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Efficacy and Safety Evaluation of Sintilimab in Patients With Advanced or Recurrent Non-squamous NSCLC

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03607539
Recruitment Status : Active, not recruiting
First Posted : July 31, 2018
Last Update Posted : January 10, 2020
Sponsor:
Information provided by (Responsible Party):
Innovent Biologics (Suzhou) Co. Ltd.

Brief Summary:
Efficacy and Safety Evaluation of IBI308 in Patients with Advanced or Recurrent Non-squamous NSCLC

Condition or disease Intervention/treatment Phase
Lung Neoplasms Drug: Sintilimab Drug: Pemetrexed Drug: Platinum Drug: Placebos Phase 3

Detailed Description:

Sintilimab is expected to increase the PFS from 6 months to 9.2 months. Anti-PD-1 therapy in Chinese non-squamous NSCLC naïve patients will be investigated in this clinical trial.

Additionally the correlation between PD-L1 expression and the response to Sintilimab treatment in Chinese non-squamous NSCLC as well as the role of iRECIST in immune checkpoint inhibitor treatment evaluation will also be assessed.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 378 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Randomized, Double-blinded, Phase III Study of Pemetrexed Plus Platinum Chemotherapy With or Without Sintilimab (IBI308) in First Line Advanced or Metastatic Non-squamous Non-small Cell Lung Cancer Subjects (Orient-11)
Actual Study Start Date : August 23, 2018
Estimated Primary Completion Date : September 2020
Estimated Study Completion Date : July 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Sintilimab in combination with pemetrexed and platinum
Injection; dosage form: 10ml: 100mg; frequency: 200mgQ3W (qualer 3 weeks); duration: randomization to the date of the first documented tumor progression per RECIST v1.1 criteria Sintilimab 200mg + pemetrexed/ platinum 4 cycles then Sintilimab 200mg + pemetrexed maintains
Drug: Sintilimab
10 mL:100 mg,200mg,Q3W (qualer 3 weeks), day1, I.V.
Other Name: IBI308

Drug: Pemetrexed
500mg/m^2; Q3W (qualer 3 weeks), day1, I.V.

Drug: Platinum
Q3W (qualer 3 weeks), day1, I.V.; first 4 cycles.

Placebo Comparator: Sitilimab Placebo Comparator
placebo 200mg + pemetrexed/ platinum 4 cycles then Sintilimab 200mg + pemetrexed maintains
Drug: Pemetrexed
500mg/m^2; Q3W (qualer 3 weeks), day1, I.V.

Drug: Platinum
Q3W (qualer 3 weeks), day1, I.V.; first 4 cycles.

Drug: Placebos
10 mL:100 mg,200mg,Q3W (qualer 3 weeks), day1, I.V.




Primary Outcome Measures :
  1. PFS (Progression Free Survival) [ Time Frame: up to 24 months after randomization ]
    Time from the first dose of study drug to the first disease progression (imaging)


Secondary Outcome Measures :
  1. OS (overall survival) [ Time Frame: up to 24 months after randomization ]
    Time from the first use of the study drug to the death of the subject

  2. ORR (overall response rate) [ Time Frame: up to 24 months after randomization ]
    The proportion of patients whose tumor volume has reduced to a predetermined value and can maintain the minimum time limit is the sum of complete and partial mitigation

  3. DCR (Disease control rate) [ Time Frame: up to 24 months after randomization ]
  4. TTR (Time to response) [ Time Frame: up to 24 months after randomization ]
  5. DOR (Duration of response) [ Time Frame: up to 24 months after randomization ]
  6. 378 participants with treatment-related adverse events as assessed by CTCAE v4.03 [ Time Frame: up to 24 months after randomization ]

    The investigator will evaluate all adverse events in accordance with the NCI Adverse Event General Terminology (CTCAE) Version 4.03. Any adverse events that change the CTCAE level will be recorded in the adverse event case report form/worksheet.

    All adverse events, regardless of CTCAE level, must be assessed for serious adverse events.

    All adverse events, including serious adverse events, were collected from the signed informed consent form within 90 days of the last dose, either by the investigator or by the spontaneous reported adverse events.



Other Outcome Measures:
  1. Exploratory Outcome Measures: Explore the use of iRECIST to evaluate the efficacy ( iORR ) of subjects in the Sintilimab group [ Time Frame: up to 24 months after randomization ]
    Exploratory research is based on iRECIST(Immune Response Evaluation Criteria In Solid Tumors)clinical benefit evaluation, including evaluate iORR (immune overall response rate). This study will perform a statistical analysis of the drug administration in the trial to calculate drug exposure throughout the trial. Baseline data were analyzed by full analysis set, and all validity indicators were analyzed according to the full analysis set and the compliance set. The analysis group was randomly selected.

  2. Exploratory Outcome Measures: Explore the use of iRECIST to evaluate the efficacy (iDOR) of subjects in the Sintilimab group [ Time Frame: up to 24 months after randomization ]
    Exploratory research is based on iRECIST(Immune Response Evaluation Criteria In Solid Tumors)clinical benefit evaluation, including evaluate iDOR (immune duration of response). This study will perform a statistical analysis of the drug administration in the trial to calculate drug exposure throughout the trial. Baseline data were analyzed by full analysis set, and all validity indicators were analyzed according to the full analysis set and the compliance set. The analysis group was randomly selected.

  3. Exploratory Outcome Measures: Explore the use of iRECIST to evaluate the efficacy (iPFS) of subjects in the Sintilimab group [ Time Frame: up to 24 months after randomization ]
    Exploratory research is based on iRECIST(Immune Response Evaluation Criteria In Solid Tumors)clinical benefit evaluation, including evaluate iPFS (immune progression free survival). This study will perform a statistical analysis of the drug administration in the trial to calculate drug exposure throughout the trial. Baseline data were analyzed by full analysis set, and all validity indicators were analyzed according to the full analysis set and the compliance set. The analysis group was randomly selected.

  4. Exploratory Outcome Measures: Explore the use of iRECIST to evaluate the efficacy (iDCR) of subjects in the Sintilimab group [ Time Frame: up to 24 months after randomization ]
    Exploratory research is based on iRECIST(Immune Response Evaluation Criteria In Solid Tumors)clinical benefit evaluation, including evaluate iDCR (immune disease control rate). This study will perform a statistical analysis of the drug administration in the trial to calculate drug exposure throughout the trial. Baseline data were analyzed by full analysis set, and all validity indicators were analyzed according to the full analysis set and the compliance set. The analysis group was randomly selected.

  5. Exploring the Maximum Plasma Concentration [Cmax] characteristics of the Sintilimab population [ Time Frame: up to 24 months after randomization ]
  6. Exploratory Outcome Measures: Biomarkers (PD-L1 ) [ Time Frame: up to 24 months after randomization ]
    Explore biomarkers that potentially predict the efficacy of the Sintilimab group, including but not limited to immunohistochemical detection of PD-L1 expression in tumor specimens.

  7. Exploratory Outcome Measures: Biomarkers (T cell receptor) [ Time Frame: up to 24 months after randomization ]
    Explore biomarkers that potentially predict the efficacy of the Sintilimab group, including but not limited to T cell receptor (TCR) sequencing analysis in peripheral blood, etc.

  8. Exploratory Outcome Measures: Comparison of quality of life between patients with Sintilimab combined with chemotherapy and placebo by the Cancer Symptoms Scale (LCSS) [ Time Frame: up to 24 months after randomization ]
    The Lung Cancer Symptom Scale (LCSS) consists of nine graphical subscales that measure the quality of life of patients over the past 24 hours. The scale is divided into two parts: the patient fills in and the physician fills in. The patient part consists of 9 items, and the answers for each item are marked on one line segment. The physician part mainly evaluates the number and severity of symptoms of the patient, and uses the grade method to answer. The LCSS's nine subscales include the six major symptoms of lung cancer patients: loss of appetite, fatigue, cough, difficulty breathing, hemoptysis and pain. The remaining three subscales include the patient's self-leveling of lung cancer symptoms and how the disease affects daily activities.

  9. Exploratory Outcome Measures: [ Time Frame: up to 24 months after randomization ]

    Comparing the PFS between below groups:

    1. Experimental group who accept new anticancer treatment after PD (progressive disease).
    2. The chemotherapy group were cross-accepted the Sintilimab

  10. Comparison of quality of life between patients with Sintilimab combined with chemotherapy and placebo by the European Cancer Research and Treatment Group Cancer Survival Scale (EORTC QLQ-C30) [ Time Frame: up to 24 months after randomization ]
    EORTC's QLQ-C30 (Quality of life qustionnaire-C30) is a core scale for all cancer patients. It has 30 entries and can be divided into 15 dimensions, with 5 functional dimensions (body, role, cognition, mood and social function), 3 symptoms. Dimensions (fatigue, pain, nausea and vomiting), 1 overall health/quality of life dimension, and 6 single items.

  11. Exploring the Area Under the Curve of the Sintilimab population [ Time Frame: up to 24 months after randomization ]


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 and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion criteria

  1. Sign written informed consent before any trial-related processes are implemented;
  2. Age ≥ 18 years and <75 years;
  3. Life expectancy exceeds 3 months;
  4. The investigator confirmed at least one measurable lesion according to RECIST 1.1.

    A measurable lesion located in the field of previous radiation therapy or after local treatment may be selected as a target lesion if it is confirmed to have progressed;

  5. According to the International Lung Cancer Research Association and the American Association for the Classification of Cancer Classification, the 8th edition of the TNM (Tumor Node Metastasis) staging of lung cancer, a histologically or cytologically confirmed locally advanced (IIIB/IIIC phase) that cannot be treated surgically and cannot undergo radical concurrent chemoradiotherapy, Patients with metastatic or recurrent (stage IV) non-squamous NSCLC;
  6. Confirmed for patients with EGFR (Epidermal growth factor receptor) or ALK (Anaplastic lymphoma kinase) targeted therapy (documentary evidence of no tumor EGFR-sensitive mutations and no ALK gene rearrangement)
  7. The Eastern Cancer Cooperative Group (ECOG) has a performance score of 0 or 1;
  8. Have not received any systematic anti-tumor treatment for advanced disease; The patient may have received adjuvant chemotherapy as long as the disease relapses at least 6 months after the last dose of chemotherapy is completed;
  9. Adequate hematologic function, defined as absolute neutrophil count ≥1.5×10^9 /L, platelet count ≥100 ×10^9 /L, hemoglobin ≥9g/dL (no blood transfusion or erythropoietin (EPO) within 7 days) Dependency);
  10. Adequate liver function, defined as total bilirubin levels ≤ 1.5 times normal upper limit (ULN) and aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels ≤ 2.5 times ULN in all patients, or for recorded liver Patients with metastasis, AST and ALT levels ≤ 5 times ULN;
  11. Adequate renal function, defined as serum creatinine ≤ 1.5 times ULN or measured or calculated creatinine clearance ≥ 60 ml / min (Cockcroft-Gault formula);
  12. Coagulation function is adequate, defined as international normalized ratio (INR) or prothrombin time (PT) ≤ 1.5 times normal upper limit (ULN); if the subject is receiving anticoagulant therapy, as long as the PT is used in anticoagulant drugs Within the scope;
  13. Female subjects of childbearing age should be negative for urine or serum pregnancy test within 72 hours prior to the first study drug administration (Day 1, Day 1). If the urine pregnancy test results are positive or cannot be confirmed as negative, a blood pregnancy test is required.
  14. If there is a risk of conception, male and female patients are required to use high-efficiency contraception (ie, an annual failure rate of less than 1%) and continue until at least 180 days after stopping the trial treatment; Note: If abstinence is the usual lifestyle of the subject and the preferred method of contraception, abstinence can be accepted as a method of contraception.

Exclusion criteria:

  1. Histological squamous cell-dominated NSCLC; Mixed cell types must distinguish between dominant cell morphology, and if small cell types are present, the subject is not eligible for inclusion;
  2. Currently participating in interventional clinical research or treatment, or receiving other research drugs or using research equipment within 4 weeks before the first dose;
  3. Previously received the following therapies: anti-PD-1, anti-PD-L1 or anti-PD-L2 drugs or against another stimulatory or synergistic inhibition of T cell receptors [eg CTLA-4 (Cytotoxic T lymphocyte antigen-4), OX-40 (also called CD134, cluster of differentiation134), CD137] agent;
  4. Received a traditional Chinese medicine with anti-tumor effect, or an immunomodulatory drug (thymosin, interferon, interleukin) within 2 weeks before the first dose, or received major surgery within 3 weeks before the first dose;
  5. Pulmonary radiation therapy of >30 Gy within 6 months prior to the first dose;
  6. Completed palliative radiotherapy within 7 days prior to the first dose;
  7. Clinical active diverticulitis, abdominal abscess, gastrointestinal obstruction and peritoneal metastasis;
  8. Have received a physical organ or blood system transplant;
  9. There is clinically uncontrollable pleural effusion/peritoneal effusion;
  10. known to have severe allergic reactions (≥3 grade) to the active ingredients of Sintilimab, pemetrexed, cisplatin, carboplatin and or any excipients;
  11. Active autoimmune diseases requiring systemic treatment (eg, using a disease-modifying drug, corticosteroid or immunosuppressant) within 2 years prior to the first dose. Alternative therapies (such as thyroxine, insulin, or physiological corticosteroids for adrenal or pituitary insufficiency) are not considered systemic treatments;
  12. Diagnosis of immunodeficiency or study of systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study.

    Physiological doses of corticosteroids (≤10 mg/day of prednisone or equivalent) are permitted;

  13. Has not fully recovered from the toxicity and/or complications caused by any intervention before starting treatment (ie, ≤1 or reaching baseline, excluding fatigue or alopecia);
  14. Other malignant tumors were diagnosed within 5 years prior to the first dose, with the exception of radical cutaneous basal cell carcinoma, cutaneous squamous cell carcinoma, and/or radically resected carcinoma in situ;
  15. Active central nervous system (CNS) metastasis and / or cancerous meningitis. Patients with treated brain metastases who have remained clinically stable for at least 2 weeks and have no new or advanced brain metastases may be enrolled and discontinued hormone therapy 3 days prior to the first study drug. Patients with known untreated, asymptomatic brain metastases can be enrolled, but regular imaging assessments of the brain must be performed.
  16. There is a history of (non-infectious) pneumonia requiring steroid therapy or the presence of interstitial lung disease 1 year before the first dose;
  17. There are active infections that require systemic treatment;
  18. Subjects who are unable or unwilling to receive folic acid or vitamin B12 supplementation;
  19. There are known cases of mental illness or substance abuse that may have an impact on compliance with the test requirements;
  20. A history of human immunodeficiency virus (HIV) infection (ie, HIV 1/2 antibody positive) is known.
  21. Untreated active hepatitis B;

    Note: Controlled (treated) hepatitis B subjects also meet the inclusion criteria if the following criteria are met:

    At least 4 weeks of HBV (Hepatitis B virus) antiviral therapy must have been received prior to the first dose of study drug, and the HBV viral load is <1000 copies/ml (200 IU/ml). Subjects who are receiving HBV therapy and have a viral load of <1000 copies/ml (200 IU/ml) should receive antiviral therapy throughout the study treatment period.

    For subjects with anti-HBc (hepatitis B core antigen)(+), HBsAg(-), anti-HBs(-), and HBV viral load (-), prophylactic anti-HBV therapy is not required, but viral reactivation is closely monitored;

  22. Active HCV (Hepatitis C virus)-infected subjects (HCV antibody positive and HCV-RNA levels above the lower limit of detection);
  23. Vaccination of live vaccine within 30 days before the first dose (1st cycle, 1st day); Note: Inactivated virus vaccines for seasonal influenza, injectable drugs are permitted; however, live attenuated influenza vaccines (such as FluMist®) are not allowed for intranasal administration;
  24. There may be a history of illness or disease evidence, treatment or laboratory abnormalities that may interfere with the subject's full participation in the study, or the investigator believes that participating in the study is not in the best interests of the subject, including dialysis.

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): NCT03607539


Locations
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China
Sun Yat-Sen University Cancer Center
Guangzhou, China
Sponsors and Collaborators
Innovent Biologics (Suzhou) Co. Ltd.
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Innovent Biologics (Suzhou) Co. Ltd.
ClinicalTrials.gov Identifier: NCT03607539    
Other Study ID Numbers: CIBI308C302
First Posted: July 31, 2018    Key Record Dates
Last Update Posted: January 10, 2020
Last Verified: January 2020

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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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Lung Neoplasms
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Neoplasms
Lung Diseases
Respiratory Tract Diseases
Pemetrexed
Antineoplastic Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Folic Acid Antagonists
Nucleic Acid Synthesis Inhibitors