Trial Title:
The Efficacy and Safety of HIPEC Combined With PD-1 and SOX Chemotherapy for the Translational Treatment of GC or EGJC With PM
NCT ID:
NCT06427252
Condition:
Gastric Cancer, Metastatic
Conditions: Official terms:
Stomach Neoplasms
Conditions: Keywords:
gastric cancer
peritoneal metastasis
HIPEC
immunotherapy
Study type:
Interventional
Study phase:
Phase 2
Overall status:
Not yet recruiting
Study design:
Allocation:
N/A
Intervention model:
Single Group Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
HIPEC
Description:
In the experimental group, HIPEC treatment (paclitaxel, 3000 ml of physiological saline
at 43°C for 60 min) was performed on the first day after the first exploratory laparotomy
and on the third day after the radical surgery for a total of 2-3 times (total amount of
paclitaxel was 175 mg/m2 ), with an interval of not more than 72 h. Intravenous systemic
therapy was started 3 weeks after the completion of HIPEC treatment. systemic therapy.
Arm group label:
HIPEC plus PD-1 plus SOX therapy
Intervention type:
Drug
Intervention name:
Systemic therapy
Description:
1. Tirilizumab: 200 mg, i.v., D1, Q3W;
2. oxaliplatin: 130mg/m2, i.v., D1, Q3W;
3. Herceptin: a tri-weekly dosing regimen with an initial loading dose of 8 mg/kg
followed by 6 mg/kg Q3W.
4. Tegeo: Oral administration: 40 mg per dose for BSA <1.25, 50 mg per dose for BSA
1.25 to 1.5, and 60 mg per dose for BSA ≥1.5, twice daily for each treatment cycle
D1-D14, Q3W;
Arm group label:
HIPEC plus PD-1 plus SOX therapy
Summary:
Gastric cancer (GC) with peritoneal metastasis has a poor prognosis and short survival.
In recent years, heat intraperitoneal perfusion chemotherapy (HIPEC) has gained better
efficacy in the treatment of peritoneal metastases of many malignant tumors, including GC
with peritoneal metastasis. The use of immune checkpoint inhibitors (ICIs) in the
treatment of advanced GC has made significant progress in recent years. And studies
showed that patients who were responded to immunotherapy combined with chemotherapy as
the first-line treatment were able to achieve significant survival benefit after radical
resection. However, whether HIPEC combined with immunotherapy for peritoneal metastatic
gastric cancer improves the R0 resection rate and prolongs survival time is currently
unclear. Therefore, we conducted this prospective multicenter clinical trial to explore
the effective dose and safety of the combination of systemic chemotherapy, HIPEC,
anti-PD-1 and anti-HER-2 therapy, which will provide a clinical basis for the treatment
of advanced GC.
Detailed description:
Gastric cancer (GC) is the 5th most common malignant tumor worldwide, and it causes the
4th most tumor-related deaths among all malignant tumors. China is a large country with
40% of the total number of GC cases worldwide. Despite the advances in medical detection
methods, most of the GC patients in China are in the advanced stage at the time of
diagnosis, in which peritoneal metastasis is one of the common metastatic patterns of
advanced GC, and the presence of peritoneal metastasis accounts for about 46% of patients
with distant metastasis detected at the first diagnosis. The prognosis of GC patients
with peritoneal metastasis is extremely poor, and compared with other metastatic organs,
patients with stage IV GC with peritoneal metastasis have a worse prognosis and shorter
survival.
The treatment of peritoneal metastasis of GC has been based on systemic chemotherapy with
reference to advanced GC, but it is difficult for traditional chemotherapeutic agents to
reach the peritoneal lesions due to the existence of blood-peritoneal barrier. In recent
years, heat intraperitoneal perfusion chemotherapy (HIPEC) has gained better efficacy in
the treatment of peritoneal metastases of many malignant tumors, including GC.HIPEC
allows chemotherapeutic drugs to act directly on tumor tissues while reducing the impact
on other parts of the body; the warming effect is synergistic with the antitumor effects
of chemotherapeutic drugs and helps the drugs to act more efficiently on the
intraperitoneal tumor cells; moreover, the chemotherapeutic drugs are absorbed through
the peritoneum and then enter the liver via the portal vein route, which is beneficial to
preventing liver metastasis. HIPEC currently has four applications and indications in the
clinic: firstly, palliative application to improve the quality of life for GC abdominal
metastasis with a large amount of carcinomatous ascites; secondly, therapeutic
application of radical gastric cancer surgery + cytoreductive surgery + HIPEC for the
treatment of GC; third, prophylactic application, radical gastric cancer surgery +
peritoneal hyperthermia chemotherapy, targeting people with high risk of peritoneal
recurrence, especially patients with T3-4 or positive lymph nodes; fourth, neoadjuvant
application, neoadjuvant chemotherapy combined with peritoneal hyperthermia chemotherapy
before radical gastric cancer treatment, in order to reduce the risk of peritoneal
implantation of gastric cancer and to increase the possibility of radical surgery.
However, there is a lack of high-level evidence-based medical evidence on the efficacy
and safety of HIPEC as a translational treatment for GC with peritoneal metastasis.
The use of immune checkpoint inhibitors (ICIs) in the treatment of advanced GC has made
significant progress in recent years. The KEYNOTE series of studies evaluated the safety
and efficacy of PD-L1 antibody as a first-line treatment for advanced GC, among which the
results of KEYNOTE-859 confirmed that the combination of Pembrolizumab and chemotherapy
is expected to be a HER-2 negative advanced gastric/esophagogastric junctional cancer
first-line treatment option. A recent retrospective study by Chinese scholars
demonstrated that patients with stage IV GC who were responded to the immunotherapy
combined with chemotherapy as the first-line treatment were able to achieve significant
survival benefit after radical resection. However, whether HIPEC combined with
immunotherapy for peritoneal metastatic gastric cancer improves the R0 resection rate and
prolongs survival time is currently unclear.
Therefore, we conducted this prospective multicenter clinical trial trying to combine the
specificity of HIPEC for peritoneal metastases with immunotherapy for advanced GC, aiming
to evaluate the efficacy and feasibility of multimodal treatment regimens, such as HIPEC
in combination with immunotherapy, for the transformative treatment of peritoneal
metastases of GC or EJ junctional cancer and to explore the effective dose and safety of
the combination of systemic chemotherapy, HIPEC, anti-PD-1 and anti-HER-2 therapy, which
will provide a clinical basis for the treatment of advanced GC.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
1. patients with a pathologically confirmed primary diagnosis of
gastric/esophagogastric junctional cancer who have not undergone chemotherapy,
radiotherapy, or other antitumor therapy prior to the start of the clinical trial;
2. age 18 to 75 years Eastern Coorperative Oncology Group (ECOG): 0 to 1 points;
3. diagnosis of metastatic adenocarcinoma of the peritoneum [peritoneal cancer index
(PCI) ≤ 20 points] with or without ascites (beyond the pelvis but not reaching full
abdominal ascites) by laparoscopic exploration;
4. Voluntarily sign the informed consent form.
5. good cardiac function for resection with curative intent. If clinically indicated,
patients with underlying ischemic, valvular heart disease or other severe heart
disease should be evaluated preoperatively by a cardiologist;
6. normal function of major organs and subjects are required to meet the following
laboratory criteria: 1) Absolute neutrophil count (ANC) ≥ 1.5x109/L in the last 14
days without granulocyte colony-stimulating factor (GCSF); 2) Platelets ≥ 100 x
109/L in the absence of blood transfusion in the last 14 days; 3) Hemoglobin > 9
g/dL without transfusion or erythropoietin use in the last 14 days; 4) Total
bilirubin ≤ 1.5 x upper limit of normal (ULN); enrollment is also allowed if total
bilirubin > 1.5 x ULN but direct bilirubin ≤ ULN; 5) Aspartate aminotransferase
(AST) and alanine aminotransferase (ALT) ≤ 2.5 x ULN.
6) Blood creatinine ≤1.5×ULN and creatinine clearance (calculated using the
Cockcroft-Gault formula) ≥60 ml/min; 7) good coagulation function, defined as
International Normalized Ratio (INR) or Prothrombin Time (PT) ≤ 1.5 x ULN; 8) Normal
thyroid function, defined as thyrotropin (TSH) within the normal range. If baseline
TSH is outside the normal range, subjects may also be enrolled if total T3 (or FT3)
and FT4 are within the normal range; 9) Cardiac enzyme profiles within the normal
range (enrollment will be allowed if the investigator determines that the laboratory
abnormality is not of clinical significance); 7) Thyroid function: thyroid
stimulating hormone (TSH) and free thyroxine (FT3/FT4) in the normal range or mildly
abnormal without clinical significance; 8. weight of 40 kg or more (including 40
kg), or BMI > 18.5; 9. female patients must meet:
- Menopausal (defined as absence of menstruation for at least 1 year with no confirmed
cause other than menopause) status, or surgically sterilized (removal of ovaries
and/or uterus), or patients of childbearing potential must also meet the following
requirements:
- Pregnancy test within 7 days prior to first dose must be negative;
- Agree to use contraception with an annual failure rate of < 1% or remain abstinent
(avoid heterosexual intercourse) (at least 120 days from signing the informed
consent form until at least 9 months after the last dose of the test drug and at
least 9 months after the procedure (contraceptive methods with an annual failure
rate of < 1% include bilateral tubal ligation, male sterilization, proper use of
hormonal contraceptives that suppress ovulation, hormone-releasing intrauterine
contraceptives, and copper-containing intrauterine devices). .;
- No breastfeeding is allowed. 10. The subject reads and fully understands the patient
instructions and signs the informed consent form.
Exclusion Criteria:
1. the patient has a previous (within 5 years) or concurrent other malignant tumor;
2. patients who are preparing for or have previously received organ or bone marrow
transplantation;
3. have had a blood transfusion within 2 weeks prior to the first dose, or have a
history of bleeding, and any bleeding event with a severity rating of 3 or more on
the CTCAE 4.0 within 4 weeks prior to screening;
4. abnormal coagulation with bleeding tendency (INR in the absence of anticoagulants at
normal values > 1.5); patients treated with anticoagulants or vitamin K antagonists
such as warfarin, heparin, or their analogues; the use of low-dose warfarin (1 mg
orally once daily) for prophylactic purposes is permitted, provided the
International Normalized Ratio of the prothrombinogen time (INR) is ≤ 1.5, or
Small-dose aspirin (no more than 100 mg daily);
5. an actinic/venous thrombotic event within 6 months prior to screening, such as
cerebrovascular accident (including transient ischemic attack), deep vein thrombosis
(except for venous thrombosis due to intravenous cannulation for pre-chemotherapy,
which has resolved in the judgment of the investigator), and pulmonary embolism;
6. myocardial infarction, poorly controlled arrhythmia (including QTc interval ≥ 450 ms
in men and ≥ 470 ms in women) within 6 months prior to the first dose (QTc interval
is calculated using the Fridericia formula);
7. the presence of NYHA class III-IV cardiac insufficiency or cardiac ultrasound: LVEF
(left ventricular ejection fraction) <50%;
8. urine protein ≥++ and confirmed 24-hour urine protein quantification >1.0 g;
9. have multiple factors that interfere with oral administration of medications (e.g.,
inability to swallow, chronic diarrhea, and intestinal obstruction)
10. pleural effusion with clinical symptoms requiring clinical intervention;
11. human immunodeficiency virus (HIV) infection;
12. active tuberculosis;
13. long-standing unhealed wounds or incompletely healed fractures;
14. patients with pre-existing and current interstitial pneumonitis, pneumoconiosis,
radiation pneumonitis, drug-associated pneumonitis, and severely impaired lung
function that may interfere with the detection and management of suspected
drug-associated pulmonary toxicity
15. the presence of a known active or suspected autoimmune disease, except those who are
in a stable state of that disease at the time of enrollment (not requiring systemic
immunosuppressive therapy);
16. a history of severe chronic autoimmune disease, such as systemic lupus
erythematosus; a history of inflammatory bowel disease, such as ulcerative
enteritis, Crohn's disease, or chronic diarrheal disease, such as irritable bowel
syndrome; a history of tuberculosis or tuberculosis; a history of active hepatitis
B, hepatitis C, or HIV; or well-controlled non-severe immune disorders, such as
dermatitis, arthritis, or psoriasis, may be eligible. .. Hepatitis B virus titers <
500copy/ml may be enrolled;
17. patients requiring treatment with systemic corticosteroids (> 10 mg/day prednisone
efficacy dose) or other immunosuppressive drugs within 14 days prior to the first
dose or during the study period. However, enrollment is permitted if patients are
allowed to use topical topical or inhaled steroids, or adrenal hormone replacement
therapy at doses ≤ 10 mg/day prednisone efficacy dose in the absence of active
autoimmune disease;
18. any active infection requiring systemic administration of anti-infective therapy
within 14 days prior to the first dose; except for prophylactic antibiotic therapy
(e.g., for the prevention of urinary tract infections or chronic obstructive
pulmonary disease);
19. treatment with a live vaccine within 28 days prior to the first dose; except
inactivated viral vaccines for seasonal influenza;
20. prior treatment with antibodies/drugs targeting immune checkpoints, e.g., PD-1,
PD-L1, CTLA-4 inhibitors, etc;
21. have received treatment with immunologically-affecting related drugs or medical
technologies (including but not limited to the following: thymopentin, thymofacine,
interferon, CAR-T therapy, etc.) within 6 months prior to the first dose of the drug
22. is receiving treatment in another clinical study or is scheduled to begin treatment
in this study less than 1 month from the end of treatment in the previous clinical
study;
23. has a known history of allergy or intolerance to any study medication or its
components
24. patients with a history of alcoholism, drug abuse, and substance abuse. Patients who
have stopped drinking alcohol may be enrolled;
25. patients with non-compliance with medical advice, non-adherence to prescribed
medication, or incomplete information that may affect the judgment of efficacy or
safety;
26. pregnant or lactating female patients;
27. patients with conditions that may increase the risk of study participation and study
medication, or other severe, acute, and chronic conditions that, in the judgment of
the investigator, make participation in a clinical study unsuitable.
28. other conditions that, in the judgment of the investigator, make them unsuitable for
this clinical trial.
Gender:
All
Minimum age:
18 Years
Maximum age:
75 Years
Healthy volunteers:
No
Start date:
May 31, 2024
Completion date:
May 31, 2026
Lead sponsor:
Agency:
The First Affiliated Hospital with Nanjing Medical University
Agency class:
Other
Source:
The First Affiliated Hospital with Nanjing Medical University
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT06427252
