Lisa Lupinacci

High sustained efficacy of a prophylactic quadrivalent human papillomavirus types 6/11/16/18 L1 virus-like particle vaccine through 5 years of follow-up

Human papillomavirus (HPV) causes cervical, vulvar, and vaginal cancers, precancerous dysplasia, and genital warts. We report data for the longest efficacy evaluation to date of a prophylactic HPV vaccine. In total, 552 women (16–23 years) were enrolled in a randomised, placebo-controlled study of a quadrivalent HPV 6/11/16/18 L1 virus-like-particle vaccine with vaccination at months 0, 2, and 6. At regular intervals through 3 years, subjects underwent gynaecologic examination, cervicovaginal sampling for HPV DNA, serum anti-HPV testing, and Pap testing, with follow-up biopsy as indicated. A subset of 241 subjects underwent two further years of follow-up. At 5 years post enrolment, the combined incidence of HPV 6/11/16/18-related persistent infection or disease was reduced in vaccine-recipients by 96% (two cases vaccine versus 46 placebo). There were no cases of HPV 6/11/16/18-related precancerous cervical dysplasia or genital warts in vaccine recipients, and six cases in placebo recipients (efficacy=100%; 95% CI:12–100%). Through 5 years, vaccine-induced anti-HPV geometric mean titres remained at or above those following natural infection. In conclusion, a prophylactic quadrivalent HPV vaccine was effective through 5 years for prevention of persistent infection and disease caused by HPV 6/11/16/18. This duration supports vaccination of adolescents and young adults, which is expected to greatly reduce the burden of cervical and genital cancers, precancerous dysplasia, and genital warts.

First-in-Man Clinical Trial of the Oral Pan-AKT Inhibitor MK-2206 in Patients With Advanced Solid Tumors

PURPOSE AKT signaling is frequently deregulated in human cancers. MK-2206 is a potent, oral allosteric inhibitor of all AKT isoforms with antitumor activity in preclinical models. A phase I study of MK-2206 was conducted to investigate its safety, maximum-tolerated dose (MTD), pharmacokinetics (PKs), pharmacodynamics (PDs), and preliminary antitumor efficacy. PATIENTS AND METHODS Patients with advanced solid tumors received MK-2206 on alternate days. Paired tumor biopsies were mandated at the MTD for biomarker studies. PD studies incorporated tumor and hair follicle analyses, and putative predictive biomarker studies included tumor somatic mutation analyses and immunohistochemistry for phosphatase and tensin homolog (PTEN) loss. RESULTS Thirty-three patients received MK-2206 at 30, 60, 75, or 90 mg on alternate days. Dose-limiting toxicities included skin rash and stomatitis, establishing the MTD at 60 mg. Drug-related toxicities included skin rash (51.5%), nausea (36.4%), pruritus (24.2%), hyperglycemia (21.2%), and diarrhea (21.2%). PKs (area under the concentration-time curve from 0 to 48 hours and maximum measured plasma concentration) were dose proportional. Phosphorylated serine 473 AKT declined in all tumor biopsies assessed (P = .015), and phosphorylated threonine 246 proline-rich AKT substrate 40 was suppressed in hair follicles at 6 hours (P = .008), on days 7 (P = .028) and 15 (P = .025) with MK-2206; reversible hyperglycemia and increases in insulin c-peptide were also observed, confirming target modulation. A patient with pancreatic adenocarcinoma (PTEN loss; KRAS G12D mutation) treated at 60 mg on alternate days experienced a decrease of approximately 60% in cancer antigen 19-9 levels and 23% shrinkage in tumor measurements. Two patients with pancreatic neuroendocrine tumors had minor tumor responses. CONCLUSION MK-2206 was well tolerated, with evidence of AKT signaling blockade. Rational combination trials are ongoing to maximize clinical benefit with this therapeutic strategy.

HPV antibody levels and clinical efficacy following administration of a prophylactic quadrivalent HPV vaccine

The efficacy of the quadrivalent Human Papillomavirus (HPV) vaccine is thought to be mediated by humoral immunity. We evaluated the correlation between quadrivalent HPV vaccine-induced serum anti-HPV responses and efficacy. 17,622 women were vaccinated at day 1, and months 2 and 6. At day 1 and at 6-12 months intervals for up to 48 months, subjects underwent Papanicolaou and genital HPV testing. No immune correlate of protection could be found due to low number of cases. Although 40% of vaccine subjects were anti-HPV 18 seronegative at end-of-study, efficacy against HPV 18-related disease remained high (98.4%; 95% CI: 90.5-100.0) despite high attack rates in the placebo group. These results suggest vaccine-induced protection via immune memory, or lower than detectable HPV 18 antibody titers.

Phase I trial of vorinostat combined with bortezomib for the treatment of relapsing and/or refractory multiple myeloma.

UNLABELLED Preclinical studies have shown that targeted combination therapy consisting of vorinostat and bortezomib has antitumor activity in multiple myeloma (MM). We examined this drug combination in advanced relapsing and/or refractory MM patients (n = 34). Although the maximum tolerated dose was not reached, the study found this combination regimen generally well tolerated and clinically active in relapsed and/or refractory MM patients. BACKGROUND Development of targeted therapies for MM has improved response rates and increased patient survival, but ultimately the disease becomes refractory and progresses. Vorinostat combined with bortezomib has demonstrated synergistic antiproliferative and proapoptotic activity in preclinical models of MM. The objectives of this study were to determine the maximum tolerated dose for vorinostat with bortezomib in patients with advanced MM and to evaluate the clinical benefit of this new drug combination. PATIENTS AND METHODS Patients ≥ 18 years old with relapsed and/or refractory MM were enrolled into escalating dose cohorts of vorinostat and bortezomib combination therapy. Thirty-four patients were enrolled and were evaluable for safety and efficacy analyses. RESULTS All patients reported adverse events, 89% of which were mild to moderate in severity. Thirteen patients experienced 29 serious adverse events, 12 (41%) of which were considered drug-related. The maximum tolerated dose was not reached. Partial responses were observed in 9 (27%) patients. Minimal responses were observed in 2 additional patients (6%), and another 20 patients (59%) experienced disease stabilization. CONCLUSION Vorinostat with bortezomib is generally well-tolerated and has clinical activity in patients with relapsed and/or refractory MM. Response rates were similar in patients previously exposed to bortezomib and patients who were naive to bortezomib therapy.

Impact of a prophylactic quadrivalent human papillomavirus (types 6, 11, 16, 18) L1 virus-like particle vaccine in a sexually active population of North American women

OBJECTIVE The purpose of this study was to inform policy regarding human papillomavirus (HPV) vaccination in North America. We measured the clinical impact of HPV-6/-11/-16/-18 vaccination in North American women. STUDY DESIGN The study enrolled 21,954 women, the majority aged 16-25, across 5 studies of a quadrivalent HPV vaccine or its HPV-16 vaccine prototype. The North American subjects (n = 5996) were pooled from these trials, and the prevalence of HPV-6/-11/-16/-18 exposure was measured. The impact of vaccination on the burden of anogenital HPV lesions in an intention-to-treat population (regardless of enrollment HPV status) was calculated. RESULTS At enrollment, the median age was 20 years; 13% of the women had had a Papanicolaou test abnormality, and 76% of the women had negative tests results for all 4 vaccine HPV types. With approximately 3 years of follow-up evaluations in the intention-to-treat population (regardless of enrollment HPV status), vaccination reduced the rate of HPV-16- and -18-related precancers and HPV-6/-11/-16/-18-related genital lesions by 66.4% (95% CI, 42.7%-81.1%) and 57.7% (95% CI, 27.3%-76.3%), respectively. CONCLUSION The administration of HPV vaccine to sexually active North American women reduced the burden of HPV-6/-11/-16/-18-related disease. Catch-up vaccination programs in this population are warranted.

Interrogating Two Schedules of the AKT Inhibitor MK-2206 in Patients with Advanced Solid Tumors Incorporating Novel Pharmacodynamic and Functional Imaging Biomarkers

Purpose: Multiple cancers harbor genetic aberrations that impact AKT signaling. MK-2206 is a potent pan-AKT inhibitor with a maximum tolerated dose (MTD) previously established at 60 mg on alternate days (QOD). Due to a long half-life (60–80 hours), a weekly (QW) MK-2206 schedule was pursued to compare intermittent QW and continuous QOD dosing. Experimental Design: Patients with advanced cancers were enrolled in a QW dose-escalation phase I study to investigate the safety and pharmacokinetic–pharmacodynamic profiles of tumor and platelet-rich plasma (PRP). The QOD MTD of MK-2206 was also assessed in patients with ovarian and castration-resistant prostate cancers and patients with advanced cancers undergoing multiparametric functional magnetic resonance imaging (MRI) studies, including dynamic contrast-enhanced MRI, diffusion-weighted imaging, magnetic resonance spectroscopy, and intrinsic susceptibility-weighted MRI. Results: A total of 71 patients were enrolled; 38 patients had 60 mg MK-2206 QOD, whereas 33 received MK-2206 at 90, 135, 150, 200, 250, and 300 mg QW. The QW MK-2206 MTD was established at 200 mg following dose-limiting rash at 250 and 300 mg. QW dosing appeared to be similarly tolerated to QOD, with toxicities including rash, gastrointestinal symptoms, fatigue, and hyperglycemia. Significant AKT pathway blockade was observed with both continuous QOD and intermittent QW dosing of MK-2206 in serially obtained tumor and PRP specimens. The functional imaging studies demonstrated that complex multiparametric MRI protocols may be effectively implemented in a phase I trial. Conclusions: Treatment with MK-2206 safely results in significant AKT pathway blockade in QOD and QW schedules. The intermittent dose of 200 mg QW is currently used in phase II MK-2206 monotherapy and combination studies (NCT00670488). Clin Cancer Res; 20(22); 5672–85. ©2014 AACR.

A phase I dose-escalation study of oral MK-2206 (allosteric AKT inhibitor) with oral selumetinib (AZD6244; MEK inhibitor) in patients with advanced or metastatic solid tumors.

3004 Background: The PI3K-Akt and RAF/MEK/ERK pathways represent two of the most frequently activated growth factor signaling pathways in human cancer. Inhibition of both pathways could yield greater benefits than inhibiting either pathway alone. The objectives of this phase I study were to examine the safety, pharmacokinetics (PK), pharmacodynamics (PD) and preliminary antitumor activity of the novel combination of MK-2206 with selumetinib. This investigational study represents a new approach to early-stage drug development with the collaboration of two pharmaceutical companies co-developing early stage targeted agent combinations ( NCT01021748 ). METHODS Eligible patients with advanced solid tumors were treated with MK-2206 either every other day (QOD) or once weekly (QW), in combination with selumetinib administered continuously either once daily (QD) or twice daily (BID). RESULTS To date, 33 patients have been treated on five dose levels. In the MK-2206 QOD dosing schedule, dose-limiting Grade 3 macular skin rash was reported in 2/3 evaluable patients at MK-2206 45 mg QOD with selumetinib 75mg BID; the tolerable dose was MK-2206 45 mg QOD with selumetinib 75 mg QD. For QW MK-2206, dose-limiting acneiform rash (n=1), stomatitis (n=1) and detached retinal pigment epithelium (n=1) were observed in 3/7 evaluable patients treated at MK-2206 90 mg QW with selumetinib 75mg BID; dose reduction to MK-2206 90mg QW/ selumetinib 50 mg BID was not tolerated due to dose-limiting acneiform rash in 2/ 4 evaluable patients. An intermediate dose of MK-2206 90mg once weekly with selumetinib 75mg QD was tolerable. Preliminary assessment of PK/PD data suggest no apparent drug-drug interactions with the PK profile of each drug administered in this combination. CONCLUSIONS MK2206 at 45 mg QOD, or 90 mg QW is well tolerated in combination with selumetinib 75 mg QD in patients with advanced cancer.

Doravirine/Lamivudine/Tenofovir Disoproxil Fumarate is Non-inferior to Efavirenz/Emtricitabine/Tenofovir Disoproxil Fumarate in Treatment-naive Adults With Human Immunodeficiency Virus–1 Infection: Week 48 Results of the DRIVE-AHEAD Trial

In Human Immunodeficiency Virus–1 treatment-naive adults, a fixed combination of doravirine/lamivudine/tenofovir disoproxil fumarate demonstrated non-inferior antiretroviral efficacy to efavirenz/emtricitabine/tenofovir disoproxil fumarate at week 48, with similar immunologic effects, low viral drug resistance rates, and significantly fewer neuropsychiatric adverse events.

A248 Vorinostat plus Bortezomib in MM: A Phase I Study

myeloma (MM). We report safety and efficacy data from the phase I portion, to determine the maximum tolerated dose (MTD) of cyclophosphamide in the VDCR combination. Methods: Patients received bortezomib 1.3 mg/m2 (days 1, 4, 8, 11), dexamethasone 40 mg (days 1, 8, 15), lenalidomide 15 mg (days 1-14), plus cyclophosphamide 100, 200, 300, 400, or 500 mg/m2 (days 1, 8) for up to eight 21-day cycles, then bortezomib 1.3 mg/m2 (days 1, 8, 15, 22) for four 42-day maintenance cycles. Patients could discontinue therapy after cycle 4 to undergo stem cell transplantation. Patients received prophylactic antibiotics, acyclovir, transfusion support, and concomitant anticoagulants as required. Results: Twenty-five of 26 patients enrolled were treated (Table 1; median age 61 years; 52% ISS stage lI/III; 44% KPS 80%). At data cut-off, median treatment duration is 4 cycles (range, 2-11 cycles); 9 patients have undergone successful transplantation and 11 remain on treatment. Two patients experienced doselimiting toxicity (grade 4 neutropenia > 7 days, dose level 4; grade 3 herpes zoster, dose level 5); MTD was not reached. The recommended phase II cyclophosphamide dose is 500 mg/m2. The most common toxicities were constipation (64%), fatigue (60%), and nausea (52%). Hematologic toxicities were acceptable. Peripheral neuropathy (56%) included 8% grade 3 (no grade 4). No DVT/PE was reported. Preliminary response rates are: 100% PR, 68% VGPR, 32% CR/nCR, 28% CR/sCR, 20% sCR (Table 1). Conclusion: VDCR is feasible, well tolerated, and highly active in front-line MM. Phase I enrollment is complete; phase ll enrollment is ongoing.

Effects of quadrivalent human papillomavirus vaccination – Authors' reply

Cost-effectiveness analysis as referenced by Davide Mauri and Nikolaos Polyzos constitutes one of several sources of information considered by policymakers in developing and developed worlds in making decisions about the optimum efficient use of health-care resources. The WHO Commission on Macroeconomics and Health has suggested that interventions costing less than three times a countrys per capita gross domestic product per disability-adjusted life year gained can be regarded as good value and analysts have equivalently applied this threshold to analyses that use quality-adjusted life years (QALYs). Preliminary results from a cost-effectiveness analysis of vaccination with quadrivalent HPV 6/11/16/18 vaccine in Mexico suggest a cost/QALY ratio well below this threshold in that country. Previous analyses in developed world settings have consistently shown that vaccination of girls and young women has a cost-effectiveness ratio within the range typically regarded as cost-effective. In countrieswith the fewest resources direct assistance and public-private partnerships can help deliver needed medicines to the population at or below development costs-eg the ivermectin donation for river blindness. Marc Arbyn states that if the cases of vaccine-type-related disease are subtracted from disease due to all types there are a larger number of cases in women who received vaccine than in those who received placebo. This subtraction assumes that the subset of disease cases due to vaccine HPV types and the subset of cases due to non-vaccine HPV types are mutually exclusive which is not the case. Coinfections with vaccine and non-vaccine types are common. In the presence of coinfection the effect of such a subtraction is to ignore the presence of non-vaccine HPV types in disease where a vaccine-type HPV has also been detected. The effect of the subtraction is to preferentially attribute co-infected disease cases only to the vaccine HPV types. Individuals in the placebo group are more likely to have their non-vaccine type-related disease discounted in this way. Owing to the high efficacy of the vaccine individuals in the vaccine group have less vaccine-type-related disease and so those in the vaccine group have fewer such coinfection cases. To illustrate this point an analysis of the numbers of individuals with disease due to vaccine and non-vaccine HPV types in the intention-to-treat population of protocols 013 and 015 is presented in the figure. The parts shaded blue would be the result of subtraction similar to Arbyns subtraction. However the total numbers of cases of disease related to non-vaccine HPV types are 226+56=282 cases in the vaccine group and 193+106=299 cases in the placebo group. There is not an excess of cases caused by non-vaccine HPV types in the vaccine group. (full text)