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

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.

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.

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