Resectable Stage IIA to IIIB Non-small Cell Lung Cancer
Conditions
Brief summary
An open label, randomized study of neoadjuvant nivolumab and chemotherapy, with or without sub-ablative stereotactic body radiation therapy, for resectable stage IIA to IIIB non-small cell lung cancer
Detailed description
Primary Objective * To compare the complete pathological response rate after 3 cycles of neoadjuvant nivolumab and platinum-based doublet chemotherapy vs. the same regimen with the addition of sub-ablative stereotactic radiation therapy (8 Gy x 3) directed at the primary lung tumor. Secondary Objectives * To characterize the rate of Major Pathological Response (MPR), defined as ≤ 10% residual viable tumor cells at the time of surgical resection in the primary tumor and lymph nodes, as assessed by local pathology laboratory. * To characterize rates of Event Free Survival (EFS), defined as survival without documented disease progression per RECIST v1.1 that precludes surgery for local or distant disease recurrence. Exploratory Objectives * To characterize the rate of pathological downstaging of biopsy confirmed positive lymph nodes not in the stereotactic body radiation therapy (SBRT) field. * To characterize rates of Disease-Free Survival (DFS), defined as survival without local or distant recurrence or occurrence of new primary NSCLC. * To characterize rates of Overall Survival (OS) after study enrollment. * To characterize the incidence of adverse events, graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. * To describe surgical safety and the incidence and severity of surgery-related adverse events. * To characterize rates of clearance of circulating tumor DNA (ctDNA) following neoadjuvant therapy and definitive surgical treatment * To evaluate whole tumor RNA-sequencing (RNAseq) from pre- and post- treatment tissue samples to assess for predictors and signatures of pathologic response. * To evaluate of gene expression in pre- and post-treatment blood samples to assess for predictors and signatures of complete pathologic response. * To assess the expression characteristics of PD-L1, infiltrating immune cells and tumor mutational burden (TMB), and their association with clinical outcomes.
Interventions
DRUGNivolumab
Patients randomized to the Nivolumab + Platinum Doublet Chemotherapy only arm will receive three cycles of nivolumab at a dose of 360 mg every three weeks along with a platinum-based chemotherapy doublet (cisplatin or carboplatin plus pemetrexed for adenocarcinoma, cisplatin or carboplatin plus docetaxel, paclitaxel, or gemcitabine for squamous NSCLC) with sub-ablative stereotactic radiation therapy (8 Gy x 3) directed at the primary lung tumor
RADIATION(8gy x 3)
sub-ablative stereotactic radiation therapy (8 Gy x 3) directed at the primary lung tumor
DRUGPlatinum Doublet
Standard of care doublet platinum therapy
Sponsors
Montefiore Medical Center
Bristol-Myers Squibb
Penn State University
Washington University School of Medicine
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Patient has histologically or cytologically proven clinical stages IIA (tumors \> 4 cm), IIB, IIIA, and IIIB (T3 or T4, N2) NSCLC (AJCC version 8) and is considered eligible for surgical resection with curative intent. Patients with 2 primary non-small cell lung cancers are allowed. 2. Measurable disease, as defined by RECIST v1.1. 3. Parenchymal lung tumor deemed to be amenable to treatment with sub-ablative stereotactic body radiation therapy, as determined by a co-investigator from Radiation Oncology 4. Written informed consent and Health Insurance Portability and Accountability Act (HIPAA) obtained from the subject prior to performing any protocol-related procedures. 5. Age \> 18 years at time of study entry 6. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. 7. Adequate normal organ and marrow function as defined below: * Hemoglobin ≥ 9.0 g/dL * Absolute neutrophil count (ANC) ≥ 1.5 x 109/L (\> 1500 per mm3) * Platelet count ≥ 100 x 109/L (\>100,000 per mm3) * Serum bilirubin ≤ 1.5 x institutional upper limit of normal (ULN). This will not apply to subjects with confirmed Gilbert's syndrome (persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis or hepatic pathology), who will be allowed only in consultation with their physician. * Aspartate aminotransferase (SGOT)/Alanine Aminotransferase (SGPT), and alkaline phosphatase ≤ 2.5 x institutional upper limit of normal (ULN). * Serum creatinine clearance\>50 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of creatinine clearance (CL): Males: Creatinine CL (mL/min) = Weight (kg) x (140 - Age) . 72 x serum creatinine (mg/dL) Females: Creatinine CL (mL/min) = Weight (kg) x (140 - Age) x 0.85 72 x serum creatinine (mg/dL) 8. Evidence of post-menopausal status or negative urinary or serum pregnancy test for female pre-menopausal patients. Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause. The following age-specific requirements apply: Women \<50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy or hysterectomy). Women ≥50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced menopause with last menses \>1 year ago, had chemotherapy-induced menopause with last menses \>1 year ago, or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy). 9. Subject is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up. 10. No prior therapy for their lung cancer.
Exclusion criteria
Subjects should not enter the study if any of the following
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Complete Pathological Response Rate | After 3 cycles. Each cycle is defined as 3 weeks | Complete pathological response (CPR) rate observed after neoadjuvant therapy and surgical resection. Complete pathological response will be defined as the absence of tumor cells in the resected specimen upon histopathological examination. CPR rate will be reported as a percentage along with a 95% Confidence Interval for each study arm. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Major Pathological Response | After 3 cycles. Each cycle is defined as 3 weeks | Major Pathological Response (MPR) rate will be assessed. MPR will be defined as ≤ 10% residual viable tumor cells, at the time of surgical resection, in the primary tumor and resected lymph nodes, as assessed by local pathology laboratory. MPR rate and corresponding 95% Clopper-Pearson confidence intervals will be calculated for each treatment arm. |
| Event Free Survival | From the time of enrollment up to approximately 5 years | Event free survival (EFS) will be defined as survival without evidence of documented disease progression, per RECIST v1.1 criteria, that precludes surgery for local or distant disease recurrence. Results will be summarized by study arm. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORBrendon Stiles, MD
Montefiore Medical Center
Outcome results
None listed