Clinical trial NCT06580574: Immune Checkpoint Inhibitors for Organ Preservation in Non-metastatic dMMR/MSI-H Gastric or Colon Cancers
Official title: Sintilimab With Selective Combination of Sintilimab, IBI310 and Lenvatinib Used for Organ Preservation in Non-metastatic Gastric or Colon Cancers With Mismatch Repair Deficiency or High Microsatellite Instability
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Gastric Cancer
Colon Cancer
MSI-H
DMMR Cancer
Keywords: Organ preservation
immunotherapy
anti-VEGF
Lead sponsor: Peking University
Sponsor class: OTHER
First posted: 2024-08-30
Enrollment: 38
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This study intends to explore the role of PD1/PDL1 antibody with selective combination of Sintilimab, IBI310 and Lenvatinib in organ preservation in non-metastatic dMMR/MSI-H gastric or colon cancers with mismatch repair deficiency or high microsatellite instability


Eligibility criteria: Inclusion Criteria:

* Subjects are able to comprehend the informed consent form, and voluntarily sign the informed consent form.
* Subjects are ≥18 years old on the day of signing the informed consent form, with no gender restrictions.
* Histologically confirmed gastric cancer or colon cancer, without distant metastasis based on CR or MR.
* ECOG performance status of 0-2.
* dMMR confirmed by immunohistochemistry or MSI-H confirmed by PCR and NGS. If MSI status and MMR status were not consistent, whether to enroll this patient should be determine by investigators. Patients with MMR heterogeneity in tumors could not be included.
* Patients who are about to receive or are receiving 24 weeks of PD1/PDL1 antibody monothearpy and have not had the first efficacy assessment.
* Archived tumor tissue samples or freshly obtained tumor tissue samples are available.
* Female subjects of childbearing potential or male subjects with partners of childbearing potential agree to use highly effective contraception from 7 days before the first dose until 120 days after the last dose. Female subjects of childbearing potential must have a negative serum pregnancy test within 7 days before the first dose.
* Subjects have the ability and willingness to comply with the study protocol's visits, treatment plan, laboratory tests, and other study-related procedures.
* For patients who are about to receive combination of Sintilimab, IBI310 and Lenvatinib. subjects should have good organ function within the first 7 days of initial dosing: HGB ≥ 80g/L, NEU ≥ 1.0\*10\^9/L, PLT ≥ 75\*10\^9/L, Cr≤1.5×ULN or CrCl≥50mL/min（Cockcroft-Gault method), TBiL ≤ 1.5×ULN, ALT and AST ≤3 ×ULN; urine protein \<2+; if urine protein ≥ 2+, 24 hour urinary protein quantity \<2g; INR, APTT, PT ≤ 1.5 ×ULN

Exclusion Criteria:

* Distant metastasis;
* Previous treatment including CTLA4 blockade;
* Subjects with interstitial lung disease or a history of non-infectious pneumonia requiring oral or intravenous corticosteroid treatment.
* Subjects with active autoimmune diseases requiring systemic treatment before the start of the study or those considered at risk of recurrence or planned treatment for autoimmune diseases as judged by the investigator. Except for these conditions: a) skin diseases that do not require systemic treatment (e.g., vitiligo, alopecia, psoriasis, or eczema); b) hypothyroidism caused by autoimmune thyroiditis, requiring stable doses of hormone replacement therapy; c) type 1 diabetes requiring stable doses of insulin replacement therapy; d) childhood asthma fully resolved with no need for intervention in adulthood; e) the investigator judges that the disease will not relapse without external triggering factors.
* Subjects with a history of other malignant tumors within 5 years, excluding cured skin squamous cell carcinoma, basal cell carcinoma, non-invasive bladder carcinoma, localized low-risk prostate cancer (defined as stage ≤T2a, Gleason score ≤6, and prostate-specific antigen (PSA) ≤10 ng/mL (if measured) in patients who have undergone curative treatment and have no biochemical recurrence of prostate-specific antigen (PSA)), in situ cervical/breast carcinoma, or Lynch syndrome.
* Subjects with uncontrolled comorbidities, including but not limited to: a) active HBV or HCV infection; b) subjects who are HBsAg positive and/or HCV antibody positive during screening must undergo HBV DNA and/or HCV RNA testing. Only subjects with HBV DNA ≤500 IU/mL (or ≤2000 copies/mL) and/or HCV RNA negative can be enrolled; HBV DNA monitoring will be at the discretion of the investigator based on the subject's condition during the trial; c) known HIV infection or AIDS history; d) active tuberculosis; e) uncontrolled hypertension (resting blood pressure ≥160/100 mmHg), symptomatic congestive heart failure (NYHA II-IV), unstable angina or myocardial infarction within 6 months, or the presence of QTc prolongation or the risk of arrhythmia (baseline QTc \>470 msec \<Fridericia method correction\>, refractory hypokalemia, long QT syndrome, atrial fibrillation with resting heart rate \>100 bpm, or severe valvular heart disease); f) active bleeding that cannot be controlled after medical treatment.
* History of allogeneic bone marrow or organ transplantation.
* Previous history of allergic reactions, hypersensitivity reactions, or intolerance to antibody drugs (e.g., severe allergic reactions, immune-mediated hepatotoxicity, immune-mediated thrombocytopenia, or anemia).
* Pregnant and/or lactating females.
* For patients who are about to receive combination of Sintilimab, IBI310 and Lenvatinib: a) Subjects with a history of gastrointestinal perforation or fistula within 6 months before the first dose. If the perforation or fistula has been treated with resection or repair, and the disease is judged to be recovered or improved by the investigator, then enrollment is allowed. b) Subjects who have undergone major surgery within 28 days before the first dose (e.g., major abdominal or thoracic surgery; excluding drainage, diagnostic puncture, or peripheral vascular access replacement). c) Subjects who require systemic corticosteroids (≥10 mg/day prednisone or equivalent) or immunosuppressive therapy for a continuous 7-day period within 14 days before the first dose. Inhaled or locally applied steroids and physiological replacement doses of steroids due to adrenal insufficiency are allowed. Short-term (≤7 days) corticosteroids for prophylaxis (e.g., contrast dye allergy) or treatment of non-autoimmune diseases (e.g., delayed hypersensitivity reaction caused by exposure to allergens) are allowed. d) Toxicity from previous antitumor treatments has not recovered to Grade ≤2 (NCI-CTCAE v5.0) or baseline, except for alopecia, skin pigmentation (allowed at any level), and immune-related adverse reactions requiring physiological replacement (e.g., hypothyroidism, hypopituitarism, type 1 diabetes).

Primary outcomes:
measure: Organ preservation rate
timeFrame: The status of cCR or near-cCR and the possibility of organ preservation will be evaluated after completion of PD1/PDL1 antibody monotherapy, 12 weeks after Sintilimab, IBI310 and Lenvatinib, and 24 weeks after Sintilimab, IBI310 and Lenvatinib
Secondary outcomes:
measure: Organ preservation rate after completion of PD1/PDL1 antibody monotherapy
timeFrame: The status of cCR or near-cCR and the possibility of organ preservation will be evaluated after completion of PD1/PDL1 antibody monotherapy, an average of 24 weeks
measure: Organ preservation rate after completion of selective combination of Sintilimab, IBI310 and Lenvatinib
timeFrame: The status of cCR or near-cCR and the possibility of organ preservation will be evaluated 12 weeks and 24 weeks after Sintilimab, IBI310 and Lenvatinib
measure: Objective response rate of selective combination of Sintilimab, IBI310 and Lenvatinib
timeFrame: Baseline up to withdrawal of consent, progressive disease, unacceptable toxicity, or surgery (whichever occurs first), up to 8 years
measure: Disease control rate of selective combination of Sintilimab, IBI310 and Lenvatinib
timeFrame: Baseline up to withdrawal of consent, progressive disease, unacceptable toxicity, or surgery (whichever occurs first), up to 8 years
measure: 3 year organ preservation rate
timeFrame: From first dose of PD1/PDL1 antibody until the date of surgery, assessed up to 3 years
measure: 3 year disease free survival rate
timeFrame: From first dose of PD1/PDL1 antibody until disease progression (local or distant), secondary tumor or death (whichever occurs first), assessed up to 3 years
measure: 3 year overall survival rate
timeFrame: From first dose of PD1/PDL1 antibody until death, assessed up to 3 years
measure: 5 year overall survival rate
timeFrame: From first dose of PD1/PDL1 antibody until death, assessed up to 5 years
measure: 3 year local recurrence free survival rate
timeFrame: From first dose of PD1/PDL1 antibody until first local failure or death (whichever occurs first), assessed up to 3 years
measure: 3 year distant metastasis free survival rate
timeFrame: From first dose of PD1/PDL1 antibody until distant metastasis or death (whichever occurs first), assessed up to 3 years
measure: 3 year surgery free survival rate
timeFrame: From first dose of PD1/PDL1 antibody until radical surgery or death (whichever occurs first), assessed up to 3 years
measure: Treatment-related adverse event of combination of Sintilimab, IBI310 and Lenvatinib
timeFrame: From first dose of Sintilimab, IBI310 and Lenvatinib to 30 days after last dose of treatment.
measure: Quality of life of combination of Sintilimab, IBI310 and Lenvatinib for gastric cancer patients
timeFrame: From first dose of PD1/PDL1 antibody until death, assessed up to 8 years
measure: Quality of life of combination of Sintilimab, IBI310 and Lenvatinib for colon cancer patients
timeFrame: From first dose of PD1/PDL1 antibody until death, assessed up to 8 years
measure: Rate of complications
timeFrame: From 7 days before surgery to 12 days after surgey
measure: Rate of mortality
timeFrame: From 7 days before surgery to 12 days after surgey
Other outcomes:
measure: Exploratory outcome-Proportion and location of different immune cell subsets at baseline and during treatment associated with cCR or near cCR
timeFrame: From baseline to withdrawal of consent or death (whichever occurs first), up to 8 years
measure: Exploratory outcome-Tumor gene alterations associated with cCR or near cCR
timeFrame: From baseline to withdrawal of consent or death (whichever occurs first), up to 8 years
measure: Exploratory outcome-Baseline clinical and pathological characteristics associated with cCR or near cCR
timeFrame: From baseline to withdrawal of consent or death (whichever occurs first), up to 8 years
measure: Exploratory outcome-Baseline and longitudinal on-treatment MR image characteristics associated with cCR or near cCR
timeFrame: From baseline to withdrawal of consent or death (whichever occurs first), up to 8 years
Locations:
city: Beijing
country: China
facility: Beijing Cancer Hospital
state: Beijing
Study officials:
affiliation: Peking University Cancer Hospital & Institute
name: Lin Shen
role: PRINCIPAL_INVESTIGATOR
References: