A Phase 2 Study of Neoadjuvant Pembrolizumab-Based Combination Immunotherapy in the Treatment of Early Stage Non-Small Cell Lung Cancer
Overview
- Phase
- Phase 2
- Intervention
- Pembrolizumab
- Conditions
- Lung Non-Small Cell Carcinoma
- Sponsor
- University of California, San Francisco
- Locations
- 1
- Primary Endpoint
- Proportion of patients with a >= 2-fold increase in the number of tumor-infiltrating immune cells (TIICs) in post- versus (vs.) pre-pembrolizumab treatment tumor specimens
- Status
- Withdrawn
- Last Updated
- 4 years ago
Overview
Brief Summary
This phase II trial studies how well pembrolizumab with or without chemotherapy works when given before surgery in treating patients with stage I-IIIA non-small cell lung cancer. Immunotherapy with pembrolizumab, may induce changes in body?s immune system and may interfere with the ability of tumor cells to grow and spread. Drugs used in chemotherapy, such as cisplatin and pemetrexed, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving pembrolizumab with or without chemotherapy may shrink the cancer prior to surgery and decrease the likelihood of the cancer returning following surgery.
Detailed Description
PRIMARY OBJECTIVES: I. To determine the impact of neoadjuvant pembrolizumab-based combination therapy on the composition, phenotype, and function of tumor-infiltrating immune cells (TIICs) in patients with early stage non-small cell lung cancer (NSCLC). SECONDARY OBJECTIVES: I. To determine the safety and tolerability of neoadjuvant pembrolizumab alone and in combination with chemotherapy as measured by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) 5.0. II. To determine the clinical efficacy of neoadjuvant pembrolizumab alone and in combination with chemotherapy. EXPLORATORY OBJECTIVES: I. To explore the relationship between changes in TIICs and clinical efficacy in patients with early stage NSCLC treated with neoadjuvant pembrolizumab-based combination therapy. II. To characterize changes in the frequency and number of circulating immune cells induced by neoadjuvant pembrolizumab-based combination therapy in patients with early stage NSCLC. III. To determine the impact of neoadjuvant pembrolizumab-based combination therapy on the composition and phenotype of the tumor microenvironment (including tumor and stromal cells) in patients with NSCLC. III. To determine the change in T cell repertoire within the tumor and blood induced by neoadjuvant pembrolizumab-based combination therapy in patients with early stage NSCLC. IV. To explore molecular profiles to identify potentially predictive biomarkers for patients with early stage NSCLC treated with immunotherapy. OUTLINE: Patients are assigned to 1 of 2 cohorts. COHORT A: Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1. Treatment repeats every 21 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients then undergo surgery within 4 weeks following study treatment. COHORT B: Patients receive pembrolizumab IV over 30 minutes and chemotherapy (cisplatin/pemetrexed) IV on day 1. Treatment repeats every 21 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients then undergo surgery within 4 weeks following study treatment. After completion of study treatment, patients are followed up every 3 months for up to 2 years.
Investigators
Matthew Gubens, MD
Principal Investigator
University of California, San Francisco
Eligibility Criteria
Inclusion Criteria
- •Histologically or cytologically confirmed NSCLC, performed on a biopsy that occurred within the last 60 days
- •Computed tomography (CT) within the last 30 days showing radiographic stage I to IIIa lung cancer (mediastinal staging biopsy is allowed but not required) by the American Joint Committee on Cancer (AJCC) 8th edition
- •Documentation that the patient is a candidate for surgical resection of their lung cancer by an American Board of Thoracic Surgery-certified surgeon
- •Measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 as assessed by the investigator
- •Adequate tissue specimens for correlative biomarker analysis. The patient should be willing to provide tissue from a newly obtained core or excisional biopsy of a tumor lesion. Newly-obtained is defined as a specimen obtained up to 8 weeks (56 days) prior to initiation of treatment on day
- •Patients for whom newly-obtained samples cannot be provided (e.g. inaccessible or patient safety concern) may submit an archived specimen only upon agreement from the principal investigator
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
- •Resolution of all acute toxic effects of prior chemotherapy, radiotherapy or surgical procedures to NCI CTCAE version (v)5.0 grade 1
- •Be willing and able to provide written informed consent for the trial
- •Absolute neutrophil count (ANC) \>= 1500 cells/ microlitre(uL) (within 10 days prior to the start of trial treatment)
Exclusion Criteria
- •Is ineligible for an operation based on medical or oncologic contraindications to surgery
- •Is currently participating in or has participated in a trial of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of trial treatment
- •Note: Patients who have entered the follow-up phase of an investigational trial may participate as long as it has been 4 weeks after the last dose of the previous investigational agent
- •Has any component of small cell tumor in the specimen, e.g. mixed NSCLC/small cell
- •Has received prior therapy with an anti-Programmed cell death protein 1 (PD-1), anti-Programmed death-ligand 1 (PD-L1) , or anti-Programmed death-ligand 2 (PD-L2) agent or with an agent directed to another stimulatory or co-inhibitory T cell receptor (e.g., cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), OX-40, CD137)
- •Has severe hypersensitivity \>= grade 3) to pembrolizumab and/or any of its excipients
- •Has a history of (non-infectious) pneumonitis / interstitial lung disease that required treatment with steroids or has current pneumonitis / interstitial lung disease that requires steroids
- •Has a known history of human immunodeficiency virus (HIV) infection
- •Note: No HIV testing is required unless mandated by local health authority
- •Has a known history of hepatitis B (defined as hepatitis B surface antigen \[HBsAg\] reactive) or known active hepatitis C virus (HCV) (defined as HCV ribonucleic acid \[RNA\] \[qualitative\] is detected) infection
Arms & Interventions
Cohort A (pembrolizumab)
Patients receive 200mg pembrolizumab IV over 30 minutes on day 1. Treatment repeats every 21 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients then undergo surgery within 4 weeks following study treatment.
Intervention: Pembrolizumab
Cohort A (pembrolizumab)
Patients receive 200mg pembrolizumab IV over 30 minutes on day 1. Treatment repeats every 21 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients then undergo surgery within 4 weeks following study treatment.
Intervention: Therapeutic Conventional Surgery
Cohort B (pembrolizumab, cisplatin pemetrexed)
Patients receive 200mg pembrolizumab IV over 30 minutes and chemotherapy (cisplatin/pemetrexed) IV on day 1. Treatment repeats every 21 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients then undergo surgery within 4 weeks following study treatment.
Intervention: Cisplatin
Cohort B (pembrolizumab, cisplatin pemetrexed)
Patients receive 200mg pembrolizumab IV over 30 minutes and chemotherapy (cisplatin/pemetrexed) IV on day 1. Treatment repeats every 21 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients then undergo surgery within 4 weeks following study treatment.
Intervention: Pembrolizumab
Cohort B (pembrolizumab, cisplatin pemetrexed)
Patients receive 200mg pembrolizumab IV over 30 minutes and chemotherapy (cisplatin/pemetrexed) IV on day 1. Treatment repeats every 21 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients then undergo surgery within 4 weeks following study treatment.
Intervention: Pemetrexed
Cohort B (pembrolizumab, cisplatin pemetrexed)
Patients receive 200mg pembrolizumab IV over 30 minutes and chemotherapy (cisplatin/pemetrexed) IV on day 1. Treatment repeats every 21 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients then undergo surgery within 4 weeks following study treatment.
Intervention: Pemetrexed Disodium
Cohort B (pembrolizumab, cisplatin pemetrexed)
Patients receive 200mg pembrolizumab IV over 30 minutes and chemotherapy (cisplatin/pemetrexed) IV on day 1. Treatment repeats every 21 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients then undergo surgery within 4 weeks following study treatment.
Intervention: Therapeutic Conventional Surgery
Outcomes
Primary Outcomes
Proportion of patients with a >= 2-fold increase in the number of tumor-infiltrating immune cells (TIICs) in post- versus (vs.) pre-pembrolizumab treatment tumor specimens
Time Frame: Up to 2 years
Will be summarized by descriptive statistics (median and range).
Secondary Outcomes
- Clinical Benefit Rate(Up to 2 years)
- Median Progression-Free Survival (PFS)(24 months)
- Overall Response Rate(Up to 2 years)
- Proportion of participants reporting treatment-related adverse events (AEs)(Up to 2 years)