A Phase 1/2 trial of SRA737 (a Chk1 inhibitor) administered orally in patients with advanced cancer.

BACKGROUND: This was a first-in-human Phase 1/2 open-label dose-escalation study of the novel checkpoint kinase 1 (Chk1) inhibitor SRA737. METHODS: Patients with advanced solid tumours enrolled in dose-escalation cohorts and received SRA737 monotherapy orally on a continuous daily (QD) dosing schedule in 28-day cycles. Expansion cohorts included up to 20 patients with prospectively selected, pre-specified response predictive biomarkers. RESULTS: In total, 107 patients were treated at dose levels from 20-1300 mg. The maximum tolerated dose (MTD) of SRA737 was 1000 mg QD, the recommended Phase 2 dose (RP2D) was 800 mg QD. Common toxicities of diarrhoea, nausea and vomiting were generally mild to moderate. Dose-limiting toxicity at daily doses of 1000 and 1300 mg QD SRA737 included gastrointestinal events, neutropenia and thrombocytopenia. Pharmacokinetic analysis at the 800 mg QD dose showed a mean Cmin of 312 ng/mL (546 nM), exceeding levels required to cause growth delay in xenograft models. No partial or complete responses were seen. CONCLUSIONS: SRA737 was well tolerated at doses that achieved preclinically relevant drug concentrations but single agent activity did not warrant further development as monotherapy. Given its mechanism of action resulting in abrogating DNA damage repair, further clinical development of SRA737 should be as combination therapy. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov NCT02797964.

Policymakers' and healthcare providers' perspectives on the introduction of oral pre-exposure prophylaxis for key populations in Ghana.

BACKGROUND: Key populations (KPs) such as female sex workers (FSWs), men who have sex with men (MSM), people who inject drugs (PWID), and their partners contribute more than a quarter (27.5%) of new HIV infection in Ghana. Oral pre-exposure prophylaxis (PrEP) can substantially reduce HIV acquisition among this group. While the available research indicates KPs willingness to take PrEP in Ghana, little is known about the position of policymakers and healthcare providers on the introduction of PrEP for KPs. METHODS: Qualitative data were collected from September to October 2017 in the Greater Accra (GA) and Brong-Ahafo (BA) regions of Ghana. Key informant interviews were conducted with 20 regional and national policymakers and supplemented with In-depth Interviews with 23 healthcare providers to explore their level of support for PrEP and their perspectives on challenges and issues to consider for oral PrEP implementation in Ghana. Thematic content analysis was used to unearth the issues emerging from the interviews. RESULTS: Policymakers and healthcare providers in both regions expressed strong support for introducing PrEP for KPs. Key concerns regarding oral PrEP introduction included potential for behavioral disinhibition, non-adherence and side effects of medication, cost and long-term financial implications, and stigma related to HIV and key populations. Participants stressed the need to integrate PrEP into existing services and the provision of PrEP should start with high risk groups like sero-discordant couples, FSWs and MSM. CONCLUSIONS: Policymakers and providers recognize the value of PrEP in cubing new HIV infections but have concerns about disinhibition, non-adherence, and cost. Therefore, the Ghana health service should roll-out a range of strategies to address their concerns including: sensitization with providers to mitigate underlying stigma towards KPs, particularly MSM, integration of PrEP into existing services, and innovative strategies to improve continued use of PrEP.

MOMENTUM: momelotinib vs danazol in patients with myelofibrosis previously treated with JAKi who are symptomatic and anemic.

Hallmark features of myelofibrosis (MF) are cytopenias, constitutional symptoms and splenomegaly. Anemia and transfusion dependency are among the most important negative prognostic factors and are exacerbated by many JAK inhibitors (JAKi). Momelotinib (MMB) has been investigated in over 820 patients with MF and possesses a pharmacological and clinical profile differentiated from other JAKi by inhibition of JAK1, JAK2 and ACVR1. MMB is designed to address the complex drivers of iron-restricted anemia and chronic inflammation in MF and should improve constitutional symptoms and splenomegaly while maintaining or improving hemoglobin in JAKi-naive and previously JAKi-treated patients. The MOMENTUM Phase III study is designed to confirm and extend observations of safety and clinical activity of MMB.

Lay abstract The most important features of myelofibrosis (MF) are low blood cell counts and symptoms including tiredness, night sweats and itching, along with increased size of the spleen, which may cause a feeling of fullness and pain. Low red blood cell counts (anemia) may mean regular blood transfusions are needed and this is one of the signs MF is getting worse. Drugs called JAK inhibitors (JAKi) are available to treat MF, but can have a side effect of making blood cell counts lower. Momelotinib (MMB) is a different type of JAKi to the ones currently available, and is an experimental drug for MF. MMB is designed to treat symptoms and spleen like other JAKi, but also to improve blood cell counts. MMB has already been given to more than 820 patients with MF in other clinical studies. Some of the patients in these studies had been treated with different JAKi before, and others got MMB as their first JAKi treatment. The MOMENTUM Phase III study is designed to collect more information on the safety and effectiveness of MMB in MF.

Experimental Treatment of Ebola Virus Disease with TKM-130803: A Single-Arm Phase 2 Clinical Trial.

BACKGROUND: TKM-130803, a small interfering RNA lipid nanoparticle product, has been developed for the treatment of Ebola virus disease (EVD), but its efficacy and safety in humans has not been evaluated. METHODS AND FINDINGS: In this single-arm phase 2 trial, adults with laboratory-confirmed EVD received 0.3 mg/kg of TKM-130803 by intravenous infusion once daily for up to 7 d. On days when trial enrolment capacity was reached, patients were enrolled into a concurrent observational cohort. The primary outcome was survival to day 14 after admission, excluding patients who died within 48 h of admission. After 14 adults with EVD had received TKM-130803, the pre-specified futility boundary was reached, indicating a probability of survival to day 14 of ≤0.55, and enrolment was stopped. Pre-treatment geometric mean Ebola virus load in the 14 TKM-130803 recipients was 2.24 × 109 RNA copies/ml plasma (95% CI 7.52 × 108, 6.66 × 109). Two of the TKM-130803 recipients died within 48 h of admission and were therefore excluded from the primary outcome analysis. Of the remaining 12 TKM-130803 recipients, nine died and three survived. The probability that a TKM-130803 recipient who survived for 48 h will subsequently survive to day 14 was estimated to be 0.27 (95% CI 0.06, 0.58). TKM-130803 infusions were well tolerated, with 56 doses administered and only one possible infusion-related reaction observed. Three patients were enrolled in the observational cohort, of whom two died. CONCLUSIONS: Administration of TKM-130803 at a dose of 0.3 mg/kg/d by intravenous infusion to adult patients with severe EVD was not shown to improve survival when compared to historic controls. TRIAL REGISTRATION: Pan African Clinical Trials Registry PACTR201501000997429.

Efficacy and safety of a diffusion-based extended-release fluticasone propionate intra-articular injection (EP-104IAR) in knee osteoarthritis (SPRINGBOARD): a 24-week, multicentre, randomised, double-blind, vehicle-controlled, phase 2 trial.

BACKGROUND: Corticosteroids are among the few effective treatments for knee osteoarthritis, but short duration of action limits their utility. EP-104IAR, a long-acting formulation of fluticasone propionate for intra-articular injection, optimises the action of fluticasone propionate through novel diffusion-based extended-release technology. The SPRINGBOARD trial assessed the efficacy, safety, and pharmacokinetics of EP-104IAR in people with knee osteoarthritis. METHODS: SPRINGBOARD was a randomised, vehicle-controlled, double-blind, phase 2 trial done at 12 research sites in Denmark, Poland, and Czech Republic. We recruited adults aged 40 years or older with primary knee osteoarthritis (Kellgren-Lawrence grade 2-3) who reported Western Ontario and McMaster Universities Osteoarthritis Arthritis Index (WOMAC) pain scores of at least 4 and no more than 9 out of 10. Participants were randomly assigned (1:1) to receive one intra-articular dose of 25 mg EP-104IAR or vehicle control. Randomisation was done via interactive web-based access to a central predefined computer-generated list with block size of six (allocated by clinical site). Participants and assessors were masked to treatment allocation. Participants were followed up for 24 weeks. The primary outcome was the difference between groups in change in WOMAC pain score from baseline to week 12, analysed in all participants who were randomly assigned and received treatment. Safety, including laboratory analyses, and pharmacokinetics from quantification of fluticasone propionate in peripheral blood were assessed in all participants who received a dose of randomly assigned treatment. A person with lived experience of knee osteoarthritis was involved in study interpretation and writing of the report. This trial is registered with ClinicalTrials.gov, NCT04120402, and the EU Clinical Trials Register, EudraCT 2021-000859-39, and is complete. FINDINGS: Between Sept 10, 2021, and Nov 16, 2022, 1294 people were screened for eligibility, and 319 were randomly assigned to EP-104IAR (n=164) or vehicle control (n=155). One participant in the EP-104IAR group was excluded from all analyses because treatment was not administered due to an adverse event. 318 participants (135 [42%] male and 183 [58%] female, 315 [99%] White) received randomly assigned treatment and were included in the primary analysis and safety analysis (EP-104IAR, n=163; vehicle control, n=155). At week 12, least squares mean change in WOMAC pain score from baseline was -2·89 (95% CI -3·22 to -2·56) in the EP-104IAR group and -2·23 (-2·56 to -1·89) in the vehicle control group, with a between-group difference of -0·66 (-1·11 to -0·21; p=0·0044); a significant between-group difference persisted to week 14. 106 (65%) of 163 participants in the EP-104IAR group had one or more treatment-emergent adverse event compared with 89 (57%) of 155 participants in the vehicle control group. Effects on serum glucose and cortisol concentrations were minimal and transient. There were no treatment-emergent deaths or treatment-related serious adverse events. Plasma concentrations of fluticasone propionate showed a blunted initial peak with terminal half-life of approximately 18-20 weeks. INTERPRETATION: These phase 2 results suggest that EP-104IAR has the potential to offer clinically meaningful pain relief in knee osteoarthritis for an extended period of up to 14 weeks, longer than published data for currently marketed corticosteroids. There were minimal effects on glucose and cortisol, and stable fluticasone propionate concentrations in plasma. The safety and efficacy of EP-104IAR will be further evaluated in phase 3 trials, including the possibility of bilateral and repeat dosing with EP-104IAR. FUNDING: Eupraxia Pharmaceuticals. TRANSLATION: For the Danish translation of the abstract see Supplementary Materials section.

A Phase I/II Trial of Oral SRA737 (a Chk1 Inhibitor) Given in Combination with Low-Dose Gemcitabine in Patients with Advanced Cancer.

PURPOSE: This was a Phase I/II trial of the novel checkpoint kinase 1 (Chk1) inhibitor SRA737 given in combination with gemcitabine. Its objectives were to establish the safety profile, recommended Phase 2 dose (RP2D), pharmacokinetics profile, and clinical activity of SRA737. PATIENTS AND METHODS: Patients with advanced solid tumors were enrolled into dose-escalation cohorts and treated in 28-day cycles with oral SRA737 on days 2, 3, 9, 10, 16, and 17, and intravenous gemcitabine on days 1, 8, and 15. Treatment was continued until progression. Each expansion cohort included up to 20 patients with specific genetically defined tumors. RESULTS: The RP2D was determined to be 500 mg SRA737 combined with low-dose (250 mg/m2) gemcitabine. Of 143 enrolled patients, 77 were treated at doses of at least 500 mg SRA737 combined with 250 mg/m2 gemcitabine. Common toxicities of nausea, vomiting, fatigue, and diarrhea were primarily mild to moderate, and rarely led to treatment discontinuation. Anemia, neutropenia, and thrombocytopenia were grade ≥3 in 11.7%, 16.7%, and 10% of patients treated at the RP2D, respectively. The objective response rate (ORR) was 10.8% overall and notably the ORR in anogenital cancer was 25%. Partial tumor responses were observed in anogenital cancer, cervical cancer, high-grade serous ovarian cancer, rectal cancer, and small cell lung cancer. CONCLUSIONS: SRA737 in combination with low-dose gemcitabine was well tolerated with lower myelotoxicity than has been seen at standard doses of gemcitabine or with other combinations of Chk1 inhibitors with gemcitabine. Tumor responses were observed in anogenital and other solid tumors.

A phase II study of oportuzumab monatox: an immunotoxin therapy for patients with noninvasive urothelial carcinoma in situ previously treated with bacillus Calmette-Guérin.

PURPOSE: A phase II study was performed to assess the efficacy and tolerability of intravesical oportuzumab monatox in patients with urothelial carcinoma in situ of the bladder. Bacillus Calmette-Guérin treatment had previously failed in all patients. MATERIALS AND METHODS: A total of 46 patients received 1 induction cycle of 6 (cohort 1) or 12 (cohort 2) weekly intravesical oportuzumab monatox (VB4-845) instillations of 30 mg, followed by up to 3 maintenance cycles of 3 weekly administrations every 3 months. RESULTS: A complete response to oportuzumab monatox was seen in 9 of 22 patients (41%) in cohort 1 and 9 of 23 (39%) in cohort 2 at the 3-month evaluation. A total of 20 patients (44%) achieved a complete response. Two other patients without carcinoma in situ who achieved a complete response were not included in the study due to the development of noninvasive papillary (Ta) disease. Median time to recurrence in patients who achieved a complete response was 274 and 408 days in cohorts 1 and 2, respectively. Overall 7 patients (16%) remained disease-free. Post-study assessment demonstrated that these patients were still disease-free at last followup (18 to 25 months). The most common adverse events were mild to moderate reversible bladder symptoms. CONCLUSIONS: Oportuzumab monatox was effective and well tolerated in patients with bacillus Calmette-Guérin refractory carcinoma in situ of the bladder. These results demonstrate the clinical benefit of oportuzumab monatox and support its continued development for the second line treatment of nonmuscle invasive bladder cancer.

A phase 1b study of erlotinib and momelotinib for the treatment of EGFR-mutated, tyrosine kinase inhibitor-naive metastatic non-small cell lung cancer.

INTRODUCTION: Preclinical evidence suggests the feedforward cytokine loop of interleukin-6/Janus kinases (JAK)/STAT3 plays a role in epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) resistance in EGFR-mutated non-small cell lung cancer (NSCLC). METHODS: In this phase 1b study, the JAK1/2 and TANK-binding kinase 1 (TBK1) inhibitor momelotinib was evaluated in combination with erlotinib in patients with EGFR TKI-naive, EGFR-mutated NSCLC. After erlotinib lead-in (50, 75, 100, or 150 mg oral daily [QD]), momelotinib was combined and dose escalated in a 3 + 3 study design. The primary endpoint of maximum tolerated dose (MTD) of momelotinib was determined based on the incidence of dose-limiting toxicities (DLTs) during the first 28-day cycle. Secondary endpoints included efficacy and pharmacokinetics (PK). RESULTS: Eleven patients were enrolled across 3 dose levels of momelotinib (100 mg QD, 200 mg QD, and 100 mg twice daily [BID]). The MTD was momelotinib 200 mg QD in combination with erlotinib. Two DLTs of grade 4 neutropenia without fever and grade 3 diarrhea occurred at momelotinib 100 mg BID. Most common treatment-emergent adverse events included diarrhea, dry skin, fatigue, and decreased appetite; the vast majority being grades 1-2. The overall response rate was 54.5% (90% CI 27.1-80.0; all partial) and median progression-free survival was 9.2 months (90% CI 6.2-12.4). Momelotinib did not affect the PK of erlotinib. CONCLUSIONS: The JAK1/2 and TBK1 inhibitor momelotinib in combination with erlotinib did not appear to enhance benefit over the historical data of erlotinib monotherapy in patients with EGFR-mutated NSCLC. CLINICALTRIALS. GOV IDENTIFIER: NCT02206763.

Perspectives of Policymakers on the Introduction and Scale-Up of HIV Self-Testing and Implication for National HIV Programming in Ghana.

Background: HIV self-testing (HIVST) has the potential to greatly increase HIV testing uptake, particularly among key populations (KPs) at higher risk for HIV. Studies have shown high acceptability and feasibility of HIVST among various target populations globally. However, less is known about the perspectives of policymakers, who are critical to the success of HIVST implementation. Their views on barriers to the introduction and scale-up of self-testing are critical to understand in order for HIVST to become part of the national HIV guidelines. We sought to understand policymakers' perspectives of challenges and facilitators to the introduction of HIVST at the client and structural levels. Method: Key informant interviews (KIIs) were conducted with national and regional level policymakers involved in the HIV response. Twenty policymakers were purposively selected from Greater Accra (capital) and Brong-Ahafo (outlying) regions. Qualitative content analysis was used to arrive at the results after the verbatim transcripts were coded. Results: Client-level challenges included lack of pre-test counseling, the need for confirmatory testing if reactive, potential for poor linkage to care and treatment, and client-level facilitator from policy makers' perspectives included increase testing modality that would increase testing uptake. Structural-level challenges mentioned by policymakers were lack of a national policy and implementation guidelines on HIVST, cost of HIVST kits, supply chain management of HIVST commodities, data monitoring and reporting of positive cases. The structural-level appeal of HIVST to policymakers were the reduced burden on health system and HIVST's contribution to achieving testing targets. Despite the challenges mentioned, policymakers unanimously favored and called for the introduction of HIVST in Ghana. Conclusions: Findings indicate that a non-conventional HIV testing strategy such as HIVST is highly acceptable to policymakers. However, successful introduction of HIVST hinges on having national guidelines in place and stakeholder consultations to address various individual and structural -level implementation issues.

A pharmacokinetic analysis of diclofenac potassium soft-gelatin capsule in patients after bunionectomy.

The clinical utility of diclofenac potassium, a nonsteroidal anti-inflammatory drug, may be lessened by inconsistent gastrointestinal absorption. Diclofenac potassium liquid filled soft-gelatin capsule (DPSGC) is an investigational formulation that uses ProSorb dispersion technology to facilitate rapid and consistent gastrointestinal absorption. In this study, the pharmacokinetic (PK) properties of DPSGC are investigated and compared with a commercially available oral diclofenac potassium tablet in patients after primary unilateral first metatarsal bunionectomy. In an open-label, randomized study, 53 patients received ProSorb-D 12.5 mg (the liquid equivalent of DPSGC), DPSGC 25 mg, DPSGC 50 mg, or immediate-release diclofenac potassium 50-mg tablet administered every 8 hours for a 24-hour inpatient period followed by 7 days of outpatient dosing. Diclofenac steady-state PK was evaluated over an 8-hour sampling period 4 days after surgery. Delayed and/or multiple peaks in the diclofenac plasma concentration-time course profiles occurred more frequently with the commercially available oral diclofenac potassium 50-mg tablet than with the other DPSGC formulations. PK data for ProSorb-D 12.5-mg liquid, DPSGC 25 mg, DPSGC 50 mg, and diclofenac potassium 50-mg tablet revealed mean peak plasma concentrations (Cmax) of 302, 749, 1006, and 902 ng/mL, respectively, whereas area under the plasma concentration curve values were 316, 595, 1029, and 1166 ng-hour/mL, respectively. Mean times to Cmax (tmax) were 0.49, 0.63, 0.95, and 1.26 h, respectively. When compared with absorption characteristics of diclofenac potassium 50-mg tablet, DPSGC was more rapidly and consistently absorbed after bunionectomy. These characteristics should be advantageous when rapid pain relief is desired.

ACVR1/JAK1/JAK2 inhibitor momelotinib reverses transfusion dependency and suppresses hepcidin in myelofibrosis phase 2 trial.

Momelotinib (MMB) is a JAK1/2 and ACVR1 inhibitor with demonstrated clinical activity in all 3 hallmarks of myelofibrosis (MF): anemia, constitutional symptoms, and splenomegaly. In this phase 2 open-label translational biology study (NCT02515630) of 41 transfusion-dependent patients with MF, we explored mechanisms underlying the favorable activity of MMB on MF-associated iron-restricted anemia, including its impact on serum hepcidin levels, and markers of iron storage and availability, erythropoiesis, and inflammation. A transfusion-independent response (TI-R), defined as red blood cell transfusion independence (TI) ≥12 weeks at any time on study, occurred in 17 patients (41%; 95% confidence interval [CI], 26%-58%), including 14 patients (34%; 95% CI, 20%-51%) who achieved TI-R by week 24. In addition, 78% of TI nonresponse (TI-NR) patients achieved a ≥50% decrease in transfusion requirement for ≥8 weeks. Adverse events (AEs) were consistent with previous studies of MMB in MF, with cough, diarrhea, and nausea as the most common. Twenty-one patients experienced grade ≥3 AEs, most commonly anemia and neutropenia. Consistent with preclinical data, daily MMB treatment led to an acute and persistent decrease in blood hepcidin associated with increased iron availability and markers of erythropoiesis. Baseline characteristics associated with TI-R were lower inflammation and hepcidin as well as increased markers of erythropoiesis and bone marrow function. Overall, the study demonstrates that MMB treatment decreases hepcidin in conjunction with improving iron metabolism and erythropoiesis, suggesting a mechanistic explanation for the reduced transfusion dependency observed in transfusion-dependent MF patients treated with MMB, thereby addressing the key unmet medical need in the MF population.

Adenocarcinoma of the cervix metastatic from a colon primary and diagnosed from a routine pap smear in a 17-year-old woman: a case report.

BACKGROUND: Carcinoma metastatic to the uterine cervix is very rare. The most frequent nongenital primary sites are the stomach and colon. CASE: A 17-year-old woman presented to the office for an annual gynecologic examination. The Pap smear and cervical biopsy of a 1.5-cm lesion were positive for adenocarcinoma. Subsequent surgery revealed a sigmoid tumor with extensive abdominal and pelvic carcinomatosis. Following 2 cycles of ineffective chemotherapy, the patient died 4 months after her initial visit to the gynecologist. CONCLUSION: To our knowledge, this was the youngest patient in the literature with colon cancer metastatic to the cervix. This case focuses attention on the diagnostic challenge posed by an incidental finding of a cervical adenocarcinoma in the presence of an asymptomatic primary tumor.

Phase 2 study of safety and efficacy of nimotuzumab in pediatric patients with progressive diffuse intrinsic pontine glioma.

BACKGROUND: The prognosis of diffuse intrinsic pontine glioma (DIPG) remains poor, with no drug proven to be effective. METHODS: Patients with clinically and radiologically confirmed, centrally reviewed DIPG, who had failed standard first-line therapy were eligible for this multicenter phase II trial. The anti-epidermal growth factor receptor (EGFR) antibody, nimotuzumab (150 mg/m(2)), was administered intravenously once weekly from weeks 1 to 7 and once every 2 weeks from weeks 8 to 18. Response evaluation was based on clinical and MRI assessments. Patients with partial response (PR) or stable disease (SD) were allowed to continue nimotuzumab. RESULTS: Forty-four patients received at least one dose of nimotuzumab (male/female, 20/24; median age, 6.0 years; range, 3.0-17.0 years). All had received prior radiotherapy. Treatment was well tolerated. Eighteen children experienced serious adverse events (SAEs). The majority of SAEs were associated with disease progression. Nineteen patients completed 8 weeks (W8) of treatment: There were 2 PRs, 6 SDs, and 11 progressions. Five patients completed 18 weeks (W18) of treatment: 1 of 2 patients with PR at W8 remained in PR at W18, and 3 of 6 children with SD at W8 maintained SD at W18. Time to progression following initiation of nimotuzumab for the 4 patients with SD or better at W18 was 119, 157, 182 and 335 days, respectively. Median survival time was 3.2 months. Two patients lived 663 and 481 days from the start of nimotuzumab. CONCLUSIONS: Modest activity of nimotuzumab in DIPG, which has been shown previously, was confirmed: A small subset of DIPG patients appeared to benefit from anti-EGFR antibody treatment.

A Phase I study of an intravesically administered immunotoxin targeting EpCAM for the treatment of nonmuscle-invasive bladder cancer in BCGrefractory and BCG-intolerant patients.

PURPOSE: A Phase I dose-escalation study was performed to determine the maximum tolerated dose (MTD) of the immunotoxin VB4-845 in patients with nonmuscle-invasive bladder cancer (NMIBC) refractory to or intolerant of bacillus Calmette-Guerin (BCG). Secondary objectives included evaluation of the safety, tolerability, pharmacokinetics, immunogenicity, and efficacy of VB4-845. PATIENTS AND METHODS: Sixty-four patients with Grade 2 or 3, stage Ta or T1 transitional cell carcinoma or in situ carcinoma, either refractory to or intolerant of BCG therapy, were enrolled. Treatment was administered in ascending dose cohorts ranging from 0.1 to 30.16 mg. After receiving weekly instillations of VB4-845 to the bladder via catheter for 6 consecutive weeks, patients were followed for 4-6 weeks post-therapy and assessed at week 12. RESULTS: An MTD was not determined, as a dose-limiting toxicity was not identified over the dose range tested. VB4-845 therapy was safe and well tolerated with most adverse events reported as mild; as a result, no patients were removed from the study in response to toxicity. By the end of the study, the majority of patients had developed antibodies to the exotoxin portion of VB4-845. A complete response was achieved in 39% of patients at the 12-week time point. CONCLUSIONS: VB4-845 dosed on a weekly basis for 6 weeks was very well tolerated at all dose levels. Although an MTD was not determined at the doses administered, VB4-845 showed evidence of an antitumor effect that warrants further clinical investigation for the treatment of NMIBC in this patient population.

Single-dose pharmacokinetic study of rapidly dispersing diclofenac potassium formulations in healthy volunteers.

OBJECTIVE: The clinical utility of diclofenac potassium, a commonly prescribed analgesic that provides mild to moderate pain relief, may be hindered by its delayed, depressed, and/or inconsistent absorption characteristics. A diclofenac potassium formulation using proprietary dispersion technology (ProSorb) was developed to overcome these limitations. The authors evaluated and compared the pharmacokinetics (PK) of 2 investigational diclofenac potassium liquid filled soft gelatin capsule (DPSGC) preparations and one investigational diclofenac liquid formulation, each incorporating the proprietary dispersion technology, to establish bioequivalence and identify a formulation for further clinical study. RESEARCH DESIGN AND METHODS: In an open-label, single-dose, three-way crossover, relative bioavailability study, 24 healthy volunteers were randomized to receive each of the 25-mg DPSGC formulations (development processes A and B) and the 1-mL (25-mg) liquid diclofenac formulation (similar to the fill liquid used in the DPSGC products) during three inpatient visits. Each dose was separated by 3 days. Plasma samples were collected at preselected time points through 6 hours post dose. Diclofenac concentrations were determined using a validated HPLC method. Bioequivalence was established within the 80% to 125% acceptance range. Safety and tolerability were monitored throughout. RESULTS: Area under the plasma concentration-time curves (AUC(0-)(t)) for the three formulations were between 577 and 585 ng-hr/mL and peak plasma concentrations (C(max)) were between 958 and 1087 ng/mL, with the DPSGC process B group having the highest C(max). The times to C(max) (t(max)) were all below 30 minutes, with the liquid formulation producing the shortest t(max) (15 minutes). Plasma concentration-time course profiles were similar for all three rapidly dispersing diclofenac potassium formulations. One mild adverse event was observed (lingual paresthesia) and one participant discontinued due to an unrelated event (acute tonsillitis). CONCLUSIONS: These data show that diclofenac potassium formulations using proprietary dispersion technology are rapidly and consistently absorbed. These characteristics may be beneficial in settings where rapid and consistent drug absorption is desirable. These results may differ in other patient populations such as those experiencing pain or illness.

A phase I clinical study of VB4-845: weekly intratumoral administration of an anti-EpCAM recombinant fusion protein in patients with squamous cell carcinoma of the head and neck.

VB4-845 is a scFv-Pseudomonas exotoxin A fusion construct that targets epithelial cell adhesion molecule (EpCAM). A phase I trial was conducted to determine the maximum tolerated dose (MTD) of VB4-845 when administered as weekly intratumoral (IT) injections to patients with squamous cell carcinoma of the head and neck (SCCHN). Secondary objectives included the evaluation of the safety, tolerability, pharmacokinetic profile, and immunogenicity, and a preliminary assessment of tumor response. Twenty patients with advanced, recurrent SCCHN were treated weekly for four weeks in ascending dose cohorts of 100, 200, 330, 500, 700, and 930 microg. The MTD was established as 930 microg with a dose limiting toxicity of elevated liver enzymes in two of five patients. VB4-845 therapy was well tolerated with common treatment-related adverse events of injection site reactions, fever, gastrointestinal disorders, and elevated liver enzyme levels. All patients developed antibodies to VB4-845 by the end of the study, but only seven patients had neutralizing antibodies. Preliminary efficacy data found 87.5% of EpCAM-positive patients had a positive response to VB4-845 therapy. Noninjected dermal metastases were also resolved in one patient. VB4-845 IT therapy is safe and feasible and warrants further clinical evaluation for the treatment of SCCHN.