Hypoxia-activated prodrugs and (lack of) clinical progress: The need for hypoxia-based biomarker patient selection in phase III clinical trials

Hypoxia-activated prodrugs (HAPs) are designed to specifically target the hypoxic cells of tumors, which are an important cause of treatment resistance to conventional therapies. Despite promising preclinical and clinical phase I and II results, the most important of which are described in this review, the implementation of hypoxia-activated prodrugs in the clinic has, so far, not been successful. The lack of stratification of patients based on tumor hypoxia status, which can vary widely, is sufficient to account for the failure of phase III trials. To fully exploit the potential of hypoxia-activated prodrugs, hypoxia stratification of patients is needed. Here, we propose a biomarker-stratified enriched Phase III study design in which only biomarker-positive (i.e. hypoxia-positive) patients are randomized between standard treatment and the combination of standard treatment with a hypoxia-activated prodrug. This implies the necessity of a Phase II study in which the biomarker or a combination of biomarkers will be evaluated. The total number of patients needed for both clinical studies will be far lower than in currently used randomize-all designs. In addition, we elaborate on the improvements in HAP design that are feasible to increase the treatment success rates. Keywords: Hypoxia-activated prodrugs, Phase III clinical trial, Biomarker, Hypoxi

Prevalent and Persistent Oncogenic HPV Types in a Cohort of Women Living with HIV Prior to HPV Vaccination

Objective: To describe prevalent and persistent oncogenic HPV types detected in women living with HIV (WLWH) in Canada, including in women with cervical dyskaryosis, and to determine predictors of type-specific HPV persistence. Methods: 252 women were eligible for this sub-analysis of a prospective vaccine immunogenicity cohort study (2 HPV DNA results, ≥1 cervical cytology result pre vaccination). Demographic and clinical data were collected alongside cervical samples for cytology and HPV DNA typing between 2008-2015. Results: Pre-vaccination, HPV16 and HPV52 were the most prevalent oncogenic HPV types. Forty-five percent of participants were infected with ≥1 oncogenic HPV type and one-third of participants had a persistent oncogenic infection. HPV16, 45, and 52 were the most frequently persistent types. Seventeen percent of women had persistent infections with oncogenic HPV types not within currently available vaccines (HPV35/39/51/56/59/68/82). Lower CD4 count significantly predicted HPV persistence (p=0.024). Cervical cytology was 82.9% normal, 2.4% atypical squamous cells of undetermined significance, 11.5% low-grade squamous intraepithelial lesions, and 2.8% high-grade squamous intraepithelial lesions. Conclusion: Unvaccinated WLWH were infected with a wide range of oncogenic HPV types. Our findings highlight the importance of optimal HIV treatment and continued cervical cancer screening as key steps towards global elimination of cervical cancer.Medicine, Faculty ofNon UBCObstetrics and Gynaecology, Department ofReviewedFacultyResearcherGraduat

qHPV Vaccine Efficacy in Women with HIV

Background: Human papillomavirus (HPV) vaccination is safe and efficacious in women without HIV. While good immunogenicity has been observed in women living with HIV (WLWH), efficacy data in this population are needed. Methods: We enrolled 420 females aged ≥9 years (range: 9-65) living with HIV. Participants were to receive 3 doses of qHPV vaccine (0/2/6 months). The main endpoint was vaccine failure (i.e., incident persistent qHPV infection, cervical intraepithelial neoplasia of grade 2 or higher (CIN2+), or genital warts). We compared these rates to published rates in vaccinated and unvaccinated women without HIV as well as unvaccinated WLWH. Results: Among 279 eligible women, median follow-up was 2 years. In the intention-to treat population, the incidence rate (IR) of persistent qHPV (HPV6/11/16/18) was 2.3 per 100 person-years (/100PY) (95% confidence interval [CI]=1.1-4.1) and IR of genital warts was 2.3/100PY (95% CI=1.2-4.1). In the per-protocol efficacy population, IR of persistent qHPV was 1.0/100PY (95% CI=0.3-2.6) and of genital warts was 1.0/100PY (95% CI=0.3-2.5). No cases of CIN2+ occurred. Reported rates of qHPV-related infection and disease within the vaccinated women without HIV, unvaccinated women without HIV, and the vaccinated WLWH: 0.1 (95% CI=0.02-0.03), 1.5 (95% CI=1.1- 2.0), and 1.2 (95% CI=0.2-3.4) /100PY, respectively. The rate of persistent qHPV among vaccinated WLWH was lower than among unvaccinated WLWH (2.3 vs. 6.0/100PY). Conclusions: Vaccinated WLWH may be 53 at higher risk for vaccine failure than vaccinated women without HIV. However, overall rates of vaccine failure were low and rates of persistent qHPV were lower than in unvaccinated WLWH.Medicine, Faculty ofOther UBCNon UBCObstetrics and Gynaecology, Department ofReviewedFacultyResearcherGraduat