Clinical trial NCT03924050: Toripalimab Plus Pemetrexed+Platinus in Advanced Non-small-cell Lungcancer Patients Previsouly Treated EGFR-TKI
Official title: A Randomized, Double-Blind, Placebo-Controlled, Multicenter, Phase III Study of Pemetrexed + Platinum Chemotherapy With or Without Toripalimab (JS001) in Advanced Non-small Cell Lung Cancer (NSCLC) Participants With TKI-resistant EGFR-mutated Tumors
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Non-small Cell Lung Cancer
Lead sponsor: Shanghai Junshi Bioscience Co., Ltd.
Sponsor class: OTHER
First posted: 2019-04-23
Enrollment: 440
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is a Randomized, Double-Blind, Placebo-Controlled, Multicenter, Phase III Study to evaluate the efficacy and safety of Toripalimab injection (JS001) or placebo combined with chemotherapy in Advanced Non-small Cell Lung Cancer (NSCLC) Participants with TKI-resistant EGFR-mutated Tumors; and evaluate the population with the best predictive biomarkers, i.e., positive diagnosis population.

About 440 subjects with advanced non-small cell lung cancer with activated EGFR mutation will be 1:1 randomized into two groups, JS001 combined with the standard 1st-line chemotherapy will be given in the study group whereas placebo combined with standard 1st-line chemotherapy will be given in the control group. The stratification will be based on the following factors:

The history of the previous lines of EGFR-TKI treament ( 1st or 2nd generation of TKI vs. 3rd generation of TKI vs. 1st or 2nd generation of TKI + 3rd generation of TKI) ; Disease stage (IIIB-C vs. IV);


Eligibility criteria: Inclusion Criteria:

Only the patients meeting all the following criteria can be eligible to participate in the trial:

* Fully informed consent and signed ICF;
* Age of 18-75 years;
* Histologically and/or cytologically confirmed advanced or recurrent stage III B-C or IV (AJCC Version 8) NSCLC with TKI-resistant EGFR-mutated tumors, which also satisfy following conditions: Without T790M mutation in exon 20 after 1st or 2nd generation EGFR-TKI (eg, gefitinib, erlotinib, icotinib, afatinib,etc.) treatment failure;If with T790M mutation in exon 20 after 1st or 2nd generation EGFR-TKI (eg, gefitinib, erlotinib, icotinib, afatinib,etc.),participants are required to have osimertinib or other 3rd generation EGFR-TKI treatment failure prior to enrollment.Participants with osimertinib treatment failure as 1st line therapy (regardless of their EGFR T790M mutation status);Previous neoadjuvant/adjuvant chemotherapy is allowed, but the time interval between the last dose of chemotherapy and recurrence/metastasis must be at least 6 months.
* With at least one measurable disease per RECIST 1.1;
* Agree to provide formalin fixed tumor specimen after EGFR-TKI treatment failure or provide fresh biopsy tissue;
* ECOG performance status of 0-1;
* Life expectancy ≥ 3 months;
* Good organ function;
* Any adverse event resulting from prior treatment, surgery, or radiotherapy must return to grade 0 or 1 according to NCI-CTCAE v5.0, except for alopecia of any grade;
* Willing and able to follow protocol visits, treatment plans, laboratory tests and other study procedures;
* Women of childbearing potential must have negative serum pregnancy test within 3 days prior to the first dose of investigational product:

Exclusion Criteria:

* Exclusion of tumor histology or cytology confirmed the presence of small cell lung cancer components, or squamous cell carcinoma components of more than 10%;
* Combined with other driver mutations with known therapeutic drug, including but not limited to: ALK rearrangement, ROS1 mutation, BRAF600E mutation;
* Previous systematic chemotherapy for advanced NSCLC;
* Subjects with no measurable lesions;
* Subjects with cancer meningitis and spinal cord compression;
* Subjects with untreated central nervous system (CNS) tumor metastasis;
* Subjects were previously treated with an anti-PD-1, anti-PD-L1 or anti-CTLA-4 agent;
* Subjects with any active, known or suspected autoimmune disease;
* Subjects who are now participating in other clinical studies or the last dose of prior investigational drug was given in \< 4 weeks (or 5 half-lives) from the first investigational product administration of this study;
* Subjects who were expected to receive any other antitumor therapy (eg, other maintenance therapy for NSCLC, radiotherapy, and/or surgical excision);
* Subjects who received major surgery within 4 weeks prior to enrollment or were not fully recovered from prior surgery;
* Subjects with other malignancies requiring concurrent treatment;
* Subjects with grade II or above myocardial ischemia or myocardial infarction, or subjects with arrhythmia with poor control;
* Subjects with uncontrolled pleural/pericardial effusion, or with ascites requiring repeated drainage;
* Subjects with uncontrolled tumor-related pain;
* Subjects with severe allergic reactions to other monoclonal antibodies and subjects with severe allergic reactions to pemetrexed, platinum or its prophylaxis;
* Subjects with psychological disorder, alcohol alcoholism, drug abuse or drug dependency

Primary outcomes:
measure: OS
timeFrame: Approximately 5 years
Secondary outcomes:
measure: PFS (Progression Free Survival) by investigator
timeFrame: Approximately 4 years
measure: ORR (Objective Response Rate)
timeFrame: Approximately 4 years
measure: DOR (Duration of Response)
timeFrame: Approximately 4 years
measure: DCR (Disease of Response)
timeFrame: Approximately 4 years
measure: TTR (Time to Response)
timeFrame: Approximately 4 years
measure: Incidence of AEs/SAEs
timeFrame: Approximately 5 years
Other outcomes:
measure: pd-l1 mutation rate
timeFrame: Approximately 4 years
measure: immune cell classification
timeFrame: Approximately 5 years
Locations:
city: Shanghai
country: China
facility: Shanghai Pulmonary Hospital
state: Shanghai
city: Shenzhen
country: China
facility: Peking University Shenzhen Hospital
Study officials:
References:
citation: Jiang T, Wang P, Zhang J, Zhao Y, Zhou J, Fan Y, Shu Y, Liu X, Zhang H, He J, Gao G, Mu X, Bao Z, Xu Y, Guo R, Wang H, Deng L, Ma N, Zhang Y, Feng H, Yao S, Wu J, Chen L, Zhou C, Ren S. Toripalimab plus chemotherapy as second-line treatment in previously EGFR-TKI treated patients with EGFR-mutant-advanced NSCLC: a multicenter phase-II trial. Signal Transduct Target Ther. 2021 Oct 15;6(1):355. doi: 10.1038/s41392-021-00751-9.