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Neoadjuvant Immunotherapy for Resectable Gastric Cancer

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ClinicalTrials.gov Identifier: NCT03878472
Recruitment Status : Recruiting
First Posted : March 18, 2019
Last Update Posted : April 10, 2020
Sponsor:
Information provided by (Responsible Party):
Qilu Hospital of Shandong University

Brief Summary:

1. Target population: patients with resectable locally advanced proximal (including gastroesophageal junction, fundus and upper body) gastric cancer. (cT3-4aN+M0) 2. Primary objective:

  1. To evaluate the pathological remission rate (PRR) of PD-1 antibody monotherapy or in combination with anti-angiogenesis VEGFR2-TKI apatinib ± S1 ± Oxaliplatin in neoadjuvant (preoperative) treatment of resectable locally advanced proximal gastric cancer.
  2. To evaluate the relationship between tumor pathological remission and biomarkers related to immunotherapy.

3. Secondary objectives:

  1. To evaluate the imaging objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) of PD-1 antibody alone or in combination with apatinib ± S1 ± Oxaliplatin in neoadjuvant therapy for locally advanced gastric cancer.
  2. To evaluate the safety of PD-1 antibody or in combination with apatinib ± S1 ± Oxaliplatin in neoadjuvant (preoperative) treatment of resectable locally advanced proximal gastric cancer.

Trial design: This is a monocenter, open, single arm, phase II study to evaluate the efficacy and safety of PD-1 antibody or in combination with apatinib ± S1 ± Oxaliplatin in neoadjuvant treatment of resectable locally advanced proximal gastric cancer.


Condition or disease Intervention/treatment Phase
Gastric Cancer Drug: SHR1210 Drug: apatinib Drug: S1 Drug: Oxaliplatin Phase 2

Detailed Description:

Several important clinical trials including MAGIC, FLOT4, POET, RTOG 9904 and TOPGEAR have identified the efficacy and safety of neoadjuvant treatment in treating locally advanced GEJ cancer or gastric cancer.

patients with resectable locally advanced proximal gastric cancer will receive neoadjuvant treatment of PD-1 antibody or in combination with apatinib ± S1 ± Oxaliplatin.

The investigators will shut down the study in advance, if situations below happens: 1) 1 treatment related death, >3 disease progression or >2 hyper-progressive disease happen during the first stage; 2) 2 treatment related death, >6 disease progression or >4 hyper-progressive disease happen during the whole study.

Patients with abnormal autoimmune status, unfavorable body function, factors impeding drug taking, absorption and metabolism will be excluded. Study participants with disease progression or severe/ intolerant toxicity during treatment will withdraw the study.

Hyper-progressive disease is defined as 1) progression 2) more than doubled growth rate 3) tumor volume increase >50% in 2 months after initialing the treatment.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase II Clinical Study of Neoadjuvant Therapy for Resectable Locally Advanced Gastric Cancer With PD-1 Antibody or in Combination With Apatinib ± S1±Oxaliplatin
Actual Study Start Date : April 1, 2019
Estimated Primary Completion Date : December 31, 2020
Estimated Study Completion Date : December 31, 2024

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Stomach Cancer
Drug Information available for: Oxaliplatin

Arm Intervention/treatment
Experimental: Neoadjuvant immunotherapy with PD-1 Drug: SHR1210
In 28 ± 3 and 14 ± 3 days before surgery, every patients will received SHR-1210 (200mg iv q2w).

Experimental: Neoadjuvant immunotherapy with PD-1+apatinib Drug: SHR1210
In 28 ± 3 and 14 ± 3 days before surgery, every patients will received SHR-1210 (200mg iv q2w).

Drug: apatinib
In 28 ± 3 and 14 ± 3 days before surgery, every patients will received apatinib (250mg orally every day until 10 ± 2 days before surgery).

Experimental: Neoadjuvant immunotherapy with PD-1+apatinib+S1 Drug: SHR1210
In 28 ± 3 and 14 ± 3 days before surgery, every patients will received SHR-1210 (200mg iv q2w).

Drug: apatinib
In 28 ± 3 and 14 ± 3 days before surgery, every patients will received apatinib (250mg orally every day until 10 ± 2 days before surgery).

Drug: S1
In 28 ± 3 and 14 ± 3 days before surgery, every patients will received S1 (30mg/m2, bid, po, d1-d9).

Experimental: Neoadjuvant immunotherapy with PD-1+apatinib+S1+Oxaliplatin Drug: SHR1210
In 28 ± 3 and 14 ± 3 days before surgery, every patients will received SHR-1210 (200mg iv q2w).

Drug: apatinib
In 28 ± 3 and 14 ± 3 days before surgery, every patients will received apatinib (250mg orally every day until 10 ± 2 days before surgery).

Drug: S1
In 28 ± 3 and 14 ± 3 days before surgery, every patients will received S1 (30mg/m2, bid, po, d1-d9).

Drug: Oxaliplatin
In 28 ± 3 and 14 ± 3 days before surgery, every patients will received Oxaliplatin (130mg/m2, ivdrip, d1).




Primary Outcome Measures :
  1. pathological remission rate (PRR) rate of PD-1 antibody monotherapy or in combination with anti-angiogenesis VEGFR2-TKI apatinib ± S1 ± Oxaliplatin in neoadjuvant (preoperative) treatment of resectable locally advanced proximal gastric cancer. [ Time Frame: 5 months after the last subject participating in ]
    rate of patients with < 2/3 residual tumor lesion (Grade 1b, 2, 3) in surgical specimen compared to baseline


Secondary Outcome Measures :
  1. objective response rate (ORR) of PD-1 antibody monotherapy or in combination with anti-angiogenesis VEGFR2-TKI apatinib ± S1 ± Oxaliplatin in neoadjuvant (preoperative) treatment of resectable locally advanced proximal gastric cancer. [ Time Frame: Time Frame: 36 months after the last subject participating in ]
    rate of patients with complete remission (CR) or partial remission (PR) based on RESIST1.1. ORR was evaluated by chest, abdominal & pelvic CT/MRI. Evaluation will be conducted on 9w&15w during preoperative treatment, every 6 weeks during adjuvant SOX, and every 0.5 year after all treatments.

  2. progression free survival (PFS)of PD-1 antibody monotherapy or in combination with anti-angiogenesis VEGFR2-TKI apatinib ± S1 ± Oxaliplatin in neoadjuvant (preoperative) treatment of resectable locally advanced proximal gastric cancer. [ Time Frame: Time Frame: 36 months after the last subject participating in ]
    PFS is defined as time interval from recruitment to tumor progression or censoring. Tumor progression is defined as below: 1) relapse of primary lesion 2) emerging of new lesion 3) distant metastasis 4) death of any reason 5)tumor progression according to RESIST 1.1 on CT/MRI.

  3. overall survival (OS) of PD-1 antibody monotherapy or in combination with anti-angiogenesis VEGFR2-TKI apatinib ± S1 ± Oxaliplatin in neoadjuvant (preoperative) treatment of resectable locally advanced proximal gastric cancer. [ Time Frame: Time Frame: 36 months after the last subject participating in ]
    OS is defined as time interval from recruitment to all-caused death or censoring.

  4. Safety as measured by the rate of AEs, deaths and laboratory abnormalities (e.g. Grade 3 or higher per CTCAE v4 ) [ Time Frame: Time Frame: 1 month after the last date of treatment ]

    Adverse events (AE) of chemo- and radio-therapy will be graded and documented according to NCI-CTC AE v4.03 from the beginning of treatment to 1 months after the last date of treatment. Documentary will include severity, lasting period and occurrence time. Main AEs include vomiting, diarrhea, anemia, leukopenia, thrombocytopenia, hand-foot syndrome, epidermal capillary hyperplasia, immune related adverse events (including pneumonia, interstitial lung disease, AST/ALT elevations, rash, diarrhea, hypothyroidism and hyperthyroidism) and hyper-progressive tumor.

    AEs of surgery refer to complications which happen during or in 30 days after operation. Severe complications after operation such as abdominal or GI tract bleeding, anastomotic fistula, pancreatic fistula of grade B or above, incision complications (infection, bleeding, rupture) will be observed and classified by Clavien-Dindo grading.


  5. R0 resection rate [ Time Frame: 5 months after the last subject participating in ]
    To evaluate the R0 resection rate of PD-1 antibody monotherapy or in combination with anti-angiogenesis VEGFR2-TKI apatinib ± S1 ± Oxaliplatin in neoadjuvant (preoperative) treatment of resectable locally advanced proximal gastric cancer.

  6. Tumor pathological remission and immunotherapy related biomarkers [ Time Frame: Time Frame: 36 months after the last subject participating in ]
    To evaluate the relationship between tumor pathological remission and immunotherapy related biomarkers, including tumor genome, tumor microenvironment and host immune system response biomarker



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Aged 18-70 years old, both genders, histologically documented gastric cancer.
  2. Newly diagnosed locally advanced, potentially resectable disease without any prior antitumor treatment
  3. clinically diagnosed stage T3-4aN+M0 according to ultrasound endoscopy or enhanced CT/MRI scan.
  4. Eligible and reasonably suitable for potentially curative resection
  5. Written (signed) informed consent.
  6. Pathological tissue available
  7. ECOG: 0-1.
  8. Adequate organ function.
  9. Willingness to provide blood and tissue samples for research purposes.
  10. Good compliance with the study procedures, including lab and auxiliary examination and treatment.
  11. Female patients should not be pregnant or breast feeding.
  12. Agree to take contraception measures during treatment and in 120 days after last dose of SHR-1210.
  13. Life expectancy of at least 6 months.

Exclusion Criteria:

  1. patients with distant metastasis or unresectable primary lesion.
  2. History of chemotherapy, radiation, immunotherapy, or radical resection of gastric cancer.
  3. patients with active autoimmune disease or history of refractory autoimmune disease.
  4. patients with active malignant tumor in recent 2 years, except the tumor studied in this research or cured locally tumor like resected basal cell or squamous cell skin cancer, superficial bladder cancer, cervical carcinoma in situ.
  5. uncontrollable pleural effusion, pericardial effusion, or ascites in 2 weeks before recruitment.
  6. patients who have digestive tract bleeding in 2 weeks before recruitment or with high risk of bleeding.
  7. perforation / fistula of GI tract in 6 months before recruitment.
  8. pulmonary disease history: interstitial pulmonary disease, non-infective pneumonitis, pulmonary fibrosis, acute pulmonary disease.
  9. uncontrollable systemic diseases, including diabetes, hypertension etc.
  10. severe chronic or active infections in need of systemic antibacterial, antifungal, or antiviral treatment, including TB or HIV, etc.
  11. patients with untreated chronic hepatitis B or HBV DNA over 500 IU/ml or positive HCV RNA.
  12. patients with any cardiovascular risk factors below: (1)cardiac chest pain occurring in 28 days before recruitment, defined as moderate pain that limits daily activity.

(2)pulmonary embolism with symptoms occurring in 28 days before recruitment. (3)acute myocardial infarction occurring in 6 months before recruitment. (4)any history of heart failure reaching grade 3/4 of NYHA in 6 months before recruitment.

(5)ventricular arrhythmias of Grade 2 or grater in 6 months before recruitment, or accompanied by supraventricular tachyarrhythmias requiring medical treatment.

(6)cerebrovascular accident within 6 months before recruitment. 14. patients with peripheral neuropathy NCI CTC AE grade 1, except those with only deep tendon reflex disappearing.

15. moderate or severe renal injury [creatinine clearance rate≤50 ml/min (according to Cockcroft & Gault equation)], or Scr>ULN.

16. dipyrimidine dehydrogenase (DPD) deficiency. 17. allergic to any drug in this study. 18. history of allogeneic stem cell transplantation or organ transplantation. 19. use of steroids (dosage>10mg/d prednisone) or other systemic immune suppressive therapy in 14 days before recruitment, except patients treated with regimens below: a. steroids for hormone replacement (dosage>10mg/d prednisone); b. steroids for local application with little systemic absorption; c. short -term (≤ 7 days) steroids for preventing allergy or vomiting.

20. vaccinated with live vaccine in 4 weeks before recruitment. 21. for patients with uncontrolled epilepsy, CNS diseases or history of mental disorder, researchers should evaluate whether their diseases will impede their signing of informed consent or compliance of treatment.

22. existing of potential situation which will impede drug administration or affect toxicity analysis or alcohol/ drug abuse.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03878472


Contacts
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Contact: Lian Liu, Doctor +8613705319315 tounao@126.com

Locations
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China, Shandong
Qilu hospital of Shandong univertisy Recruiting
Jinan, Shandong, China, 250012
Contact: Lian Liu, doctor         
Sponsors and Collaborators
Qilu Hospital of Shandong University
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Responsible Party: Qilu Hospital of Shandong University
ClinicalTrials.gov Identifier: NCT03878472    
Other Study ID Numbers: NIPASS2019
First Posted: March 18, 2019    Key Record Dates
Last Update Posted: April 10, 2020
Last Verified: March 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Stomach Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Stomach Diseases
Oxaliplatin
Apatinib
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action