Statistical Analysis Report

Phase III study on the efficacy and safety of autologous dendritic cell therapy (Denvax) on advanced stage cancer patients belonging to solid cancers, multiple myeloma and lymphoma.

Introduction

This document describes data management procedures, statistical analysis and reporting of the Phase III study on the efficacy of autologous dendritic cell therapy (Denvax) on advanced stage cancer patients belonging to solid cancers, multiple myeloma and lymphomas. Trial was conducted during 2005-2008 after the ethics committee approval. All the patients were enrolled after satisfying the study inclusion and exclusion criteria and signing the informed consent. Few subjects were enrolled based on waiver criteria adopted by institutional ethics committee in the mid of trial to allow willing patients to initiate this therapy at stage II and III disease. The idea was to evaluate efficacy of Denvax to stop relapse of cancer in this group.

Objective

Primary objective of the study was to evaluate safety of the product Denvax and determine the symptomatic benefit in terms of improvement in quality of life (QoL) in advanced stage cancer patients. Progression-free (PFS) and Overall Survival (OS) were also assessed as secondary parameters including determining median survival by Kaplan Meier graph.

Sample size

Total of 330 patients were enrolled in the study to meet the objective. Two subjects did not take the dose; therefore 328 patients were included in the analysis.

For single arm study, such sample size is considered adequate to characterize the efficacy and safety of a phase III study of autologous dendritic cell therapy (Denvax) on advanced stage cancer patients belonging to solid cancers, multiple myeloma and lymphomas.

Data management

Each patient data demography and baseline characteristics, vitals, laboratory values, performance and survival status was collected in case report form. Data

processing was performed in MS Excel 2003 and PC SAS 9.1.3 for analysis and reporting.

Adverse event verbatim terms were coded using MedDRA 10.0 (Medical Dictionary) preferred term.

Missing or unknown data was treated as it is; no imputation was attempted in the analysis.

Analysis Population

All enrolled population: Those subjects who have enrolled and signed the ICF.

Intention-To-Treat (ITT) population: Those subjects who have taken at least one dose and have post baseline data.

Safety Population: Same as ITT population.

Statistical Methods

All the available data were analyzed using descriptive statistics. Continuous parameters like Age and Weight were summarized with mean, standard deviation and categorical values like Gender with counts and percentage. Change values were analyzed using paired T-test for Weight gain and Exact 95% confidence interval for the Benefit outcome. Incidence analysis was performed for the adverse events data, subjects were counted once in case there are multiple occurrences of an event.

Results          

Table 1 depicts demography profile and disease baseline characteristics. Both the sexes were equally represented (Male=55%) with average age 50 years, weight 54 kg and height 172 cm. Most of the participants had at least one treatment with chemotherapy (76%) and one-third subjects were treated by surgery and radiation also.

 As shown in the Table 2, incidences of at least one Adverse Event was noted in 65% (212/328) of subjects and most of them were mild and moderate in intensity and considered as drug related (Table 3, 64% incidences were drug related).

Only one case, pt#0173 has shown worsened pain after 7 days of the first dose with severe intensity and outcome was unresolved. This patient was having advanced stage WHO grade IV glioma and probably not responded to Denvax and had uncontrolled disease progression.  

Table 4 summarizes the laboratory values at baseline and post-dose, most of the changes are minor and may not have much biological significance.

A slight weight gain less than a kg was reported during the study (Table 5).

Table 6 has estimated the survival benefit approximately 71% with 95% Confidence Interval=66 to 76%).

Table 7 summarizes the vital signs and appears all the values are within the normal range.

Remarkable shift has been noted at the post dose in terms of ECOG performance status (Table 8, 70% subjects have shown ECOG score 2 or less as compared to the baseline which was ~40%).

Kaplan-Meier graph (Figure 1) describes the median survival of the patients. Data were available for 328 patients among which 61 cases (18.6%) are censored either data was not available or survival was unknown. As shown in the table 9, median overall survival is 240 days and mean is 360.58 days.

Enclosures

1.  Table 1 

2.  Table 2 

3.  Table 3 

4.   Table 4 

5.   Table 5 

6.   Table 6 

7.   Table 7  

8.   Table 8 

9.   Table 9  

10. Figure – 1