Clinical trial NCT02176369: Maintenance Low Dose Oral Navelbine In Patients With Non Small Cell Lung Cancer - MA.NI.LA Trial
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Non-small Cell Lung Cancer Stage IIIB
Non-small Cell Lung Cancer Stage IV
Keywords: Non small cell lung cancer (NSCLC)
Lung tumor in advanced phase
Lead sponsor: Fondazione IRCCS Istituto Nazionale dei Tumori, Milano
Sponsor class: OTHER
Collaborators: name: Regione Lombardia
First posted: 2014-06-27
Enrollment: 120
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Progression Free Survival (PFS)
timeFrame: 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 outcomes:
measure: Overall Survival (OS)
timeFrame: 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
measure: Objective Tumor Response Rate (ORR, CR+PR)
timeFrame: 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
measure: Duration of Response (only in patients in CR or PR)
timeFrame: 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
measure: Duration of Post Progression Survival
timeFrame: 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
measure: Quality of Life (QoL) according to EORTC QLC30, EORTC QOL-LC13
timeFrame: 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
measure: Overall Safety Profile
timeFrame: Assessed at every cycle (3wks) and 28d after last dose intake up to 18 months after LPI
Other outcomes:
Locations:
city: Benevento
country: Italy
facility: Ospedale di Gesù Fatebenefratelli
state: BN
city: Brindisi
country: Italy
facility: ASL Brindisi - Stabilimento Ospedaliero Di Summa-Perrino
state: BR
city: Bolzano
country: Italy
facility: ASP di Bolzano - Comprensorio sanitario di Bolzano
state: BZ
city: Chieti
country: Italy
facility: Ospedale Civile SS. Annunziata
state: CH
city: Catania
country: Italy
facility: A. Ospedaliero-Universitaria Policlinico Vittorio Enmanuele
state: CT
city: Genova
country: Italy
facility: A.O. Villa Scassi
state: GE
city: Milano
country: Italy
facility: Fondazione IRCCS Istituto Nazionale dei Tumori
state: MI
city: Vizzolo Predabissi
country: Italy
facility: A.O. Ospedale di Circolo di Melegnano - P.O. Vizzolo Predabissi
state: MI
city: Palermo
country: Italy
facility: A.O. V. Cervello
state: PA
city: Palermo
country: Italy
facility: Casa di Cura La Maddalena
state: PA
city: Piacenza
country: Italy
facility: AUSL Piacenza - Ospedale Guglielmo da Saliceto
state: PC
city: Pordenone
country: Italy
facility: A.O. Santa Maria Degli Angeli
state: PN
city: Prato
country: Italy
facility: Azienda USL 4 Prato - O.C. Misericordia e Dolce
state: PO
city: Rovigo
country: Italy
facility: Azienda Ulss18 - Ospedale S.M. della Misericordia
state: RO
city: Sondalo
country: Italy
facility: Ospedale Morelli
state: SO
city: Sondrio
country: Italy
facility: A.O. Valtellina e Valchiavenna - Ospedale di Sondrio
state: SO
city: Busto Arsizio
country: Italy
facility: A.O. Ospedale di Circolo di Busto Arsizio
state: VA
city: Varese
country: Italy
facility: Ospedale di Circolo e Fondazione Macchi
state: VA
city: Peschiera del Garda
country: Italy
facility: Casa di Cura Dott. Pederzoli
state: VR
city: Viterbo
country: Italy
facility: AUSL Viterbo - Ospedale di Belcolle
state: VT
Study officials:
affiliation: Fondazione IRCCS Istituto Nazionale dei Tumori, Milano
name: Marco Platania, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: A.O. Valtellina e Valchiavenna - Ospedale di Sondrio
name: Alessandro Bertolini, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: A.O. Ospedale di Circolo di Melegnano - P.O. Vizzolo Predabissi
name: Andrea De Monte
role: PRINCIPAL_INVESTIGATOR
affiliation: AUSL Piacenza - Ospedale Guglielmo da Saliceto
name: Luigi Cavanna, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: A.O. Ospedale di Circolo di Busto Arsizio
name: Marco Bregni, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Azienda Ulss18 - Ospedale S.M. della Misericordia - Rovigo
name: Yasmina Modena, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: AUSL Viterbo - Ospedale di Belcolle
name: Fabrizio Nelli, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Azienda USL 4 Prato - O.C. Misericordia e Dolce
name: Daniele Pozzessere, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: A. Ospedaliero-Universitaria Policlinico Vittorio Emanuele - Catania
name: Hector Soto Parra, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Casa di Cura Dott. Pederzoli - Peschiera del Garda
name: Anna Paola Fraccon, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: ASL Brindisi - Stabilimento Ospedaliero Di Summa-Perrino
name: Saverio Cinieri, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: A.O. Santa Maria Degli Angeli - Pordenone
name: Alessandro Del Conte, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Casa di Cura La Maddalena - Palermo
name: Vittorio Gebbia, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: A.O. Villa Scassi - Genova
name: Manlio Mencoboni, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: ASP di Bolzano - Comprensorio sanitario di Bolzano
name: Silvia Vattemi, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Ospedale Morelli - Sondalo
name: Mario Saverio Fumanò, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: A.O.V. Cervello - Palermo
name: Francesco Verderame, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Ospedale Civile SS. Annunziata - Chieti
name: Luciana Irtelli, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Ospedale di Circolo e Fondazione Macchi, Varese
name: Graziella Pinotti, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Ospedale Sacro Cuore di Gesù Fatebenefratelli - Benevento
name: Antonio Febbraro, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: ASUR Marche Area Vasta 2 - Ospedale E. Profili - Fabriano (AN)
name: Rosa Rita Silva, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: A.O. Fatebenefratelli ed Oftalmico - Milano
name: Gabriella Farina, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Ospedale Civile SS. Annunziata - Sassari
name: Antonio Pazzola, MD
role: PRINCIPAL_INVESTIGATOR
References: