Study of Vinorelbine and Cisplatin as Induction Therapy With Radiotherapy in Patients With Unresectable NSCLC (NORA)

Phase II Clinical Trial With Metronomic Oral Vinorelbine and Tri-weekly Cisplatin as Induction Therapy and Subsequent Concomitantly With Radiotherapy (RT) in Patients With Lung Cancer (NSCLC) Locally Advanced Unresectable

Phase II clinical trial with metronomic oral vinorelbine and tri-weekly cisplatin as induction therapy and subsequent concomitantly with radiotherapy (RT) in patients with lung cancer (NSCLC) locally advanced unresectable

Study Overview

• Status: Completed
• Conditions: Lung Cancer
• Intervention / Treatment: Drug: Vinorelbine; Drug: Cisplatin; Drug: Vinorelbine; Drug: Cisplatin; Radiation: Radiotherapy

Detailed Description

Hypothesis: At present, administration of concomitant chemotherapy and radiation therapy is considered a treatment of choice for patients with unresectable stage III tumor selected clinically.

There is at present a systemic considered standard treatment in combination with radical radiotherapy. Nor is it established a dose of standard radiation therapy, but it is known that should never be less than 60Gy57.

Vinorelbine has shown a strong radio-sensitizer in-vitro37 effect. In the phase II study, The combination of oral vinorelbine with cisplatin as induction therapy and then concomitantly with radiotherapy (66Gy) has provided very encouraging efficacy results. Recently in the vortex scheme cisplatin study with oral vinorelbine concomitant maintained with radiation from the second cycle of chemotherapy was tested.

It is therefore a priority in this segment pathology seeking treatment regimens that improve the effectiveness and toxicity. Metronomic chemotherapy started with the idea of administering a cytostatic divided doses, for an extended period without interruption, can provide the advantage of exposing patients to significant dose chemotherapy without worsening the toxicity profile. All this makes it an attractive treatment strategy, and can also maintain radio sensitizing effect during concomitance.

• Study Type: Interventional
• Enrollment (Actual): 68
• Phase: Phase 2

Contacts and Locations

Study Locations

• Spain
  • Alicante, Spain, 03010
    • H.G.U. Alicante
  • Barcelona, Spain, 08041
    • Hospital de la Santa Creu i Sant Pau
  • Jaén, Spain, 23007
    • Hospital de Jaen
  • Lugo, Spain, 27003
    • Hospital Universitario Lucus Augusti
  • Madrid, Spain
    • H. Clínico San Carlos
  • Madrid, Spain, 28035
    • H.U. Puerta de Hierro
  • Madrid, Spain, 28040
    • Hospital Fundacion Jimenez Diaz
  • Madrid, Spain, 28006
    • H. de la Princesa
  • Palma de Mallorca, Spain, 07198
    • H. Son Llatzer
  • San Sebastian, Spain, 20014
    • H. de Donostia
  • Sevilla, Spain, 41009
    • Hospital Virgen de La Macrena
  • Zaragoza, Spain, 50009
    • Hospital Clinico Lozano Blesa
  • Alicante
    • Elche, Alicante, Spain, 03203
      • Hospital General Universitario de Elche
  • Barcelona
    • Badalona, Barcelona, Spain, 08916
      • Ico-Badalona
  • Castelló
    • Castelló de la Plana, Castelló, Spain, 12002
      • Hospital Provincial de Castellon
  • Mallorca
    • Palma de Mallorca, Mallorca, Spain, 07014
      • H. Son Espases
  • Valencia
    • Xàtiva, Valencia, Spain, 46800
      • Hospital Lluis Alcanyis
  • Vizcaya
    • Bilbao, Vizcaya, Spain, 48013
      • Hospital de Basurto

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion criteria:

• Patients with histologically confirmed recent non small cell lung cancer unresectable stage IIIA and IIIB.
• Perform a baseline positron emission tomography (PET-CT) to rule out the presence of distant disease and confirm that it is a non-NSCLC radical surgical treatment candidate.
• The positive mediastinal lymph nodes by PET-CT must be confirmed histologically. Mediastinal involvement may be considered without histologically observe when there is a mass of lymph nodes where the margins are not distinguished.
• At least one measurable lesion on computerized tomography (CT).
• Performance status 0-1.
• Life expectancy> 12 weeks.
• Age ≥18 years and ≤ 75 years.
• Right renal function: creatinine ≤ 1.5 mg / dl or creatinine clearance> 60 ml / min.
• Right hematologic function: hemoglobin> 10 g / dl, neutrophils ≥ 1500 / mm3 and platelets ≥ 100,000 / mm3.
• Right hepatic function: bilirubin ≤ 1.5 times the upper limit of each center, transaminases ≤ 2.5 above the normal limit.
• Right lung function without bronchodilators: defined by a forced expiratory volume in 1 second (FEV1)> 50% of predicted normal volume and lung diffusing capacity for carbon monoxide (DLCO)> 40% of predicted normal.
• The proportion of normal lung exposed to> 20 Gy RT (V20) shall be ≤ 35%.This must be fulfilled before the start of treatment cycle 3.
• Signature of informed consent.

Exclusion Criteria:

• Weight loss> 10% in the 3 months prior to study entry.
• Intestinal problems that do not ensure proper absorption of oral vinorelbine.
• Pregnant or lactating women. Women of childbearing potential should have a negative pregnancy test, and both men and women under this condition should take contraceptive measures throughout the study.
• symptomatic sensory neuropathy> grade 1 toxicity criteria according to the CTCAE v4.
• Comorbidities uncontrolled.
• syndrome of the superior vena cava.
• pleural or pericardial effusion: are both considered as indicative of metastatic disease unless proven otherwise. Those who still remain cytologically negative for malignancy, are exudates also be excluded. It may include those with pleural effusion visible on chest radiography or too small to perform diagnostic puncture safely.
• Known hypersensitivity to drugs with similar study drug structure.
• Previous treatment with anticancer drugs, previous surgery or thoracic radiotherapy for lung cancer or for other reasons.
• History of other malignancy treated properly within 5 years except carcinoma in situ of the cervix or breast skin and basal cell carcinoma.
• Concomitant treatment with other antineoplastic drug or investigational.
• Patients at any psychological, family, sociological or geographical that may hinder compliance with the study protocol and monitoring program.
• history of neurological or psychiatric disorders that impede a properly understanding of the informed consent.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: 1 Experimental group; 2 cycles of metronomic Vinorelbine 50 mg + cisplatin, followed by 2 cycles of Vinorelbine 30 mg + cisplatin concomitant with radiotherapy Induction chemotherapy: Cisplatin: 80 mg/m2 day 1 every 21 days, for 2 cycles.; Metronomic oral vinorelbine: 50mg/day, 3 days of each week for 2 cycles. Concomitant chemotherapy and radiotherapy: Cisplatin: 80 mg/m2 day 1 every 21 days, for 2 cycles.; Metronomic oral vinorelbine: 30mg/day, 3 days of each week for 2 cycles. 1 cycle equals 21 days Radiotherapy treatment: Patients will receive concomitant thoracic radiation therapy, using a technique three-dimensional conformal radiation therapy, using an accelerator linear that operates with energy rays ≥ 6 MV. The total target RTT dose will be 66 Gy in 33 daily fractions of 2 Gy, which will be prescribed in accordance with the document of ICRU reference 50 of ICRU.

Drug: Vinorelbine; Cycle 1 and 2 50 mg/day, (Monday, Wednesday and Friday); Other Names: Navelbine; Drug: Cisplatin; Cycle 1 and 2 day 1, 80 mg/m2; Drug: Vinorelbine; Cycle 3 and 4 30 mg/day, (Monday, Wednesday and Friday); Other Names: Navelbine; Drug: Cisplatin; Cycle 3 and 4 day 1, 80 mg/m2; Radiation: Radiotherapy; concomitant therapy during cycles 3 and 4. Total dose: 66Gy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free Survival	To evaluate the efficacy in terms of progression-free survival (PFS) of oral metronomical vinorelbine and cisplatin as an induction treatment and then with concomitant radiotherapy. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions The PFS is defined as the time from the moment of patient inclusion to the documentation of progression or death from any cause (patients who die without evidence of progression, will be considered events on the date of death).	From patient inclusion up to the date of first documented progression or date of death from any cause, whichever came first, up to 24 months.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective Response Rate 6 Month	The objective response rate will be calculated from the sum of the number of patients whose best response is complete response, partial response and stable disease divided by the total number of patients eligible for the analysis. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions.	From the start of the treatment of the patient to 6 month afther the treatment end
Overall Survival (Estimated)	Overall survival will be measured from the date of patient inclusion until death or loss of follow-up. In patients who have not died, the duration of survival will be censored on the date of the last contact if the patient causes loss of follow-up or on the date of the latest news.	From the date of randomization until end of follow up or death, up to 24 months.

Collaborators and Investigators

• Sponsor: Spanish Lung Cancer Group
• Investigators: Study Chair: Mariano Provencio, MD, Hospital Puerta de Hierro; Principal Investigator: Bartomeu Massutí, MD, Hospital General Universitario de Alicante; Principal Investigator: Teresa Morán, MD, Germans Trias i Pujol Hospital; Principal Investigator: José Luis González Larriba, MD, Hospital San Carlos, Madrid; Principal Investigator: Manuel Dómine, MD, Instituto de Investigación Sanitaria de la Fundación Jiménez Díaz; Principal Investigator: José Miguel Sánchez, MD, Hospital de La Princesa; Principal Investigator: Ramón de las Peñas, MD, Hospital Provincial de Castellon; Principal Investigator: María Guirado, MD, Hospital Gnral de Elche; Principal Investigator: Dolores Isla, MD, Hospital Lozano Blesa; Principal Investigator: Raquel Marsé, MD, Hospital Son Espases; Principal Investigator: Mª Angeles Sala, MD, Hospital de Basurto; Principal Investigator: Juan Coves, MD, Hospital Son Llatzer; Principal Investigator: Ana Laura Ortega, MD, Hospital de Jaen; Principal Investigator: David Vicente, MD, Hospital Universitario Virgen Macarena; Principal Investigator: Regina Gironés, MD, Hospital Lluis Alcanyis; Principal Investigator: Alfredo Paredes, MD, Hospital de Donostia; Principal Investigator: Margarita Majem, MD, Hospital Sant Pau i de la Santa Creu; Principal Investigator: Sergio Vázquez, MD, Hospital Lucus Agusti

Publications and helpful links

General Publications

• Provencio M, Majem M, Guirado M, Massuti B, de Las Penas R, Ortega AL, Domine M, Marse R, Sala MA, Paredes A, Moran T, Vazquez S, Coves J, Larriba JLG, Sanchez JM, Vicente D, Farre N, Fornos LF, Zapata I, Franco F, Serna-Blasco R, Romero A, Isla D. Phase II clinical trial with metronomic oral vinorelbine and tri-weekly cisplatin as induction therapy, subsequently concomitant with radiotherapy (RT) in patients with locally advanced, unresectable, non-small cell lung cancer (NSCLC). Analysis of survival and value of ctDNA for patient selection. Lung Cancer. 2021 Mar;153:25-34. doi: 10.1016/j.lungcan.2021.01.005. Epub 2021 Jan 10.

Helpful Links

• Web page of the sponsor where users can find more information about Fundación GECP studies

Study record dates

Study Major Dates

• Study Start (Actual): April 15, 2016
• Primary Completion (Actual): April 15, 2019
• Study Completion (Actual): December 16, 2019

Study Registration Dates

• First Submitted: February 2, 2016
• First Submitted That Met QC Criteria: March 15, 2016
• First Posted (Estimated): March 16, 2016

Study Record Updates

• Last Update Posted (Estimated): January 11, 2024
• Last Update Submitted That Met QC Criteria: April 14, 2023
• Last Verified: April 1, 2023

More Information

Terms related to this study

• Keywords: Lung Cancer; Cancer Lung Disease; NORA; GECP 15/02; Metronomic administration
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms; Lung Diseases; Neoplasms by Site; Respiratory Tract Neoplasms; Thoracic Neoplasms; Lung Neoplasms; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Phytogenic; Cisplatin; Vinorelbine
• Other Study ID Numbers: GECP 15/02_NORA; 2015-003312-21 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO