Trial Title:
The Sequential Combination of FOLFOX and Toripalimab for Perioperative Immuno-Oncology Therapy of HER2-negative Adenocarcinoma of the Esophagogastric Junction (Siewert I/II):
NCT ID:
NCT05986227
Condition:
Gastroesophageal Adenocarcinoma
Conditions: Official terms:
Adenocarcinoma
Conditions: Keywords:
GEA
Study type:
Interventional
Study phase:
Phase 1/Phase 2
Overall status:
Not yet recruiting
Study design:
Allocation:
Randomized
Intervention model:
Parallel Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
toripalimab FOLFOX
Description:
Toripalimab（3mg/kg, q2w, IV）oxaliplatin (85 mg/m2 IV), leucovorin (400 mg/m2 IV) and 5-FU
(2400 mg/m2/day continuous IV infusion over 48 h)
Arm group label:
FOLFOX(D1)
Arm group label:
FOLFOX(D1)was combined with toripalimab(D1)
Arm group label:
FOLFOX(D1)was combined with toripalimab(D3)
Arm group label:
FOLFOX(D3) was combined with toripalimab(D1)
Summary:
The addition of immunotherapy to chemotherapy improves outcomes in patients with
HER2-negative gastroesophageal adenocarcinoma (GEA), and investigators aim to explore its
role in the perioperative setting. Moreover, optimizing the timing schedule of these two
therapies is critical when balancing efficacy and safety. This Chinese, multicenter,
open-label phase 1b/2 trial will evaluate the efficacy and toxicity of perioperative
folinic acid, fluoro-uracil, oxali-platin (FOLFOX), and toripalimab (JS001, a novel PD-1
inhibitor) in combination at various schedules in the neoadjuvant setting in patients
with HER2-negative resectable GEA: three cycles each in Arm A: FOLFOX (D1, q2w) followed
by toripalimab (D3, 3 mg/kg, q2w); Arm B: concurrent FOLFOX (D1, q2w) combined with
toripalimab (D1, 3 mg/kg, q2w); Arm C: toripalimab (D1, 3 mg/kg, q2w) followed by FOLFOX
(D3, q2w); Arm D: FOLFOX (D1, q2w) alone. The primary end-point is the dose-limiting
toxicity in Phase 1b and the pathological complete response rate in Phase 2; secondary
end-points include major pathologic response, disease-free survival, and event-free
survival.A fixed sample size of 126 patients is used in this study, with a safety run-in
period (n = 6) and cohort expansion period (n = 24), a dropout rate of 5% within 12
months of follow-up. Each arm receives three cycles of FOLFOX (D1, q2w) followed by 15
cycles of toripalimab (D1, 240 mg, q3w) in the neoadjuvant setting. Pre-treatment
biopsies, post-resection specimens, serial liquid biopsy, and gut microbiota samples on
treatment will be collected to explore the biomarkers' predictive value on diverse
schedule efficacy and safety.
Detailed description:
This Chinese, multicenter, open-label phase 1b/2 trial will evaluate the efficacy and
toxicity of perioperative folinic acid, fluoro-uracil, oxali-platin (FOLFOX), and
toripalimab (JS001, a novel PD-1 inhibitor) in combination at various schedules in the
neoadjuvant setting in patients with HER2-negative resectable GEA: three cycles each in
Arm A: FOLFOX (D1, q2w) followed by toripalimab (D3, 3 mg/kg, q2w); Arm B: concurrent
FOLFOX (D1, q2w) combined with toripalimab (D1, 3 mg/kg, q2w); Arm C: toripalimab (D1, 3
mg/kg, q2w) followed by FOLFOX (D3, q2w); Arm D: FOLFOX (D1, q2w) alone. The primary
end-point is the dose-limiting toxicity in Phase 1b and the pathological complete
response rate in Phase 2; secondary end-points include major pathologic response,
disease-free survival, and event-free survival. A fixed sample size of 126 patients is
used in this study, with a safety run-in period (n = 6) and cohort expansion period (n =
24), a dropout rate of 5% within 12 months of follow-up. Each arm receives three cycles
of FOLFOX (D1, q2w) followed by 15 cycles of toripalimab (D1, 240 mg, q3w) in the
neoadjuvant setting. Pre-treatment biopsies, post-resection specimens, serial liquid
biopsy, and gut microbiota samples on treatment will be collected to explore the
biomarkers' predictive value on diverse schedule efficacy and safety.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
- Age >/= 18 years;
- Male or Female;
- Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1;
- Histologically or cytologically confirmed locally advanced adenocarcinoma of
esophagus or gastroesophageal junction (Siewert type I/II);
- Human epidermal growth factor receptor 2 (HER2)-negative tumors;
- Clinical staging cT2-T4aNanyM0 or TanyN+M0 (UICC/AJCC 8th edition), potentially
resectable disease;
- Adequate hematologic and end organ function based on laboratory results obtained
within 14 days prior to initiation of study treatment;
- For women of childbearing potential: agreement to remain abstinent；no evidence of
pregnancy within 72 hours before the start of study regimen;
- Must be willing and able to provide written informed consent.
Exclusion Criteria:
- Known unresectable disease，cT4b disease invading aorta or trachea;
- Known distant metastases，including supraclavicular lymph nodal disease；
- Uncontrollable pleural or pericardial effusion，or ascites requiring repeated
interventions;
- Prior chemotherapy, immunotherapy, targeted therapy, thoracic radiotherapy or prior
surgical resection for an esophageal tumor;
- Poor nutritional status, BMI < 18.5 Kg/m2; if symptomatic nutritional support is
corrected before randomization, enrollment may continue to be considered after
assessment by the principal investigator;
- History of allergy to biological drugs produced by Chinese hamster ovary cells, any
component of toripalimab, tegafur, oxaliplatin or other platinum drugs;
- History of severe allergic, allergic reactions, or other hypersensitivity to
chimeric or humanized antibodies or fusion proteins;
- Patients with prior malignancies are eligible if they have been disease-free for > 5
years and are deemed by their physician to be at low risk for recurrence. Patients
with squamous or basal cell carcinoma of the skin, melanoma in situ, carcinoma in
situ of the cervix, or carcinoma in situ of the colon or rectum that have been
effectively treated are eligible, even if these conditions were diagnosed within 5
years prior to enrollment；
- History of any active autoimmune disease or autoimmune disease, including myasthenia
gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid
arthritis, inflammatory bowel disease, antiphospholipid syndrome-related vascular
thrombosis, Wegener's granulomatosis, Sjogren's syndrome, Guillain-Barre syndrome,
multiple sclerosis, vasculitis, glomerulonephritis, etc.; hypothyroidism (hormone
replacement therapy can be considered to be included);
- History of immunosuppressive drugs, or systemic hormones used to achieve
immunosuppressive purposes (dose > 10 mg/day prednisone or equivalent dose) within 2
weeks before the first use of the study drug; in the absence of active autoimmune
diseases, inhaled or local steroids are allowed and doses > 10 mg/day prednisone or
equivalent doses of adrenocorticotropic hormone replacement;
- History of type 1 diabetes, whose blood glucose is controlled after treatment with a
stable dose of insulin dosing regimen may be enrolled in this study;
- History of live attenuated vaccines are received within 4 weeks before the first use
of the study drug;
- History of major surgery or severe trauma within 4 weeks before the first use of the
study drug;
- History of eczema, psoriasis, lichen simplex chronicus, or dermatologic
manifestations of vitiligo (eg, patients with psoriatic arthritis were excluded from
the study) were permitted to enroll in this study if they met the following
conditions: a) had rash coverage less than 10% of body surface area (BSA); b) had
adequately controlled disease at baseline and required only low-potency topical
steroid therapy; c) did not have an acute exacerbation of the underlying disease
within the past 12 months without the need for PUVA (psoralen plus ultraviolet A
radiation), methotrexate, retinoids, biologics, oral calcineurin inhibitors,
high-titer, or oral steroid therapy for]；
- History of idiopathic pulmonary fibrosis, organizing pneumonia (such as
bronchiolitis obliterans), drug-induced pneumonia, idiopathic pneumonia,
interstitial pneumonia, or evidence of active pneumonia on screening chest CT scan;
- History of immunodeficiency, including HIV test positive, or suffering from other
acquired or congenital immunodeficiency diseases, or a history of organ
transplantation or allogeneic bone marrow transplantation;
- Uncontrolled cardiac clinical symptoms or diseases, including but not limited to: a)
NYHA class II or higher heart failure; b) unstable angina; c) myocardial infarction
within 1 year; d) clinically significant supraventricular or ventricular arrhythmia
that remains poorly controlled without or after clinical intervention.
- Known hereditary or acquired bleeding and thrombophilia (such as hemophilia,
coagulation dysfunction, thrombocytopenia, etc.);
- Known serious infection (CTCAE > 2) within 4 weeks before the first use of the study
drug, such as severe pneumonia requiring hospitalization, bacteremia, infectious
complications, etc.; baseline chest imaging showed active pulmonary inflammation,
symptoms and signs of infection within 14 days before the first use of the study
drug or oral or intravenous antibiotics, except for the prophylactic use of
antibiotics;
- Active pulmonary tuberculosis infection detected by medical history or CT
examination, or history of active pulmonary tuberculosis infection within 1 year
before enrollment, or history of active pulmonary tuberculosis infection more than 1
year ago but without regular treatment;
- Active hepatitis B (HBV DNA ≥ 2000 IU/mL or 104 copies/mL), hepatitis C (hepatitis C
antibody positive, and HCV RNA above the lower limit of detection of the analytical
method);
- Pregnant or lactating women;
- Other factors that may lead to forced halfway termination of the study as judged by
the investigator, such as having other serious diseases (including mental illness)
requiring concomitant treatment, alcoholism, drug abuse, family or social factors
that may affect the safety or compliance of the subject.
Gender:
All
Minimum age:
18 Years
Maximum age:
75 Years
Healthy volunteers:
No
Start date:
August 1, 2023
Completion date:
July 1, 2026
Lead sponsor:
Agency:
Cancer Institute and Hospital, Chinese Academy of Medical Sciences
Agency class:
Other
Source:
Cancer Institute and Hospital, Chinese Academy of Medical Sciences
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05986227
