis plan
All statistical analyses will be computed using the SPSS 26.0 statistical
analysis software programming.All statistical tests were two-sided, and a P-value
less than or equal to 0.05 would be considered the difference tested as
statistically significant, with credible intervals using 95% confidence.
Baseline data were analyzed by the full analysis set, and all efficacy
indicators were analyzed by the full analysis set and compliance protocol set; the
safety analysis used the safety analysis set.All data will be calculated according to
the data type: mean, standard deviation, median, minimum and maximum values
for continuous variables, and frequency and percentage for categorical data;
Kaplan-Meier method will be used, and survival curve drawn if necessary; the
above analysis will provide corresponding 95% credible interval if necessary.
Baseline is generally defined as the last observation before the first
administration (including the day).
●efficacy analysis: D FS (disease-free survival) rate, organ retention
rate, ORR, pCR rate, 2y-OS, and quality of life scale
assessment at 2 years
●safety analysis:
1)
Describe the drug exposure volume;

2)
The incidence of adverse events, serious adverse events, the
severity, and the causal relationship with the study drug were
counted.
3)
Vital signs, laboratory examination values, ECG, and changes
relative to the baseline levels of the subjects at each follow-up
point will be given descriptive statistics.Data that deviate from
the reference value range will also be counted.
Combined medication and concomitant therapy will be categorized statistics.