FIELD OF INVENTION
The present invention relates to improving outcome of current therapies for Non Small cell Lung Cancer, particularly that of Squamous cell carcinoma of the lung.

BACKGROND OF INVENTION
. Lung cancer is the leading cause of cancer-related Deaths world wide with 1.2 million new cases diagnosed every year and with 1 million deaths being recorded worldwide in 2001. Approximately 75%-85% of these patients have non small cell lung cancer and rest have small cell lung cancer. Non small cell lung cancer (NSCLC) has been further classified as per histology into adenocarcinoma, squamous cell carcinoma, large cell carcinoma etc.
Historically, first-line treatment for patients with advanced NSCLC has been platinum-based doublet chemotherapy in combination with a third-generation cytotoxic compound such as gemcitabine (Gemzar; Eli Lilly and Company, Indianapolis, IN), Paclitaxel (Taxol; Bristol-Myers Squibb, Princeton, NJ) or Docetaxel (Taxotere; Sanofi-Aventis, Bridgewater, NJ). Clinical trials of a platinum based therapy in combination with any of these agents demonstrated comparable efficacy, and meta-analyses showed that these regimens offered superior survival and symptom palliation versus best supportive care. The study conducted by Eastern Cooperative Oncology Group (ECOG) comparing four platin-based, two-drug chemotherapy regimens in more than 1100 patients suggests no significant differences in overall survival among the groups.
The first line therapy is offered irrespective of histology of the tumor. The efforts are made to improve the out come of first line therapy without any success..
Recently Bevacizumab is approved as add on therapy to first line therapy for non squamous cell lung cancer. Bevacizumab has been demonstrated in combination with first line therapy to improve outcomes over those seen with first line therapy alone in the treatment of advanced non squamous NSCLC. The two large, phase III, randomized trials leading to these relevant results have administered bevacizumab with carboplatin plus paclitaxel and cisplatin plus gemcitabine as first line therapy
Similarly it is also observed that pemetrexed is useful in non squamous carcinoma of lung. Non squamous patients treated with pemetrexed-based therapy experienced longer survival than the comparators (HR, 0.78 and 0.84 respectively), whereas squamous patients had shorter survival (HR, 1.56 and 1.23 respectively). It is recommended that it should not be used in squamous cell carcinoma of lung as it worsens the prognosis.
Thus, histology of tumor plays significant role in improvement with first line therapy by addition of a new drug.
There is a significant improvement in outcome of non squamous lung cancer recently but no further improvement is seen in patients suffering from squamous cell carcinoma.
Thus, there is a need to provide a pharmaceutical composition to improve therapy for squamous cell carcinoma of lung.

DETAIL DESCRIPTION OF FIGURE
Figure 1 shows overall survival in non small cell lung cancer
Figure 2 shows overall survival in squamous cell carcinoma of lung
Figure 3 shows overall survival in patient(s) with Adenocarcinoma

DETAILED DESCRIPTION OF THE INVENTION
Surprisingly it is observed that therapy using pharmaceutical compositions containing mycobacterium W when administered to patients suffering from non small cell carcinoma; the benefit is seen maximum in patients suffering from squamous cell carcinoma.
Following examples demonstrate the present invention without limiting the scope of the invention:

Example 1: Pharmaceutical composition as per present invention:

Each dose of 0.1 ml contains:
Mycobacterium A (heat killed) 0.50 x 109
Sodium Chloride I. P. 0.90% w/v
Thiomerosal I. P. 0.01% w/v (As a Preservative)
Water for Injection I. P. q. s to 0.1 ml

Example 2: Efficacy of Pharmaceutical composition in Squamous cell lung cancer:

In an open label, multicentric, randomized, comparative controlled clinical trial, mycobacterium w was evaluated in combination with Paclitaxel and Cisplatin for its effect on improvement in overall survival in patients with advanced non small cell lung cancer.

Agent Dose Route Schedule
Paclitaxel 175 mg/m2 IV over 3 hrs before Cisplatin Day 1 of each cycle
Cisplatin 100 mg/m2 IV over a hr after completion of Paclitaxel through separate IV line Day 1 of each cycle
Mycobacterium W 0.1 ml* Intradermal 0.1 ml over each deltoid on first visit & 0.1 ml subsequently At least 1 week prior to first cycle & every 2nd & 3rd wek of all the cycles
* Containing 0.50 x 109 heat killed mycobacterium W.

The study was conducted on total 221 patients.

Dosage Schedule:
Test arm received Paclitaxel + Cisplatin by intravenous infusion on day 1 of a 21 days cycle for a total of 4 cycles. In addition, mycobacterium W was given intradermally at least one week prior to the first cycle of chemotherapy and then in every second and third week of all the cycles of chemotherapy.
Control arm received only chemotherapy (Paclitaxel + Cisplatin) by intravenous infusion on a 21 days cycle x 4 cycles.

The patients enrolled in the trial met following Inclusion Criteria:
• Histologically or cytologically confirmed Non-Small Cell Lung Cancer, Stage IIIB or IV.
• Age: 18 years and above
• ECOG status in 0-1 range
• Absolute neutrophil count = 1500/mm3, Platelet count = 1,00,000/mm3
• Hemoglobin = 9.0g/dL
• AST and ALT = 2.5 times Upper Limit of Normal (ULN) (5 times ULN if liver metastasis present)
• Bilirubin not greater than 1.5 times ULN (3 times ULN if liver involvement).
• Creatinine = upper limit of normal (ULN)
• Negative pregnancy test for women of child bearing potential prior to entry into the trial
• Ability to understand and the willingness to sign a written informed consent document

Following patients were excluded:
• Patient who had received cytotoxic chemotherapy or radiotherapy prior to entering the study
• Patient with systematic brain metastasis
• History of allergic reaction attributed to Paclitaxel, Cisplatin or mycobacterium w or any of their ingredients
• Pregnant women or nursing women
• Uncontrolled intercurrent illness that would limit compliance with study requirements
• HIV positive patients
• Previous splenectomy

Efficacy Analysis:
All the analysis reported is as per protocol. Survival was defined as the time from randomization to death from any cause, and progression free survival as the time from randomization to documented disease progression or death.

Results:
A total of 221 patients were enrolled in the trial, of which 109 were allocated to the test arm and 112 to the control arm. Both the groups were comparable in all baseline characteristics (Table-1).
Table-1 Baseline Characteristics

Parameters Test

N=109 Control

N=112
Sex [No.(%)]
Female

Male
18 (16.6%)
14 (12.5%)
91 (83.4%) 98 (87.5%)
Age (yrs) 56.4±11.0 56.9 ± 10.4
Weight (Kg) 49.8±10.7 50.5± 8.9
ECOG I 63 (57.8%) 66 (58.9%)
ECOG 0 46 (42.2%) 46 (41.1%)
Stage of Disease IIIB 54 (49.54%) 61 (54.46%)
Stage of Disease IV 55 (50.46%) 51 (45.54%)
NSCLC Type
Adenocarcinoma 45 50
Squamous Cell Carcinoma 19 24
Others 42 34
Large Cell Carcinoma 3 4

Use of mycobacterium W is associated with significant improvement in overall survival (Figure 1) in test arm in comparison to the control arm. Median over all survival was 233 days in control arm and was improved by 66 days to 299 days in test arm.

Improvement in survival appears to be more in patients with Squamous cell carcinoma (Figure 2) in comparison to those with Adenocarcinoma (Figurer 3), with median survival 364 days and 283 days, respectively. The difference in median survival in relation to control group was 110, and 56 days, respectively. Thus improvement in survival is almost double compared to adenocarcinoma.

Date: 11-01-2011 For, CADILA Pharmaceuticals Ltd,

___________________________
Dr. Bakulesh M. Khamar
Executive Director – Research

Sheet 1

Date: 11-01-2011 For, CADILA Pharmaceuticals Ltd,

___________________________
Dr. Bakulesh M. Khamar
Executive Director – Research

Sheet 2

Date: 11-01-2011 For, CADILA Pharmaceuticals Ltd,

___________________________
Dr. Bakulesh M. Khamar
Executive Director – Research

Sheet 3

Date: 11-01-2011
For, CADILA Pharmaceuticals Ltd,

___________________________
Dr. Bakulesh M. Khamar
Executive Director – Research