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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03383302
Recruitment Status : Unknown
Verified May 2020 by Royal Marsden NHS Foundation Trust.
Recruitment status was:  Recruiting
First Posted : December 26, 2017
Last Update Posted : May 19, 2020
Sponsor:
Collaborator:
Bristol-Myers Squibb
Information provided by (Responsible Party):
Royal Marsden NHS Foundation Trust

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. 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 until 1 year of total treatment unless any study drug discontinuation criteria are met.

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.


Condition or disease Intervention/treatment Phase
Non-small Cell Lung Cancer Stage II Non-small Cell Lung Cancer Stage I Radiation: Stereotactic body radiotherapy Drug: Nivolumab Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 31 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description: This is a single arm, phase Ib/II open label study of nivolumab administered on completion of SBRT to patients with early stage NSCLC.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Stereotactic Body Radiotherapy Radiotherapy With Immunotherapy in Early Stage Non-small Cell Lung Cancer: Tolerability and Lung Effects
Actual Study Start Date : January 1, 2018
Estimated Primary Completion Date : June 2021
Estimated Study Completion Date : January 2022

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Lung Cancer
Drug Information available for: Nivolumab

Arm Intervention/treatment
Experimental: Arm 1 Tolerabilty
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
Patients will receive a total of 54 Gy if delivered in 3 fractions or 55 Gy if delivered in 5 fractions.
Other Name: SBRT

Drug: Nivolumab
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 given every 14 days at a flat dose of 240 mg, to be administered as a 30 minute IV infusion.
Other Names:
  • L01XC17
  • Opdivo




Primary Outcome Measures :
  1. Assessment of lung toxicity (pneumonitis) from treatment with Nivolumab after SBRT for early stage NSCLC [ Time Frame: Six months from final dose of SBRT administered for each patient ]
    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.


Secondary Outcome Measures :
  1. Adverse events (toxicity) assessment using CTCAE v.4 [ Time Frame: 24 months from last dose of SBRT ]
    Frequency of treatment related adverse events of all grades and grade ≥ 3 as per CTCAE v. 4 after treatment with Nivolumab following SBRT

  2. Number of doses of Nivolumab received by patients within 16 weeks of commencing adjuvant nivolumab after SBRT for early stage NSCLC [ Time Frame: Within 16 weeks of each patient commencing treatment with Nivolumab after SBRT ]
    The proportion of patients receiving at least 1, 2, 3, 4, 5 and 6 doses of Nivolumab within 16 weeks of commencing treatment with Nivolumab after SBRT for early stage NSCLC

  3. Disease relapse [ Time Frame: 24 months from last dose of SBRT ]
    To assess local, local-regional and distant disease relapse rates

  4. Relapse at specified timepoints [ Time Frame: 3, 6, 12 and 24 months from the date of first fraction of SBRT for each patient ]
    Local, loco-regional and distant rates of relapse at 3, 6, 12 and 24 months

  5. Overall survival [ Time Frame: Overall survival rate (OS) at 6, 12 and 24 months ]
    Overall survival rate (OS) of the 31 patients at 6, 12 and 24 months

  6. Disease free survival [ Time Frame: Disease Free Survival (DFS) at 6, 12 and 24 months ]
    Disease Free Survival (DFS) rate of the 31 patients at 6, 12 and 24 months

  7. Health-related quality of life (HRQoL) using Patient Generated Subjective Global Assessment in patients treated with Nivolumab after SBRT for early stage NSCLC [ Time Frame: 24 months from last dose of SBRT ]
    Estimation of HRQoL using the Patient Generated Subjective Global Assessment in patients treated with Nivolumab after SBRT for early stage NSCLC.

  8. Health-related quality of life (HRQoL) using European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) in patients treated with Nivolumab after SBRT for early stage NSCLC [ Time Frame: 24 months from last dose of SBRT ]
    Estimation of HRQoL using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30).

  9. HRQoL using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Lung Cancer 13 (EORTC QLQ-LC13) in patients treated with Nivolumab after SBRT for early stage NSCLC. [ Time Frame: 24 months from last dose of SBRT ]
    Estimation of HRQoL in patients treated with Nivolumab after SBRT for early stage NSCLC using the Eurpoean Organisation for Research and Treatment of Cancer Ouality of Life Questionnaire Lung Cancer 13 (EORTC QLQ-LC13).


Other Outcome Measures:
  1. Impact on lung function [ Time Frame: 24 months from last dose of SBRT ]
    Assessment of rates of toxicity within percentage of predicted FEV1 bands & DLCO bands

  2. OS rates in PD-L1 expressers (≥ 1%) and non-expressers (< 1%) [ Time Frame: 24 months from last dose of SBRT ]
    OS rates at 6, 12 & 24 months will be described according to PD-L1 expression

  3. DFS rates in PD-L1 expressers (≥ 1%) and non-expressers (< 1%) [ Time Frame: 24 months from last dose of SBRT ]
    DFS at 6, 12 & 24 months will be described according to PD-L1 expression

  4. OS rates (squamous and non-squamous) [ Time Frame: 24 months from last dose of SBRT ]
    OS rates at 6, 12 & 24 months will be described according to squamous and non-squamous subgroups

  5. DFS rates (squamous and non-squamous) [ Time Frame: 24 months from last dose of SBRT ]
    DFS rates at 6, 12 & 24 months will be described according to squamous and non-squamous subgroups

  6. Measuring immune cell responses with treatment [ Time Frame: 4 years from recruitment of first patient ]
    Measuring change in T cell receptor sub-types during treatment



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • 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
  • Tumour stage T1-3 (≤5cm), N0 M0 (UICC v.7) 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
  • Not suitable for surgery because of medical co-morbidity, lesion is technically inoperable or patient declines surgery after surgical assessment (or option of assessment)
  • Peripheral lesions, i.e., outside a 2cm radius of main airways and proximal bronchial tree. This is defined as 2cm from the bifurcation of the second order bronchus, e.g., where the right upper lobe bronchus splits.
  • 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)

    1. . Female CrCl= [(140- age in years) X weight in kg X 0.85) ÷ (72 X serum creatinine in mg/ dL)]
    2. . 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
  • Males and Females ≥ 18 years of age
  • Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin [HCG]) in the screening period and within 24 hours prior to the start of study drug.
  • Women must not be breastfeeding during the study treatment and for a period up to 23 weeks post treatment completion
  • WOCBP must agree to follow instructions for method(s) of contraception during the study treatment and for a total of 23 weeks post treatment completion
  • Males who are sexually active with WOCBP must agree to follow instructions for method(s) for contraception for a total of 31 weeks post treatment completion.

Exclusion Criteria:

  • Any tumour that is not clinically definable on the treatment planning CT scan e.g. surrounded by consolidation or atelectasis
  • 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, 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 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
  • History of allergy to study drug components

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03383302


Contacts
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Contact: Andrea Pejenaute 020 8915 6667 andrea.pejenaute@rmh.nhs.uk
Contact: Victoria Pittordou 080 8915 6766 Stile.Study@rmh.nhs.uk

Locations
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United Kingdom
Royal Marsden Hospital Recruiting
Sutton, United Kingdom, SM2 5PT
Contact: Merina Ahmed    020 8915 6766    STILE.Study@rmh.nhs.uk   
Sponsors and Collaborators
Royal Marsden NHS Foundation Trust
Bristol-Myers Squibb
Investigators
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Principal Investigator: Merina Ahmed Royal Marsden NHS Foundation Trust
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Responsible Party: Royal Marsden NHS Foundation Trust
ClinicalTrials.gov Identifier: NCT03383302    
Other Study ID Numbers: CCR4644
First Posted: December 26, 2017    Key Record Dates
Last Update Posted: May 19, 2020
Last Verified: May 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
Keywords provided by Royal Marsden NHS Foundation Trust:
Non-small cell lung cancer
NSCLC
Additional relevant MeSH terms:
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Lung Neoplasms
Carcinoma, Non-Small-Cell Lung
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Neoplasms
Lung Diseases
Respiratory Tract Diseases
Carcinoma, Bronchogenic
Bronchial Neoplasms
Nivolumab
Antineoplastic Agents, Immunological
Antineoplastic Agents
Immune Checkpoint Inhibitors
Molecular Mechanisms of Pharmacological Action