2.1 Recommended Dosage

In Combination with Cisplatin 100 mg/m2

• The recommended dose of NAVELBINE is 25 mg/m 2 administered as an intravenous injection or infusion over 6 to 10 minutes on Days 1, 8, 15, and 21 of a 28 day cycle in combination with cisplatin 100 mg/m 2 on Day 1 only of each 28 day cycle.

In Combination with Cisplatin 120 mg/m2

• The recommended dose of NAVELBINE is 30 mg/m 2 administered as an intravenous injection or infusion over 6 to 10 minutes once a week in combination with cisplatin 120 mg/m 2 on Days 1 and 29, then every 6 weeks.

Single-Agent

• The recommended dose of NAVELBINE is 30 mg/m 2 administered intravenously over 6 to 10 minutes once a week.

2.2 Dose Modifications

Myelosuppression

[see Warnings and Precautions (5.1)]

Hold or decrease the dose of NAVELBINE in patients with decreased neutrophil counts using the following schema.

Hepatic Impairment/Toxicity

[seeWarnings and Precautions (5.2) and Use in Specific Populations(8.6)]

Reduce NAVELBINE dose in patients with elevated serum total bilirubin concentration according to the following schema:

Concurrent Myelosuppression and Hepatic Impairment/Toxicity

In patients with both myelosuppression and hepatic impairment/toxicity, administer the lower of the doses based on the corresponding starting dose of NAVELBINE determined from the above schemas.

Neurologic Toxicity

[see Warnings and Precautions (5.5)]

Discontinue NAVELBINE for for Common Terminology Criteria for Adverse Events (CTCAE) Grade 2 or higher peripheral neuropathy or autonomic neuropathy causing constipation.

2.3 Preparation and Administration

Preparation

Dilute NAVELBINE in an intravenous bag to a concentration between 0.5 mg/mL and 2 mg/mL. Use one of the following recommended solutions for dilution:

• 5% Dextrose Injection, USP
• 0.9% Sodium Chloride Injection, USP
• 0.45% Sodium Chloride Injection, USP
• 5% Dextrose and 0.45% Sodium Chloride Injection, USP
• Ringer's Injection, USP
• Lactated Ringer's Injection, USP

Stability and Storage Conditions of Diluted Solutions

Diluted NAVELBINE may be used for up to 24 hours under normal room light when stored in polyvinyl chloride bags at 5° to 30°C (41° to 86°F).

Administration

Administer diluted NAVELBINE over 6 to 10 minutes into the side port of a free-flowing intravenous line followed by flushing with at least 75 to 125 mL of one of the solutions.

NAVELBINE must only be administered intravenously. It is extremely important that the intravenous needle or catheter be properly positioned before any NAVELBINE is injected.

Parenteral drug products should be visually inspected for particulate matter and discoloration prior to administration whenever solution and container permit. If particulate matter is seen, NAVELBINE should not be administered.

Management of Suspected Extravasation

• If NAVELBINE leakage into surrounding tissue occurs or is suspected, immediately stop administration of NAVELBINE and initiate appropriate management measures in accordance with institutional policies [see Warnings and Precautions (5.4)].

2.4 Procedures for Proper Handling and Disposal

NAVELBINE is a cytotoxic drug. Follow applicable special handling and disposal procedures 1.

Exercise caution in handling and preparing the solution of NAVELBINE. The use of gloves is recommended. If the solution of NAVELBINE contacts the skin or mucosa, immediately wash the skin or mucosa thoroughly with soap and water.

Avoid contamination of the eye with NAVELBINE. If exposure occurs, flush the eyes with water immediately and thoroughly.

Discard unused portion.

5.1 Myelosuppression

Myelosuppression manifested by neutropenia, anemia and thrombocytopenia occur with NAVELBINE as a single agent and in combination with cisplatin [see Adverse Reactions (6.1 and 6.2)]. Neutropenia is the major dose-limiting toxicity with NAVELBINE. Grade 3-4 neutropenia occurred in 53% of patients treated with NAVELBINE at 30 mg/m 2 per week. Dose adjustment due to myelosuppression occurred in 51% of patients (Study 2). In clinical trials with NAVELBINE administered at 30 mg/m 2 per week, neutropenia resulted in hospitalizations for pyrexia and/or sepsis in 8% of patients. Death due to sepsis occurred in 1% of patients. Neutropenia nadirs occur between 7 and 10 days after dosing with neutropenia count recovery usually occurring within the following 7 to 14 days.

Monitor complete blood counts prior to each dose of NAVELBINE. Do not administer NAVELBINE to patients with neutrophil counts <1,000 cells/mm 3. Adjustments in the dosage of NAVELBINE should be based on neutrophil counts obtained on the day of treatment [ see Dosage and Administration (2.2)].

5.2 Hepatic Toxicity

Drug-induced liver injury manifest by elevations of aspartate aminotransferase and bilirubin can occur in patients receiving NAVELBINE as a single agent or in combination with cytotoxic agents. Assess hepatic function prior to initiation of NAVELBINE and periodically during treatment. Reduce the dose of NAVELBINE for patients who develop elevations in total bilirubin > 2 times upper limit of normal [see Dosage and Administration (2.2)and Use in Specific Populations (8.6))].

5.3 Severe Constipation and Bowel Obstruction

Severe and fatal paralytic ileus, constipation, intestinal obstruction, necrosis, and perforation occur with NAVELBINE administration. Institute a prophylactic bowel regimen to mitigate potential constipation, bowel obstruction and/or paralytic ileus, considering adequate dietary fiber intake, hydration, and routine use of stool softeners.

5.4 Extravasation and Tissue Injury

Extravasation of NAVELBINE can result in severe irritation, local tissue necrosis and/or thrombophlebitis. If signs or symptoms of extravasation occur, immediately stop administration of NAVELBINE and institute recommended management procedures [see Dosage and Administration (2.2)and Adverse Reaction (6.1)].

5.5 Neurologic Toxicity

Sensory and motor neuropathies, including severe neuropathies, occur in patients receiving NAVELBINE. Monitor patients for new or worsening signs and symptoms of neuropathy such as paresthesia, hyperesthesia, hyporeflexia and muscle weakness while receiving NAVELBINE. Discontinue NAVELBINE for CTCAE Grade 2 or greater neuropathy [see Dosage and Administration (2.2) and Adverse Reaction (6.1)].

5.6 Pulmonary Toxicity and Respiratory Failure

Pulmonary toxicity, including severe acute bronchospasm, interstitial pneumonitis, acute respiratory distress syndrome (ARDS) occurs with use of NAVELBINE. Interstitial pneumonitis and ARDS included fatalities. The mean time to onset of interstitial pneumonitis and ARDS after vinorelbine administration was one week (range 3 to 8 days) [see Adverse Reactions (6.1)].

Interrupt NAVELBINE in patients who develop unexplained dyspnea, or have any evidence of pulmonary toxicity. Permanently discontinue NAVELBINE for confirmed interstitial pneumonitis or ARDS.

5.7 Embryo-Fetal Toxicity

Based on findings from animal studies and its mechanism of action, NAVELBINE can cause fetal harm when administered to a pregnant woman. In animal reproduction studies in mice and rabbits, embryo and fetal toxicity were observed with administration of vinorelbine at doses approximately 0.33 and 0.18 times the human therapeutic dose, respectively.

Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with NAVELBINE and for 6 months after the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with NAVELBINE and for 3 months after the final dose [see Use in Specific Populations (8.1, 8.3)].

6.1 Clinical Trials Experience

Because clinical trials are conducted under varying designs and in different patient populations, the adverse reaction rates reported in one clinical trial may not be easily compared to those rates reported in another clinical trial, and may not reflect the rates actually observed in clinical practice.

Single Agent

The data below reflect exposure to NAVELBINE as a single agent administered at a dose of 30 mg/m2 on a weekly basis to 365 patients enrolled in 3 controlled studies for metastatic NSCLC and advanced breast cancer. The population included 143 previously untreated metastatic NSCLC patients (Study 3) who received a median of 8 doses of NAVELBINE. The patients were aged 32 to 79 (median 61 years), 71% were male, 91% White, 48% had adenocarcinoma histology. The data also reflect exposure to NAVELBINE in 222 patients with previously treated advanced breast cancer who received a median of 10 doses of NAVELBINE. NAVELBINE is not indicated for the treatment of breast cancer.

Selected adverse reactions reported in these studies are provided in Tables 1 and 2. The most common adverse reactions (≥ 20%) of single agent NAVELBINE were leukopenia, neutropenia, anemia, Aspartate aminotransferase (AST) elevation, nausea, vomiting, constipation, asthenia, injection site reaction, and peripheral neuropathy. The most common (≥ 5%) Grade 3 or 4 adverse reactions were neutropenia, leukopenia, anemia, increased total bilirubin, AST elevation, injection site reaction and asthenia. Approximately 49% of NSCLC patients treated with NAVELBINE experienced at least one dose reduction due to an adverse reaction. Thirteen percent of patients discontinued NAVELBINE due to adverse reactions. The most frequent adverse reactions leading to NAVELBINE discontinuation were asthenia, dyspnea, nausea, constipation, anorexia, myasthenia and fever.

Table 1: Hematologic Adverse Reactions Experienced in > 5% of Patients Receiving NAVELBINE*†:

*Grade based on modified criteria from the National Cancer Institute version 1.

†Patients with NSCLC had not received prior chemotherapy. The majority of the remaining patients had received prior chemotherapy.

Table 2: Non-hematologic Adverse Reactions Experienced in > 5% of Patients Receiving NAVELBINE*†:

*Grade based on modified criteria from the National Cancer Institute version 1.

†Patients with NSCLC had not received prior chemotherapy. The majority of the remaining patients had received prior chemotherapy.

‡ Incidence of paresthesia plus hypesthesia.

Myelosuppression: In clinical trials, Grade 3-4 neutropenia, anemia, and thrombocytopenia occurred in 69%, 9% and 1%, respectively of patients receiving single-agent NAVELBINE. Neutropenia is the major dose-limiting toxicity.

Neurotoxicity: neurotoxicity was most commonly manifested as constipation, paresthesia, hypersthesia, and hyporeflexia. Grade 3 and 4 neuropathy was observed in 1% of the patients receiving single agent NAVELBINE.

Injection site reactions: Injection site reactions, including erythema, pain at injection site, and vein discoloration, occurred in approximately one third of patients; 5% were severe. Phlebitis (chemical phlebitis) along the vein proximal to the site of injection was reported in 10% of patients.

Cardiovascular toxicity: Chest pain occurred in 5% of patients; myocardial infarction occurred in less than 0.1% of patients.

Pulmonary Toxicity and Respiratory Failure: Dyspnea (shortness of breath) was reported in 3% of patients; it was severe in 2%. Interstitial pulmonary changes were documented.

Other: Hemorrhagic cystitis and the syndrome of inappropriate ADH secretion were each reported in <1% of patients.

In Combination with Cisplatin

Table 3 presents the incidence of selected adverse reactions, occurring in ≥ 10% of NAVELBINE treated patients reported in a randomized trial comparing the combination of NAVELBINE 25 mg/m 2 administered every week of each 28-day cycle and cisplatin 100 mg/m 2 administered on day 1 of each 28-day cycle versus cisplatin alone at the same dose and schedule in patients with previously untreated NSCLC (Study 1).

Patients randomized to NAVELBINE plus cisplatin received a median of 3 cycles of treatment and those randomized to cisplatin alone received a median of 2 cycles of treatment. Thirty-Five percent of the eligible patients in the combination arm required treatment discontinuation due to an adverse reaction compared to 19% in the cisplatin alone arm. The incidence of Grade 3 and 4 neutropenia was significantly higher in the NAVELBINE plus cisplatin arm (82%) compared to the cisplatin alone arm (5%). Four patients in the NAVELBINE plus cisplatin arm died of neutropenic sepsis. Seven additional deaths were reported in the combination arm: 2 from cardiac ischemia, 1 cerebrovascular accident, 1 multisystem failure due to an overdose of NAVELBINE, and 3 from febrile neutropenia.

Table 3: Adverse Reactions Experienced by > 10% of Patients on NAVELBINE plus Cisplatin versus Single-Agent Cisplatin*

*Graded according to the standard SWOG criteria version 1.

†Categorical toxicity grade not specified

Table 4 presents the incidence of selected adverse reactions, occurring in ≥ 10% of NAVELBINE treated patients reported in a randomized trial of NAVELBINE plus cisplatin, vindesine plus cisplatin and NAVELBINE as a single agent in patients with stage III or IV NSCLC who had not received prior chemotherapy. A total of 604 patients received either NAVELBINE 30 mg/m 2 every week plus cisplatin 120 mg/m 2 on Day 1 and Day 29, then every 6 weeks thereafter (N=207), vindesine 3 mg/m 2 for 6 weeks, then every other week thereafter plus cisplatin 120 mg/m 2 on Days 1 and Day 29, then every 6 weeks thereafter (N=193) or NAVELBINE 30mg/m 2 every week (N=204).

Patients randomized to NAVELBINE plus cisplatin received a median of 15 weeks of treatment, vindesine plus cisplatin 12 weeks and NAVELBINE received 13 weeks. Grade 3 and 4 neutropenia was significantly greater in the NAVELBINE plus cisplatin arm (78%) compared to vindesine plus cisplatin (48%) and NAVELBINE as a single agent (53%). Neurotoxicity, including peripheral neuropathy and constipation, was reported in 44% (Grade 3-4, 7%) of the patients receiving NAVELBINE plus cisplatin, 58% (Grade 3-4, 17%) of the patients receiving vindesine and cisplatin and 44% (Grade 3-4, 8.5%) of the patients receiving NAVELBINE as a single agent.

Study discontinuation due to an adverse reaction was required in 27, 22 and 10% of the patients randomized to NAVELBINE plus cisplatin, vindesine plus cisplatin and cisplatin alone arms, respectively.

Table 4: Adverse Reactions Experienced by > 10 % of Patients from a Comparative Trial of NAVELBINE Plus Cisplatin versus Vindesine Plus Cisplatin versus Single Agent NAVELBINE*

* Grade based on criteria from the World Health Organization (WHO).

† n=194 to 207; all patients receiving NAVELBINE/cisplatin with laboratory and non-laboratory data.

‡ n=173 to 192; all patients receiving vindesine/cisplatin with laboratory and non-laboratory data.

§ n=165 to 201; all patients receiving NAVELBINE with laboratory and non-laboratory data.

¦ Categorical toxicity grade not specified.

¶ Neurotoxicity includes peripheral neuropathy and constipation.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of NAVELBINE. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Infections and infestations: pneumonia

Immune system disorders: anaphylactic reaction, pruritus, urticaria, angioedema

Nervous system disorders: loss of deep tendon reflexes, muscular weakness, gait disturbance, headache

Ear and labyrinth disorders: vestibular disorder, hearing impaired

Cardiac disorders: tachycardia

Respiratory disorders: pulmonary edema

Vascular disorders: pulmonary embolism, deep vein thrombosis, hypertension, hypotension, flushing, vasodilatation

Gastrointestinal disorders: mucosal inflammation, dysphagia, pancreatitis

Skin disorders: generalized cutaneous reactions (rash), palmar-plantar erythrodysesthesia syndrome

Musculoskeletal and connective tissue disorders: jaw pain, myalgia, arthralgia

General disorders and administration site conditions: injection site rash, urticaria, blistering, sloughing of skin

Injury, poisoning and procedural complications: radiation recall phenomenon, dermatitis, esophagitis

Laboratory abnormalities: electrolyte imbalance including hyponatremia

Other: tumor pain, back pain, abdominal pain

7.1 CYP3A Inhibitors

Exercise caution in patients concurrently taking drugs known to inhibit CYP3A. Concurrent administration of NAVELBINE with a CYP3A inhibitor may cause an earlier onset and/or an increased severity of adverse reactions.

8.1 Pregnancy

Risk Summary

Based on findings from animal studies and its mechanism of action [see Clinical Pharmacology (12.1))], NAVELBINE can cause fetal harm when administered to a pregnant woman. Available human data are insufficient to inform the drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction studies in mice and rabbits, embryo and fetal toxicity were observed with administration of vinorelbine at doses approximately 0.33 and 0.18 times the human therapeutic dose, respectively ( see Data). Advise pregnant women of the potential risk to a fetus.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies are 2 to 4% and 15 to 20%, respectively.

Data

Animal Data

In a mouse embryofetal development study, administration of a single dose of vinorelbine at a dose level of 9 mg/m2 or greater (approximately 0.33 times the recommended human dose based on body surface area) was embryotoxic and fetotoxic. Vinorelbine was embryotoxic and fetotoxic to pregnant rabbits when administered every 6 days during the period of organogenesis at doses of 5.5 mg/m2 (approximately 0.18 times the recommended human dose based on body surface area) or greater. At doses that did not cause maternal toxicity in either species, vinorelbine administration resulted in reduced fetal weight and delayed ossification.

8.2 Lactation

Risk Summary

There are no data on the presence of vinorelbine in human milk or its effects on the breastfed infant or on milk production. Because of the potential for serious adverse reactions in breastfed infants from vinorelbine, advise women not to breastfeed during treatment with NAVELBINE and for 9 days after the final dose.

8.3 Females and Males of Reproductive Potential

Pregnancy Testing

Verify pregnancy status in females of reproductive potential prior to initiating NAVELBINE [see Use in Specific Populations (8.1)].

Contraception

Females

NAVELBINE can cause fetal harm when administered to pregnant women [see Use in Specific Populations (8.1)]. Advise female patients of reproductive potential to use effective contraception during treatment with NAVELBINE and for 6 months after the final dose.

Males

NAVELBINE may damage spermatozoa [see Nonclinical Toxicology (13.1)]. Advise males with female sexual partners of reproductive potential to use effective contraception during treatment with NAVELBINE and for 3 months after the final dose.

Infertility

Males

Based on animal findings, NAVELBINE may impair fertility in males [see Nonclinical Toxicology (13.1)].

8.4 Pediatric Use

The safety and effectiveness of NAVELBINE in pediatric patients have not been established. Results from a single-arm study of NAVELBINE administered at the dose of 33.75 mg/m 2 (for 35 patients) or at the dose of 30mg/m 2 (for 11 patients) every week during 6 weeks followed by 2 weeks of rest was evaluated (courses of 8 weeks).Forty-six patients age 1 to 25 (median 11 years) with recurrent solid malignant tumors, including rhabdomyosarcoma or undifferentiated sarcoma (N=21 patients), neuroblastoma (N= 4 patients), and central nervous system (CNS) tumors (N=21 patients) were enrolled. The most significant grade 3 or 4 hematological adverse reactions were neutropenia (70%) and anemia (33%). The most significant grade 3 or 4 non-hematological toxicity adverse reactions were motor (15%) or cranial (13%) neuropathy, hypoxia (13%) and dyspnea (11%). Objective tumor response was observed in 2 out of 21 patients with rhabdomyosarcoma or undifferentiated sarcoma. No objective tumor response was observed in patients with CNS tumors (N=21) or neuroblastoma (N=4).

8.5 Geriatric Use

Of the 769 number of patients who received NAVELBINE alone and NAVELBINE in combination with Cisplatin in studies 1, 2 and 3, 247 patients were 65 years of age or older. No overall differences in safety, efficacy and pharmacokinetic parameters were observed between these patients and younger patients. [see Clinical Pharmacology (12.3)].

8.6 Hepatic Impairment

The influence of hepatic impairment on the pharmacokinetics of NAVELBINE has not been evaluated, but the liver plays an important role in the metabolism of NAVELBINE. Elevations of aspartate aminotransferase occur in > 60% of the patients receiving NAVELBINE alone (6% Grade 3-4). Therefore, exercise caution in patients with hepatic impairment. Reduce the dose of NAVELBINE for patients with elevated serum total bilirubin concentrations [see Dosage and Administration (2.2) and Warnings and Precautions (5.2)].

12.1 Mechanism of Action

Vinorelbine is a vinca alkaloid that interferes with microtubule assembly. The antitumor activity of vinorelbine is thought to be due primarily to inhibition of mitosis at metaphase through its interaction with tubulin. Vinorelbine may also interfere with: 1) amino acid, cyclic AMP, and glutathione metabolism, 2) calmodulin-dependent Ca++-transport ATPase activity, 3) cellular respiration, and 4) nucleic acid and lipid biosynthesis. Vinorelbine inhibited mitotic microtubule formation in intact mouse embryo tectal plates at a concentration of 2 μM inducing a blockade of cells at metaphase, but produced depolymerization of axonal microtubules at a concentration

40 μM, suggesting a modest selectivity of vinorelbine for mitotic microtubules.

12.3 Pharmacokinetics

The pharmacokinetics of vinorelbine were studied in 49 patients who received doses of 30 mg/m 2 administered as 15- to 20-minute constant-rate infusions. Vinorelbine concentrations in plasma decay in a triphasic manner.

Distribution

Steady-state volume of distribution (V SS) values range from 25.4 to 40.1 L/kg. Vinorelbine demonstrated high binding to human platelets and lymphocytes. The free fraction was approximately 0.11 in human plasma over a concentration range of 234 to 1169 ng/mL. The binding to plasma constituents in cancer patients ranged from 79.6% to 91.2%. Vinorelbine binding was not altered in the presence of cisplatin, 5-fluorouracil, or doxorubicin.

Elimination

The terminal phase half-life averages 27.7 to 43.6 hours and the mean plasma clearance ranges from 0.97 to 1.26 L/hr/kg.

Metabolism

Vinorelbine undergoes substantial hepatic elimination in humans, with large amounts recovered in feces. Two metabolites of vinorelbine have been identified in human blood, plasma, and urine; vinorelbine N-oxide and deacetylvinorelbine. Deacetylvinorelbine has been demonstrated to be the primary metabolite of vinorelbine in humans, and has been shown to possess antitumor activity similar to vinorelbine. Therapeutic doses of vinorelbine (30 mg/m 2) yield very small, if any, quantifiable levels of either metabolite in blood or urine. The metabolism of vinorelbine is mediated by hepatic cytochrome P450 isoenzymes in the CYP3A subfamily.

Excretion

After intravenous administration of radioactive vinorelbine, approximately 18% and 46% of administered radioactivity was recovered in urine and feces, respectively. In a different study, 10.9% + 0.7% of a 30-mg/m 2 intravenous dose was excreted as parent drug in urine.

Specific Populations

Elderly: Age has no effect on the pharmacokinetics (CL, V SS and t 1/2) of vinorelbine.

Drug Interactions

The pharmacokinetics of vinorelbine are not influenced by the concurrent administration of cisplatin.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

The carcinogenic potential of NAVELBINE has not been studied. Vinorelbine has been shown to affect chromosome number and possibly structure in vivo (polyploidy in bone marrow cells from Chinese hamsters and a positive micronucleus test in mice). It was not mutagenic in the Ames test and gave inconclusive results in the mouse lymphoma TK Locus assay.

Vinorelbine did not affect fertility to a statistically significant extent when administered to rats on either a once-weekly (9 mg/m 2, approximately one third the human dose) or alternate-day schedule (4.2 mg/m 2, approximately 0.14 times the human recommended dose) prior to and during mating. In male rats, administration of vinorelbine twice weekly for 13 or 26 weeks at dose levels of 2.1 and 7.2 mg/m 2 (approximately 0.07 and 0.24 times the recommended human dose), respectively, resulted in decreased spermatogenesis and prostate/seminal vesicle secretion.

14.1 Combination Use with Cisplatin

The safety and efficacy of NAVELBINE in combination with cisplatin was evaluated in two randomized, multicenter trials.

Cisplatin 100mg/m2

Study 1 was a randomized, multicenter, open-label trial of NAVELBINE plus cisplatin and cisplatin alone for the treatment of stage IV or stage IIIb NSCLC patients with malignant pleural effusion or multiple lesions in more than one lobe of the ipsilateral lung who had not received prior chemotherapy. A total of 432 patients were randomized 1:1 to receive either NAVELBINE 25 mg/m 2 on Day 1 then every week of each 28-day cycle with cisplatin 100 mg/m 2 administered on Day 1 of each 28-day cycle (N=214) or cisplatin 100 mg/m 2 on Day 1 of each 28-day cycle (N=218).

Patient demographics and disease characteristics were similar between arms. Of the overall study population, the median age was 64 (range 33-84), 66% were male, 80% were Caucasian, 92% had stage IV disease and 8% stage IIIB, 53% had adenocarcinoma, 21% squamous cell, 14% large cell histology. The major efficacy outcome measure was overall survival. The efficacy results are presented in Table 7 and Figure 1.

Table 7. Efficacy Results (Study 1)

Cisplatin 120mg/m2

Study 2 was a randomized, 3-arm, open-label, multicenter trial of NAVELBINE plus cisplatin, vindesine plus cisplatin and NAVELBINE as a single agent for the treatment of patients with stage III or IV NSCLC who had not received prior chemotherapy. The study was conducted in Europe. A total of 612 patients were randomized 1:1:1 to receive NAVELBINE 30 mg/m 2 every week of a 6-week cycle plus cisplatin 120 mg/m 2 on Day 1 and Day 29, then every 6 weeks thereafter (N=206); and vindesine 3 mg/m 2 for 6 weeks, then every other week thereafter plus cisplatin 120 mg/m 2 on Days 1 and Day 29, then every 6 weeks thereafter (N=200) or NAVELBINE 30mg/m 2 every week of a 6-week cycle (N=206). The main efficacy outcome measure was to compare overall survival between NAVELBINE plus cisplatin and vindesine plus cisplatin. The other efficacy outcome measure was to compare overall survival in the better of the two combination regimens to that of NAVELBINE single agent.

Patient demographics were in general similar between arms: the median age of the overall population was 60 years (range 30 to 75), 90% were male, 78% had WHO performance status of 0 or 1. Tumor characteristics were in general similar with the exception of histologic subtype of NSCLC. Adenocarcinoma was the histologic subtype in 32% of patients in the NAVELBINE plus cisplatin arm, 40% of patients in vindesine plus cisplatin arm and 28% of patients on the NAVELBINE arm. Ten percent of the patients had stage IIIA disease, 28% stage IIIB and 50% stage IV. Twelve percent of the patients had received prior surgery or radiotherapy.

The efficacy results of Study 2 are presented in Table 8.

Table 8. Efficacy Results (Study 2)

1n/a = not applicable

14.2 Single Agent

The safety and efficacy of NAVELBINE as a single agent was evaluated in one randomized multi-center trial.

Study 3 was a randomized, open-label clinical trial of NAVELBINE or fluorouracil (FU) plus leucovorin (LV) in patients with Stage IV NSCLC who had not received prior chemotherapy A total of 211 patients were randomized 2:1 to receive NAVELBINE 30 mg/m 2 weekly of an 8-week cycle (N=143) or FU 425 mg/m 2 bolus intravenously plus LV 20 mg/m 2 bolus intravenously daily for 5 days of a 4-weeks cycle (N=68).

Patient demographics and disease characteristics were in general similar between arms. In the overall population, the median age was 61 years (range 32 - 83), 74% were male, 88% were White, 46% had adenocarcinoma histology. Fifty percent of the patients had Karnofsky performance status ≥ 90 in the NAVELBINE arm compared to 38% in the FU and LV arm.

The primary efficacy outcome of the study was overall survival. The median survival time was 30 weeks versus 22 weeks for patients receiving NAVELBINE versus FU/LV, respectively (P=0.06). Partial objective responses were observed in 11.1% (95% CI=6.2%, 17.9%) and 3.5% (95% CI=0.4%, 11.9%) of patients who received NAVELBINE and FU/LV, respectively.