Clinical Trials

* On December 23, 2015, Transgene announced that the results from the Phase 2b part of the Phase 2b/3 TIME trial with TG4010 immunotherapy in non-small cell lung cancer (NSCLC) have been published in The Lancet Oncology. The article is entitled “TG4010 immunotherapy and first-line chemotherapy for advanced non-small-cell lung cancer (TIME): results from the phase 2b part of a randomised, double-blind, placebo-controlled, phase 2b/3 trial,” by E. Quoix et al.

The article discusses the results of this 222-patient randomized, double-blind, placebo-controlled study evaluating TG4010 in combination with first-line chemotherapy in Stage IV NSCLC patients. As previously reported, improvements were seen in progression-free survival, overall survival, response rate and duration of response in the TG4010 group compared to control, and these improvements were even more notable in patients with a “low” level of the triple positive activated lymphocytes (TrPAL1 ) biomarker, as well as in those patients with both low TrPAL and non-squamous disease. TG4010 was well tolerated, and the nature and incidence of adverse events in the TG4010 arm were consistent with previous Phase 2 clinical trials. The most frequent TG4010-related adverse events were mild to moderate injection site reactions. 

* On September 8, 2015, Transgene  announced the presentation by Dr. Elisabeth Quoix of final data from the Phase 2b part of the TIME trial with TG4010 MUC1 targeted immunotherapy in non-small cell lung cancer (NSCLC) at the 16th World Conference on Lung Cancer in Denver, CO, USA. The overall survival (OS) data confirm the strength of previously reported improvements and are significant in patients with a “low” level of triple positive activated lymphocytes (TrPAL2), as well as in those patients with low TrPAL and non-squamous disease. Elisabeth Quoix, M.D., Head of the Department of Pulmonology at the University Hospital of Strasbourg and Coordinating Investigator of the TIME study, said: "Lung cancer remains a devastating disease and there is an urgent need for new treatments. Immunotherapies are an area of great promise, and I look forward to the further development of TG4010 in combination with chemotherapy, as well as with immune checkpoint inhibitors, in this important indication."

The TIME trial is a randomized, double-blind, placebo-controlled study evaluating TG4010 in combination with chemotherapy in the first-line treatment of advanced (Stage IV) NSCLC patients. A total of 222 patients were enrolled in the Phase 2b portion of the trial. The primary objective of the Phase 2b part of the study was to analyze progression-free survival (PFS); OS, response rate, duration of response and the safety of TG4010 in combination with chemotherapy were also assessed. Data presented indicated that patients with low levels of TrPAL at baseline showed statistically significant differences in both PFS and OS when treated with TG4010 compared to placebo; a higher response rate and duration of response two times longer than the placebo group were also observed. These improvements were even more notable in the subgroup of patients with both non-squamous disease and low levels of TrPAL. In this important subgroup of patients, 40% were still alive at 24 months in the group treated with TG4010 plus chemotherapy compared to 19% in the control group. Key data presented are outlined below:

*Confidence Interval

In addition, as previously reported, clear activity was also seen with TG4010 in patients having low levels (<5%) of tumor cells expressing PD-L1 (programmed death-ligand 1). TG4010 was well tolerated, and the nature and incidence of adverse events in the TG4010 arm were consistent with previous Phase 2 clinical trials. The most frequent TG4010-related adverse events were mild to moderate injection site reactions. To date, over 350 patients have been treated with TG4010. Further development of TG4010 in NSCLC is planned in combination with chemotherapy and with immune checkpoint inhibitors, such as anti-PDL1 and anti-PD1 inhibitors. 

* On June 1, 2015, Transgene announced the presentation1 of new data from the Phase 2b part of the TIME trial with the TG4010 MUC1 targeted immunotherapy in non-small cell lung cancer (NSCLC) at the 2015 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, IL USA. The more mature data confirmed the strength of the previously reported improvements in progression-free survival (PFS) and overall survival (OS), particularly in patients with non-squamous tumors. In addition, patients treated with TG4010 plus chemotherapy demonstrated improved response rates and a longer median duration of response compared to the control group.
Also of note, in a retrospective analysis of PD-L1 expression in patient tumor cells from the trial, strong activity was seen with TG4010 in patients having low levels (<5%) of tumor cells expressing PD-L1, which accounted for approximately 70% of patientsin the TIME trial. PD-L1 (programmed death-ligand 1) is a protein that is believed to play a major role in suppressing the immune system and is an important target for cancer treatment.

(Abstract #3034. Quoix, E. et al. Results of the phase IIb part of TIME study evaluating TG4010 immunotherapy
in stage IV non-small cell lung cancer (NSCLC) patients receiving first line chemotherapy.)

* On September 29, 2014, Transgene announced the presentation of more mature data from the Phase 2b part of the TIME trial with TG4010 MUC1 targeted immunotherapy at the European Society of Medical Oncology (ESMO) 2014 Congress in Madrid, Spain. The data presented show promising and consistent results in progression-free survival (PFS) and overall survival (OS), particularly in the large subgroup of patients with non-squamous disease  A total of 222 patients were enrolled in the Phase 2b portion of the trial, and enrollment is now completed. The primary endpoint of the Phase 2b part of the study is to prospectively validate the TrPAL predictive biomarker3; the safety and efficacy of TG4010 in combination with chemotherapy in this patient population were also assessed, including in pre-specified subgroups. On May 27, 2014, the Company announced that the primary endpoint of PFS in the normal TrPAL group was met. The high TrPAL group has not yet met the required number of events to conduct the primary analysis. A recent analysis was conducted with a more mature data set. In the subgroup of patients with non-squamous histology - 88% of patients in the trial - statistically significant differences in PFS, as well as compelling and clinically meaningful differences in OS, continue to be observed. The OS data continue to mature. Consistent with previous communications, these improvements were even more notable in the so-called “low”4 TrPAL groups of patients. Key data are outlined below:  1 TG4010 was well tolerated, and the nature and incidence of adverse events in the TG4010 arm were consistent with previous Phase 2 clinical trials. The most frequent TG4010-related adverse

2 The primary endpoint is based on a Bayesian probability analysis of progression-free survival (PFS) from the Phase 2b part of the TIME trial and an earlier Phase 2 study (TG4010.09) in advanced NSCLC patients. (see press release of May 27, 2014)

3 The level of triple positive activated lymphocytes: CD16+CD56+CD69+ (TrPAL) cells at baseline using a pre-defined threshold level, the so-called “upper limit of normal” or ULN; patients were classified as “normal” or “high” TrPAL using this method.

4 The level of TrPAL cells at baseline as determined using a quartile approach; “low” TrPAL patients were in the three lowest quartiles.

Intent-to-treat (ITT)Progression-Free SurvivalOverall SurvivalSubgroupTotal # of patients (TG4010/placebo)Hazard Ratio (95% confidence interval)+Hazard Ratio (95% confidence interval)+Non-squamous195 (97/98)0.71 (0.51, 0.97)0.73 (0.50, 1.07)++Non-squamous, low TrPAL131 (64/67)0.60 (0.41, 0.88)0.70 (0.45, 1.10)++++ Stratified Cox proportional hazards model ++ Overall survival analysis based on 56% of possible events +++ Overall survival analysis based on 60% of possible events were mild to moderate injection site reactions. To date, over 350 patients have been treated with TG4010 and the product has been consistently well tolerated across trials.  Recent interactions with regulatory authorities have encouraged Transgene to move forward with the preparations for the Phase 3 part of the TIME trial. This trial is planned to enroll only patients with non-squamous disease. Transgene is seeking a global development and commercialization partner for TG4010 and talks are ongoing with potential partners.

* On September 8, 2014, Transgene provided an update on one of its lead development programs, TG4010 MUC-1 targeted cancer immunotherapy. Updated data, although still maturing, for overall survival (OS), a secondary endpoint in the TG4010 TIME trial, show an improvement in line with that observed with the progression-free survival (PFS) data from the study, as reported earlier this year. Updated results will be presented at the European Society of Medical Oncology (ESMO) 2014 Congress in Madrid, September 26-30, 2014.

* On May 27, 2014, Transgene announced results in an update incorporating more mature data from the Phase 2b part of the Phase 2b/3 TIME trial with TG4010 MUC-1 targeted immunotherapy in patients with advanced non-small cell lung cancer. Following an analysis conducted with a more mature dataset, the primary endpoint of progression-free survival (PFS) to validate the TrPAL predictive biomarker was met in the normal TrPAL3 group. The high TrPAL group had not yet met the required number of events to conduct the primary analysis. Importantly, in the subgroup of patients of non-squamous histology (191 out of 217 patients), the vast majority of patients in the trial, the difference in PFS was statistically significant and clinically meaningful with a p value of 0.02 and a stratified log rank hazard ratio (HR) of 0.71 [0.51; 0.98] (intent-to-treat analysis). As expected, in this non-squamous population, the PFS HR observed was even more notable in the normal TrPAL subgroup of patients. TG4010 was well tolerated, and the nature and incidence of adverse events in the TG4010 arm were consistent with previous Phase 2 clinical trials. To date, over 350 patients have been treated with TG4010. Data for overall survival, a secondary endpoint in the TIME trial, although not yet mature, are suggesting a clinically meaningful improvement in line with the one observed with the PFS data. Detailed results from the TIME trial, including overall survival, are expected to be presented at a major medical meeting later this year. The Company will be interacting with regulatory authorities to discuss the data from the TIME trial in preparation of the phase 3 part of the trial.

* On April 28, 2014,Transgene has announced that Novartis has informed the company that it will not exercise its option for the global development and commercialization rights to TG4010 MUC1 targeted cancer immunotherapy. As a result, Transgene retains all rights to the program. Transgene said that the company is committed to start a Phase 3 trial in advanced lung cancer as rapidly as possible as the data obtained with this cancer immunotherapy are compelling. The company will be actively looking for a partner to co-develop and commercialize TG4010. Plans for the Phase 3 part of the TIME trial in MUC1+ patients with Stage IV non-small cell lung cancer (NSCLC) are well advanced, and Transgene is working to move into Phase 3 in the second half of this year, contingent on discussions with regulatory authorities. The data from the Phase 2b part of the TIME trial continue to mature; Transgene expects detailed results to be presented at a major medical meeting later this year, probably at the next ESMO congress.

* On January 8, 2014, Transgene has announced preliminary results from the Phase 2b part of the Phase 2b/3 TIME trial evaluating TG4010 MUC-1 targeted immunotherapy in combination with chemotherapy versus placebo plus chemotherapy in the first-line treatment of MUC-1 positive advanced non-small cell lung cancer (NSCLC) patients. The primary objective of the Phase 2b part of the study was to validate the triple-positive activated lymphocytes (TrPAL) predictive biomarker1; the safety and efficacy of TG4010 in combination with various chemotherapy regimens in this patient population were also assessed. The predictive value of the TrPAL biomarker, which was identified in an earlier Phase 2 study in advanced NSCLC patients (the TG4010.09 study), was assessed by comparing progression-free survival (PFS) between the two arms in two subgroups of patients according to their TrPAL  level (normal or high) at the time they entered the trial (baseline).  A total of 210 patients (170 normal TrPAL level, 40 high TrPAL level) were enrolled in the study, and the current analyses were conducted per protocol after 89 progression events had occurred in the normal TrPAL group.  For the primary analysis, a patient’s TrPAL level was determined using a threshold based on an assessment of TrPAL levels in healthy people, a so-called “upper limit of normal” (ULN) threshold. The study did not meet its primary endpoint when the ULN threshold was used. However a second pre-planned PFS analysis, described below, was performed on the entire study population using a quartile approach similar to the one performed in the prior TG4010.09 study. This analysis and the data generated, which is discussed below, will lead to a refined threshold, which is different than the ULN threshold, for the Phase 3 part of the trial.

With this threshold the quartile analysis showed that, in the 75% of patients having the lower baseline level of TrPAL (i.e., the three lowest quartiles) and who received TG4010, there was a clinically meaningful improvement in PFS, as indicated by a greater than 25% reduction in the risk of progression or death compared to placebo. Conversely, in the 25% of patients with the higher level of TrPAL (highest quartile) and who received TG4010 there was no improvement In PFS.