Trial Title:
PD-1 Inhibitors Plus Chemoradiotherapy for Metastatic Nasopharyngeal Carcinoma: an Open-label Single-arm, Phase II Trial
NCT ID:
NCT05520814
Condition:
Nasopharyngeal Carcinoma
PD-1 Inhibitors
Chemoradiotherapy
Conditions: Official terms:
Carcinoma
Nasopharyngeal Carcinoma
Immune Checkpoint Inhibitors
Conditions: Keywords:
PD-1 inhibitors
concurrent
metastatic
nasopharyngeal carcinoma
chemoradiotherapy
Study type:
Interventional
Study phase:
Phase 2
Overall status:
Active, not recruiting
Study design:
Allocation:
N/A
Intervention model:
Single Group Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
PD-1 inhibitors
Description:
treprizumab injection 240mg / carrilizumab injection 200mg / Tirelizumab injection 200mg
* q21d (until the disease progresses, intolerable toxicity or the investigator / subject
decides to withdraw from the study, and the duration of PD-1 inhibitor is not more than
96 weeks)
Arm group label:
metastatic nasopharyngeal carcinoma
Intervention type:
Radiation
Intervention name:
chemoradiotherapy
Description:
Chemotherapy:
1. GP: gemcitabine 1g/m2 D1, 8 Cisplatin 80 mg/m2 d1
* Treatment courses every 3 weeks
2. Cisplatin 80mg/m2 d1 or carboplatin area under the curve 5mg/ml/min * Treatment
courses every 3 weeks
Radiotherapy: All the metastatic lesions received radiation dose from 30 to 60Gy
according to different metastatic sites.
Arm group label:
metastatic nasopharyngeal carcinoma
Summary:
programmed cell death-1 (PD-1) inhibitors has been recommended as the first-line
treatment for recurrent/metastatic nasopharyngeal carcinoma (R/M NPC), but
progression-free survival (PFS) and overall survival (OS) was still unsatisfactory. Basic
studies have already confirmed PD-1 inhibitors had concurrent synergistic effect with
chemotherapy and radiotherapy. Few studies concerned about the treatment pattern for
concurrent PD-1 inhibitors combination with chemoradiation for R/M NPC. There was still
much uncertainties about the timing, fraction dose and total dose for PD-1 inhibitors
combination with radiation. Therefore, we aimed to explore the substantial effect and
toxicity of this new pattern for R/M NPC.
Detailed description:
Nasopharyngeal carcinoma (NPC) is one of the most common malignant tumors of the head and
neck, which is derived from the epithelial cells of the nasopharynx. According to the
statistics of global cancer data in 2020, there are about 129100 newly diagnosed cases of
nasopharyngeal carcinoma (NPC) in the world every year, the incidence rate is less than 5
/ 100000, and about 73000 people die from NPC every year. There are obvious ethnic and
regional differences in the incidence of nasopharyngeal carcinoma. From the global
perspective, it is more likely to occur in the yellow race, and southern China and
Southeast Asia are high incidence regions of nasopharyngeal carcinoma. According to
statistics, the incidence rate of nasopharyngeal carcinoma in southern China is as high
as 30.29/100000 males and 13.09/100000 females. The incidence rate of male was higher
than that of female. Because nasopharyngeal carcinoma is sensitive to radiotherapy and
chemotherapy, and because it is adjacent to the spinal cord, brainstem, temporal lobe,
optic nerve, cochlea, mandible and other important tissue structures, it cannot be
treated surgically. Therefore, radiotherapy (RT) or radiotherapy combined with
chemotherapy (chemotherapy) is the standard treatment for nasopharyngeal carcinoma.
Although the diagnosis and treatment of nasopharyngeal carcinoma have been greatly
improved under the background of the development of imaging technology and the era of
precision radiotherapy, the situation it faces is still not optimistic. On the one hand,
4% - 10% of newly diagnosed nasopharyngeal carcinoma has distant metastasis; on the other
hand, about 10% of nasopharyngeal carcinoma has local and regional recurrence after
intensity modulated radiation therapy (IMRT) ± chemotherapy, and 15% - 30% of patients
have distant metastasis after radical treatment. Therefore, recurrence and metastasis are
still the main causes of treatment failure of nasopharyngeal carcinoma. This poses a
severe challenge to the treatment mode of nasopharyngeal carcinoma (NPC).
In the era of traditional treatment, surgery is the first choice for the treatment of
recurrent nasopharyngeal carcinoma. The standard treatment for patients with recurrent or
metastatic nasopharyngeal carcinoma (R / M NPC) that cannot be cured by surgery is
platinum based dual drug palliative systemic chemotherapy. At present, the GP regimen of
gemcitabine combined with cisplatin is the standard first-line treatment for R / M NPC,
but the progression free survival (PFS) of first-line chemotherapy is still less than 7
months, and the median overall survival (OS) is difficult to exceed 30 months [17]. In
view of the limited progress of chemotherapy drugs, we urgently need new treatment
schemes to prolong the survival time of R / M NPC patients. Immunotherapy is a hot topic
in R / M NPC Research in recent years, and it is expected to prolong the long-term
survival of patients. Immunotherapy also has a large number of clinical studies in R / M
NPC patients, making the treatment of nasopharyngeal carcinoma enter an era of
immunotherapy.
The occurrence of nasopharyngeal carcinoma is related to the chronic infection of Epstein
Barr virus (EBV). Nasopharyngeal carcinoma cells infected with EBV express target
proteins of CD4 and CD8 positive T cells (CD4 + T and CD8 + T), and nasopharyngeal
carcinoma cells infected with EBV undergo four different latent cycles (phase 0-IV). The
researchers found that NPC cells expressed specific latent proteins (EBNA1, LMP1, LMP2
and lmp2b) in latent phase II. Through basic research, it was found that these four
latent proteins are EBV antigens expressed by nasopharyngeal carcinoma cells, contain
more CD4 + T and CD8 + T cell epitopes, and are almost only expressed in nasopharyngeal
carcinoma cells. Therefore, these four latent proteins are ideal targets for immune
precision therapy. On the other hand, there are a large number of tumor infiltrating
lymphocytes (TILs) in tumor tissues, including a large number of CD4 + T and CD8 + T
lymphocytes, which can accurately attack EBV antigens expressed by nasopharyngeal
carcinoma cells. However, in patients with nasopharyngeal carcinoma with high lymphocyte
infiltration, tumor cells can still continue to grow. This phenomenon indicates that
there is an immunosuppressive microenvironment in nasopharyngeal carcinoma. Immunotherapy
can effectively improve the immunosuppressive microenvironment, making immunotherapy more
widely used in the occurrence, development and clinical diagnosis and treatment of
nasopharyngeal carcinoma. Inhibitory receptors expressed by T cells, antigen-presenting
cells and other cells exert corresponding immune effects after binding with their
corresponding ligands, which are collectively referred to as "immune checkpoints". Among
them, programmed death receptor-1 (PD-1) and its ligand programmed death ligand-1 (PD-L1)
are important targets of immunotherapy.
PD-L1 (also known as CD274 and B7-H1) is a type I transmembrane protein containing 290
amino acids in the immunoglobulin superfamily, which is similar to the immunoglobulin
light chain. In 1999, it was found that it is expressed in the heart, placenta, lung and
skeletal muscle and regulates T cell proliferation. Through anti-T cell receptor and CD28
costimulatory signal, it binds to its main receptor PD-1 in trans and CIS, thereby
inhibiting the function of anti-tumor PD-1 positive T cells. PD-L1 also interacts in cis
and trans with another known receptor, the immune co signaling molecule CD80, to prevent
co stimulation of T cells. PD-1 / PD-L1 pathway maintains the normal immune state of the
body. In the tumor microenvironment, PD-L1 expressed or overexpressed on the surface of
tumor cells binds to the PD-1 target expressed on the surface of T cells, inhibits the
normal function of T cells, weakens the recognition and response ability of T cells to
tumor cells, thereby realizing tumor immune escape and forming an immunosuppressive
microenvironment. In short, the main anti-tumor mechanism of PD-1 / PD-L1 inhibitors is
to block PD-1 and its ligand PD-L1, which are involved in attenuating the activation
pathway of T cells, and prevent or reverse the acquired peripheral tolerance to tumor
antigens, thus leading to T cell recovery, reducing T cell failure or death, increasing T
cell memory and anti-tumor immune cell infiltration in tumors, enhancing T cell activity,
playing an anti-cancer role, and significantly prolonging the survival of patients. Some
researchers further found that PD-L1 overexpression was common in NPC patients, which may
be related to EBV infection. Comprehensive analysis shows that there are a large number
of immune cells in NPC tissues, but due to EBV infection and other reasons, NPC cells
overexpress PD-L1, resulting in immunosuppressive effect. The use of PD-1 immune
checkpoint inhibitors can theoretically reactivate the immune response, so that
lymphocytes infiltrating the tumor microenvironment of nasopharyngeal carcinoma can play
an immune role, and ultimately achieve the goal of tumor suppression. Immunotherapy based
on PD-1 / PD-L1 immune checkpoint inhibitors has made a breakthrough in the treatment of
nasopharyngeal carcinoma. At present, many studies on anti-PD-1 monoclonal antibody in
nasopharyngeal carcinoma have been officially published.
Keynote-028 study is a non randomized, multicenter phase I and B clinical trial to
explore the efficacy and safety of pembrolizumab in patients with PD-L1 positive
nasopharyngeal carcinoma. Twenty seven NPC patients with PD-L1 expression who could not
be operated or distant metastasis and failed standard treatment were included in the
study. The median follow-up time was 20 months, the objective response rate (ORR) was
25.9%, the median PFS was 6.5 months, and the median OS was 16.5 months. PD-L1 expression
had a certain correlation with the treatment effect. The incidence of drug-related
adverse events (AES) was 74.1%, and the incidence of grade 3-5 AES was 29.6%. This study
showed that pabilizumab showed strong antitumor activity and manageable safety in
pd-l1-positive recurrent / metastatic nasopharyngeal carcinoma. Similar to pabolizumab,
the nci-9742 study is a single arm, multicenter phase II clinical study on nivolumab. 44
patients with nasopharyngeal carcinoma who progressed after the treatment of advanced
platinum containing regimen were enrolled in the study, and received the single drug
treatment regimen of nabulizumab. The final results showed that 1 patient obtained Cr, 8
patients obtained pr (ORR 20.5%), the 1-year OS rate was 59%, and the tolerance was good.
The results of the study confirmed that the monotherapy of nabulizumab may be effective
and safe for advanced nasopharyngeal carcinoma.
At present, PD-1 monoclonal antibody has shown a certain efficacy in patients with
recurrent / metastatic nasopharyngeal carcinoma. The median PFS of immunomonotherapy used
in the posterior line treatment of R / M NPC is mostly 3-4 months, and the median OS is
concentrated in 16-17 months. The overall incidence of side effects is lower than that of
chemotherapy, and it is well tolerated. It can bring longer survival benefits for
patients, but the benefit population is small (20% - 30%).
In 2021, the cancer prevention and treatment center of Sun Yat sen University led two
phase III, double-blind, randomized controlled clinical studies of immunotherapy combined
with gemcitabine and cisplatin (GP) chemotherapy for advanced first-line nasopharyngeal
carcinoma: captain-1st study and jupiter-02 study. Captain-1st study [45] confirmed that
in the first-line treatment of locally recurrent or metastatic nasopharyngeal carcinoma,
carrilizumab combined with GP chemotherapy was used for the first-line treatment of R / M
NPC, with a median PFS of 10.8 months, an orr of 88.1%, a median duration of remission
(DOR) of 9.9 months, and good safety. The jupiter-02 study [46] confirmed that in the
first-line treatment of locally recurrent or metastatic nasopharyngeal carcinoma, the
first-line treatment of R / M NPC with treprizumab combined with GP chemotherapy had a
median PFS of 11.7 months, HR of 0.52, and median dor of 10.0 months. The risk of death
was reduced by 40%, and the safety was good. These two studies confirmed that although
the adverse reactions of chemotherapy combined with PD-1 mAb were different compared with
the placebo group, the overall safety was controllable.
Compared with PD-1 inhibitor immunomonotherapy, PD-1 monoclonal antibody combined
chemotherapy can bring longer survival benefits to patients in the treatment of recurrent
/ metastatic nasopharyngeal carcinoma, obtain better treatment effect and controllable
safety. However, some patients still have poor treatment effect, with an effective rate
of about 50%, which poses a severe challenge to the era of immunotherapy for recurrent /
metastatic nasopharyngeal carcinoma.
At present, a large number of basic studies have confirmed that PD-1 inhibitors have
synergistic effects with radiotherapy. Radiotherapy can stimulate the immune response,
promote the death of immunogenic cells and release tumor associated antigen (TAA), and
enhance the homing of immune cells to tumors, thus transforming immunologically "cold"
tumors into "hot" tumors. In addition, radiotherapy induces an increase in PD-L1
expression on tumor cells, making them more susceptible to continuous effects of PD-1 /
PD-L1 inhibitors, thus promoting longer survival time and higher response rate. In
addition, radiotherapy may cause distant effect, shrink the target tumor outside the
radiation field area, and may also increase the aggregation of T cells in the tumor
microenvironment, promote cytokine secretion and antigen presentation.
Recently, Professor Chen Mingyuan from the cancer prevention and treatment center of Sun
Yat sen University led an open, single arm, phase II clinical study to explore the
efficacy and safety of treprizumab combined with intensity modulated conformal
radiotherapy (IMRT) in the treatment of recurrent nasopharyngeal carcinoma (rnpc) [63].
In this study, 25 patients with unresectable rnpc were included. All patients received
treprizumab combined with IMRT, with a median IMRT dose of 60.21 Gy. The results showed
that after 3 months of radiotherapy, the objective response rate (ORR) was 79.2% and the
disease control rate was 95.8% in 24 evaluable patients. The median PFS was 18.67 months,
the 12-month PFS rate was 91.8%, and the median OS was not reached. In terms of safety,
the most common adverse events (AES) were all grade 1-2, and the safety was manageable.
It has been proved that treprizumab combined with IMRT showed promising antitumor
activity in patients with recurrent nasopharyngeal carcinoma, achieved good remission
rate and PFS outcome, and was well tolerated.
At present, PD-1 inhibitor immunomonotherapy or combined chemotherapy has been widely
used in patients with recurrent / metastatic nasopharyngeal carcinoma, and it is also the
first-line treatment for R / M NPC recommended by international and domestic guidelines.
However, few studies have focused on the simultaneous combination of PD-1 inhibitors and
chemoradiotherapy. More trials are needed to explore the possibility of combining PD-1
inhibitors with chemoradiotherapy, which may be a new treatment strategy for these
patients.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
1. Voluntarily participate in the trial and sign the informed consent for the study in
writing.
2. Age ≥ 18 years old (when signing the informed consent for this study).
3. Metastatic disease after primary standard treatment (patients who had metastatic
diseases over six months after treatment)
4. Metastatic lesions are not suitable for surgery.
5. According to recist1.1 evaluation criteria, there are measurable lesions (1-5
measurable lesion).
6. The physical state of the Eastern Cooperative Oncology Group (ECoG) was 0-1.
7. Tumor tissue can be provided for PD-L1 expression detection: newly obtained biopsy
(within 90 days before the start of study treatment) is preferred. If biopsy tissue
cannot be provided for detection, archived tissue wax block can be provided for
post-section detection.
8. Urine pregnancy test was negative (female), and contraceptive measures were taken
from the trial period to 3 months after the end of the trial.
9. The function of main organs is normal, and the blood routine examination shall meet
the following standards: WBC ≥ 4.0 × 109/L,ANC≥2.0 × 109/L, PLT≥100 × 109 / L, Hb ≥
90g / L (no blood transfusion and blood products within 14 days, no correction with
G-CSF and other hematopoietic stimulating factors); Biochemical examination shall
meet the following standards: TBIL ≤ 2.0 × ULN,ALT、AST≤2.5 × ULN, bun and cre ≤ 1.5
× The clearance rate of ULN or endogenous creatinine ≥ 60ml / min (Cockcroft Gault
formula); Good coagulation function: defined as international normalized ratio (INR)
or prothrombin time (PT) ≤ 1.5 times ULN; If the subject is receiving anticoagulant
treatment, as long as Pt is within the proposed scope of use of anticoagulant drugs;
The myocardial enzyme spectrum was within the normal range.
10. According to the judgment of the investigator, the patient was considered to be able
to comply with the protocol.
Exclusion Criteria:
1. Locally advanced nasopharyngeal carcinoma has disease progression (PD) within 6
months after systemic treatment.
2. It is known that any component of the investigational drug or preparation has caused
severe hypersensitivity, including severe hypersensitivity to other monoclonal
antibodies, gemcitabine, taxol, fluorouracil, platinum and other related compounds
(NCI ctcaev5.0 ≥ grade 3).
3. According to the criteria of common adverse event terminology (NCI ctcaev5.0), there
were peripheral neuropathy ≥ grade 2.
4. Other malignant tumors occurred within 5 years or present at the same time.
5. Interstitial lung disease or non communicable pneumonia (including past history and
present condition); Local interstitial pneumonia induced by radiotherapy is
excluded.
6. Have uncontrolled systemic diseases, including diabetes, hypertension, acute lung
disease, etc.
7. Active infections requiring systemic treatment, including active tuberculosis.
8. Uncontrollable pleural effusion, pericardial effusion or ascites requiring repeated
drainage.
9. There are obvious cardiovascular diseases, heart failure classified as grade 2 or
above by the New York Heart Association (NYHA), previous myocardial infarction
within 3 months, unstable arrhythmia (including QT interval ≥ 480 MS) or unstable
angina pectoris.
10. Active central nervous system metastasis and / or cancerous meningitis (before the
first administration, except for patients with stable brain metastases: subjects
with brain metastases who have received previous treatment can participate in the
study, provided that they are clinically stable for at least 2 weeks, there is no
evidence of new or expanded brain metastases, and steroids are stopped 3 days before
the administration of the study drug. Except for subjects with asymptomatic brain
metastases: they have no neurological symptoms, do not need corticosteroids, and
have no lesions > 1.5cm, and they need regular brain tests as disease sites Imaging
examination.)
11. Active hepatitis B or C, meeting any of the following conditions: hepatitis B virus
deoxyribonucleic acid (HBV DNA) in peripheral blood is positive (the result is
greater than the detection limit of the analysis method); Hepatitis C virus RNA (HCV
RNA) in peripheral blood was positive (the result was greater than the detection
limit of the analysis method).
12. Patients with a history of immune deficiency, including HIV positive and / or other
acquired and congenital immune deficiency diseases, and / or patients with a history
of organ transplantation.
13. Active autoimmune diseases that may worsen when receiving systemic steroid therapy
or any other form of immunosuppressive therapy (except for patients with type I
diabetes, vitiligo, psoriasis or hypothyroidism or hyperthyroidism that do not
require immunosuppressive therapy).
14. Immunosuppressive drugs are used, except for the following cases: intranasal,
inhaled, topical steroids or local steroid injections (e.g., intra-articular
injections), physiological doses of systemic corticosteroids (≤ 10 mg / day
prednisone or equivalent dose), steroid pre medication for hypersensitivity
reactions (e.g., CT scan pre medication).
15. Major surgery was performed within 4 weeks before enrollment, and / or there were
unhealed wounds, ulcers or fractures.
16. Live virus vaccine (seasonal influenza vaccine and coronavirus vaccine without live
virus are allowed to be inoculated) was inoculated within 4 weeks before enrollment.
17. Currently participate in and receive research treatment, or participate in research
drug trials and receive research treatment or use research devices within 4 weeks
before enrollment.
18. Patients with known drug abuse and / or psychosis have severe intellectual or
cognitive impairment, which may interfere with the cooperation with the trial
requirements.
19. Pregnancy, lactation, and / or expected pregnancy or childbirth during the trial
period, from the beginning of the screening visit to 180 days after the last dose of
study drug.
20. Anti-PD-L1, anti-PD-L2, anti-CD137, anti-CTLA-4 antibodies and / or any other
antibody or drug specifically targeting T cell costimulation or immune checkpoint
pathway.
21. patients who cannot follow the trial protocol or cooperate with follow-up.
Gender:
All
Minimum age:
18 Years
Maximum age:
70 Years
Healthy volunteers:
No
Locations:
Facility:
Name:
Sichuan Cancer Hospital
Address:
City:
Chendu
Zip:
610041
Country:
China
Start date:
August 1, 2018
Completion date:
December 31, 2023
Lead sponsor:
Agency:
Sichuan Cancer Hospital and Research Institute
Agency class:
Other
Source:
Sichuan Cancer Hospital and Research Institute
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05520814