Evaluation of the safety, tolerability, pharmacokinetics and pharmacodynamics of SM17 in healthy volunteers: results from pre-clinical models and a first-in-human, randomized, double blinded clinical trial.

Background: Alarmins mediate type 2 T helper cell (Th2) inflammation and serve as upstream signaling elements in allergic inflammation and autoimmune responses. The alarmin interleukin (IL)-25 binds to a multi-domain receptor consisting of IL-17RA and IL-17RB subunits, resulting in the release of Th2 cytokines IL-4, IL-5, IL-9 and IL-13 to drive an inflammatory response. Therefore, the blockage of IL-17RB via SM17, a novel humanized monoclonal antibody, offers an attractive therapeutic target for Th2-mediated diseases, such as asthma.

A phase I thorough QT/QTc study evaluating therapeutic and supratherapeutic doses of avacopan in healthy participants.

This phase I thorough QTc, double-blind, randomized, placebo- and positive-controlled, parallel group, multiple-dose study evaluated avacopan's effect on cardiac repolarization using concentration-QTc (C-QTc) as the primary analysis. Avacopan 30 mg b.i.

Pharmacokinetic Evaluation of the CYP3A4 and CYP2C9 Drug-Drug Interaction of Avacopan in 2 Open-Label Studies in Healthy Participants.

Avacopan, a complement 5a receptor (C5aR) antagonist approved for treating severe active antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis, was evaluated in 2 clinical drug-drug interaction studies. The studies assessed the impact of avacopan on the pharmacokinetics (PK) of CYP3A4 substrates midazolam and simvastatin and CYP2C9 substrate celecoxib, and the influence of CYP3A4 inhibitor itraconazole and inducer rifampin on the PKs of avacopan. The results indicated that twice-daily oral administration of 30 mg of avacopan increased the area under the curve (AUC) of midazolam by 1.

Single- and multiple-dose pharmacokinetics of methylphenidate administered as methylphenidate transdermal system or osmotic-release oral system methylphenidate to children and adolescents with attention deficit hyperactivity disorder.

This was a 1-month, multicenter, open-label, randomized study to determine single- and multiple-dose pharmacokinetics of d,l-methylphenidate (MPH) after MPH transdermal system (MTS) and osmotic-release oral system MPH (OROS MPH) dosing in children (6-12 years) and adolescents (13-17 years) who had a diagnosis of attention deficit hyperactivity disorder. The pharmacokinetic population consisted of 33 children and 31 adolescents. Accumulation of d-MPH was 34% in children and 57% in adolescents after multiple fixed doses of MTS for 7 days and 76% and 94%, respectively, after 28 days of dosing.

A phase II trial of thalidomide in patients with refractory leiomyosarcoma of the uterus and correlation with biomarkers of angiogenesis: a gynecologic oncology group study.

Objectives: To evaluate the efficacy and adverse events (AEs) of thalidomide in previously treated, measurable, persistent or recurrent leiomyosarcoma (LMS) of the uterus, and to explore associations between angiogenic markers and treatment or clinical outcome.

Methods: Eligible, consenting patients were treated until disease progression or toxicity intervened with daily starting dose of 200 mg thalidomide/day that was increased by 200 mg every 2 weeks to a target dose of 1000 mg/day. End-points included progression-free survival (PFS)>or=6 months, toxicity, response, PFS and survival.

Intraperitoneal catheter outcomes in a phase III trial of intravenous versus intraperitoneal chemotherapy in optimal stage III ovarian and primary peritoneal cancer: a Gynecologic Oncology Group Study.

Objectives: To evaluate reasons for discontinuing intraperitoneal (IP) chemotherapy, and to compare characteristics of patients who did versus did not successfully complete six cycles of IP chemotherapy.

Methods: In a phase III trial, women with optimal stage III ovarian or peritoneal carcinoma were randomly allocated to receive IP therapy (paclitaxel 135 mg/m(2) intravenously (IV) over 24 h, cisplatin 100 mg/m(2) IP day 2, paclitaxel 60 mg/m(2) IP day 8) every 21 days for six cycles. Patients unable to receive IP therapy were treated with the alternate (IV) regimen.

Carboplatin plus paclitaxel in the treatment of advanced or recurrent endometrial carcinoma.

Purpose: To evaluate the efficacy and safety of the combination of carboplatin plus paclitaxel in patients with advanced, metastatic and recurrent endometrial cancer.

Methods: Medical records were retrospectively reviewed to identify endometrial cancer patients treated in the Gynecologic Cancer Program of the Cleveland Clinic with carboplatin/paclitaxel who had both a histologic diagnosis of endometrial adenocarcinoma and either measurable (CT scan, physical examination) or evaluable (CA-125 criteria) disease.

Results: From 1994 to 2003, 22 individuals (median age 65 years) meeting the above noted criteria received a total of 23 courses of carboplatin (AUC 4-6)/paclitaxel (135-175 mg/m2) administered on a 21-day schedule (median six cycles/patient).

Prolonged disease-free and treatment-free survival in platinum-resistant ovarian cancer following extended (>1 year) administration of single-agent paclitaxel: A case report and discussion of potential clinical implications.

Background: The optimal duration of therapy for women with platinum-resistant ovarian cancer who respond to second-line treatment programs remains undefined.

Case Report: A patient with well-documented platinum-resistant ovarian cancer who responded to single-agent paclitaxel (175 mg/m2 over 3 hours q 28-35 days) was continued on this program for a total of 15 cycles delivered over a period of 16 months. The patient has subsequently remained without evidence of disease recurrence >7 years following discontinuation of this treatment regimen.

Phase 2 trial of prolonged administration of oral topotecan in platinum/taxane-refractory ovarian, fallopian tube, and primary peritoneal cancers.

Objectives: Preclinical and clinical data have demonstrated the importance of schedule in optimizing the cytotoxic potential of topotecan, one of the most active agents in ovarian cancer. The availability of oral topotecan permits the exploration of the clinical utility of prolonged treatment programs employing this drug.

Methods: Patients with platinum/taxane resistant ovarian and primary peritoneal cancers were treated with oral topotecan at an initial fixed dose of 1.

Thrombocytopenia associated with second-line carboplatin-based chemotherapy for ovarian, fallopian tube, and primary peritoneal cavity cancers.

Purpose: There are limited data available in the oncology literature regarding the risk of thrombocytopenia associated with carboplatin-based second-line treatment of ovarian cancer, outside the setting of patients participating in clinical trials.

Methods: To examine this clinically-relevant issue, we conducted a retrospective review of the medical records of women with ovarian cancer treated in the Gynecologic Cancer Program of the Cleveland Clinic from 1994 through November 2003, who received >2 second-line carboplatin-based regimens.

Results: A total of 176 second-line carboplatin-based programs were delivered to the 152 patients (median age 61 years; range 39-87 years) identified through this review.

Phase 2 trial of interferon-beta as second-line treatment of ovarian cancer, fallopian tube cancer, or primary carcinoma of the peritoneum.

Objective: The protocol was designed to examine the biological effects and clinical activity of interferon-beta in patients with platinum/taxane-resistant ovarian cancer.

Methods: Patients with resistant ovarian and fallopian tube cancers and primary peritoneal carcinoma were treated with recombinant human interferon-beta (Rebif, Serono International) at doses ranging from 6 to 24 million international units (MIU)/day, based on their tolerance to therapy. Levels of IP-10, an interferon-inducible protein, were measured in the serum to evaluate the biological effects of the drug.

Phase 2 trial of carboplatin plus tamoxifen in platinum-resistant ovarian cancer and primary carcinoma of the peritoneum.

Objectives: A previously reported phase 2 trial suggested substantial clinical activity associated with the combination of a platinum agent and tamoxifen in the treatment of platinum-resistant ovarian cancer. We wished to confirm or refute this observation in a patient population with well-characterized platinum-resistant disease.

Methods: Patients with ovarian or fallopian tube cancers or primary carcinoma of the peritoneum whose disease had either failed to respond to a platinum-based regimen or had responded but experienced a "treatment-free interval (TFI)" of < or =3 months, or if the TFI was >3 months they had been retreated and failed a platinum-based program, were eligible for entry into this phase 2 single institution protocol.

Duration of response to second-line, platinum-based chemotherapy for ovarian cancer: implications for patient management and clinical trial design.

Purpose: Limited information is available regarding the influence of the duration of a prior response on the length of a subsequent response to platinum chemotherapy in recurrent ovarian cancer.

Patients And Methods: We retrospectively reviewed the medical records of women with ovarian cancer treated at the Cleveland Clinic from 1993 through April 2003 who received two or more platinum-based regimens for recurrence of the malignancy. Patients were considered to have responded to second-line therapy if they satisfied specific criteria, including favorable effects on both measurable or assessable disease.

Examples of the marked variability in the relationship between the serum CA-125 antigen level and cancer-related symptoms in ovarian cancer.

Objective: While the clinical utility of the serum CA-125 antigen level in demonstrating objective evidence of regression or progression of disease in women with ovarian cancer is well-established, the relationship between both the absolute value of this tumor maker, or its rate of change over time, and the short-term clinical course (e.g., development of cancer-related symptoms) in individual patients remains poorly defined.

Survival following the documentation of platinum and taxane resistance in ovarian cancer: a single institution experience involving multiple phase 2 clinical trials.

Objectives: There are very limited data in the oncology literature regarding the survival of women with both platinum and taxane-refractory ovarian cancer.

Methods: To examine this issue, we retrospectively reviewed the survival of patients treated on one (or more) of four previously reported nonrandomized single-agent phase 2 trials (topotecan, liposomal doxorubicin, gemcitabine, docetaxel), involving women with well-characterized platinum/taxane-resistant ovarian, fallopian tube, and primary peritoneal cancers. Following their most recent treatment with both classes of agents, patients must have either not responded to therapy or experienced a treatment-free interval of <3 months before documented disease progression.

Use of tamoxifen in asymptomatic patients with recurrent small-volume ovarian cancer.

Objectives: Tamoxifen, a well-tolerated oral hormonal agent with biological activity in ovarian cancer, is a potentially attractive option in asymptomatic patients with recurrent disease. Unfortunately, the clinical utility of the drug in this specific setting has not been well documented.

Patients And Methods: A retrospective review was conducted of patients with cancers of the ovary, fallopian tube, and primary cancer of the peritoneum at the Cleveland Clinic who experienced recurrence of the malignancy, in the absence of large volume disease (by physical exam and radiographic evaluation) or any cancer-related symptoms, and who received tamoxifen (20 mg [most patients] or 40 mg/day) before re-initiation of cytotoxic chemotherapy.

Proteome analysis of adipogenesis.

Adipose tissue plays a crucial endocrine role in controlling whole body glucose homeostasis and insulin sensitivity. Given the substantial rise in obesity and obesity-related diseases such as diabetes, it is important to understand the molecular basis of adipocyte differentiation and its control. Many studies have successfully exploited gene array technology to monitor changes in the profile of expressed genes during adipocyte differentiation, although this method only measures changes at the level of individual mRNA species.

Experience with the management of neutropenia in gynecologic cancer patients receiving carboplatin-based chemotherapy.

Objective. There exists limited information in the medical literature regarding the incidence and severity of carboplatin-associated neutropenia, outside the setting of a clinical trial. We wished to examine this issue in a large single institution experience involving patients receiving both single agent and combination carboplatin-based chemotherapy for management of a female pelvic malignancy.

Phase 2 trial of carboplatin, paclitaxel, and irinotecan in ovarian, fallopian tube, and primary peritoneal cancers.

Objective: Our goal in this nonrandomized phase 2 trial was to evaluate the toxicity and obtain preliminary data on the potential efficacy of a novel three-drug combination regimen (carboplatin-paclitaxel-irinotecan) when employed as initial therapy of advanced ovarian cancer or as second-line treatment in the setting of a prolonged (>or=12 months) treatment-free interval.

Methods: Patients with a histologically confirmed diagnosis of advanced ovarian cancer, primary adenocarcinoma of the peritoneum, or fallopian tube cancer were enrolled in the study. Patients received carboplatin (AUC 5), paclitaxel (150 mg/m(2) over 3 h), and irinotecan (100 mg/m(2) over 90 min).

Phase 2 trial of single agent docetaxel in platinum and paclitaxel-refractory ovarian cancer, fallopian tube cancer, and primary carcinoma of the peritoneum.

Objective: Previously reported data have suggested the lack of complete cross-resistance between docetaxel and paclitaxel in ovarian cancer. We wished to evaluate the biological and clinical activity of docetaxel in a patient population with well-characterized platinum and paclitaxel-refractory ovarian cancer.

Methods: In this single-institution phase 2 trial, 30 women with advanced ovarian cancer whose disease had either failed to respond to primary platinum-paclitaxel chemotherapy or where the cancer had progressed within 3 months of their last treatment with both a platinum agent and paclitaxel were treated with single agent docetaxel (75 mg/m(2) q 3 weeks).

Expanded experience with an intradermal skin test to predict for the presence or absence of carboplatin hypersensitivity.

Purpose: Carboplatin-associated hypersensitivity is increasingly recognized as a potentially serious toxicity when this agent is administered for more than six total cycles.

Patients And Methods: Our group has used a predictive skin test in women with gynecologic cancers who have previously received more than six cumulative cycles of platinum-based chemotherapy. Thirty minutes before all subsequent carboplatin courses, a 0.

Initial experience with a novel desensitization strategy for carboplatin-associated hypersensitivity reactions: carboplatin-hypersensitivity reactions.

Purpose: Carboplatin hypersensitivity is an increasingly recognized toxicity in individuals receiving >6 cumulative courses of this important antineoplastic agent. We wished to determine if a novel multi-pronged approach to re-treating patients with a high risk for this potentially serious side effect could permit the safe delivery of this class of cytotoxic drugs.

Methods: Five patients with gynecologic malignancies who had either experienced a documented carboplatin hypersensitivity reaction ( n =4) or had a "positive" carboplatin skin test ( n =1), received a multi-drug oral regimen administered over several days which was designed to block known mediators of anaphylaxis.

Carboplatin plus paclitaxel combination chemotherapy: impact of sequence of drug administration on treatment-induced neutropenia.

Objective: While the importance of the sequence of administration of cisplatin and paclitaxel on the degree of observed neutropenia has been documented, there is limited information available in the oncology literature to determine whether there exists sequence-dependent toxicity for the combination of carboplatin plus paclitaxel.

Methods: Patients with advanced gynecologic malignancies were randomized to receive either carboplatin (AUC 6), followed by paclitaxel (175 mg/m(2) over 3 h) (C-P), or the same doses of the agents delivered in the opposite sequence (P-C). The primary endpoint was the degree of neutropenia experienced during the initial treatment course.

Phase 2 trial of pegylated liposomal doxorubicin in advanced endometrial cancer.

Purpose: To evaluate the efficacy and toxicity of pegylated liposomal doxorubicin in patients with advanced endometrial cancer.

Methods: Pegylated liposomal doxorubicin was administered at a dose of 40 mg/m2, and repeated on an every 28-day schedule.

Results: A total of 19 patients were enrolled in this phase 2 trial.