NADIMII: NADIM II: Neo-Adjuvant Immunotherapy

Sponsor

Fundación GECP (Other)

Overall Status

Active, not recruiting

CT.gov ID

NCT03838159

Collaborator

(none)

Enrollment

Locations

Arms

114.6

Anticipated Duration (Months)

3.6

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This is an open-label, randomised, two-arm, phase II, multi-centre clinical trial.

90 patients will be enrolled in this trial to examine the pathological Complete Response defined as the absence of residual tumor in lung and lymph nodes comparing patients treated with chemo-immunotherapy versus chemotherapy alone.

Condition or Disease	Intervention/Treatment	Phase
Non Small Cell Lung Cancer	Drug: Paclitaxel Drug: Carboplatin Drug: Nivolumab	Phase 2

Detailed Description

This is an open-label, randomised, two-arm, phase II, multi-centre clinical trial.

Patients randomised to the experimental arm will receive Nivolumab 360mg + Paclitaxel 200mg/m2 + Carboplatin AUC5 for 3 cycles every 21 days as neoadjuvant treatment followed by surgery and 6 months of adjuvant treatment with Nivolumab 480 mg Q4W. Patients randomized to the control arm will receive Paclitaxel 200mg/m2 + Carboplatin AUC5 for 3 cycles every 21 days followed by surgery.

The primary objective is pathological Complete Response (pCR) defined as the absence of residual tumor in lung and lymph nodes comparing patients treated with chemo-immunotherapy versus chemotherapy alone.

Patient accrual is expected to be completed within 3 years excluding a run-in-period of 3 months. Treatment and follow-up are expected to extend the study duration to a total of 8.5 years. Patients will be followed 5 years after adjuvant treatment or surgery. The study will end once survival follow-up has concluded.

Study Design

Study Type:

Interventional

Actual Enrollment :

90 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Randomized Phase II Study of Neo-adjuvant Chemo/Immunotherapy Versus Chemotherapy Alone for the Treatment of Locally Advanced and Potentially Resectable Non-small Cell Lung Cancer (NSCLC) Patients.

Actual Study Start Date :

May 15, 2019

Anticipated Primary Completion Date :

Nov 30, 2027

Anticipated Study Completion Date :

Nov 30, 2028

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Experimental: Neo-Adjuvant Immunotherapy Neoadjuvant treatment (200 mg/m3 Paclitaxel+ AUC5 Carboplatin+ 360 mg Nivolumab) will start within 1-3 days from randomisation. 3 cycles will be administered at 21-day (+/- 3 days) intervals (QW3) prior to surgery. Before surgery a tumor assessment will be done. Patients must leave the study if there is evidence of progression. Patients with stable disease or partial response may be considered for surgery. Surgery: Surgery must be done within the 3rd-4th week (+7 days) from day 21 cycle 3 of neoadjuvant treatment (day 42-49 after day 1 of cycle 3) . Adjuvant treatment:Nivolumab: 480 mg Q4W (+/- 3 days) for 6 months (6 cycles). Patients that are R0 confirmed by surgical pathology evaluation will receive the first adjuvant administration within the 3rd to 8th week (+ 7 days) from surgery and for 6 months.	Drug: Paclitaxel Paclitaxel must be administered by infusion over 3 hours in dextrose (D5W) or normal saline (NS). The concentration must not exceed 1.2 mg/ml. The infusions must be mixed as soon as possible before the start of each infusion since the stability of paclitaxel beyond 24 hours is not known. In-line filtration is obligatory since a small number of fibers within the acceptable limits of the USP Particulate Matter Test for LVP have been reported. Cellulose acetate filters of 0.22-micron pore size (such as IVEX II) can be used. The solution that shows excessive particulate matter must be rejected. Other Names: Taxol Drug: Carboplatin Carboplatin must be administered at the end of the Paclitaxel infusion Other Names: Paraplatin Drug: Nivolumab Nivolumab is a soluble protein consisting of 4 polypeptide chains, which include 2 identical heavy chains and 2 identical light chains. The administration of nivolumab infusion must be completed within 24 hours of preparation. Other Names: Opdivo
Active Comparator: Control: Neo-Adjuvant Chemotherapy Neoadjuvant treatment (200mg/m3 Paclitaxel+ AUC5 Carboplatin). It will start within 1-3 days from randomisation. 3 cycles will be administered at 21-day (+/- 3 days) intervals (QW3) prior to surgery. Before surgery a tumor assessment will be done. Patients must leave the study if there is evidence of progression. Patients with stable disease or partial response may be considered for surgery. Surgery: Surgery must be done within the 3rd-4th week (+7 days) from day 21 cycle 3 of neoadjuvant treatment (day 42-49 after day 1 of cycle 3)	Drug: Paclitaxel Paclitaxel must be administered by infusion over 3 hours in dextrose (D5W) or normal saline (NS). The concentration must not exceed 1.2 mg/ml. The infusions must be mixed as soon as possible before the start of each infusion since the stability of paclitaxel beyond 24 hours is not known. In-line filtration is obligatory since a small number of fibers within the acceptable limits of the USP Particulate Matter Test for LVP have been reported. Cellulose acetate filters of 0.22-micron pore size (such as IVEX II) can be used. The solution that shows excessive particulate matter must be rejected. Other Names: Taxol Drug: Carboplatin Carboplatin must be administered at the end of the Paclitaxel infusion Other Names: Paraplatin

Arm

Intervention/Treatment

Experimental: Experimental: Neo-Adjuvant Immunotherapy

Neoadjuvant treatment (200 mg/m3 Paclitaxel+ AUC5 Carboplatin+ 360 mg Nivolumab) will start within 1-3 days from randomisation. 3 cycles will be administered at 21-day (+/- 3 days) intervals (QW3) prior to surgery. Before surgery a tumor assessment will be done. Patients must leave the study if there is evidence of progression. Patients with stable disease or partial response may be considered for surgery. Surgery: Surgery must be done within the 3rd-4th week (+7 days) from day 21 cycle 3 of neoadjuvant treatment (day 42-49 after day 1 of cycle 3) . Adjuvant treatment:Nivolumab: 480 mg Q4W (+/- 3 days) for 6 months (6 cycles). Patients that are R0 confirmed by surgical pathology evaluation will receive the first adjuvant administration within the 3rd to 8th week (+ 7 days) from surgery and for 6 months.

Drug: Paclitaxel

Paclitaxel must be administered by infusion over 3 hours in dextrose (D5W) or normal saline (NS). The concentration must not exceed 1.2 mg/ml. The infusions must be mixed as soon as possible before the start of each infusion since the stability of paclitaxel beyond 24 hours is not known. In-line filtration is obligatory since a small number of fibers within the acceptable limits of the USP Particulate Matter Test for LVP have been reported. Cellulose acetate filters of 0.22-micron pore size (such as IVEX II) can be used. The solution that shows excessive particulate matter must be rejected.

Other Names:

Taxol

Drug: Carboplatin

Carboplatin must be administered at the end of the Paclitaxel infusion

Other Names:

Paraplatin

Drug: Nivolumab

Nivolumab is a soluble protein consisting of 4 polypeptide chains, which include 2 identical heavy chains and 2 identical light chains. The administration of nivolumab infusion must be completed within 24 hours of preparation.

Other Names:

Opdivo

Active Comparator: Control: Neo-Adjuvant Chemotherapy

Neoadjuvant treatment (200mg/m3 Paclitaxel+ AUC5 Carboplatin). It will start within 1-3 days from randomisation. 3 cycles will be administered at 21-day (+/- 3 days) intervals (QW3) prior to surgery. Before surgery a tumor assessment will be done. Patients must leave the study if there is evidence of progression. Patients with stable disease or partial response may be considered for surgery. Surgery: Surgery must be done within the 3rd-4th week (+7 days) from day 21 cycle 3 of neoadjuvant treatment (day 42-49 after day 1 of cycle 3)

Drug: Paclitaxel

Other Names:

Taxol

Drug: Carboplatin

Carboplatin must be administered at the end of the Paclitaxel infusion

Other Names:

Paraplatin

Outcome Measures

Primary Outcome Measures

Evaluation of the pathological complete response (pCR) [From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 45 months.]
The pathological complete response is defined as the absence of residual tumor in lung and lymph nodes in patients treated with chemo-immunotherapy versus patients treated with chemotherapy alone.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Previously untreated patients with histologically- or cytologically- documented NSCLC who present stage IIIA disease (according to 8th version of the International Association for the Study of Lung Cancer Staging Manual in Thoracic Oncology) and also, potentially resectable locally advanced NSCLC patients' stage IIIB with T3N2 disease according to 8th edition can be included.

PET/CT including IV contrast (CT of diagnostic quality) will be performed at baseline (28 days +10 before randomization)

Tumor should be considered resectable before study entry by a multidisciplinary team
ECOG (Performance status) 0-1
Screening laboratory values must meet the following criteria and should be obtained within 14 days prior to randomization.

Neutrophils ≥ 1500×109/L ii. Platelets ≥ 100 x×109/L iii. Hemoglobin > 9.0 g/dL iv. Serum creatinine ≤ 1.5 x ULN or creatinine clearance (CrCl) ≥ 40 mL/min v. AST/ALT ≤ 3 x ULN vi. Total Bilirubin ≤ 1.5 x ULN (except subjects with Gilbert Syndrome, who can have total bilirubin < 3.0 mg/dL) vii. The patients need to have a forced expiratory volume (FEV1) ≥ 1.2 liters or >40% predicted value viii. INR/APTT within normal limits

All patients are notified of the investigational nature of this study and signed a written informed consent in accordance with institutional and national guidelines, including the Declaration of Helsinki prior to any trial-related intervention
Patients aged > 18 years
Women of childbearing potential, including women who had their last menstrual period in the last 2 years, must have a negative serum or urine pregnancy test within 7 days before randomization.
All sexually active men and women of childbearing potential must use an effective contraceptive method (two barrier methods or a barrier method plus a hormonal method) during the study treatment and for a period of at least 12 months following the last administration of trial drugs
Patient capable of proper therapeutic compliance and accessible for correct follow-up
Measurable or evaluable disease (according to RECIST 1.1 criteria)

Exclusion Criteria:

All patients carrying activating mutations in the TK domain of EGFR or any variety of alterations in the ALK gene.
Patients with active, known or suspected autoimmune disease. Subjects with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune thyroiditis only requiring hormone replacement or unexpected conditions of recurrence in the absence of an external trigger are allowed to be included.
Patients with a condition requiring systemic treatment with either corticosteroids (>10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of randomization. Inhaled or topical steroids, and adrenal replacement steroid doses > 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease.
Patients with a history of interstitial lung disease cannot be included if they have symptomatic ILD (Grade 3-4) and/or poor lung function. In case of doubt please contact trial team.
Patients with other active malignancy requiring concurrent intervention and/or concurrent treatment with other investigational drugs or anti-cancer therapy
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 complete remission was achieved at least 2 years prior to study entry AND no additional therapy is required during the study period.
Any medical, mental or psychological condition which in the opinion of the investigator would not permit the patient to complete the study or understand the patient information
Patients who have had prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell costimulation or immune checkpoint pathways
Patients with positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection
Patients with known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS)
Patients with history of allergy to study drug components excipients
Women who are pregnant or in the period of breastfeeding
Sexually active men and women of childbearing potential who are not willing to use an effective contraceptive method during the study

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	ICO Badalona	Badalona	Barcelona	Spain	08916
2	ICO Hospitalet	Hospitalet de Llobregat	Barcelona	Spain	08908
3	Hospital Universitario Insular de Gran canaria	Las Palmas De Gran Canaria	Gran Canaria	Spain	35016
4	Complejo Hospitalario Universitario A Coruña	A Coruña	La Coruña	Spain	15006
5	Hospital Universitario Puerta de Hierro	Majadahonda	Madrid	Spain	28222
6	Complejo Hospitalario Universitario de Vigo	Vigo	Pontevedra	Spain	36036
7	Hospital Universitario de Cruces	Baracaldo	Vizcaya	Spain	48903
8	Hospital General de Alicante	Alicante		Spain	03010
9	Hospital Universitari Dexeus	Barcelona		Spain	08028
10	Hospital Universitari Vall d' Hebron	Barcelona		Spain	08035
11	Hospital Clínic de Barcelona	Barcelona		Spain	08036
12	Hospital de Sant Pau	Barcelona		Spain	08041
13	Hospital Universitario Reina Sofía	Córdoba		Spain	14004
14	Hospital Dr. Josep Trueta	Girona		Spain	17007
15	Hospital Clínico San Carlos	Madrid		Spain	28040
16	Hospital Universitario Fundación Jiménez Díaz	Madrid		Spain	28040
17	Hospital Universitario 12 de Octubre	Madrid		Spain	28041
18	Hospital Universitario La Paz	Madrid		Spain	28046
19	Hospital General Universitario de Málaga	Málaga		Spain	29010
20	Hospital Clínico de Salamanca	Salamanca		Spain	37007
21	Hospital Virgen del Rocío	Sevilla		Spain	41013
22	Hospital Clínico Universitario de Valencia	Valencia		Spain	46010
23	Hospital General de Valencia	Valencia		Spain	46014
24	Hospital Clínico Universitario de Valladolid	Valladolid		Spain	47003
25	Hospital Clínico Lozano Blesa	Zaragoza		Spain	50009