SBRT With Immunotherapy in Early Stage Non-small Cell Lung Cancer: Tolerability and Lung Effects

NCT03383302 | Completed Phase 1 DMC FDA Drug

• 1 other identifier: CCR4644
• Study Type: interventional
• Target: 29
• Locations: 1 country
• Sites: 1

Brief Summary

This is a single arm, multi-centre, phase II open label study of nivolumab with stereotactic body radiotherapy (SBRT) for early stage non-small cell lung cancer. SBRT will be delivered in either 3 or 5 fractions for peripheral disease or 8 fractions in central disease. A flat dose of 240 mg nivolumab infusion will begin after the final fraction of SBRT, within 24 hours and typically on the same day. Nivolumab will subsequently be given every 2 weeks at a flat dose of 240 mg for a further 13 cycles followed by Nivolumab 480mg Q4W for 7 cycles until 20 cycles in total are complete, unless any study drug discontinuation criteria are met. Treatment (20 cycles) will take a minimum of 1 year to complete but may exceed this timeframe if treatment delays are encountered. (Patients who have enrolled on Nivolumab Q2W 240mg regimen for 26 cycles and are beyond cycle 14 will receive 26 cycles Q2W in total to complete treatment). Assessment of toxicities will be performed at each clinic visit during treatment, at 30 days after the final nivolumab infusion and until 100 days after the final nivolumab infusion. Changes in spirometry values and PFTs will be assessed throughout the trial. Relapse rates will be assessed with staging CT scans at 3, 6, 12, 18 and 24 months post SBRT. An exploratory assessment will be made of the effect pre-treatment pulmonary function tests (PFTs) have on outcome measures.

Conditions

Non-small Cell Lung Cancer Stage II; Non-small Cell Lung Cancer Stage I

Keywords

Non-small cell lung cancer; NSCLC

Outcome Measures

Primary Outcomes (1)

• Assessment of lung toxicity (pneumonitis) from treatment with Nivolumab after SBRT for early stage NSCLC

  Rate of grade ≥ 3 pneumonitis with nivolumab after stereotactic body radiotherapy (SBRT) within 6 months of the final fraction of SBRT. A rate that exceeds 20% will be deemed unacceptable and will lead to a rejection of the null hypothesis.

  Six months from final dose of SBRT administered for each patient

Secondary Outcomes (9)

• Adverse events (toxicity) assessment using CTCAE v.4

  24 months from last dose of SBRT

• Number of doses of Nivolumab received by patients within 16 weeks of commencing adjuvant nivolumab after SBRT for early stage NSCLC

  Within 16 weeks of each patient commencing treatment with Nivolumab after SBRT

• Disease relapse

  24 months from last dose of SBRT

• Relapse at specified timepoints

  3, 6, 12 and 24 months from the date of first fraction of SBRT for each patient

• Overall survival

  Overall survival rate (OS) at 6, 12 and 24 months

Other Outcomes (6)

• Impact on lung function

  24 months from last dose of SBRT

• OS rates in PD-L1 expressers (≥ 1%) and non-expressers (< 1%)

  24 months from last dose of SBRT

• DFS rates in PD-L1 expressers (≥ 1%) and non-expressers (< 1%)

  24 months from last dose of SBRT

Study Arms (1)

Arm 1 Tolerabilty

EXPERIMENTAL

This is a single arm study of nivolumab administered on completion of stereotactic body radiotherapy (SBRT) to patients with early stage NSCLC. The first 5 patients to enroll must have Eastern Co-operative Oncology Group (ECOG) performance status \< 2 at the time of first dose of investigational medical product (IMP). An Independent Data Monitoring Committee (IDMC) will meet when the first 5 patients have reached 3 months follow up from their 1st dose of nivolumab or have withdrawn consent to follow-up. The IDMC, if satisfied with the safety data from the initial 5 patients, may recommend escalation to include recruitment of patients with ECOG performance status of 2.

Radiation: Stereotactic body radiotherapy; Drug: Nivolumab

Interventions

Stereotactic body radiotherapy RADIATION

Patients will receive a total of 54 Gy if delivered in 3 fractions, 55 Gy if delivered in 5 fractions or 60 Gy if delivered in 8 fractions.

Also known as: SBRT

Arm 1 Tolerabilty

Nivolumab DRUG

Nivolumab is a human immunoglobulin G4 (IgG4) monoclonal antibody, that binds to the PD-1 receptor and blocks interaction with its ligands PD-L1 and PD-L2. Nivolumab will be administered intravenously at a flat dose of 240 mg q2w over 30 minutes for 13 cycles followed by 480mg q4w over 60 minutes for 7 cycles, until 20 cycles in total to complete (a minimum of 1 year of treatment if no delays are encountered).

Also known as: L01XC17, Opdivo

Arm 1 Tolerabilty

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Subjects must have signed and dated a Research Ethics Committee (REC) approved written informed consent form in accordance with regulatory and institutional guidelines. This must be obtained before the performance of any protocol related procedures that are not part of normal subject care
• Subjects must be willing and able to comply with scheduled visits, treatment schedule, and laboratory tests
• ECOG Performance status (PS) 0-2
• Minimum of first 5 patients to be PS 0-1
• PS 2 patients to be enrolled only following recommendation by the Independent Data Monitoring Committee (IDMC)
• Patients with histological diagnosis of NSCLC, all histological sub-types are eligible
• Not suitable for surgery because of medical co-morbidity, lesion is technically inoperable or patient declines surgery after surgical assessment (or option of assessment)
• Single or synchronous/metachronous primary NSCLC lesions, tumour stage T1-3 (≤6cm), N0 M0 (UICC v.8) as determined by the local MDT based on minimum investigations of CT chest/abdomen within 8 weeks and FDG-PET within 6 weeks of 1st fraction of SBRT. Where the radiological nodal status is equivocal then only eligible if possible nodal disease is subsequently confirmed as pathologically negative with mediastinoscopy or endoscopic bronchial or oesophageal ultra-sound biopsy as necessary
• For synchronous tumours one lesion must have a histological diagnosis of NSCLC. For the other lesion a radiological diagnosis of NSCLC as determined by lung MDT is sufficient. (Upon diagnosis of metachronous primary NSCLC these lesions require biopsy for trial entry)
• Tumour stage T1-3 termed as 'central' disease within 2cm of main airways and proximal bronchial tree, but not abutting these structures (ultra-central), are suitable for entry. Up to 5 patients with 'central' primary NSCLC (up to 2 lesions) can be enrolled and followed up for 3 months following their final fraction of radiotherapy at which stage an IDMC meeting is required to assess further 'central' primary NSCLC recruitment
• Screening laboratory values must meet the following criteria prior to commencement of treatment:
• i) WBCs ≥ 2000/μL ii) Neutrophils ≥1500/μL iii) Platelets ≥ 100 X10³/μL iv) Haemoglobin ≥ 9.0 g/dL v) Serum creatinine of ≤ 1.5 X ULN or creatinine clearance (CrCl)/glomerular filtration rate (GFR) \> 40 mL/minute (using Cockcroft/Gault formula or as assessed by local practice)
• Female CrCl= \[(140- age in years) X weight in kg X 0.85) ÷ (72 X serum creatinine in mg/ dL)\]
• Male CrCl= \[(140- age in years) X weight in kg X 1.00) ÷ (72 X serum creatinine in mg/ dL)\] vi) AST ≤ 3 X ULN vii) ALT ≤ 3 X ULN viii) Total bilirubin ≤ 1.5 X ULN (except subjects with Gilbert Syndrome, who must have total bilirubin \< 50 μmol/L)
• No prior adjuvant or foreseen neo-adjuvant or adjuvant chemotherapy is allowed

You may not qualify if:

• Any tumour that is not clinically definable on the treatment planning CT scan e.g. surrounded by consolidation or atelectasis
• 'Ultra-central' tumours, i.e. those adjacent to the hilar structures, with the gross tumour volume directly abutting a main bronchus
• Subjects with active, known autoimmune disease. Subjects with Type I diabetes mellitus, residual hypothyroidism due to an autoimmune condition requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enrol.
• Subjects with a condition requiring systemic treatment with either corticosteroids (\> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of the first dose of study drug administration. Inhaled or topical steroids and adrenal replacement steroid doses \> 10 mg daily prednisone or equivalent are permitted in the absence of active autoimmune disease
• Subjects with previous malignancies (except non-melanoma skin cancers, early stage NSCLC treated with SBRT or surgery and current lesion not considered to be relapsed NSCLC, and the following in situ cancers: bladder, gastric, colon, endometrial, cervical/dysplasia, melanoma or breast) are excluded unless a complete remission was achieved at least 2 years prior to study entry AND no additional therapy is required during the study period
• Patient with known interstitial lung disease or active, non-infectious pneumonitis
• Previous conventional radiotherapy to the chest or mediastinum. Patients who have had previous breast radiotherapy may be eligible at the discretion of the Chief Investigator
• Any serious or uncontrolled medical disorder or active infection that, in the opinion of the Investigator, may increase the risk associated with study participation, study drug administration, or would impair the ability of the subject to receive protocol therapy
• All toxicities attributed to prior anti-cancer therapy other than alopecia and fatigue must have resolved to Grade 1 (NCI CTCAE v.4.0) or baseline before administration of study drug
• Subjects must have recovered from the effects of major surgery or significant traumatic injury at least 14 days before the first dose of study treatment
• Subjects who received prior therapy with anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways) or who have previously taken part in a randomized BMS clinical trial for nivolumab or ipilimumab
• Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS)
• Positive test for hepatitis B virus (HBV) using HBV surface antigen (HBVsAg) test or positive test for hepatitis C virus (HCV) using HCV ribonucleic acid (RNA) or HCV antibody test indicating acute or chronic infection
• o Patients with a positive HCV antibody but no detection of HCV RNA indicating no current infection are eligible
• Patients who have received a live vaccine within 30 days prior to the first dose of trial treatment

Sponsors & Collaborators

• Royal Marsden NHS Foundation Trust: lead
• Bristol-Myers Squibb: collaborator

Study Sites (1)

Royal Marsden Hospital

Sutton, SM2 5PT, United Kingdom

Location

MeSH Terms

Conditions

Carcinoma, Non-Small-Cell Lung

Interventions

Radiosurgery; Nivolumab

Condition Hierarchy (Ancestors)

Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Radiotherapy; Therapeutics; Stereotaxic Techniques; Neurosurgical Procedures; Surgical Procedures, Operative; Investigative Techniques; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Merina Ahmed

  Royal Marsden NHS Foundation Trust

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: This is a single arm, phase Ib/II open label study of nivolumab administered on completion of SBRT to patients with early stage NSCLC.

Study Record Dates

• First Submitted: November 23, 2017
• First Posted: December 26, 2017
• Study Start: February 8, 2018
• Primary Completion: August 12, 2024
• Study Completion: June 26, 2025
• Last Updated: August 1, 2025

Record last verified: 2025-07

Data Sharing

• IPD Sharing: Will not share

Locations

GB (1)