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Pembrolizumab and Chemotherapy Neoadjuvant/Adjuvant of NSCLC

Primary Purpose

Stage IIIB(N2) Non-small Cell Lung Cancer, Stage IIA Non-small Cell Lung Cancer, Stage IIB Non-small Cell Lung Cancer

Status
Not yet recruiting
Phase
Phase 2
Locations
China
Study Type
Interventional
Intervention
Pembrolizumab 200 mg IV infusion
Sponsored by
Peking University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Stage IIIB(N2) Non-small Cell Lung Cancer focused on measuring Early stage NSCLC, neoadjuvant, adjuvant, pembrolizumab

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria: Male/female participants who are at least 18 years of age on the day of signing informed consent with histologically confirmed diagnosis of [Stage II, IIIA or IIIB(N2) NSCLC (AJCC Version 8)] will be enrolled in this study. Note: mixed cellularity tumors are allowed. tumor should be considered resectable in terms of surgeon's determinations before study entry by investigators. Lymph nodes disease are recommended to have pathological confirmation. A PET-CT may be utilized as a surrogate for pathologic staging by site's feasibility. Male participants: A male participant must agree to use a contraception as detailed in Appendix 3 of this protocol during the treatment period and for at least 1 year after the last dose of study treatment and refrain from donating sperm during this period. Female participants: A female participant is eligible to participate if she is not pregnant (see Appendix 3), not breastfeeding, and at least one of the following conditions applies: Not a woman of childbearing potential (WOCBP) as defined in Appendix 3 OR A WOCBP who agrees to follow the contraceptive guidance in Appendix 3 during the treatment period and for at least [180 days after the last dose of carboplatin and for at least 120 days after the last dose of pembrolizumab, whichever occurs latest]. The participant (or legally acceptable representative if applicable) provides written informed consent for the trial and may also provide consent for future biomedical research. Have measurable disease based on RECIST 1.1. Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions. Participants suspected with secondary lung cancer (eg. ground glass nodules) were also eligible for this study (For solid nodules, biopsy, if available, should be performed in case of any intrapulmonary metastasis). Archival tumor tissue sample or newly obtained [core, incisional or excisional] biopsy of a tumor lesion not previously irradiated has been provided. Formalin-fixed, paraffin embedded (FFPE) tissue blocks are preferred to slides. Newly obtained biopsies are preferred to archived tissue. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. Evaluation of ECOG is to be performed within 7 days prior to the first dose of study intervention. Have adequate organ function as defined in the following table. Specimens must be collected within 10 days prior to the start of study intervention. Exclusion Criteria: Have confirmed sensitizing EGFR mutation or ALK alterations. Note: EGFR and ALK testing will be performed in local hospital, and do not need to be sent to the central laboratory. A WOCBP who has a positive urine pregnancy test within 72 hours prior to treatment (see Appendix 3). If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. Note: in the event that 72 hours have elapsed between the screening pregnancy test and the first dose of study treatment, another pregnancy test (urine or serum) must be performed and must be negative in order for subject to start receiving study medication. Has one of the following tumor locations/types: NSCLC involving the superior sulcus Large cell neuro-endocrine cancer Sarcomatoid tumor Has had an allogenic tissue/solid organ transplant. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX 40, CD137). Has received prior systemic anti-cancer therapy including investigational agents for the current malignancy prior to [allocation]. Has received prior radiotherapy within 2 weeks of start of study intervention or radiation-related toxicities requiring corticosteroids. Has received a live vaccine or live-attenuated vaccine within 30 days before the first dose of study intervention. Administration of killed vaccines is allowed. Note: please refer to Section 5.5.2 for information on COVID-19 vaccines Has received an investigational agent or has used an investigational device within 4 weeks prior to study intervention administration. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug. Known additional malignancy that is progressing or has required active treatment within the past 5 years. Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin or carcinoma in situ, excluding carcinoma in situ of the bladder, that have undergone potentially curative therapy are not excluded. Has a known severe hypersensitivity (≥Grade 3) to any of the study chemotherapy agents and/or to any of their excipients. Has active autoimmune disease that has required systemic treatment in the past 2 years except replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid) Has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease. Has an active infection requiring systemic therapy. Has a known history of Human Immunodeficiency Virus (HIV) infection. Note: No HIV testing is required unless mandated by local health authority. Concurrent active Hepatitis B (defined as HBsAg positive and/or detectable HBV DNA) and Hepatitis C virus (defined as anti-HCV Ab positive and detectable HCV RNA) infection. Note: Hepatitis B and C screening tests are not required unless: Known history of HBV and HCV infection As mandated by local health authority Has a history or current evidence of any condition, therapy, or laboratory abnormality or other circumstance that might confound the results of the study, interfere with the participant's participation for the full duration of the study, such that it is not in the best interest of the participant to participate, in the opinion of the treating investigator. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial. Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of trial treatment. Participants who have had major surgery within 14 days of first treatment.

Sites / Locations

  • Peking University

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Pembrolizumab + Chemotherapy

Arm Description

Non-squamous NSCLC: pembrolizumab 200mg as at least 30-minute IV infusion on Day 1, followed by pemetrexed at a dose of 500mg/m2 IV over 30 minutes or per institutional standard with Carboplatin at a dose of AUC 5 over 120 minutes or per institutional standard, of a 3-week treatment cycle, for up to 4 cycles. Squamous NSCLC: pembrolizumab 200mg as at least 30-minute IV infusion on Day 1, followed by nab-paclitaxel at a dose of 135mg/m2 IV over 30 minutes or per institutional standard with Carboplatin at a dose of AUC 5 over 120 minutes or per institutional standard, of a 3-week treatment cycle, for up to 4 cycles. Nab-paclitaxel will also be administered at the dose of 135mg/m2 for over 30 minutes IV infusion or per institutional standard on day 8 of each 3-week treatment cycle.

Outcomes

Primary Outcome Measures

pCR rate
pCR in eligible stage IIA-IIIB (N2) NSCLC participants (AJCC Version 8, no known sensitizing EGFR or ALK alterations) following neoadjuvant pembrolizumab plus chemotherapy
Post-treatment proportion of CXCL13+PD1+ CD8 T cells in all CD8 T cells
Post-treatment proportion of CXCL13+PD1+ CD8 T cells in all CD8 T cells in single cell RNA-seq data

Secondary Outcome Measures

MPR in eligible stage IIA-IIIB (N2) NSCLC participants (AJCC Version 8, no known sensitizing EGFR or ALK alterations) following neoadjuvant pembrolizumab plus chemotherapy
MPR rate evaluated by investigator based on protocol defined criteria (the proportion of participants having ≤10% viable tumor cells in the resected primary tumor and all resected lymph nodes).
Event-free survival (EFS)
EFS is defined as the time from study intervention to the first of the following events: Radiographic disease progression per RECIST 1.1 (for participants who have not had or will not have surgery, participants who have gross residual disease after an incomplete resection [R2 resection]); Local progression (primary tumor or regional lymph nodes) precluding planned surgery; Inability to resect the tumor; Local or distant recurrence (for participants who are disease free after surgery or participants with microscopic positive margins [R1 resection]); Death due to any cause.
Number of Participants with One or More Adverse Events
Participant experiencing AEs, participant discontinuing study intervention due to AEs, and participant experiencing perioperative complications.
PD-L1 expression and status of pre-treatment tumor sample
PD-L1 expression and status of pre-treatment tumor biopsy

Full Information

First Posted
May 30, 2023
Last Updated
May 30, 2023
Sponsor
Peking University
Collaborators
Merck Sharp & Dohme LLC, Shanghai Pulmonary Hospital, Shanghai, China, Guangdong Provincial People's Hospital, Cancer Institute and Hospital, Chinese Academy of Medical Sciences
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1. Study Identification

Unique Protocol Identification Number
NCT05894889
Brief Title
Pembrolizumab and Chemotherapy Neoadjuvant/Adjuvant of NSCLC
Official Title
Single Cell Analysis of CXCL13+PD1+ CD8 T Cell in Association With Resistance to Pembrolizumab and Chemotherapy Neoadjuvant/Adjuvant of NSCLC
Study Type
Interventional

2. Study Status

Record Verification Date
May 2023
Overall Recruitment Status
Not yet recruiting
Study Start Date
October 1, 2023 (Anticipated)
Primary Completion Date
April 1, 2026 (Anticipated)
Study Completion Date
August 1, 2027 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Peking University
Collaborators
Merck Sharp & Dohme LLC, Shanghai Pulmonary Hospital, Shanghai, China, Guangdong Provincial People's Hospital, Cancer Institute and Hospital, Chinese Academy of Medical Sciences

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This study is to evaluate the efficacy and safety of neoadjuvant pembrolizumab plus chemotherapy following by pembrolizumab adjuvant in stage IIA-IIIB (N2) NSCLC participants without sensitizing EGFR/ALK mutation. The study will also investigate the role of CXCL13+PD1+ CD8 T cells in association with pathological response / resistance to neoadjuvant immunotherapy by comparing the proportion of CXCL13+PD1+ CD8 T cells in all CD8 T cells in post-treatment (surgical sample) between MPR group and non-MPR group.
Detailed Description
Lung cancer is still the world's leading cancer in terms of mortality. Although the early screening of lung cancer has made great achievements, for example, many lung cancer patients were already in the middle and late stage of lung cancer when they were diagnosed. The majority of patients with resected Stage II and IIIA NSCLC are destined to suffer tumor recurrence despite the administration of standard adjuvant or neoadjuvant therapy. In recent years, neoadjuvant immunotherapy based on PD-1 receptor has provided new opportunities for surgery of locally advanced NSCLC, including the positive results from KEYNOTE-671 and KEYNOTE-091 study. However the mechanism of immunotherapy response and resistance are still less understood. CXCL13+ PD1+ CD8 T cells demonstrate an exhausted phenotype and have been proposed as a surrogate of tumor antigen-specific T cell, a key subset of tumor-infiltrating immune cells that have successfully recognized and killed tumor cells but kept from continued functioning by immune checkpoints including PD-L1. Research on T cell exhaustion in chronic viral infection has also suggested that T cell exhaustion is a result of chronic antigen stimulation, corroborating with the notion that exhausted T cells inside the tumor microenvironment represents successful tumor immune recognition Therefore, in this study, we hypothesize that patients with resectable stage IIA-ⅢB(N2) non-small cell lung cancer (NSCLC) without sensitizing EGFR/ALK mutation could benefit from pembrolizumab combined with chemotherapy. Based on the single cell analysis of the pre-treatment and post-treatment samples, we hypothesize that lack of CXCL13+PD1+ T cells is one of the major resistance mechanisms of PD1/PD-L1 blockade.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Stage IIIB(N2) Non-small Cell Lung Cancer, Stage IIA Non-small Cell Lung Cancer, Stage IIB Non-small Cell Lung Cancer, Stage IIIA Non-small Cell Lung Cancer
Keywords
Early stage NSCLC, neoadjuvant, adjuvant, pembrolizumab

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Model Description
Single Group Assignment
Masking
None (Open Label)
Masking Description
None(Open Label)
Allocation
N/A
Enrollment
70 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Pembrolizumab + Chemotherapy
Arm Type
Experimental
Arm Description
Non-squamous NSCLC: pembrolizumab 200mg as at least 30-minute IV infusion on Day 1, followed by pemetrexed at a dose of 500mg/m2 IV over 30 minutes or per institutional standard with Carboplatin at a dose of AUC 5 over 120 minutes or per institutional standard, of a 3-week treatment cycle, for up to 4 cycles. Squamous NSCLC: pembrolizumab 200mg as at least 30-minute IV infusion on Day 1, followed by nab-paclitaxel at a dose of 135mg/m2 IV over 30 minutes or per institutional standard with Carboplatin at a dose of AUC 5 over 120 minutes or per institutional standard, of a 3-week treatment cycle, for up to 4 cycles. Nab-paclitaxel will also be administered at the dose of 135mg/m2 for over 30 minutes IV infusion or per institutional standard on day 8 of each 3-week treatment cycle.
Intervention Type
Biological
Intervention Name(s)
Pembrolizumab 200 mg IV infusion
Other Intervention Name(s)
Drug: nab-paclitaxel IV infusion, Drug: Carboplatin IV infusion, Drug: Pemetrexed IV infusion
Intervention Description
Biological: Pembrolizumab 200 mg IV infusion Drug: nab-paclitaxel IV infusion Drug: Carboplatin IV infusion Drug: Pemetrexed IV infusion
Primary Outcome Measure Information:
Title
pCR rate
Description
pCR in eligible stage IIA-IIIB (N2) NSCLC participants (AJCC Version 8, no known sensitizing EGFR or ALK alterations) following neoadjuvant pembrolizumab plus chemotherapy
Time Frame
Up to approximately 16 months
Title
Post-treatment proportion of CXCL13+PD1+ CD8 T cells in all CD8 T cells
Description
Post-treatment proportion of CXCL13+PD1+ CD8 T cells in all CD8 T cells in single cell RNA-seq data
Time Frame
Up to approximately 16 months
Secondary Outcome Measure Information:
Title
MPR in eligible stage IIA-IIIB (N2) NSCLC participants (AJCC Version 8, no known sensitizing EGFR or ALK alterations) following neoadjuvant pembrolizumab plus chemotherapy
Description
MPR rate evaluated by investigator based on protocol defined criteria (the proportion of participants having ≤10% viable tumor cells in the resected primary tumor and all resected lymph nodes).
Time Frame
Up to approximately 16 months
Title
Event-free survival (EFS)
Description
EFS is defined as the time from study intervention to the first of the following events: Radiographic disease progression per RECIST 1.1 (for participants who have not had or will not have surgery, participants who have gross residual disease after an incomplete resection [R2 resection]); Local progression (primary tumor or regional lymph nodes) precluding planned surgery; Inability to resect the tumor; Local or distant recurrence (for participants who are disease free after surgery or participants with microscopic positive margins [R1 resection]); Death due to any cause.
Time Frame
Up to approximately 46 months
Title
Number of Participants with One or More Adverse Events
Description
Participant experiencing AEs, participant discontinuing study intervention due to AEs, and participant experiencing perioperative complications.
Time Frame
Up to approximately 46 months
Title
PD-L1 expression and status of pre-treatment tumor sample
Description
PD-L1 expression and status of pre-treatment tumor biopsy
Time Frame
Up to approximately 16 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Male/female participants who are at least 18 years of age on the day of signing informed consent with histologically confirmed diagnosis of [Stage II, IIIA or IIIB(N2) NSCLC (AJCC Version 8)] will be enrolled in this study. Note: mixed cellularity tumors are allowed. tumor should be considered resectable in terms of surgeon's determinations before study entry by investigators. Lymph nodes disease are recommended to have pathological confirmation. A PET-CT may be utilized as a surrogate for pathologic staging by site's feasibility. Male participants: A male participant must agree to use a contraception as detailed in Appendix 3 of this protocol during the treatment period and for at least 1 year after the last dose of study treatment and refrain from donating sperm during this period. Female participants: A female participant is eligible to participate if she is not pregnant (see Appendix 3), not breastfeeding, and at least one of the following conditions applies: Not a woman of childbearing potential (WOCBP) as defined in Appendix 3 OR A WOCBP who agrees to follow the contraceptive guidance in Appendix 3 during the treatment period and for at least [180 days after the last dose of carboplatin and for at least 120 days after the last dose of pembrolizumab, whichever occurs latest]. The participant (or legally acceptable representative if applicable) provides written informed consent for the trial and may also provide consent for future biomedical research. Have measurable disease based on RECIST 1.1. Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions. Participants suspected with secondary lung cancer (eg. ground glass nodules) were also eligible for this study (For solid nodules, biopsy, if available, should be performed in case of any intrapulmonary metastasis). Archival tumor tissue sample or newly obtained [core, incisional or excisional] biopsy of a tumor lesion not previously irradiated has been provided. Formalin-fixed, paraffin embedded (FFPE) tissue blocks are preferred to slides. Newly obtained biopsies are preferred to archived tissue. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. Evaluation of ECOG is to be performed within 7 days prior to the first dose of study intervention. Have adequate organ function as defined in the following table. Specimens must be collected within 10 days prior to the start of study intervention. Exclusion Criteria: Have confirmed sensitizing EGFR mutation or ALK alterations. Note: EGFR and ALK testing will be performed in local hospital, and do not need to be sent to the central laboratory. A WOCBP who has a positive urine pregnancy test within 72 hours prior to treatment (see Appendix 3). If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. Note: in the event that 72 hours have elapsed between the screening pregnancy test and the first dose of study treatment, another pregnancy test (urine or serum) must be performed and must be negative in order for subject to start receiving study medication. Has one of the following tumor locations/types: NSCLC involving the superior sulcus Large cell neuro-endocrine cancer Sarcomatoid tumor Has had an allogenic tissue/solid organ transplant. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX 40, CD137). Has received prior systemic anti-cancer therapy including investigational agents for the current malignancy prior to [allocation]. Has received prior radiotherapy within 2 weeks of start of study intervention or radiation-related toxicities requiring corticosteroids. Has received a live vaccine or live-attenuated vaccine within 30 days before the first dose of study intervention. Administration of killed vaccines is allowed. Note: please refer to Section 5.5.2 for information on COVID-19 vaccines Has received an investigational agent or has used an investigational device within 4 weeks prior to study intervention administration. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug. Known additional malignancy that is progressing or has required active treatment within the past 5 years. Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin or carcinoma in situ, excluding carcinoma in situ of the bladder, that have undergone potentially curative therapy are not excluded. Has a known severe hypersensitivity (≥Grade 3) to any of the study chemotherapy agents and/or to any of their excipients. Has active autoimmune disease that has required systemic treatment in the past 2 years except replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid) Has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease. Has an active infection requiring systemic therapy. Has a known history of Human Immunodeficiency Virus (HIV) infection. Note: No HIV testing is required unless mandated by local health authority. Concurrent active Hepatitis B (defined as HBsAg positive and/or detectable HBV DNA) and Hepatitis C virus (defined as anti-HCV Ab positive and detectable HCV RNA) infection. Note: Hepatitis B and C screening tests are not required unless: Known history of HBV and HCV infection As mandated by local health authority Has a history or current evidence of any condition, therapy, or laboratory abnormality or other circumstance that might confound the results of the study, interfere with the participant's participation for the full duration of the study, such that it is not in the best interest of the participant to participate, in the opinion of the treating investigator. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial. Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of trial treatment. Participants who have had major surgery within 14 days of first treatment.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Zemin Zhang, PhD
Phone
+86 18201293339
Email
zemin@pku.edu.cn
Facility Information:
Facility Name
Peking University
City
Beijing
State/Province
Beijing
Country
China
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Zemin Zhang, PhD
Phone
+86 18201293339
Email
zemin@pku.edu.cn

12. IPD Sharing Statement

Plan to Share IPD
No

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Pembrolizumab and Chemotherapy Neoadjuvant/Adjuvant of NSCLC

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