Date: 2016-12-13
Type of information: Results
phase: 2
Announcement: results
Company: Genticel (France)
Product: GTL001/ProCervix®
Action
mechanism: therapeutic vaccine/immunotherapy product. GTL001/ProCervix® is an investigational vaccine designed to cure women who are already infected by the HPV16 or HPV18 virus types. It uses the Adenylate Cyclase (CyaA), a protein vector delivering the E7 antigens from HPV 16 and HPV18. The CyaA vector directly targets professional antigen presenting cells. Through its unique delivery mode, CyaA allows the antigen to induce strong CD4+ and CD8+ T cell responses.
Disease: treatment of adult women already infected with human papillomavirus (HPV) genotype 16 or 18
Therapeutic area: Infectious diseases
Country: Belgium, Finland, France, Germany, The Netherlands, Spain, UK
Trial
details: RHEIA-VAC (Research on HPV Eradication In Adults by VACcination) is a Phase II study of the ProCervix therapeutic vaccine. ProCervix is used for HPV 16 and/or 18 infected women, who have normal cervix cytology or ASCUS (Atypical Squamous Cells of Undetermined Significance)/LSIL(Low grade Squamous Intra-epithelial Lesions) (mild cervical cellular dyskaryosis). RHEAIA-VAC is a double-blinded, randomized and placebo-controlled efficacy study. Viral clearance at 12 months is the primary endpoint. The trial has enrolled 239 HPV 16/18 positive patients at 39 investigational sites in seven Western Europe countries. The trial consists of a treated arm with 117 patients and a placebo arm with 116 patients. A total of 232 evaluable patients are included in the topline results per protocol efficacy analysis. Enrolled patients are required to be HPV 16 and/or 18 positive with normal, LSIL or ASCUS cytology. Patients with CIN2+ were excluded by colposcopy/histology. All patients received either 2 inter-dermal injections of 600 µg of GTL001 or 2 inter-dermal injections of placebo 6 weeks apart, and in both cases 2 applications of imiquimod cream 5%, 15 minutes and 24 hours after each injection of vaccine or placebo. The patients in both arms who received the full dose of vaccine or placebo were assessed for viral clearance at 12 months as the primary endpoint, and for secondary endpoints including maintenance of viral clearance and progression to CIN2+.
Viral clearance is assessed using a type specific, sensitive and quantitative HPV PCR assay. All patients in the trial continue to be followed for safety at 18 and 24 months and efficacy at 15, 18 and 24 months after their second injection. Additional data, including maintenance of viral clearance, viral load dynamics, and progression to CIN2+ will be evaluated. (NCT01957878)
Latest
news: * On December 13, 2016, Genticel announced the final results (24-month time point) of the phase 2 trial of its HPV16/18 immunotherapeutic candidate, GTL001. The final data at month 24 showed no statistical differences in viral clearance rates between the GTL001 and placebo groups. No consistent statistical differences between groups were demonstrated in any of the secondary endpoints (confirmed and sustained clearance) over the 2-year duration of the trial. The incidence of subjects progressing to high-grade lesions was identical in both groups. A significant increase in anti-CyaA1 antibodies following treatment was observed in the GTL001 group, but not in the placebo group. The significant increase in anti-CyaA titers in the treated group persisted during the entire course of the study. * On January 27, 2016, Genticel announced initial results from the ongoing randomized, double-blind, placebo controlled phase 2 clinical study of its immunotherapeutic candidate, GTL001, designed to clear HPV 16 and/or 18 infection. While there was no statistical difference in viral clearance between treatment and placebo in the overall study population at 12 months, there was a clear separation in 2 predefined subgroups, namely patients with normal cytology and patients less than 30 years old at baseline. Statistically significant viral clearance data at 18 months in the overall population will be determinant to trigger phase 3 preparation. These data will be reported in Q3 2016. The independent DSMB (Data Safety and Monitoring Board) recommended on January, 26, 2016, the continuation of the study per protocol. n = 117 57 (48.7%) n = 116 46 (39.7%) n = 32 20 (62.5%) n = 30 12 (38.7%) n = 29 17 (58.6%) n = 28 9 (32.1%) These results strongly suggest that Genticel’s antigen delivery technology is effective in these 2 subgroups of patients. While HPV positive women with normal cytology represent only 25% of the study population, they account for over 70% of the women infected with HPV 16/18 in the general population. The results are also consistent with those of the phase 1 study of GTL001, in which the study population comprised exclusively women with normal cytology (NILM). In addition, it has been observed that it takes longer to clear infection in women with abnormal cervical cytology than in women with normal cytology. It has also been shown that higher viral loads at baseline are associated with longer time to complete clearance. Because abnormal cytology, which represents over 70% of this phase 2 study population, is usually associated with higher viral load, it can be expected that viral clearance will take longer. GTL001 viral clearance data collected at 18 months may therefore demonstrate a statistically significant therapeutic effect in the overall population at a later time point than 12 months. The phase 2 study continues to collect additional data that will be reported at 18 and 24 months. In this phase 2 study, GTL001 appears to be generally safe and well-tolerated with the expected transient local reactions at injection site identified as the most common adverse events. There is no unexpected safety signal has been observed in the study. * On July 10, 2014, Genticel announced that the enrollment of the Phase II RHEIA-VAC study has reached the halfway mark of its recruitment target. The study is on track with Genticel’s initial projections. All of the 39 investigation sites across seven European countries (Belgium, Finland, France, Germany, the Netherlands, Spain and the UK) are fully operational. Furthermore, the Data and Safety Monitoring Board (DSMB), an independent committee of experts who monitor safety data every six months during the study, met as scheduled on July 1st and recommended pursuing the RHEIA-VAC study as planned. * On March 4, 2014, Genticel has announced that it has started a phase II study with its lead product ProCervix®, a therapeutic vaccine designed to induce a curative cellular immune response in patients infected with HPV16 and/or HPV18. ProCervix® is targeted at women already infected by the HPV16 and/or HPV18 viruses before high-grade lesions or cancer occur. It is the first therapeutic vaccine to address the medical need of this high-risk population, because the preventive HPV vaccines are only effective in people who are not yet infected. The Phase I study was conducted at the Vaccine and Infectious Disease Institute of the University of Antwerp, Belgium under the direction of Professor Pierre Van Damme. The results indicated that ProCervix® has a satisfactory safety, local tolerance and immunogenicity profile. This study revealed the dose and vaccination regime required for further development. The clearance of HPV virus and maintenance of virus-free status was also markedly higher in the patients treated with ProCervix versus those in the placebo group.
The 12-month results announced in January 2016 showed no overall difference in viral clearance between the treatment and placebo groups, but a trend towards a significant difference in sub-group analyses was observed, most notably in the NILM2 sub-group. The interim analysis at 18 months demonstrated that overall viral clearance, or by sub-group, did not statistically differ from the natural clearance observed in the placebo
group. Other than the first days following each vaccination, GTL001 and imiquimod were generally well tolerated
with no unexpected safety signal identified at any point during the study. Benedikt Timmerman, PhD, MBA, Chief Executive Officer of Genticel, said: “Genticel will now end its HPV therapeutics development program and the Company remains focused on seeking new drug candidates, as well as moving forward with our partnership with the Serum Institute, which recently resulted in a $1.2 million milestone payment to Genticel based on the successful completion of the last preclinical milestone.”
The 24-month trial enrolled 239 patients (of which 233 were evaluable for the primary endpoint) and is evaluating the efficacy of GTL001, plus imiquimod, to clear HPV 16 and 18 infections, as compared to placebo in infected women 25 to 50 years old with normal (NILM), LSIL or ASCUS cytology and exclusion of CIN2+1 by colposcopy/histology. Previous studies indicate a natural viral clearance of 40 to 50% at 12 months in HPV 16/18 positive women. An interim analysis at 12 months following the last injection shows no statistical difference in viral clearance rates between placebo and treatment. However, there is a statistically significant separation between the treated group compared to the placebo group in 2 prospectively defined subpopulations: women with normal cytology and women younger than 30. Data are summarized in the table below:Viral clearance at 12 months GTL001 Placebo Primary endpoint (overall population) p=0.110 Normal cytology at baseline P=0.018 < 30 years old at baseline P=0.049
* On July 7, 2015, Genticel announced that the independent Data Safety Monitoring Board (DSMB) recommends thecontinuation, per protocol, of its phase 2 clinical trial of GTL001/ProCervix® in patients infected with HPV 16 and/or 18, the two HPV types responsible for 70% of cervical cancer cases. Half of the 236 vaccinated patients have now reached 12 months post-vaccination. In addition, patient and physician engagement remains extremely strong, with a 98 percent retention rate of the participants in the study. GTL001 previously obtained encouraging safety, tolerability and immunogenicity results from a European phase 1 study in 47 patients. Based on these results, in 2014 Genticel initiated the current European phase 2 clinical trial to evaluate the efficacy and safety of GTL001 in clearing HPV infection in women aged 25 to 50. Recruitment was completed by November 2014 and all vaccinations were administered by December 2014. The initial 12-month efficacy data from this phase 2 trial will be available in the first half of 2016. Genticel also received in June 2015 the FDA clearance to conduct a US phase 1 study of GTL001 in 20 patients aged 25 to 65 to evaluate its safety profile in a broader age range. Patient recruitment in this study will begin in the second half of 2015.
