Trial Title:
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
NCT ID:
NCT05500092
Condition:
Resectable Stage IIA to IIIB Non-small Cell Lung Cancer
Conditions: Official terms:
Lung Neoplasms
Carcinoma, Non-Small-Cell Lung
Cisplatin
Gemcitabine
Docetaxel
Nivolumab
Pemetrexed
Study type:
Interventional
Study phase:
Phase 2
Overall status:
Recruiting
Study design:
Allocation:
Randomized
Intervention model:
Parallel Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
Nivolumab
Description:
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
Arm group label:
Nivolumab + Platinum Doublet Chemotherapy
Arm group label:
Nivolumab + Platinum Doublet Chemotherapy + SBRT (8gy x 3)
Intervention type:
Radiation
Intervention name:
(8gy x 3)
Description:
sub-ablative stereotactic radiation therapy (8 Gy x 3) directed at the primary lung tumor
Arm group label:
Nivolumab + Platinum Doublet Chemotherapy + SBRT (8gy x 3)
Intervention type:
Drug
Intervention name:
Platinum Doublet
Description:
Standard of care doublet platinum therapy
Arm group label:
Nivolumab + Platinum Doublet Chemotherapy
Arm group label:
Nivolumab + Platinum Doublet Chemotherapy + SBRT (8gy x 3)
Other name:
Carboplatinum
Other name:
Cisplatin
Other name:
Pemetrexed
Other name:
Docetaxel
Other name:
Gemcitabine
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 ctDNA (circulating tumor DNA) following
neoadjuvant therapy and definitive surgical treatment
- To evaluate whole tumor RNAseq (RNA-sequencing) 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 TMB
(tumor mutational burden), and their association with clinical outcomes.
Criteria for eligibility:
Criteria:
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 exclusion criteria are
fulfilled:
1. Participation in another clinical study with an investigational product during the
last 3 weeks.
2. Active other primary malignancy excepting:
- Malignancy treated with curative intent and with no known active disease and of
low potential risk for recurrence.
- Adequately treated non-melanoma skin cancer or lentigo maligna without evidence
of disease.
- Adequately treated carcinoma in situ without evidence of disease eg, cervical
cancer in situ, in-situ urinary bladder cancer, treated localized prostate
cancer and ductal carcinoma-in situ.
3. Current or prior use of immunosuppressive medication within 14 days before the first
dose of nivolumab, with the exceptions of intranasal, inhaled, topical steroids, or
local steroid injections (e.g., intra articular injection), corticosteroids or
systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day
of prednisone, or an equivalent corticosteroid, and steroids as premedication for
hypersensitivity reactions (e.g., CT scan premedication).
4. Patients with Grade ≥2 neuropathy.
5. Previous receipt of immunotherapy.
6. Active or prior documented autoimmune or inflammatory disorders that has required
systemic treatment in the past year (including inflammatory bowel disease [e.g.,
colitis or Crohn's disease systemic lupus erythematosus, Sarcoidosis syndrome, or
Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid
arthritis, hypophysitis, uveitis, etc]). No active diverticulitis within the
previous 3 months. The following are exceptions to this criterion:
- Patients with vitiligo or alopecia
- Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on
hormone replacement
- Any chronic skin condition that does not require systemic therapy
- Patients without active disease in the last 5 years may be included but only
after consultation with the study physician
- Patients with celiac disease controlled by diet alone
7. History of allogeneic organ transplant.
8. History of hypersensitivity to nivolumab or any excipient.
9. Uncontrolled intercurrent illness that would limit compliance with study
requirements, substantially increase risk of incurring AEs or compromise the ability
of the patient to give written informed consent.
10. Active infection including tuberculosis (clinical evaluation that includes clinical
history, physical examination and radiographic findings, and tuberculosis (TB)
testing in line with local practice), active hepatitis B (known positive HBV surface
antigen (HBsAg) result), active hepatitis C.
11. Female patients who are pregnant or breastfeeding or male or female patients of
reproductive potential who are not willing to employ effective birth control from
screening to 90 days after the last dose of nivolumab monotherapy.
12. History of interstitial lung disease, idiopathic pulmonary fibrosis, pneumonitis
(including drug induced), or evidence of active pneumonitis on screening chest CT
scan.
13. Receipt of the last dose of therapy (chemotherapy, immunotherapy, endocrine therapy,
targeted therapy, biologic therapy, tumor embolization, monoclonal antibodies, or
other investigational agent) for an accepted other malignancy as defined in Section
3.3.2 within 30 days prior to the first dose of study drug for lung cancer.
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
Montefiore Medical Center-Albert Einstein College of Medicine
Address:
City:
Bronx
Zip:
10461
Country:
United States
Status:
Recruiting
Start date:
January 25, 2023
Completion date:
July 2025
Lead sponsor:
Agency:
Montefiore Medical Center
Agency class:
Other
Collaborator:
Agency:
Bristol-Myers Squibb
Agency class:
Industry
Source:
Montefiore Medical Center
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05500092
