Trial Title:
Neoadjuvant Chemoimmunotherapy and Extrafascial Hysterectomy for IB2 Cervical Cancer
NCT ID:
NCT06289751
Condition:
Cervical Cancer
Neoadjuvant Chemoimmunotherapy
Radical Hysterectomy
Extrafascial Hysterectomy
Conditions: Official terms:
Uterine Cervical Neoplasms
Paclitaxel
Albumin-Bound Paclitaxel
Cisplatin
Study type:
Interventional
Study phase:
Phase 2
Overall status:
Recruiting
Study design:
Allocation:
N/A
Intervention model:
Single Group Assignment
Intervention model description:
a multicentre, single-arm, phase 2 trial
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
Cadonilimab
Description:
10 mg/kg (body weight), 60 min, IV. Repeat every 3 weeks for a total of 3 cycles
Arm group label:
Neoadjuvant chemoimmunotherapy for ⅠB2 cervical cancer
Other name:
Cadonilimab Injection
Other name:
AK104
Intervention type:
Drug
Intervention name:
Paclitaxel-albumin
Description:
260 mg/m2 for 30 min. Repeat every 3 weeks for a total of 3 cycles.
Arm group label:
Neoadjuvant chemoimmunotherapy for ⅠB2 cervical cancer
Other name:
Injectable paclitaxel (albumin bound)
Intervention type:
Drug
Intervention name:
Cisplatin
Description:
75-80 mg/m2, IV, 1 mg/min. Repeat every 3 weeks for a total of 3 cycles.
Arm group label:
Neoadjuvant chemoimmunotherapy for ⅠB2 cervical cancer
Other name:
Cisplatin injection
Intervention type:
Procedure
Intervention name:
Extrafascial hysterectomy
Description:
Extrafascial hysterectomy + pelvic lymphadenectomy (or SLN mapping) (For participants who
meet ConCerv criteria)
Arm group label:
Neoadjuvant chemoimmunotherapy for ⅠB2 cervical cancer
Intervention type:
Procedure
Intervention name:
Radical hysterectomy
Description:
Radical hysterectomy + pelvic lymphadenectomy ± para-aortic lymphadenectomy (or SLN
mapping) (For participants who do not meet ConCerv criteria)
Arm group label:
Neoadjuvant chemoimmunotherapy for ⅠB2 cervical cancer
Intervention type:
Procedure
Intervention name:
Cone biopsy
Description:
Cold knife conization (CKC) (For participants with tumor size ≤2 cm after 3 cycles of
chemo-immunotherapy)
Arm group label:
Neoadjuvant chemoimmunotherapy for ⅠB2 cervical cancer
Summary:
This study is an exploratory clinical trial to investigate the feasibility of neoadjuvant
chemoimmunotherapy plus extrafascial hysterectomy and pelvic lymph node dissection in
patients with stage IB2 (2018 FIGO) cervical cancer and to observe the response rate to
treatment, adverse effects and complications, and to assess the survival rate of
patients.
Detailed description:
In China, cervical cancer is the malignant tumor of the female reproductive tract with
the highest incidence rate, and there will be about 112,000 new cases of cervical cancer
and 14,000 deaths in China in 2022, with the number of incidence cases accounting for 1/5
of the global total. In recent years, with the early detection of cervical cancer and the
wide application of HPV vaccine, more and more patients have been diagnosed at an early
stage, which has prompted researchers to conduct in-depth studies and investigations into
the treatment of early cervical cancer. to conduct in-depth studies and investigations.
For a long time, the standard treatment for early-stage cervical cancer has been wide
radical hysterectomy combined with pelvic lymph node dissection, with satisfactory
results and 5-year overall survival rates ranging from 73% to 98%. The core of radical
hysterectomy is wide hysterectomy, which ensures complete removal of the cervix and
uterine body and achieves negative margins. However, this procedure is associated with
high complications. In addition to ligamentous penetration, there are important
neurovascular vessels in the parietal tissues, which will increase the risk of
intraoperative complications such as bleeding, nerve injury, urinary tract and bowel
injury, etc. Postoperative complications such as urinary retention, urinary incontinence,
defecation difficulties, constipation, and sexual dysfunction may also occur in the
immediate and long-term future, which will cause serious problems to the patient's
quality of life, especially to the family harmony and social role of young patients.
Realization brings serious disturbances.
It has been controversial whether radical hysterectomy is necessary to remove
paracervical tissue in early-stage cervical cancer. Studies have reported that the
probability of paracervical infiltration is less than 1% in patients with tumors less
than 2 cm in diameter, no lymphovascular invasion, and no metastasis in the pelvic lymph
nodes, which provides a theoretical basis for conservative surgery. Extrafascial
hysterectomy is a conservative surgical procedure that does not involve removal of
parietal tissue and may be a safe and effective alternative to radical hysterectomy as an
option for patients with unreserved fertility needs in early-stage, low-risk cervical
cancer. In 2018, researchers used the SEER database to analyze and collect information
from the period of January 1998 to December 2012 on patients who were diagnosed from
January 1998 to December 2012 who were < 45 years of age with stage IB1 cervical cancer,
comparing the two surgical modalities of performing non-radical excision and radical
excision for cervical cancer, showed no significant difference in disease-free survival
between the two groups. Thus, radical surgery did not show better oncologic outcomes
compared to cervical conization, hysterectomy, or hysterectomy alone in patients with
stage IB1 disease. Based on the ConCerV trial, the first multicenter prospective trial to
evaluate the use of conservative surgery for early-stage, low-risk cervical cancer, the
2023 NCCN guidelines suggest that early-stage, low-risk cervical cancer should be treated
with radical hand surgery if it meets the ConCerv criteria (tumor size ≤2 cm, depth of
infiltration ≤10 mm, and no metastatic lesions on imaging), a conservative surgical
approach is feasible, i.e, cone excision with negative margins + pelvic lymph node
dissection or SLN mapping for those who will preserve fertility, and total extrafascial
hysterectomy + pelvic lymph node dissection or SLN mapping for those who will not
preserve fertility. In particular, at the 2023 American Society of Clinical Oncology
(ASCO) Annual Meeting, an international randomized controlled phase III trial (SHAPE)
initiated by the Canadian Cancer Trials Group compared the prognostic profile of patients
with early-stage, low-risk cervical cancer who underwent radical hysterectomy and pelvic
lymph node dissection with those who underwent hysterectomy and pelvic lymph node
dissection alone, which showed that patients who underwent simple hysterectomy had a
non-inferior 3-year pelvic recurrence rate to those who underwent radical hysterectomy,
and that the simple hysterectomy group had a significantly lower incidence of acute
adverse events and postoperative urinary retention and improved vaginal function. The
above clinical trials provide strong clinical evidence for conservative surgery for
early-stage, low-risk cervical cancer and have led to a series of major guideline updates
as well as an expansion of our focus to conservative surgical management of patients with
early-stage cervical cancer at stage 1B1 or higher.
For stage IB2 cervical cancer with tumor diameters of 2-4 cm, the current standard of
care is radical hysterectomy, with a 5-year recurrence-free survival rate of 87%. An
analysis of the 2018 SEER database showed that tumor lesion size ≥2 cm was an independent
risk factor for disease progression, and other studies and literature reviews have shown
that lesion size is one of the most important predictors of prognosis, with a
statistically significantly higher risk of recurrence for lesions ≥2 cm. This may be
related to the fact that larger tumor diameters simultaneously increase the proportion of
vascular-positive, deep interstitial infiltration, etc., thereby increasing postoperative
risk factors and the proportion of patients requiring adjuvant therapy after surgery.
Thus, current guidelines only recommend non-extensive total extrafascial hysterectomy for
low-risk early-stage cervical cancer, which has not been extended to patients with stage
IB2, and direct conservative surgery in this population is rarely reported in the
literature.
Neoadjuvant chemotherapy is commonly used in the preoperative treatment of patients with
cervical cancer with local tumor diameter >4 cm. Neoadjuvant chemotherapy can reduce
the size of the tumor lesion, decrease the risk of deep mesenchymal infiltration of
paracervical tissue, paracervical metastasis, and positive margins for lymph node
metastasis, increase the feasibility of radical surgery, and decrease the proportion of
postoperative adjuvant therapy. There is increasing data to support that in patients with
tumors ≥2 cm in diameter, cervical conization or radical hysterectomy after neoadjuvant
chemotherapy preserves fertility and that the proportion of patients with intermediate
and high risk factors requiring postoperative radiotherapy decreases significantly, with
better oncologic and fertility outcomes. This also brings a new dawn for patients with
stage 1B2 cervical cancer to undergo conservative surgery. With the rapid development of
immunotherapy phase and treatment, the neoadjuvant treatment modality in combination with
immune checkpoint inhibitors can significantly improve the EFS, pathological remission
rate, etc. in numerous solid tumors. Immunotherapy has achieved remarkable results in the
treatment of advanced cervical cancer, and the treatment strategy of immune checkpoint
inhibitors combined with chemotherapy has become the first-line treatment for advanced or
recurrent PD-L1 expression-positive cervical cancer, and Cemiplimab has been added as a
preferred regimen for the second-line medication for recurrent metastatic cervical cancer
in the new NCCN guideline of 2024, which is not limited to PD-L1 expression-positive
population. The latest studies in cervical cancer have shown that the introduction of
immunotherapy into the neoadjuvant treatment phase greatly improved the pathological
remission rate of patients with locally advanced cervical cancer (IB3, IIA2 and tumor
diameter ≥4cm stage IIB/IIIC1r) to 38%, and further analysis of the patients'
postoperative pathological factors showed that the incision margin positivity rate was
only 1. 2%, and the rate of paracervical tissue infiltration was only 2.5%, meanwhile,
69% of the neo-adjuvant immunotherapy tumor diameter ≤2 cm, and more than 50% of patients
had deep mesenchymal infiltration ≤1/3. Mechanistically, more and more studies have shown
that chemotherapy has an immunomodulatory effect, and chemotherapeutic agents commonly
used in neoadjuvant chemotherapy for cervical cancer, including cisplatin and paclitaxel,
can modulate the effector T-cell response by increasing tumor antigenicity, inducing the
death of immunogenic cells, disrupting the immunosuppressive pathway, and enhancing the
effector T-cell response to regulate antitumor T-cell responses. Further studies have
shown that sequential administration of chemotherapy followed by immunotherapy preserves
the ability of PD-L1 inhibitors to activate the immune response and may be a superior
dosing strategy. Therefore, based on the application of neoadjuvant chemotherapy in
conservative surgery for cervical cancer and the latest findings and theoretical basis of
immunization combined with neoadjuvant chemotherapy, the investigators expect to achieve
conservative surgical treatment for patients with stage IB2 cervical cancer through the
application of neoadjuvant immunotherapy in stage IB2 cervical cancer by reducing the
risk factors of patients to achieve therapeutic ConCerV criteria that meet the criteria
for extrafascial total hysterectomy.
Cadonilimab is the world's first PD-1/CTLA-4 bispecific tumor immunotherapy that achieves
immune cell activation by "double de-braking", i.e., indirectly releasing and activating
immune cells by simultaneously inhibiting the two immune signaling checkpoint pathways of
PD-1 and CTLA-4, thereby enhancing immune activity and strengthening the anti-tumor
effect. Anti-tumor activity. Cadonilimab, the world's first new dual antibody drug for
tumor immunotherapy and the first new bispecific antibody drug in China, was approved by
the State Drug Administration in June 2022 for the treatment of patients with recurrent
or metastatic cervical cancer who have previously failed platinum-containing
chemotherapy. In the Phase II clinical trial, the anti-tumor activity of cardunculus
monotherapy was encouraging and the long-term survival benefit was significant. At a
median follow-up of 14.6 months, the objective remission rate of Cadonilimab monotherapy
in patients with advanced cervical cancer who had failed prior platinum-containing
chemotherapy was 32.3%, with 14.1% (14 cases) achieving complete remission, 18.2% (18
cases) achieving partial remission, and the median OS had not yet been reached, with an
18-month OS rate of 51.2%. In addition, Cadonilimab has demonstrated excellent efficacy
and safety in clinical trials in a variety of tumors, including hepatocellular carcinoma,
lung cancer and neuroendocrine tumors.
This study is an exploratory clinical trial based on recent studies of immune checkpoint
inhibitors and neoadjuvant chemotherapy in patients with stage IB2 (2018 FIGO) cervical
cancer, to evaluate the feasibility of extrafascial hysterectomy plus pelvic lymph node
dissection in patients after Cadonilimab in combination with platinum-containing
chemotherapy as neoadjuvant immunotherapy, to observe the treatment response rate,
adverse effects and complications, and to assess patient survival.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
1. Clinical diagnosis of untreated stage IB cervical cancer with IB2 (FIGO, 2018
criteria; staging determined by two physicians of associate seniority or higher
after gynecologic examination and imaging evaluation);
2. At least one measurable lesion at baseline according to RECIST 1.1 criteria, with
lesion size based primarily on magnetic resonance imaging;
3. Pathologically confirmed diagnosis of cervical cancer, including cervical squamous
cell carcinoma (any grade), usual type adenocarcinoma (G1 or G2 / Silva A or B), and
adenosquamous carcinoma (G1 or G2);
4. Positive PD-L1 expression, Combined Positive Score (CPS) ≥1;
5. Patient age ≥18 years and ≤70 years;
6. ECOG score ≤1;
7. Laboratory tests: WBC ≥3. 5×109/L, NEU ≥1. 5×109/L, PLT ≥100×109/L, serum bilirubin
≤1.5 times the upper limit of normal, aminotransferase ≤1.5 times the upper limit of
normal, and BUN and Cr ≤normal;
8. Be willing to follow up and good compliance;
9. Be willing to sign the informed consent, including compliance with the requirements
and restrictions listed in the informed consent and program.
Exclusion Criteria:
1. Subjects with an active, known, or suspected autoimmune disease, or a history of an
autoimmune disease, except for the following: vitiligo, alopecia areata, Graves's
disease, psoriasis, or eczema that has not required systemic therapy within the last
2 years, hypothyroidism that is asymptomatic or requires only stable doses of
hormone replacement therapy (due to autoimmune thyroiditis), type 1 diabetes that
requires only stable doses of insulin replacement therapy, asthma that subsides
completely in childhood and does not require intervention in adulthood, or diseases
that do not recur in the absence of external triggers;
2. Prior treatment with immune checkpoint inhibitors, including, but not limited to,
other anti-PD-1, anti-PD-L1 antibodies, CTLA-4 antibodies, or antibodies against
immune co-stimulators (e.g., antibodies against ICOS, CD40, CD137, GITR, OX40
targets, etc.), or any other therapy targeting a mechanism of tumor immune action;
3. Known hypersensitivity to any component and/or any excipient of the trial prescribed
medication;
4. Immunosuppressive drugs or systemic corticosteroids for immunosuppression (> 10
mg/day of prednisone or other equivalent) within 2 weeks prior to trial dosing;
topical, ophthalmic, intra-articular, intranasal, and inhaled corticosteroids are
permitted;
5. Received herbs with antitumor effects or drugs with immunomodulatory effects (e.g.,
thymidine, interferon, interleukin-2) within 2 weeks prior to the trial;
6. Active systemic infection requiring systemic treatment;
7. Serious infection within 4 weeks prior to the first dose, including but not limited
to complications requiring hospitalization, sepsis, or severe pneumonia;
8. Patients with untreated chronic hepatitis B, or HBV carriers with chronic hepatitis
B virus (HBV) DNA greater than 1,000 IU/mL, or patients with active hepatitis C.
Inactive HBsAg carriers, patients with hepatitis B who have received treatment and
are in stable condition (HBV DNA < 1000 IU/mL), and patients with cured hepatitis C
are eligible for enrollment.HCV antibody-positive subjects will be eligible for the
study only if they have a negative HCV RNA test;
9. Known active tuberculosis (TB), patients with suspected active TB should undergo
chest X-ray and sputum examination in conjunction with clinical signs and symptoms
for exclusion;
10. Immunodeficiency or human immunodeficiency virus (HIV antibody positive);
11. Subjects with active inflammatory bowel disease or a history of such disease (e.g.,
Crohn's disease, ulcerative colitis, or chronic diarrhea). Subjects who are unable
to swallow or who have malabsorption syndrome, uncontrolled nausea, vomiting,
diarrhea, or other gastrointestinal disorders that severely interfere with drug
intake and absorption;
12. Known interstitial lung disease that is symptomatic or may interfere with detection
or treatment of immune-associated pneumonia;
13. Treatment with a live or attenuated vaccine administered within 4 weeks prior to the
first trial dose, inactivated seasonal influenza virus vaccine is permitted;
14. Patients who have received a prior allogeneic bone marrow transplant or solid organ
transplant;
15. History of primary malignant tumor within the last 5 years;
16. Subjects who have undergone major surgery (e.g., open abdomen, open chest, organ
resection, etc.) and severe trauma within 28 days prior to the first dose of the
implantable infusion device is permitted;
17. Subjects with a history of gastrointestinal perforation, gastrointestinal fistula,
or female genital fistula;
18. Uncontrolled other co-morbidities, symptoms, or medical history, including (i)
persons with one of the following cardiovascular diseases or cardiovascular risk
factors: myocardial infarction, unstable angina, pulmonary embolism,
acute/continuous myocardial ischemia, cerebral vascular accident, transient ischemic
attack, or other arterial or venous thrombosis, embolism, or cerebral ischemic event
of clinical significance/requiring pharmacologic intervention; and persons who have
had, within 6 months, a symptoms of congestive heart failure (New York Heart
Association (NYHA) class III and above); (ii) clinically significant bleeding
symptoms or a history of significant bleeding characteristics such as
gastrointestinal bleeding, gastric ulcer bleeding, or vasculitis within 1 month
prior to the first dose; (iii) clinically active hemoptysis, active diverticulitis,
abdominal abscesses, and gastrointestinal obstruction; and (iv) uncontrolled pleural
effusion, pericardial effusion, or ascites requiring Repeated drainage of ascites; ⑤
Abnormal liver or kidney development or history of surgery;
19. Pregnant or breastfeeding female patients; women of childbearing age who refuse to
accept contraceptive measures during neoadjuvant immunotherapy;
20. Concurrent participation in other interventional clinical trials; participation in
observational, non-interventional clinical trials is permitted;
21. Any condition that, in the opinion of the investigator, may result in risk in
receiving the study drug or that would interfere with the evaluation of the safety
of the study drug or the interpretation of the study results.
Gender:
Female
Minimum age:
18 Years
Maximum age:
70 Years
Healthy volunteers:
No
Locations:
Facility:
Name:
Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology
Address:
City:
Wuhan
Zip:
430030
Country:
China
Status:
Recruiting
Contact:
Last name:
Gang Chen
Phone:
086-027-8362
Email:
gumpc@126.com
Contact backup:
Last name:
Jing Chen
Phone:
086-027-8362
Email:
chenjing3223@126.com
Investigator:
Last name:
Gang Chen
Email:
Principal Investigator
Investigator:
Last name:
Kezhen Li
Email:
Principal Investigator
Facility:
Name:
Qilu Hospital of Shandong University
Address:
City:
Jinan
Zip:
250012
Country:
China
Status:
Recruiting
Contact:
Last name:
Kun Song, PhD
Phone:
086-0531-82365891
Email:
songkun2001226@163.com
Investigator:
Last name:
Kun Song, PhD
Email:
Principal Investigator
Investigator:
Last name:
Qing Zhang, PhD
Email:
Sub-Investigator
Investigator:
Last name:
Chunping Qiu, PhD
Email:
Sub-Investigator
Start date:
September 3, 2024
Completion date:
January 1, 2031
Lead sponsor:
Agency:
Tongji Hospital
Agency class:
Other
Collaborator:
Agency:
The First Affiliated Hospital of China University of Science and Technology (Anhui Provincial)
Agency class:
Other
Collaborator:
Agency:
Women Hospital, School of Medicine, Zhejiang University
Agency class:
Other
Collaborator:
Agency:
Southwest Hospital, China
Agency class:
Other
Collaborator:
Agency:
Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University
Agency class:
Other
Collaborator:
Agency:
Sichuan Cancer Hospital and Research Institute
Agency class:
Other
Collaborator:
Agency:
Qilu Hospital of Shandong University
Agency class:
Other
Collaborator:
Agency:
Beijing Friendship Hospital
Agency class:
Other
Collaborator:
Agency:
Tianjin Medical University
Agency class:
Other
Collaborator:
Agency:
West China Second University Hospital
Agency class:
Other
Collaborator:
Agency:
Xiangya Hospital of Central South University
Agency class:
Other
Collaborator:
Agency:
Gansu Provincial Maternal and Child Health Care Hospital
Agency class:
Other
Collaborator:
Agency:
Zhejiang Cancer Hospital
Agency class:
Other
Collaborator:
Agency:
Shengjing Hospital
Agency class:
Other
Source:
Tongji Hospital
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT06289751