Study of Nivolumab for Non-Small Cell Lung Cancer (Stage III) Following Neoadjuvant Chemotherapy Plus Nivolumab and Definitive Concurrent Chemoradiation Therapy

Sponsor

Sun Yat-sen University (Other)

Overall Status

Recruiting

CT.gov ID

NCT04085250

Collaborator

(none)

264

Enrollment

Locations

Arms

Anticipated Duration (Months)

Patients Per Site

1.8

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The phase II, randomised Study is to explore the efficacy and safety of nivolumab as consolidation therapy in patients with locally advanced, unresectable non-small cell lung cancer (stage III) who have not progressed following neoadjuvant chemotherapy plus nivolumab and definitive concurrent chemoradiation therapy

Condition or Disease	Intervention/Treatment	Phase
Stage III Non-small-cell Lung Cancer	Other: Neoadjuvant therapy Other: Chemotherapy concurrent with radiotherapy Radiation: Radiotherapy Drug: Nivolumab Other: Observation	Phase 2

Study Design

Study Type:

Interventional

Anticipated Enrollment :

264 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase II, Randomised Study of Nivolumab as Consolidation Therapy in Patients With Locally Advanced, Unresectable Non-Small Cell Lung Cancer (Stage III) Who Have Not Progressed Following Neoadjuvant Chemotherapy Plus Nivolumab and Definitive Concurrent Chemoradiation Therapy

Actual Study Start Date :

Nov 28, 2019

Anticipated Primary Completion Date :

Nov 27, 2023

Anticipated Study Completion Date :

Nov 27, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Nivolumab Consolidation Patients in experimental group will receive Nivolumab consolidation (360 mg) via iv infusion Q3W±3 days after the neoadjuvant therapy and concurrent chemo-radiotherapy.	Other: Neoadjuvant therapy The neoadjuvant therapy before radiotherapy comprised of Docetaxel 60 mg/m2 for 1 hour + Cisplatin 75 mg/m2+Nivolumab 360 mg, once every 3 weeks (Q3W), for a total of 2 cycles. Other: Chemotherapy concurrent with radiotherapy Docetaxel 25 mg/m2 for 1 hour +Cisplatin 25 mg/m2, once a week (QW) Radiation: Radiotherapy Hypofractionated radiation technique was used to deliver a definitive radiation dose Drug: Nivolumab Nivolumab consolidation (360 mg) via iv infusion once every 3 weeks (Q3W)±3 days after the neoadjuvant therapy and concurrent chemo-radiotherapy. Administration of nivolumab will commence on Day 1 following randomisation to Nivolumab after confirmation of eligibility and will continue on a Q3W schedule for a maximum duration of 12 months.
Active Comparator: Observation Patients in this group will receive observation after the neoadjuvant therapy and concurrent chemo-radiotherapy.	Other: Neoadjuvant therapy The neoadjuvant therapy before radiotherapy comprised of Docetaxel 60 mg/m2 for 1 hour + Cisplatin 75 mg/m2+Nivolumab 360 mg, once every 3 weeks (Q3W), for a total of 2 cycles. Other: Chemotherapy concurrent with radiotherapy Docetaxel 25 mg/m2 for 1 hour +Cisplatin 25 mg/m2, once a week (QW) Radiation: Radiotherapy Hypofractionated radiation technique was used to deliver a definitive radiation dose Other: Observation Observation after the neoadjuvant therapy and concurrent chemo-radiotherapy.

Arm

Intervention/Treatment

Experimental: Nivolumab Consolidation

Patients in experimental group will receive Nivolumab consolidation (360 mg) via iv infusion Q3W±3 days after the neoadjuvant therapy and concurrent chemo-radiotherapy.

Other: Neoadjuvant therapy

The neoadjuvant therapy before radiotherapy comprised of Docetaxel 60 mg/m2 for 1 hour + Cisplatin 75 mg/m2+Nivolumab 360 mg, once every 3 weeks (Q3W), for a total of 2 cycles.

Other: Chemotherapy concurrent with radiotherapy

Docetaxel 25 mg/m2 for 1 hour +Cisplatin 25 mg/m2, once a week (QW)

Radiation: Radiotherapy

Hypofractionated radiation technique was used to deliver a definitive radiation dose

Drug: Nivolumab

Nivolumab consolidation (360 mg) via iv infusion once every 3 weeks (Q3W)±3 days after the neoadjuvant therapy and concurrent chemo-radiotherapy. Administration of nivolumab will commence on Day 1 following randomisation to Nivolumab after confirmation of eligibility and will continue on a Q3W schedule for a maximum duration of 12 months.

Active Comparator: Observation

Patients in this group will receive observation after the neoadjuvant therapy and concurrent chemo-radiotherapy.

Other: Neoadjuvant therapy

The neoadjuvant therapy before radiotherapy comprised of Docetaxel 60 mg/m2 for 1 hour + Cisplatin 75 mg/m2+Nivolumab 360 mg, once every 3 weeks (Q3W), for a total of 2 cycles.

Other: Chemotherapy concurrent with radiotherapy

Docetaxel 25 mg/m2 for 1 hour +Cisplatin 25 mg/m2, once a week (QW)

Radiation: Radiotherapy

Hypofractionated radiation technique was used to deliver a definitive radiation dose

Other: Observation

Observation after the neoadjuvant therapy and concurrent chemo-radiotherapy.

Outcome Measures

Primary Outcome Measures

Progression-free Survival [2 years]
To assess the efficacy of Nivolumab consolidation compared with observation in terms of progression-free survival

Secondary Outcome Measures

Overall Survival(OS) [2 years]
To assess the efficacy of Nivolumab consolidation compared with observation in terms of Overall survival
Objective Response Rate(ORR) [2 years]
To assess the efficacy of Nivolumab consolidation compared with observation in terms of Objective Response Rate; To assess the efficacy of neoadjuvant chemotherapy plus nivolumab in terms of objective response rate after neoadjuvant therapy
Adverse Event [2 years]
To assess the safety of Nivolumab consolidation compared with observation in terms of adverse event
Symptoms and Health-related Quality of Life [2 years]
To assess the symptoms and health-related quality of life in patients treated with Nivolumab consolidation compared with observation
Progression-free Survival [2 years]
To assess the efficacy of neoadjuvant chemotherapy plus nivolumab in terms of progression-free survival for all patients
Overall Survival [2 years]
To assess the efficacy of neoadjuvant chemotherapy plus nivolumab in terms of overall survival for all patients

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 75 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

For inclusion in neoadjuvant therapy, patients should fulfil the following criteria:
Provision of signed, written and dated informed consent prior to any study specific procedures；
Male or female aged 18~75 years old；
Patients must have histologically- or cytologically-documented NSCLC who present with locally advanced, unresectable (Stage III) disease;
Without prior chemotherapy, radiotherapy, surgery, targeted therapy or immunotherapy;
Tumour sample requirements: Mandatory provision of an unstained, archived tumour tissue sample in a quantity sufficient to allow for analysis;
A recent tumour biopsy (taken following completion of the most recent therapy) is an optional requirement, provided that a biopsy procedure is technically feasible and the procedure is not associated with unacceptable clinical risk;
Life expectancy ≥12 weeks;
World Health Organization (WHO) Performance Status of 0 or 1;
Evidence of post-menopausal status, or negative urinary or serum pregnancy test for female pre-menopausal patients within 14 days before the use of study drug (HCG has a minimum sensitivity of 25 IU/L or equivalent);
Women must be non-breastfeeding
Women of reproductive age (WOCBP) must agree to comply with the contraceptive method during the study nivolumab treatment and for a period of 5 months following the last administration of the study treatment (i.e., 30 days [ovulation cycle] plus approximately 5 half-lives of the study drug).
Men who have sex with WOCBP must agree to comply with the contraceptive method during the study nivolumab treatment and for 7 months after the last administration of the study treatment (i.e. 90 days [sperm renewal cycle] plus approximately 5 half-life of the study drug).
Spermless men do not have to comply with contraceptive requirements. WOCBP who continues to be asexual with the opposite sex does not have to comply with contraceptive requirements, but must still undergo the pregnancy tests described in this section.
Adequate organ and marrow function as defined below:
Forced expiratory volume in 1 second (FEV1) ≥800ml
Absolute neutrophil count >1.5 x 109/L (1500 per mm3)
Platelets >100 x 109/L (100,000 per mm3)
Haemoglobin≥9.0 g/dL (5.59 mmol/L)
Serum creatinine clearance(CL) >50 mL/min by the Cockcroft-Gault formula (Cockcroft and

-Gault 1976)

Serum bilirubin ≤1.5 x upper limit of normal (ULN). ··Aspartate Transaminase(AST) and Alanine Transaminase(ALT) ≤2.5 x ULN

Exclusion Criteria:

Exclusion criteria for enrolment for neoadjuvant therapy

Patients should not enter the study if any of the following exclusion criteria are fulfilled:

Concurrent enrolment in another clinical study, unless it is an observational(non-interventional) clinical study;
Mixed small cell and non-small cell lung cancer histology;
Current or prior use of immunosuppressive medication within 28 days before the first dose of Nivolumab, with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid. Systemic steroid administration required to manage toxicities arising from radiation therapy delivered as part of the chemoradiation therapy for locally advanced NSCLC is allowed.
Prior exposure to any anti-programmed cell death protein(PD)-1 or anti-PD-L1 antibody;
Recent major surgery within 4 weeks prior to entry into the study (excluding the placement of vascular access) that would prevent administration of nivolumab;
Active or prior documented autoimmune disease within the past 2 years;
Active or prior documented inflammatory bowel disease (eg. Crohn's disease, ulcerative colitis);
History of primary immunodeficiency;
History of organ transplant that requires therapeutic immunosuppression;
Mean QT interval corrected for heart rate (QTc) ≥470 ms calculated from3 electrocardiograms (ECGs) using Bazett's Correction;
Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, active peptic ulcer disease or gastritis, active bleeding diatheses including any patient known to have hepatitis B, hepatitis C or human immunodeficiency virus (HIV), or psychiatric illness/social situations that would limit compliance with study requirements or compromise the ability of the patient to give written informed consent;
Known history of tuberculosis;
Receipt of live attenuated vaccination within 30 days prior to study entry or within30 days of receiving nivolumab;
History of another primary malignancy within 5 years prior to starting nivolumab, except for adequately treated basal or squamous cell carcinoma of the skin or cancer of the cervix in situ and the disease under study;
Female patients who are pregnant, breast-feeding or male or female patients of reproductive potential who are not employing an effective method of birth control;
Any condition that, in the opinion of the investigator, would interfere with evaluation of the nivolumab or interpretation of patient safety or study results.

Exclusion criteria for concurrent chemoradiation following neoadjuvant therapy

Patients should not enter the concurrent chemoradiation phase if any of the following exclusion criteria are fulfilled:

Patients who develop distant metastasis;
Patients who develop locoregional disease progression and the irradiation dose of normal tissue will exceed the limit as defined in Section 7.
World Health Organization (WHO) Performance Status of 2-4;
Inadequate organ and marrow function as defined below:
Forced expiratory volume in 1 second (FEV1) <800ml
Absolute neutrophil count <1.5 x 109/L (1500 per mm3)
Platelets <100 x 109/L (100,000 per mm3)
Haemoglobin<9.0 g/dL (5.59 mmol/L)
Serum creatinine CL <50 mL/min by the Cockcroft-Gault formula (Cockcroft and
Gault 1976)
Serum bilirubin >1.5 x upper limit of normal (ULN).
Aspartate Transaminase(AST) and Alanine Transaminase(ALT) >2.5 x ULN

Further exclusion criteria for randomization into Nivolumab consolidation or observation group

Patients should not enter the randomization if any of the following exclusion criteria are fulfilled:

Patients who have progressed whilst definitive platinum based, concurrent chemoradiation therapy;
Current or prior use of immunosuppressive medication within 28 days before the first dose of Nivolumab, with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid. Systemic steroid administration required to manage toxicities arising from radiation therapy delivered as part of the chemoradiation therapy for locally advanced NSCLC is allowed.
Any unresolved toxicity CTCAE >Grade 2 from the prior chemoradiation therapy will be excluded from randomization;
Patients with Grade ≥2 pneumonitis from prior chemoradiation therapy will be excluded from randomization; Any prior Grade ≥3 immune-related adverse event (irAE) while receiving any previous immunotherapy agent, or any unresolved irAE>Grade 1.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	The First People's Hospital of Foshan	Foshan	Guangdong	China	528000
2	Sun yat-sen university cancer center	Guangzhou	Guangdong	China	510000
3	The first affliated hospital of Guangzhou Medical University	Guangzhou	Guangdong	China	510000