Maintenance Low Dose Oral Navelbine In Patients With Non Small Cell Lung Cancer - MA.NI.LA Trial (ONC-MANILA12)

Maintenance Metronomic Per OS Navelbine In Advanced NSCLC Patients After Previous Platinum Based Chemotherapy: A Multicenter Randomized Best Supportive Care Controlled Phase II Study - MA.NI.LA. Trial

Non Small Cell Lung Cancer (NSCLC) represents the first cancer related cause of death worldwide with 1.4 millions of deaths every years. Current standard therapies include platinum-containing drugs but at one year from diagnosis the survival rate is still low (30-40%) .

The purpose of this study is to evaluate the role of a platinum-free drug, named Vinorelbine, administered by the so called "metronomic schedule" in order to prolong the progression free survival of patients.

Study Overview

• Status: Completed
• Conditions: Non-small Cell Lung Cancer Stage IIIB; Non-small Cell Lung Cancer Stage IV
• Intervention / Treatment: Drug: Vinorelbine

Detailed Description

Systemic therapy remains the mainstay of treatment of advanced stage NSCLC. Combination chemotherapy with a platinum-based regimen has emerged as standard therapy for patients with advanced stage disease. Observations supported by the findings of several clinical trial, established the notion that an efficacy plateau had been reached in advanced stage NSCLC patients treated with platinum-containing drugs.

Recent phase III trials suggest the benefit of "switch" and "continuing" maintenance treatment with different drugs. As "switched therapy", Vinorelbine has been selected on the base of its anti-mitotic role. In fact, the use of anti-mitotic drugs at lower dose but with higher frequency (metronomic schedule) seems to augment the anti-angiogenetic effect of this kind of drugs, thus augmenting the efficacy of the therapy.

Therefore, the purpose of the current study is to evaluate the role of a "switched maintenance" with oral vinorelbine administered as a metronomic schedule in terms of Progression Free Survival (PFS) in advanced NSCLC patients with stable disease after first line platinum based chemotherapy.

• Study Type: Interventional
• Enrollment (Actual): 120
• Phase: Phase 2

Contacts and Locations

Study Locations

• Italy
  • BN
    • Benevento, BN, Italy, 82100
      • Ospedale di Gesù Fatebenefratelli
  • BR
    • Brindisi, BR, Italy, 72100
      • ASL Brindisi - Stabilimento Ospedaliero Di Summa-Perrino
  • BZ
    • Bolzano, BZ, Italy, 39100
      • ASP di Bolzano - Comprensorio sanitario di Bolzano
  • CH
    • Chieti, CH, Italy, 66100
      • Ospedale Civile SS. Annunziata
  • CT
    • Catania, CT, Italy, 95123
      • A. Ospedaliero-Universitaria Policlinico Vittorio Enmanuele
  • GE
    • Genova, GE, Italy, 16149
      • A.O. Villa Scassi
  • MI
    • Milano, MI, Italy, 20133
      • Fondazione IRCCS Istituto Nazionale dei Tumori
    • Vizzolo Predabissi, MI, Italy, 20070
      • A.O. Ospedale di Circolo di Melegnano - P.O. Vizzolo Predabissi
  • PA
    • Palermo, PA, Italy, 90146
      • A.O. V. Cervello
    • Palermo, PA, Italy, 90146
      • Casa di Cura La Maddalena
  • PC
    • Piacenza, PC, Italy, 29121
      • AUSL Piacenza - Ospedale Guglielmo da Saliceto
  • PN
    • Pordenone, PN, Italy, 33170
      • A.O. Santa Maria degli Angeli
  • PO
    • Prato, PO, Italy, 59100
      • Azienda USL 4 Prato - O.C. Misericordia e Dolce
  • RO
    • Rovigo, RO, Italy, 45100
      • Azienda Ulss18 - Ospedale S.M. della Misericordia
  • SO
    • Sondalo, SO, Italy, 23100
      • Ospedale Morelli
    • Sondrio, SO, Italy, 23100
      • A.O. Valtellina e Valchiavenna - Ospedale di Sondrio
  • VA
    • Busto Arsizio, VA, Italy, 21052
      • A.O. Ospedale di Circolo di Busto Arsizio
    • Varese, VA, Italy, 21100
      • Ospedale di Circolo e Fondazione Macchi
  • VR
    • Peschiera del Garda, VR, Italy, 37019
      • Casa di Cura Dott. Pederzoli
  • VT
    • Viterbo, VT, Italy, 01100
      • AUSL Viterbo - Ospedale di Belcolle

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Signed and dated approved ICF
2. Histologically or cytologically confirmed diagnosis NSCLC diagnosis
3. Stage IV (using AJCC 7th edition, or wet IIIb / IV using the 6th edition), or recurrent locally advanced disease not amenable to radiation or surgery with curative intent and not amenable to concurrent chemoradiation
4. Patients with stable disease, after four-six cycles of platinum-based chemotherapy as first line therapy. Patients with partial or complete response during first line chemotherapy according to RECIST criteria can be enrolled provided that they have stable disease at the study entry.
5. Patients who may have received adjuvant treatment (containing also vinorelbine) at least 6 mos before study entry
6. ECOG performance status 0-2
7. Adequate bone marrow reserve as measured by ANC ≥ 1500/mm3, hemoglobin ≥ 9 g/dL, platelet count ≥ 100,000/μL, ≥ 1 week after last transfusion of blood products and/or last dose of hematopoietic growth factor
8. Prothrombin time (PT) or INR or aPTT ≤ 1.5 x ULN
9. Calculated creatinine clearance ≥ 30 mL/min (Cockcroft and Gault Formula)
10. AST (SGOT) and ALT (SGPT) < 2.5 x ULN, AST and ALT < 5 x ULN (if documented liver metastases)
11. Serum bilirubin < 2.0 mg/dL (patients with Gilbert's syndrome: serum bilirubin ≤ 3 x ULN
12. Alkaline phosphatase < 2.5 x ULN (patients with documented liver or bone metastases, alkaline phosphatase ≤ 5 x ULN)
13. No other obvious related major organ toxicities which would compromise the patient's ability to participate in a clinical trial
14. Allowed prior radiation therapy for local or locally advanced disease providing that any clinically significant adverse effects associated with prior therapy have recovered to Grade 1 or less
15. Women of childbearing potential must have a negative serum pregnancy test and agree to use effective birth control during the trial and for 12 wks after the last treatment dose
16. Males must agree to use effective birth control for themselves or their partner during the trial and for 12 wks after the last treatment dose
17. Life expectancy of at least 12 wks
18. Male or female, age ≥18

Exclusion Criteria:

1. Patients who have received induction therapy with platinum obtaining progressive disease
2. Patients who can benefit from pemetrexed maintenance treatment (adenocarcinoma and ECOG PS 0-1) should be excluded. Enrollment in the trial is permitted for patients who refuse maintenance with pemetrexed or in case of clinical contraindications to pemetrexed therapy (for example renal failure, creatinine clearance ≤ 45 mL/min)
3. Patients who have received, or are scheduled to receive, single agent or combination therapy consisting of chemotherapy, targeted, biological, investigational, hormonal as maintenance treatment
4. Previous treatment for metastatic disease with chemotherapy containing oral or i.v. vinorelbine formulation
5. Last dose of induction chemotherapy < 21 d prior to randomization or > 42 d prior to randomization
6. Concurrent treatment with other experimental drugs.
7. Radiation therapy within 3 wks prior to randomization (palliative radiation therapy is allowed, provided that sites of bone marrow production, i.e., iliac crests are not in the radiation field)
8. Major surgery within 4 wks prior to first study drug administration
9. Active central nervous system (CNS) metastatic disease. Patients with stable CNS disease following completion of radiation therapy and/or surgery are eligible
10. Active or chronically recurrent bleeding (e.g., active peptic ulcer disease)
11. Malabsorption syndrome or any other disorder affecting gastrointestinal absorption
12. Clinically significant infection
13. Clinically significant cardiovascular disease or condition including: congestive heart failure (CHF) requiring therapy, need for anti-arrhythmic therapy for a ventricular arrhythmia, severe conduction disturbance, angina pectoris requiring therapy, medically uncontrolled hypertension per the Investigator's discretion, myocardial infarction within 6 mos prior to first study drug administration, New York Heart Association Class II, III, or IV cardiovascular disease
14. Any other severe, acute, or chronic medical or psychiatric condition, laboratory abnormality, or difficulty complying with protocol requirements that may increase the risk associated with study participation or study drug administration or may interfere with the interpretation of study results and, in the judgment of the Investigator
15. History of neoplasm other than curatively treated non-melanoma skin cancer or other carcinoma in situ, that has been resected, unless that prior malignancy was diagnosed and definitely treated at least 3 ys previously with no subsequent evidence of recurrence

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: vinorelbine; 50 mg three times a week for a three weeks cycle	Drug: Vinorelbine; Capsule soft (20/30 mg) - 50 mg three times a week (monday, wednesday and friday) for a three weeks cycle (then recycled the next week at the same doses)Treatment will be continued until progression, unacceptable toxicity or death.; Other Names: Navelbine
No Intervention: Close observation/Best Supportive Care; Close observation/Best Supportive Care (BSC)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression Free Survival (PFS)	PFS: defined as the time from the date of randomization to the date of first documentation of progression, or of death due to any cause, whichever comes first.	Assessed at every 2 cycles (6 wks), 28d after last dose intake and, for patients discontinuing vinolbine for reason other than PD, every 6 wks during Follow Up, up to 18 mos after the enrollment of the Last Patient (LPI)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival (OS)	OS: defined as the time from the date of randomization to the date of death from any cause or the last date the patient was known to be alive.	Assessed at every cycle (3wks), 28d after last dose intake and, during Follow Up, every 3 mos except for patients discontinuing vinolbine for reason other than PD whose assessment is every 6 wks, up to 18 mos after LPI
Objective Tumor Response Rate (ORR, CR+PR)	ORR, CR+PR: defined as the proportion of patients with measurable disease at baseline achieving partial or complete overall best response according to RECIST version 1.1 criteria.	Assessed at every 2 cycles (6wks), 28d after last dose intake and, during Follow Up, every 3 mos except for patients discontinuing vinolbine for reason other than PD whose assessment is every 6 wks, up to 18 mos after LPI
Duration of Response (only in patients in CR or PR)	Duration of Response (only in patients in CR or PR): defined as the time from the date of the first documentation of confirmed objective tumor response to the date of first documentation of objective tumor progression, objective tumor recurrence, or of death due to progressive disease, whichever comes first.	Assessed every two cycles (6wks), 28d after last dose intake and, during Follow Up, every 3 mos except for patients discontinuing vinolbine for reason other than PD whose assessment is every 6 wks, up to 18 mos after LPI
Duration of Post Progression Survival	Duration of Post Progression Survival: defined as the time from the date of first documentation of objective tumor progression to the date of death from any cause or the last date the patient was known to be alive.	Assessed at 28d after last dose intake and, during Follow Up, every 3 mos except for patients discontinuing vinolbine for reason other than PD whose assessment is every 6 wks, up to 18 mos after LPI
Quality of Life (QoL) according to EORTC QLC30, EORTC QOL-LC13		Assessed at every 2 cycles (6wks), 28d after last dose intake and, for patients discontinuing vinolbine for reason other than PD, every 6 wks during Follow Up, up to 18 mos after LPI
Overall Safety Profile	Overall Safety Profile, characterized by type, frequency, severity [graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 4.0], timing and relationship to study therapy of adverse events and laboratory abnormalities.	Assessed at every cycle (3wks) and 28d after last dose intake up to 18 months after LPI

Collaborators and Investigators

• Sponsor: Fondazione IRCCS Istituto Nazionale dei Tumori, Milano
• Collaborators: Regione Lombardia
• Investigators: Principal Investigator: Marco Platania, MD, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano; Principal Investigator: Alessandro Bertolini, MD, A.O. Valtellina e Valchiavenna - Ospedale di Sondrio; Principal Investigator: Andrea De Monte, A.O. Ospedale di Circolo di Melegnano - P.O. Vizzolo Predabissi; Principal Investigator: Luigi Cavanna, MD, AUSL Piacenza - Ospedale Guglielmo da Saliceto; Principal Investigator: Marco Bregni, MD, A.O. Ospedale di Circolo di Busto Arsizio; Principal Investigator: Yasmina Modena, MD, Azienda Ulss18 - Ospedale S.M. della Misericordia - Rovigo; Principal Investigator: Fabrizio Nelli, MD, AUSL Viterbo - Ospedale di Belcolle; Principal Investigator: Daniele Pozzessere, MD, Azienda USL 4 Prato - O.C. Misericordia e Dolce; Principal Investigator: Hector Soto Parra, MD, A. Ospedaliero-Universitaria Policlinico Vittorio Emanuele - Catania; Principal Investigator: Anna Paola Fraccon, MD, Casa di Cura Dott. Pederzoli - Peschiera del Garda; Principal Investigator: Saverio Cinieri, MD, ASL Brindisi - Stabilimento Ospedaliero Di Summa-Perrino; Principal Investigator: Alessandro Del Conte, MD, A.O. Santa Maria Degli Angeli - Pordenone; Principal Investigator: Vittorio Gebbia, MD, Casa di Cura La Maddalena - Palermo; Principal Investigator: Manlio Mencoboni, MD, A.O. Villa Scassi - Genova; Principal Investigator: Silvia Vattemi, MD, ASP di Bolzano - Comprensorio sanitario di Bolzano; Principal Investigator: Mario Saverio Fumanò, MD, Ospedale Morelli - Sondalo; Principal Investigator: Francesco Verderame, MD, A.O.V. Cervello - Palermo; Principal Investigator: Luciana Irtelli, MD, Ospedale Civile SS. Annunziata - Chieti; Principal Investigator: Graziella Pinotti, MD, Ospedale di Circolo e Fondazione Macchi, Varese; Principal Investigator: Antonio Febbraro, MD, Ospedale Sacro Cuore di Gesù Fatebenefratelli - Benevento; Principal Investigator: Rosa Rita Silva, MD, ASUR Marche Area Vasta 2 - Ospedale E. Profili - Fabriano (AN); Principal Investigator: Gabriella Farina, MD, A.O. Fatebenefratelli ed Oftalmico - Milano; Principal Investigator: Antonio Pazzola, MD, Ospedale Civile SS. Annunziata - Sassari

Study record dates

Study Major Dates

• Study Start (Actual): February 1, 2013
• Primary Completion (Actual): October 27, 2018
• Study Completion (Actual): October 27, 2018

Study Registration Dates

• First Submitted: June 11, 2014
• First Submitted That Met QC Criteria: June 26, 2014
• First Posted (Estimate): June 27, 2014

Study Record Updates

• Last Update Posted (Actual): April 22, 2019
• Last Update Submitted That Met QC Criteria: April 19, 2019
• Last Verified: April 1, 2019

More Information

Terms related to this study

• Keywords: Non small cell lung cancer (NSCLC); Lung tumor in advanced phase
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms; Lung Diseases; Neoplasms by Site; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Phytogenic; Vinorelbine
• Other Study ID Numbers: ONC-MANILA12; 2012-001103-21 (EudraCT Number)