Clinical Trial Details
— Status: Not yet recruiting
Administrative data
NCT number |
NCT06289751 |
Other study ID # |
NACI-CerV-004 |
Secondary ID |
|
Status |
Not yet recruiting |
Phase |
Phase 2
|
First received |
|
Last updated |
|
Start date |
March 1, 2024 |
Est. completion date |
January 1, 2031 |
Study information
Verified date |
February 2024 |
Source |
Tongji Hospital |
Contact |
Gang Chen |
Phone |
086-027-8362 |
Email |
gumpc[@]126.com |
Is FDA regulated |
No |
Health authority |
|
Study type |
Interventional
|
Clinical Trial 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.
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 total 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 cimeplizumab 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, we 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.
Cardunolizumab 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. Cadunilizumab, 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 cardunculus 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, cardunolizumab 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 cardunilizumab in combination with platinum-containing
chemotherapy as neoadjuvant immunotherapy, to observe the treatment response rate, adverse
effects and complications, and to assess patient survival.