Nintedanib (Vargatef®) Plus Docetaxel in Second Line of Treatment in Patients With Lung Cancer (REFRACT)

Multicenter Phase II Trial of Nintedanib (Vargatef®) Plus Docetaxel in Second Line of Treatment in Patients With no Squamous Non Small Cell Lung Cancer Refractory to First Line Chemotherapy

The purpose of this study is to determine whether nintedanib (vargatef®) combined with docetaxel are effective in second line of treatment in patients with no squamous non small cell lung cancer refractory to first line chemotherapy.

Study Overview

• Status: Completed
• Conditions: Lung Neoplasms
• Intervention / Treatment: Drug: vargatef®; Drug: Docetaxel

Detailed Description

59 Patients with histologically documented stage IV NSCLC no squamous, after failure of first line chemotherapy and refractory (progressive disease during first line chemotherapy), will be enroled to receive docetaxel :75 mg/m² IV day 1 every 3 weeks with nintedanib (vargatef®):200 mg X 2/day per os day2-day21.

Tumor response (according to RECIST) will be assessed via computed tomography or magnetic resonance imaging scan every 6 weeks (evaluation of PFS) following completion of chemotherapy.

Adverse events (AEs) were graded according to the National Cancer Institute Common Toxicity Criteria, version 4.0

Quality of life(EQ5-D ) will be assessed every 6 weeks during chemotherapy. Tolerability will be assessed at each visit based on Common Terminology Criteria for Adverse Events (CTCAE), v4.0 criteria.

Total study duration per patient: approximately 12 months .

• Study Type: Interventional
• Enrollment (Actual): 59
• Phase: Phase 2

Contacts and Locations

Study Locations

• France
  • Beauvais, France
    • CH de BEAUVAIS
  • Brest, France
    • CHU Brest
  • Créteil, France
    • Service de pneumologie
  • Gap, France
    • Service de pneumologie
  • LOrient, France
    • CH de Bretagne Sud
  • Limoges, France, 87000
    • CHU de Limoges
  • Mantes La Jolie, France, 78200
    • Centre Hospitalier F. QUESNAY
  • Marseille, France
    • AP-HM
  • Marseille, France
    • Institut Paoli-Calmettes
  • Saint Etienne, France
    • Instiut de Cancérologie
  • Villefranche, France
    • Service de pneumologie

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Histologically confirmed non-squamous NSCLC,
• Metastatic NSCLC of stage IV (according to American Joint Committee on Cancers) or recurrent NSCLC)
• Patients without activating epidermal growth factor receptor (EGFR) mutation
• Patients without anaplastic lymphoma kinase (ALK) rearrangement
• Patients must have measurable lesion by RECIST 1.1
• Refractory disease defined by documented progression during the first-line chemotherapy based on a platinum doublet and third-generation drug (four or less cycles) according to RECIST V.1.1
• Age ≥18 years and < 75 years
• Performance status (PS) 0-1
• Life expectancy of more than 12 weeks.
• No history of other malignancy within the last 5 years, except for adequately treated carcinoma in situ of the cervix or basal cell or spinocellular carcinoma of the skin.
• Adequate organ function, evidenced by the following laboratory results within 3 weeks prior to randomization: Normal hepatic function: bilirubin < 1.5 x N, ALT (alanine transaminase) and AST (aspartate aminotransferase ) < 2.5 x N or <5 x N in case of liver metastasis
• Normal renal function (calculated creatinine clearance ≥ 45 mL/min).
• Normal Calcemia
• Normal haematological function (polynuclear neutrophils > 1.5 G/l, platelets > 100 G/l).
• Anticoagulation with a vitamin K antagonist and low-molecular-weight heparin (LMWH) is authorized.
• Antiplatelet treatment (aspirin authorized if < 325 mg/d)
• Treatment with dipyridamole, ticlopidine, clopidogrel is not authorized
• Women of child bearing potential must use double effective contraception.
• Men might be surgically sterile or accept to use an effective contraceptive procedure during and until 6 months after the treatment.
• Written informed consent to participate in the study.

Exclusion Criteria:

• Known hypersensitivity to the trial drugs (nintedanib (vargatef®), docetaxel), peanut, soya, to their excipients
• Controlled disease after first line treatment
• Contra indication to the use of the backbone treatment
• Patients who were withdrawn from first line treatment due to toxicity without documented disease progression or who received placebo (in the context of a clinical trial) as prior treatment are not eligible.
• Previous treatment with docetaxel
• Small-cell lung cancer, bronchioloalveolar cancer, neuroendocrine cancer.
• Previous therapy with vascular endothelial growth factor (VEGF) inhibitors except bevacizumab
• Centrally located tumour with radiographic evidence of local invasion of local blood vessels
• Radiographic evidence of cavitary or necrotic tumours at screening
• Chemo-, hormone-, radio-(except for brain and extremities) or immunotherapy or therapy with monoclonal antibodies or small tyrosine kinase inhibitors within the past 4 weeks prior to treatment with the trial drug.
• Toxicity non resolute due to prior treatment > grade I (except alopecia).
• Radiotherapy (except extremities) within the past 3 months prior to baseline imaging
• Persistence of clinically relevant therapy related toxicity from previous radiotherapy
• Active brain metastases (e.g. stable for <4 weeks, no adequate previous treatment with radiotherapy, symptomatic, requiring treatment with anti-convulsants; dexamethasone therapy will be allowed if administered as stable dose for at least one month before inclusion).
• Uncontrolled arterial hypertension.
• Concurrent radiotherapy, except for palliative bone irradiation.
• Other concurrent severe illnesses (congestive heart failure, unstable angina, significant arrhythmia or myocardial infarction less than 12 months before study entry).
• Stroke less than 6 months before study entry.
• Psychiatric or neurological disorders preventing the patient from understanding the nature of the trial
• Grade >=1 peripheral neuropathy
• Uncontrolled infection.
• Caval syndrome
• Other organic disorders preventing inclusion in the trial
• Malabsorption syndrome
• Pregnancy and breast-feeding
• Surgery less than two months before study entry.
• Follow-up not feasible.
• Incarcerated and institutionalized

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: traitment; Patients will be treated to oral nintedanib (vargatef®) 400 mg/d on days 2 to 21 of a 3-week cycle including docetaxel 75 mg/m2 by intravenous infusion on day 1	Drug: vargatef®; Patients will be treated to oral nintedanib (vargatef®) 400 mg/d on days 2 to 21 of a 3-week cycle; Other Names: Nintedanib; Drug: Docetaxel; Patients will be treated to IV docetaxel 75 mg/m² on day 1 of evry 3-week cycle; Other Names: Taxotere

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
median progression free survival	12 weeks

Secondary Outcome Measures

Outcome Measure	Time Frame
median progression free survival	12 month
Toxicity (NCIC-CTC version 4.0 criteria)	Every 3 weeks during treatment up to 12 months from inclusion
Quality of life (EQ5-D questionnaire)	every 6 weeks up to 12 months from inlcusion
Response rate	12 month

Collaborators and Investigators

• Sponsor: University Hospital, Limoges
• Collaborators: Boehringer Ingelheim
• Investigators: Principal Investigator: Alain Vergnenegre, MD, CHU Limoges

Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2015
• Primary Completion (Actual): September 26, 2020
• Study Completion (Actual): September 26, 2020

Study Registration Dates

• First Submitted: August 18, 2015
• First Submitted That Met QC Criteria: August 21, 2015
• First Posted (Estimate): August 24, 2015

Study Record Updates

• Last Update Posted (Actual): August 10, 2021
• Last Update Submitted That Met QC Criteria: August 9, 2021
• Last Verified: July 1, 2019

More Information

Terms related to this study

• 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; Enzyme Inhibitors; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Protein Kinase Inhibitors; Docetaxel; Nintedanib
• Other Study ID Numbers: I14041/REFRACT