Trial Title:
Immunotherapy With CCRT Followed by Surgery for Locally Advanced ESCC Patients
NCT ID:
NCT05743504
Condition:
Locally Advanced Esophageal Squamous Cell Carcinoma
Conditions: Official terms:
Carcinoma
Carcinoma, Squamous Cell
Esophageal Squamous Cell Carcinoma
Paclitaxel
Cisplatin
Atezolizumab
Study type:
Interventional
Study phase:
Phase 1/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:
Tiragolumab
Description:
Neoadjuvant Tiragolumab, Atezolizumab, Paclitaxel, Cisplatin and Radiotherapy Followed by
Surgery
Arm group label:
Immunotherapy with CCRT before surgery
Other name:
Atezolizumab
Other name:
Paclitaxel
Other name:
Cisplatin
Other name:
Radiotherapy
Other name:
Surgery
Summary:
The prognosis of ESCC is poor with a five-year overall survival rate of 10 to 30 %.
Randomized clinical trials have demonstrated that TMT, consisted of neoadjuvant
concurrent CCRT and radical esophagectomy, improves the overall survival for patients
with resectable locally advanced disease. As a consequence, it is mandatory to develop
new pharmacotherapeutic regimen for TMT. In our previous prospective studies, we found
higher levels of serum immune-related biomarkers, VEGF-A, TGF-β1, and soluble PD-L1,
before neoadjuvant CCRT were independent associated with inferior overall survival and
disease-free survival for locally advanced ESCC treated with neoadjuvant CCRT plus
radical esophagectomy. In the present clinical trial, we plan to investigate whether
incorporation of tiragolumab (Anti-TIGIT) and atezolizumab (Anti-PD-L1) into standard TMT
will be safe while improve the pathological complete response rate. By the present
research, we expect to develop a new TMT regimen for this poor prognostic disease.
Detailed description:
Esophageal squamous cell carcinoma (ESCC) is one of the most lethal malignancy worldwide.
The prognosis is poor with a five-year overall survival rate of 10 to 30 %. Randomized
clinical trials have demonstrated that trimodality therapy (TMT), consisted of
neoadjuvant concurrent chemoradiation (CCRT) and radical esophagectomy, improves the
overall survival for patients with resectable locally advanced disease. Despite of the
advancement, the outcome remained unsatisfactory with the median recurrence-free survival
around 20 to 25 months and median overall survival around 30 months. It is known that the
most important prognostic factor is whether a pathological complete response can be
achieved after neoadjuvant CCRT. However, the use of new generation chemotherapeutic
agent and epidermal growth factor inhibitors failed to significantly improve prognosis
comparing to the standard platinum-based regimen. As a consequence, it is mandatory to
develop new pharmacotherapeutic regimen for TMT.
In our previous prospective studies, we found higher levels of serum immune-related
biomarkers, VEGF-A, TGF-β1, and soluble PD-L1, before neoadjuvant CCRT were independent
associated with inferior overall survival and disease-free survival for locally advanced
ESCC treated with neoadjuvant CCRT plus radical esophagectomy. Recent clinical trials
have shown the efficacy of anti-PD-1 in recurrent/metastatic ESCC. Besides, preclinical
and clinical studies suggested radiotherapy might induce local inflammatory stimulus for
the immune modulating drug to boost the integrated response. In addition, preclinical
study showed promising anti-cancer efficacy by combination of fractionated radiotherapy,
anti-PD-L1 and/or anti-TIGIT immunotherapy. Though several prospective clinical trials
have shown the feasibility, safety, and activity of adding anti-TIGIT therapy to
anti-PD-L1 drug, and adding anti-PD-L1 therapy to chemotherapy in lung cancer, the safety
and activity of combing anti-PD-1/PD-L1 to CCRT or TMT remained largely undetermined. In
the present clinical trial, we plan to investigate whether incorporation of tiragolumab
(Anti-TIGIT) and atezolizumab (Anti-PD-L1) into standard TMT will be safe while improve
the pathological complete response rate. By the present research, we expect to develop a
new TMT regimen for this poor prognostic disease.
This study is a single arm open labeled trial to evaluate the safety and pathological
response of ESCC patients receiving neoadjuvant Paclitaxel/Cisplatin(TP)-CCRT plus
Tiragolumab/Atezolizumab followed by radical esophagectomy. We design to enroll 32
patients to develop the preliminary evidence for incorporating tiragolumab/atezolizumab
in locally advanced ESCC.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
1. Histologically proved squamous cell carcinoma of esophagus
2. Locally advanced disease, which are defined by TNM system of American Joint
Committee on Cancer (AJCC) Cancer Staging System (8th edition) in 2017, fulfilling
one of the following criteria:
1. T1-2N2-3M0
2. T3N1-3M0
3. Tumor judged to be operable and resectable with curative intent on the screening
assessment
4. Age ≥ 20 years
5. Medical fit for curative surgery
6. ECOG Performance Status 0 or 1
7. Adequate bone marrow reserves within 2 weeks prior to registration, defined as:
1. absolute neutrophil count (ANC) ≥ 1.5×109/L (1,500/μl)
2. platelets ≥ 100×109/L (100,000/µl)
3. hemoglobin ≥ 9.0 g/dl (may have been transfused)
8. Adequate liver function reserves within 2 weeks prior to registration, defined as:
1. hepatic transaminases (AST and ALT) ≤ 2.5 × upper limit of normal (ULN)
2. serum total bilirubin ≤ 1.5 × upper limit of normal (ULN)
9. Adequate renal function within 2 weeks prior to registration: Creatinine ≤1.5 mg/dL
10. Negative hepatitis B surface antigen (HBsAg) at screening or Positive HBsAg with HBV
DNA < 500 IU/mL (or 2500 copies/mL) at screening. Patients with detectable HBsAg or
detectable HBV DNA should be managed institutional guidelines.
a. Patients receiving anti-viral medication must have initiated treatment at least 2
weeks prior to protocol treatment and should continue treatment for at least 6
months after the final dose of study treatment
11. Negative hepatitis C virus (HCV) antibody test at screening, or positive HCV
antibody test followed by a negative HCV RNA test at screening
12. Negative serum or urine pregnancy test for women of childbearing potential
13. Women of childbearing potential and male participants must practice highly effective
contraception with a failure rate of < 1% per year during the treatment period and
for 5 months after the final dose of atezolizumab and for 90 days after the final
dose of tiragolumab
14. Patients must be able to comply with the study protocol and follow-up schedules and
provide study-specific informed consent
Exclusion Criteria:
1. Prior treatment with CD137 agonists or immune checkpoint blockade therapies,
including anti-¬CTLA-4, anti-PD-1, anti-PD-L1 and anti-¬TIGIT therapeutic antibodies
2. Prior radiotherapy to head and neck, chest, or abdomen
3. Prior chemotherapy
4. Histology consistent with adenocarcinoma, small cell carcinoma or mixed carcinoma of
esophagus or gastroesophageal junction.
5. Synchronously or metachronously diagnosed squamous cell carcinoma of aerodigestive
way, other than esophageal cancer
6. History of malignancy other than esophageal cancer within 2 years prior to
screening, with the exception of malignancies with a negligible risk of metastasis
or death (e.g., 5-year overall survival rate 90%), such as adequately treated
carcinoma in situ of the cervix, non-melanoma skin carcinoma, localized prostate
cancer, ductal carcinoma in situ, or Stage I uterine cancer
a. Patients who received endoscopic mucosal resection or dissection for superficial
mucosal cancers other than ESCC within 2 years prior to screening are eligible for
the study.
7. Prior organ transplantation including allogenic stem-cell transplantation
8. Current use of immunosuppressive medication, EXCEPT for the following:
1. intranasal, inhaled, topical steroids, or local steroid injection (e.g.,
intra-articular injection)
2. systemic corticosteroids at physiologic doses ≤ 10 mg/day of prednisone or
equivalent
3. steroids as premedication for hypersensitivity reactions (e.g., CT scan
premedication).
9. Treatment with therapeutic oral or intravenous antibiotics within 2 weeks prior to
registration
a. Patients receiving prophylactic antibiotics (e.g., to prevent a urinary tract
infection or chronic obstructive pulmonary disease exacerbation) are eligible for
the study.
10. Active autoimmune disease that might deteriorate when receiving an
immuno-stimulatory agent. Patients with diabetes type I, vitiligo, psoriasis, or
hypo- or hyperthyroid diseases not requiring immunosuppressive treatment and on
stable regimen are eligible.
11. Severe, active comorbidities which, in the judgment of the investigator, would make
the patient inappropriate for entry into this study or interfere significantly with
the proper assessment of safety and adverse events of the protocol, or limit
compliance with study requirements, defined as follows:
1. Severe infection within 4 weeks prior to registration, including, but not
limited to, hospitalization for complications of infection, bacteremia, or
severe pneumonia. Treatment with therapeutic oral or IV antibiotics within 2
weeks prior to registration. Patients receiving prophylactic antibiotics (e.g.,
to prevent a urinary tract infection or chronic obstructive pulmonary disease
exacerbation) are eligible for the study.
2. Transmural myocardial infarction < 6 months prior to registration
3. Unstable angina or congestive heart failure requiring hospitalization < 6
months prior to registration
4. Life-threatening uncontrolled clinically significant cardiac arrhythmias
5. Cerebral vascular accident/stroke (< 6 months prior to enrollment)
6. Congestive heart failure (≥ New York Heart Association Classification Class
II), or serious cardiac arrhythmia requiring medication.
7. Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects
8. Chronic obstructive pulmonary disease exacerbation or other respiratory illness
including pulmonary fibrosis requiring hospitalization or precluding study
therapy at the time of registration
9. Uncontrolled psychiatric disorder including recent (within the past year) or
active suicidal ideation or behavior
10. Laboratory abnormalities that may increase the risk associated with study
participation or study treatment administration or may interfere with the
interpretation of study results
11. Immune colitis, inflammatory bowel disease, immune pneumonitis
12. History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis
obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of
active pneumonitis on screening CT scan
13. Active tuberculosis
14. Uncontrolled or symptomatic hypercalcemia (corrected calcium > ULN)
15. Known history of testing positive for HIV or known acquired immunodeficiency
syndrome."
16. Positive Epstein-Barr virus (EBV) viral capsid antigen IgM test at screening
a. An EBV polymerase chain reaction (PCR) test should be performed as clinically
indicated to screen for active infection or suspected chronic active infection.
Patients with a positive EBV PCR test are excluded.
17. Vaccination with a live, attenuated vaccine within 4 weeks prior to initiation of
study treatment, or anticipation of need for such a vaccine during study treatment
or within 5 months after the final dose of study treatment is prohibited except for
administration of inactivated vaccines
18. History of severe allergic anaphylactic reactions to chimeric or humanized
antibodies or fusion proteins
19. Known prior severe hypersensitivity to investigational product, Chinese hamster
ovary cell products or any component in its formulations, including known severe
hypersensitivity reactions to monoclonal antibodies (NCI CTCAE v5.0 Grade ≥ 3)
20. Concurrent participation in another interventional clinical trial
21. Pregnant or breast-feeding women
22. Women of childbearing potential and male participants who are sexually active and
not willing/able to use medically acceptable forms of contraception; this exclusion
is necessary because the radiation treatment involved in this study may be
significantly teratogenic
Gender:
All
Minimum age:
20 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
National Taiwan University Hospital
Address:
City:
Taipei
Zip:
100
Country:
Taiwan
Status:
Recruiting
Contact:
Last name:
Chia-Hsien Cheng, M.D., M.S., Ph.D., FASTRO
Phone:
+886-2-2352-2846
Email:
jasoncheng@ntuh.edu.tw
Investigator:
Last name:
Chia-Hsien Cheng, PhD
Email:
Principal Investigator
Start date:
September 18, 2023
Completion date:
November 30, 2025
Lead sponsor:
Agency:
National Taiwan University Hospital
Agency class:
Other
Source:
National Taiwan University Hospital
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05743504
