Safety and clinical activity of pembrolizumab for treatment of recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-012): an open-label, multicentre, phase 1b trial.

BACKGROUND: Patients with recurrent or metastatic squamous cell carcinoma of the head and neck have few treatment options. We aimed to assess the safety, tolerability, and antitumour activity of pembrolizumab, a humanised anti-programmed death receptor 1 (PD-1) antibody, in patients with PD-L1-positive recurrent or metastatic squamous cell carcinoma of the head and neck. METHODS: This study was an open-label, multicentre, phase 1b trial of patients with recurrent or metastatic squamous cell carcinoma of the head and neck. Patients were eligible for enrolment if they were aged 18 years or older, had a confirmed diagnosis of recurrent or metastatic squamous cell carcinoma of the head and neck, and had any level of PD-L1 expression (ie, at least 1% of tumour cells or stroma that were PD-L1-positive by immunohistochemistry). Patients received pembrolizumab 10 mg/kg intravenously every 2 weeks. Primary outcomes were safety in the per-protocol population and the proportion of patients with centrally reviewed overall response per Response Evaluation Criteria In Solid Tumors (RECIST, version 1.1). Overall response was analysed in the full analysis set, which was defined as all patients who had received at least one dose of pembrolizumab, had measurable disease at baseline, and one post-baseline scan or patients without a post-baseline scan who discontinued therapy because of disease progression or a drug-related adverse event. The study is registered with ClinicalTrials.gov, number NCT01848834 and is ongoing, but no longer enrolling patients. FINDINGS: Of the 104 patients screened between June 7, 2013, and Oct 3, 2013, 81 (78%) were PD-L1-positive. Of these, 60 patients with PD-L1-positive squamous cell carcinoma of the head and neck were enrolled and treated: 23 (38%) were HPV-positive and 37 (62%) were HPV-negative. Pembrolizumab was well tolerated, with 10 (17%) of 60 patients having grade 3-4 drug-related adverse events, the most common of which were increases in alanine aminotransferase and in aspartate aminotransferase, and hyponatraemia, each occurring in two of 60 patients; one patient developed a grade 3 drug-related rash. 27 (45%) of 60 patients experienced a serious adverse event. There were no drug-related deaths. The proportion of patients with an overall response by central imaging review was 18% (eight of 45 patients; 95% CI 8-32) in all patients and was 25% (four of 16 patients; 7-52) in HPV-positive patients and 14% (four of 29 patients; 4-32) in HPV-negative patients. INTERPRETATION: Pembrolizumab was well tolerated and demonstrated clinically meaningful antitumour activity in recurrent or metastatic squamous cell carcinoma of the head and neck, supporting further study of pembrolizumab as anticancer therapy for advanced head and neck cancers. FUNDING: Merck & Co.

Evaluation of laboratory methods for diagnosis of varicella.

BACKGROUND: The incidence of varicella disease is declining as a result of vaccination, making clinical diagnosis more challenging, particularly for vaccine-modified cases. We conducted a comprehensive evaluation of laboratory tests and specimen types to assess diagnostic performance and determine what role testing can play after skin lesions have resolved. METHODS: We enrolled patients with suspected varicella disease in 2 communities. Enrollees were visited at the time of rash onset and 2 weeks later. Multiple skin lesion, oral, urine, and blood or serum specimens were requested at each visit and tested for varicella zoster virus (VZV) immunoglobulin (Ig) G, IgM, and IgA antibody by enzyme-linked immunoassay; for VZV antigen by direct fluorescent antibody; and/or for VZV DNA by polymerase chain reaction (PCR). Clinical certainty of the diagnosis of varicella disease was scored. PCR results from first-visit vesicles or scab specimens served as the gold standard in assessing test performance. RESULTS: Of 93 enrollees, 53 were confirmed to have varicella disease. Among 20 unmodified cases, PCR testing was 95%-100% sensitive for macular and/or papular lesions and for oral specimens collected at the first visit; most specimens from the second visit yielded negative results. Among 27 vaccine-modified cases, macular and/or papular lesions collected at the first visit were also 100% sensitive; yields from other specimens were poorer, and few specimens from the second visit tested positive. Clinical diagnosis was 100% and 85% sensitive for diagnosing unmodified and vaccine-modified varicella cases, respectively. CONCLUSIONS: PCR testing of skin lesion specimens remains convenient and accurate for diagnosing varicella disease in vaccinated and unvaccinated persons. PCR of oral specimens can sometimes aid in diagnosis of varicella disease, even after rash resolves.

Validity of self-reported varicella disease history in pregnant women attending prenatal clinics.

OBJECTIVE: The purpose of this study was to assess the validity of self-reported history for varicella disease relative to serological evidence of varicella immunity in pregnant women attending antenatal care at clinics located in two diverse geographical locations in the U.S. (Antelope Valley, California, and Philadelphia) with high varicella vaccination coverage. METHODS: Pregnant women attending prenatal care appointments who needed blood drawn as part of their routine care were eligible to participate. Self-reported varicella disease history was obtained via questionnaire. Varicella serostatus was determined using a whole-cell enzyme-linked immunosorbent assay to test for varicella zoster virus-specific immunoglobulin G (VZV IgG) antibodies. RESULTS: Of the 309 study participants from Antelope Valley and the 528 participants from Philadelphia who self-reported having had chickenpox disease, 308 (99.7%; 95% confidence interval [CI]: 98.2, 100) and 517 (97.9%; 95% CI: 96.3, 99.0), respectively, had serological evidence of immunity to varicella. Only 6.8% (95% CI: 3.9, 11.0) and 17.4% (95% CI: 13.1, 22.5) of women who self-reported having a negative or uncertain varicella disease history in Antelope Valley and Philadelphia, respectively, were seronegative for varicella antibodies. CONCLUSION: Despite the dramatic changes in the epidemiology of varicella that have occurred since 1995 due to the introduction and subsequent widespread use of the varicella vaccine, self-reported history of varicella continues to be a strong predictor of VZV IgG antibodies in pregnant women. Negative or uncertain history remains poorly predictive of negative serostatus.

Tolerability, safety and pharmacokinetics of ridaforolimus in combination with bicalutamide in patients with asymptomatic, metastatic castration-resistant prostate cancer (CRPC).

PURPOSE: Recent data indicate that there is a significant cross-talk between the PI3K/Akt/mTOR and androgen receptor signaling pathways. We evaluated safety and tolerability as well as potential drug-drug interaction of ridaforolimus, a mammalian target of rapamycin (mTOR) inhibitor, when combined with the androgen receptor inhibitor bicalutamide in patients with asymptomatic, metastatic castration-resistant prostate cancer. PATIENTS AND METHODS: Patients were treated with the combination of ridaforolimus 30 mg/day for 5 consecutive days each week and bicalutamide 50 mg/day. Ridaforolimus pharmacokinetics was assessed with and without bicalutamide. RESULTS: Twelve patients were enrolled including 1 screen failure. Dose reductions were required in 7 patients. Three of the 11 patients experienced a dose-limited toxicity, 1 with Grade 3 hyperglycemia and 2 with Grade 2 stomatitis leading to <75 % of planned ridaforolimus dose during the first 35 days of study treatment. The pharmacokinetic results showed no differences in exposures to ridaforolimus with and without concomitant bicalutamide administration. CONCLUSIONS: Although there was no evidence of a clinically relevant pharmacological drug-drug interaction, the occurrence of dose-limiting toxicities in 3 of 11 evaluable patients at a reduced dose of ridaforolimus of 30 mg/day suggests that this combination may not be well suited for asymptomatic or minimally symptomatic prostate cancer patients.

Vorinostat combined with bexarotene for treatment of cutaneous T-cell lymphoma: in vitro and phase I clinical evidence supporting augmentation of retinoic acid receptor/retinoid X receptor activation by histone deacetylase inhibition.

The retinoid X receptor (RXR)-agonist bexarotene and the histone deacetylase inhibitor (HDACI) vorinostat are each established monotherapies for cutaneous T-cell lymphomas (CTCLs). We investigated the combination of HDACI and retinoic acid receptor (RAR)/RXR agonists in vitro and in a phase I, multicenter, open-label, two-part dose-escalation study. The combination of bexarotene with a HDACI in vitro leads to cooperative activation of gene transcription and reduction of cell viability in human tumor cell lines. The primary clinical objective was to determine the maximum tolerated dose (MTD) of bexarotene plus vorinostat in 23 patients with CTCLs. The MTD for part I was established at vorinostat 200 mg/day plus bexarotene 300 mg/m(2)/day. The MTD for part II was not reached. Four patients had an objective response and seven patients experienced pruritus relief. We conclude that concomitant administration of vorinostat and bexarotene is feasible only if lower doses of each drug are administered relative to the product label monotherapy doses.