Clinical trial NCT03081689: Neo-Adjuvant Immunotherapy With Nivolumab for Non Small Cell Lung Cancer Patients
Official title: Neo - Adjuvant Chemo / Immunotherapy for the Treatment of Resectable Stage IIIA Non Small Cell Lung Cancer (NSCLC): A Phase II Multicenter Exploratory Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Non Small Cell Lung Cancer
Lead sponsor: Spanish Lung Cancer Group
Sponsor class: OTHER
First posted: 2017-03-16
Enrollment: 46
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: Phase II, single-arm, open-label multicenter study that assesses feasibility, safety and efficacy of combined neoadjuvant chemotherapy and immunotherapy with Nivolumab 360 mg IV Q3W + Paclitaxel 200mg/m2 + Carboplatin AUC 6 IV Q3W in resectable stage IIIA N2-NSCLC adult patients followed by adjuvant treatment for 1 year with Nivolumab 240 mg IV Q2W for 4 months and Nivolumab 480mg Q4W for 8 months.

Detailed description: Phase II, single-arm, open-label multicenter study that assesses feasibility, safety and efficacy of combined neoadjuvant chemotherapy and immunotherapy with Nivolumab 360 mg IV Q3W + Paclitaxel 200mg/m2 + Carboplatin AUC 6 IV Q3W in resectable stage IIIA N2-NSCLC adult patients followed by adjuvant treatment for 1 year with Nivolumab 240 mg IV Q2W for 4 months and Nivolumab 480mg Q4W for 8 months.

Three cycles of neoadjuvant chemotherapy in combination with nivolumab will be administered.

After completion of neoadjuvant therapy (3 cycles) and before surgery, a tumor assessment will be done. Patients have to leave the study if there is evidence of progression. Patients with in-stable disease or partial response may be considered for surgery.

The report imaging response vs pathological response rate will be evaluated.

Patients eligible for the trial are those with a histological diagnosis or cytologically proven operable and resectable non-small-cell lung cancer. The total number of patients to be included will be 46 from 23 participating sites in Spain.

Accrual period of 1.5 years or until the inclusion of the last patient necessary to achieve the sample set in the protocol of 46 patients. After that all patients will be treated for 1 year with adjuvant immunotherapy and they will be followed during 3 years after adjuvant treatment.

Eligibility criteria: Inclusion Criteria:

1. The subjects eligible for the study are those with histologically- or cytologically- documented NSCLC who present stage IIIA disease. Locally advanced patients who present stage IIIA by the previous version can be included if are considered potencially resectable. In case of N2 disease suspicion, pathological assessment by EBUS, mediastinoscopy or thoracotomy has to be carried out for N2 confirmation.
2. Tumor should be considered resectable before study entry
3. Performance Status of 0 or 1
4. Screening laboratory values must meet the following criteria and should be obtained within 14 days prior to registration/inclusion i. WBC ≥ 2000/μL ii. Neutrophils ≥ 1500/μL iii. Platelets ≥ 100 x103/μL iv. Hemoglobin \> 9.0 g/dL v. Serum creatinine ≤ 1.5 x ULN or creatinine clearance (CrCl) ≥ 40 mL/min (if using the Cockcroft-Gault formula below): a. Female CrCl = (140 - age in years) x weight in kg x 0.85

1. 72 x serum creatinine in mg/dL

b. Male CrCl = (140 - age in years) x weight in kg x 1.00

1. 72 x serum creatinine in mg/dL vi. AST/ALT ≤ 3 x ULN vii. Total Bilirubin ≤ 1.5 x ULN (except subjects with Gilbert Syndrome, who can have total bilirubin \< 3.0 mg/dL) viii. INR/APTT within normal limits

   5. The patients need to have a forced expiratory volume (FEV1) ≥ 1.2 liters

   6. All patients are notified of the investigational nature of this study and signed a written informed consent in accordance with institutional and nacional guidelines, including the Declaration of Helsinki prior to any trial-related intervention.

   7. Patients aged \> 18 years

   8. Women of childbearing potential (WOCBP) must use appropriate method(s) of contraception.

   9. Women must not be breastfeeding

   10. Men who are sexually active with WOCBP must use any contraceptive method with a failure rate of less than 1% per year.

   Exclusion Criteria:
   1. All patients carrying activating mutations in the TK domain of EGFR or any variety of alterations in the ALK gene.
   2. Patients with active, known or suspected autoimmune disease.
   3. Patients with a condition requiring systemic treatment with either corticosteroids (\>10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of enrollment.
   4. Patients with a history of interstitial lung disease cannot be included if they have sympthomatic ILD (Grade 3-4)
   5. Patients with other active malignancy requiring concurrent intervention
   6. Patients 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
   7. Any medical, mental or psychological condition which in the opinion of the investigator would not permit the patient to complete the study
   8. Patients who have had prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody,
   9. Patients with positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody)
   10. Patients with known history of testing positive for human immunodeficiency virus (HIV)
   11. Patients with history of allergy to study drug components excipients

Primary outcomes:
measure: Progression Free Survival
timeFrame: at 24 months from the first dose of neoadjuvant treatment
Secondary outcomes:
measure: Overall Survival
timeFrame: at 3 years from the first dose of neoadjuvant treatment
Other outcomes:
Locations:
city: La Coruña
country: Spain
facility: Complejo hospitalario de la coruña
state: Coruña
city: Cordoba
country: Spain
facility: Hospital Reina Sofía
state: Córdoba
city: Las Palmas De Gran Canaria
country: Spain
facility: Hospital Insular de Gran Canaria
state: Gran Canaria
city: Majadahonda
country: Spain
facility: Hospital Puerta de Hierro
state: Madrid
city: Pamplona
country: Spain
facility: Clínica Universitaria de Navarra
state: Navarra
city: Vigo
country: Spain
facility: Complejo Hospitalario de Vigo
state: Pontevedra
city: Bilbao
country: Spain
facility: Hospital de Cruces
state: Vizcaya
city: Alicante
country: Spain
facility: Hospital General de Alicante
city: Barcelona
country: Spain
facility: Hospital Universitari Quirón Dexeus
city: Barcelona
country: Spain
facility: Hospital Universitari Vall Hebrón
city: Barcelona
country: Spain
facility: Hospital Clínic de Barcelona
city: Barcelona
country: Spain
facility: Hospital de La Santa Creu I Sant Pau
city: Barcelona
country: Spain
facility: H. Duran i Reynals-ICO
city: Madrid
country: Spain
facility: H. de la Princesa
city: Madrid
country: Spain
facility: Hospital Clínico San Carlos
city: Madrid
country: Spain
facility: Hospital Fundación Jiménez Díaz
city: Madrid
country: Spain
facility: H. La Paz
city: Palma de Mallorca
country: Spain
facility: Hospital Son Espases
city: Salamanca
country: Spain
facility: Hospital Clinico de Salamanca
city: Sevilla
country: Spain
facility: Hospital Virgen de La Macrena
city: Sevilla
country: Spain
facility: Hospital Virgen Del Rocío
city: Valencia
country: Spain
facility: Hospital Clínico Universitario de Valencia
city: Valencia
country: Spain
facility: H. Gen. Univ. Valencia
city: Valencia
country: Spain
facility: Hospital La Fe
Study officials:
affiliation: spanish Lun Cancer Group
name: Mariano Provencio, MD
role: STUDY_CHAIR
References:
citation: Provencio M, Serna-Blasco R, Nadal E, Insa A, Garcia-Campelo MR, Casal Rubio J, Domine M, Majem M, Rodriguez-Abreu D, Martinez-Marti A, De Castro Carpeno J, Cobo M, Lopez Vivanco G, Del Barco E, Bernabe Caro R, Vinolas N, Barneto Aranda I, Viteri S, Pereira E, Royuela A, Calvo V, Martin-Lopez J, Garcia-Garcia F, Casarrubios M, Franco F, Sanchez-Herrero E, Massuti B, Cruz-Bermudez A, Romero A. Overall Survival and Biomarker Analysis of Neoadjuvant Nivolumab Plus Chemotherapy in Operable Stage IIIA Non-Small-Cell Lung Cancer (NADIM phase II trial). J Clin Oncol. 2022 Sep 1;40(25):2924-2933. doi: 10.1200/JCO.21.02660. Epub 2022 May 16.
citation: Provencio M, Nadal E, Insa A, Garcia-Campelo MR, Casal-Rubio J, Domine M, Majem M, Rodriguez-Abreu D, Martinez-Marti A, De Castro Carpeno J, Cobo M, Lopez Vivanco G, Del Barco E, Bernabe Caro R, Vinolas N, Barneto Aranda I, Viteri S, Pereira E, Royuela A, Casarrubios M, Salas Anton C, Parra ER, Wistuba I, Calvo V, Laza-Briviesca R, Romero A, Massuti B, Cruz-Bermudez A. Neoadjuvant chemotherapy and nivolumab in resectable non-small-cell lung cancer (NADIM): an open-label, multicentre, single-arm, phase 2 trial. Lancet Oncol. 2020 Nov;21(11):1413-1422. doi: 10.1016/S1470-2045(20)30453-8. Epub 2020 Sep 24.
citation: Sierra-Rodero B, Cruz-Bermudez A, Nadal E, Garitaonaindia Y, Insa A, Mosquera J, Casal-Rubio J, Domine M, Majem M, Rodriguez-Abreu D, Martinez-Marti A, De Castro Carpeno J, Cobo M, Lopez Vivanco G, Del Barco E, Bernabe Caro R, Vinolas N, Barneto Aranda I, Viteri S, Massuti B, Laza-Briviesca R, Casarrubios M, Garcia-Grande A, Romero A, Franco F, Provencio M. Clinical and molecular parameters associated to pneumonitis development in non-small-cell lung cancer patients receiving chemoimmunotherapy from NADIM trial. J Immunother Cancer. 2021 Aug;9(8):e002804. doi: 10.1136/jitc-2021-002804.
citation: Casarrubios M, Cruz-Bermudez A, Nadal E, Insa A, Garcia Campelo MDR, Lazaro M, Domine M, Majem M, Rodriguez-Abreu D, Martinez-Marti A, de Castro-Carpeno J, Cobo M, Lopez-Vivanco G, Del Barco E, Bernabe Caro R, Vinolas N, Barneto Aranda I, Viteri S, Massuti B, Barquin M, Laza-Briviesca R, Sierra-Rodero B, Parra ER, Sanchez-Espiridion B, Rocha P, Kadara H, Wistuba II, Romero A, Calvo V, Provencio M. Pretreatment Tissue TCR Repertoire Evenness Is Associated with Complete Pathologic Response in Patients with NSCLC Receiving Neoadjuvant Chemoimmunotherapy. Clin Cancer Res. 2021 Nov 1;27(21):5878-5890. doi: 10.1158/1078-0432.CCR-21-1200. Epub 2021 Aug 10.
citation: Laza-Briviesca R, Cruz-Bermudez A, Nadal E, Insa A, Garcia-Campelo MDR, Huidobro G, Domine M, Majem M, Rodriguez-Abreu D, Martinez-Marti A, De Castro Carpeno J, Cobo M, Lopez Vivanco G, Del Barco E, Bernabe Caro R, Vinolas N, Barneto Aranda I, Viteri S, Massuti B, Casarrubios M, Sierra-Rodero B, Tarin C, Garcia-Grande A, Haymaker C, Wistuba II, Romero A, Franco F, Provencio M. Blood biomarkers associated to complete pathological response on NSCLC patients treated with neoadjuvant chemoimmunotherapy included in NADIM clinical trial. Clin Transl Med. 2021 Jul;11(7):e491. doi: 10.1002/ctm2.491.