Activity of the Gamma Secretase Inhibitor AL101 in Desmoid Tumors: A Case Report of 2 Adult Cases.

Desmoid tumors (aggressive fibromatosis) are soft tissue mesenchymal tumors that can be locally invasive and life-threatening. Depending on the location, these tumors are often unresectable or tend to recur after surgery. To date, there are no approved systemic therapies for desmoid tumors. These tumors typically harbor mutations in the ß-catenin oncogene CTNNB1 or the tumor suppressor gene adenomatous polyposis coli, resulting in constitutive activation of the WNT pathway. The Notch pathway is part of the underlying cause for desmoid tumor development, possibly due to crosstalk with the WNT pathway, providing a rationale for Notch inhibition as a therapeutic strategy. The gamma secretase activation of the Notch receptor can be targeted with investigational gamma secretase inhibitors. In this case report, we follow the course of 2 patients with desmoid tumors treated with the highly potent, parenterally administered investigational gamma secretase inhibitor AL101, resulting in long-lasting responses. Case 1 reports on a patient with a mesenteric desmoid tumor who participated in a phase 1 trial and then transitioned into a compassionate use program; Case 2 reports on a patient with recurrent pelvic tumors receiving AL101 through a compassionate use program. After tumor progression on other systemic therapies, Cases 1 and 2 had confirmed partial responses (41% and 60% maximal tumor size decrease from baseline) recorded after 1.0 and 1.6 years of treatment with AL101, with a duration of response of 8.6+ and 2.6+ years, respectively. Also, in a phase 1 study of AL102, a potent orally administered gamma secretase inhibitor that shares structural features with AL101, a patient with a desmoid tumor was noted to have tumor shrinkage. Formal clinical testing of AL102 for the treatment of patients with desmoid tumors that are not amenable to surgery or are refractory to/recurrent from other prior therapies is currently underway.

Biomarkers in Heart Failure With Preserved Ejection Fraction: An Update on Progress and Future Challenges.

Heart failure with preserved ejection fraction (HFpEF) is a major health care problem, with no treatment available that significantly reduces mortality. HFpEF is a phenotypically diverse syndrome, which creates difficulties in establishing an accurate diagnosis, determining prognosis, and developing effective management strategies. The number of serum biomarkers being investigated to further our understanding of HFpEF is rapidly expanding. In this review, we critically appraise the current clinical utility of biomarkers in HFpEF, particularly for pathophysiological pathways involving cardiomyocyte stretch, injury, fibrosis, remodelling, systemic inflammation, and renal dysfunction. Guideline-based clinical indications for biomarker testing in HFpEF and their limitations are discussed. Investigative strategies including the use of multi-biomarker panels and standardisation of research methodologies may prove useful in developing biomarkers for HFpEF in the future.

Venetoclax for Patients With Chronic Lymphocytic Leukemia With 17p Deletion: Results From the Full Population of a Phase II Pivotal Trial.

Purpose Venetoclax is an orally bioavailable B-cell lymphoma 2 inhibitor. US Food and Drug Administration and European Medicines Agency approval for patients with 17p deleted relapsed/refractory chronic lymphocytic leukemia [del(17p) CLL] was based on results from 107 patients. An additional 51 patients were enrolled in a safety expansion cohort. Extended analysis of all enrolled patients, including the effect of minimal residual disease (MRD) negativity on outcome, is now reported. Patients and Methods Overall, 158 patients with relapsed/refractory or previously untreated (n = 5) del(17p) CLL received venetoclax 400 mg per day after an initial dose ramp up. Responses were based on 2008 International Workshop on Chronic Lymphocytic Leukemia criteria, with monthly physical exams and blood counts. Computed tomography scan was mandatory at week 36, after which assessment made was by clinical evaluation. Marrow biopsy was performed when complete remission was suspected. MRD was assessed by flow cytometry. Results Patients had a median of two prior therapies (range, zero to 10 therapies), 71% had TP53 mutation, and 48% had nodes that were ≥ 5 cm. Median time on venetoclax was 23.1 months (range, 0 to 44.2 months) and median time on study was 26.6 months (range, 0 to 44.2 months). For all patients, investigator-assessed objective response rate was 77% (122 of 158 patients; 20% complete remission) and estimated progression-free survival at 24 months was 54% (95% CI, 45% to 62%). For 16 patients who received prior kinase inhibitors, objective response rate was 63% (10 of 16 patients) and 24-month progression-free survival estimate was 50% (95% CI, 25% to 71%). By intent-to-treat analysis, 48 (30%) of 158 patients achieved MRD below the cutoff of 10-4 in blood. Common grade 3 and 4 adverse events were hematologic and managed with supportive care and/or dose adjustments. Conclusion Venetoclax achieves durable responses and was well tolerated in patients with del(17p) CLL. A high rate of blood MRD < 10-4 was achieved in this high-risk population.

Takotsubo cardiomyopathy and transient global amnesia: a shared aetiology.

Takotsubo cardiomyopathy (TTC) is associated with acute, reversible left ventricular (LV) dysfunction, while transient global amnesia (TGA) is a reversible disorder of the brain characterised by anterograde amnesia. We report an unusual case of TTC occurring concurrently in a patient with TGA, and propose that catecholamine surge induced cerebral venous congestion and cardiotoxicity is the shared aetiology that leads to the concurrent manifestation of these conditions. TTC and TGA are reversible disorders that can occur concurrently in a subset of patients due to a unifying aetiology, catecholamine excess, leading to pathophysiological changes within the brain and the myocardium.

Phase I First-in-Human Study of Venetoclax in Patients With Relapsed or Refractory Non-Hodgkin Lymphoma.

Purpose B-cell leukemia/lymphoma-2 (BCL-2) overexpression is common in many non-Hodgkin lymphoma (NHL) subtypes. A phase I trial in patients with NHL was conducted to determine safety, pharmacokinetics, and efficacy of venetoclax, a selective, potent, orally bioavailable BCL-2 inhibitor. Patients and Methods A total of 106 patients with relapsed or refractory NHL received venetoclax once daily until progressive disease or unacceptable toxicity at target doses from 200 to 1,200 mg in dose-escalation and safety expansion cohorts. Treatment commenced with a 3-week dose ramp-up period for most patients in dose-escalation cohorts and for all patients in safety expansion. Results NHL subtypes included mantle cell lymphoma (MCL; n = 28), follicular lymphoma (FL; n = 29), diffuse large B-cell lymphoma (DLBCL; n = 34), DLBCL arising from chronic lymphocytic leukemia (Richter transformation; n = 7), Waldenström macroglobulinemia (n = 4), and marginal zone lymphoma (n = 3). Venetoclax was generally well tolerated. Clinical tumor lysis syndrome was not observed, whereas laboratory tumor lysis syndrome was documented in three patients. Treatment-emergent adverse events were reported in 103 patients (97%), a majority of which were grade 1 to 2 in severity. Grade 3 to 4 events were reported in 59 patients (56%), and the most common were hematologic, including anemia (15%), neutropenia (11%), and thrombocytopenia (9%). Overall response rate was 44% (MCL, 75%; FL, 38%; DLBCL, 18%). Estimated median progression-free survival was 6 months (MCL, 14 months; FL, 11 months; DLBCL, 1 month). Conclusion Selective targeting of BCL-2 with venetoclax was well tolerated, and single-agent activity varied among NHL subtypes. We determined 1,200 mg to be the recommended single-agent dose for future studies in FL and DLBCL, with 800 mg being sufficient to consistently achieve durable response in MCL. Additional investigations including combination therapy to augment response rates and durability are ongoing.

Venetoclax plus rituximab in relapsed or refractory chronic lymphocytic leukaemia: a phase 1b study.

BACKGROUND: Selective BCL2 inhibition with venetoclax has substantial activity in patients with relapsed or refractory chronic lymphocytic leukaemia. Combination therapy with rituximab enhanced activity in preclinical models. The aim of this study was to assess the safety, pharmacokinetics, and activity of venetoclax in combination with rituximab. METHODS: Adult patients with relapsed or refractory chronic lymphocytic leukaemia (according to the 2008 Modified International Workshop on CLL guidelines) or small lymphocytic lymphoma were eligible for this phase 1b, dose-escalation trial. The primary outcomes were to assess the safety profile, to determine the maximum tolerated dose, and to establish the recommended phase 2 dose of venetoclax when given in combination with rituximab. Secondary outcomes were to assess the pharmacokinetic profile and analyse efficacy, including overall response, duration of response, and time to tumour progression. Minimal residual disease was a protocol-specified exploratory objective. Central review of the endpoints was not done. Venetoclax was dosed daily using a stepwise escalation to target doses (200-600 mg) and then monthly rituximab commenced (375 mg/m2 in month 1 and 500 mg/m2 in months 2-6). Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for adverse events version 4.0. Protocol-guided drug cessation was allowed for patients who achieved complete response (including complete response with incomplete marrow recovery) or negative bone marrow minimal residual disease. Analyses were done per protocol for all patients who commenced drug and included all patients who received at least one dose of venetoclax. Data were pooled across dose cohorts. Patients are still receiving therapy and follow-up is ongoing. The trial is registered at ClinicalTrials.gov, number NCT01682616. FINDINGS: Between Aug 6, 2012, and May 28, 2014, we enrolled 49 patients. Common grade 1-2 toxicities included upper respiratory tract infections (in 28 [57%] of 49 patients), diarrhoea (27 [55%]), and nausea (25 [51%]). Grade 3-4 adverse events occurred in 37 (76%) of 49 patients; most common were neutropenia (26 [53%]), thrombocytopenia (eight [16%]), anaemia (seven [14%]), febrile neutropenia (six [12%]), and leucopenia (six [12%]). The most common serious adverse events were pyrexia (six [12%]), febrile neutropenia (five [10%]), lower respiratory tract infection, and pneumonia (each three [6%]). Clinical tumour lysis syndrome occurred in two patients (resulting in one death) who initiated venetoclax at 50 mg. After enhancing tumour lysis syndrome prophylaxis measures and commencing venetoclax at 20 mg, clinical tumour lysis syndrome did not occur. The maximum tolerated dose was not identified; the recommended phase 2 dose of venetoclax in combination with rituximab was 400 mg. Overall, 42 (86%) of 49 patients achieved a response, including a complete response in 25 (51%) of 49 patients. 2 year estimates for progression-free survival and ongoing response were 82% (95% CI 66-91) and 89% (95% CI 72-96), respectively. Negative marrow minimal residual disease was attained in 20 (80%) of 25 complete responders and 28 (57%) of 49 patients overall. 13 responders ceased all therapy; among these all 11 minimal residual disease-negative responders remain progression-free off therapy. Two with minimal residual disease-positive complete response progressed after 24 months off therapy and re-attained response after re-initiation of venetoclax. INTERPRETATION: A substantial proportion of patients achieved an overall response with the combination of venetoclax and rituximab including 25 (51%) of 49 patients who achieved a complete response and 28 (57%) of 49 patients who achieved negative marrow minimal residual disease with acceptable safety. The depth and durability of responses observed with the combination offers an attractive potential treatment option for patients with relapsed or refractory chronic lymphocytic leukaemia and could allow some patients to maintain response after discontinuing therapy, a strategy that warrants further investigation in randomised studies. FUNDING: AbbVie Inc and Genentech Inc.

The application of supply chain management principles to emergency management logistics: An empirical study.

Key elements of supply chain theory remain relevant to emergency management (EM) logistics activities. The Supply Chain Operations Reference model can also serve as a useful template for the planning, organizing, and execution of EM logistics. Through a series of case studies (developed through intensive survey of organizations and individuals responsible for EM), the authors identified the extent supply chain theory is being adopted and whether the theory was useful for emergency logistics managers. The authors found several drivers that influence the likelihood of an organization to implement elements of supply chain management: the frequency of events, organizational resources, population density, range of events, and severity of the disaster or emergency.

Venetoclax in relapsed or refractory chronic lymphocytic leukaemia with 17p deletion: a multicentre, open-label, phase 2 study.

BACKGROUND: Deletion of chromosome 17p (del[17p]) in patients with chronic lymphocytic leukaemia confers very poor prognosis when treated with standard chemo-immunotherapy. Venetoclax is an oral small-molecule BCL2 inhibitor that induces chronic lymphocytic leukaemia cell apoptosis. In a previous first-in-human study of venetoclax, 77% of patients with relapsed or refractory chronic lymphocytic leukaemia achieved an overall response. Here we aimed to assess the activity and safety of venetoclax monotherapy in patients with relapsed or refractory del(17p) chronic lymphocytic leukaemia. METHODS: In this phase 2, single-arm, multicentre study, we recruited patients aged 18 years and older with del(17p) relapsed or refractory chronic lymphocytic leukaemia (as defined by 2008 Modified International Workshop on Chronic Lymphocytic Leukemia guidelines) from 31 centres in the USA, Canada, UK, Germany, Poland, and Australia. Patients started once daily venetoclax with a weekly dose ramp-up schedule (20, 50, 100, 200, 400 mg) over 4-5 weeks. Patients were then given daily 400 mg continuous dosing until disease progression or discontinuation for another reason. The primary endpoint was the proportion of patients achieving an overall response, assessed by an independent review committee. Activity and safety analyses included all patients who received at least one dose of study drug (per protocol). This study is registered with ClinicalTrials.gov, number NCT01889186. Follow-up is ongoing, and patients are still receiving treatment. FINDINGS: Between May 27, 2013, and June 27, 2014, 107 patients were enrolled into the study. At a median follow-up of 12·1 months (IQR 10·1-14·2), an overall response by independent review was achieved in 85 (79·4%; 95% CI 70·5-86·6) of 107 patients. The most common grade 3-4 adverse events were neutropenia (43 [40%]), infection (21 [20%]), anaemia (19 [18%]), and thrombocytopenia (16 [15%]). Serious adverse events occurred in 59 (55%) patients, irrespective of their relationship to treatment, with the most common (≥5% of patients) being pyrexia and autoimmune haemolytic anaemia (seven [7%] each), pneumonia (six [6%]), and febrile neutropenia (five [5%]). 11 patients died in the study within 30 days of the last dose of venetoclax; seven due to disease progression and four from an adverse event (none assessed as treatment related). INTERPRETATION: Results of this trial show that venetoclax monotherapy is active and well tolerated in patients with relapsed or refractory del(17p) chronic lymphocytic leukaemia, providing a new therapeutic option for this very poor prognosis population. Additionally, in view of the distinct mechanism-of-action of venetoclax, combinations or sequencing with other novel targeted agents should be investigated to further advance treatment of del(17p) chronic lymphocytic leukaemia. FUNDING: AbbVie and Genentech.

Studying navitoclax, a targeted anticancer drug, in healthy volunteers--ethical considerations and risk/benefit assessments and management.

BACKGROUND: Biopharmaceutical studies for anti-cancer drugs are typically conducted in cancer patients due to unacceptable toxicities to healthy volunteers. Navitoclax is a first-in-class, orally bioavailable, targeted Bcl-2 family protein inhibitor that has been studied in cancer patients. METHODS: A strategy that integrated the evaluation of non-clinical toxicology data and clinical data in cancer patients was employed to assess the feasibility, determine doses and establish risk management plans for studying navitoclax in healthy volunteers. Two relative bioavailability/food effect studies with either a 25 mg dose or 50 and 100 mg doses of navitoclax were conducted sequentially in healthy female volunteers of non-childbearing potential. RESULTS/CONCLUSION: Navitoclax was well-tolerated in both studies in healthy volunteers, and did not impose risks beyond the minimal levels expected in healthy volunteer studies. Compared to a similar study in cancer patients, the studies in healthy volunteers generated higher quality data in a short period of time to support formulation selection.

Time to disease progression in children with relapsed or refractory neuroblastoma treated with ABT-751: a report from the Children's Oncology Group (ANBL0621).

BACKGROUND: ABT-751, an orally bioavailable sulfonamide binds the colchicine site of beta-tubulin and inhibits microtubule polymerization. Prior phase I studies established the recommended dose in children with solid tumors as 200 mg/m(2) PO daily × 7 days every 21 days and subjects with neuroblastoma experienced prolonged stable disease. We conducted a phase 2 study (NCT00436852) in children and adolescents with progressive neuroblastoma to determine if ABT-751 prolonged the time to progression (TTP) compared to a hypothesized standard based on a historical control population. PROCEDURE: Children and adolescents (n = 91) with a median (range) age 7.7 (2.3-21.5) years and progressive neuroblastoma were enrolled and stratified by disease status into disease measureable by CT/MRI (n = 47) or disease assessable by (123) I-metaiodobenzylguanine scintigraphy (MIBG, n = 44). Response was evaluated using RECIST for measureable disease and the Curie score for MIBG-avid disease. RESULTS: ABT-751 was well tolerated. The objective response rate was 7%. The median TTP was 42 days (95% CI: 36, 56) in the measureable disease stratum and 45 days (95% CI: 42, 85) in the MIBG-avid disease stratum. TTP was similar to the historical control group (n = 136, median TTP 42 days). For the combined strata (n = 91), 1-year progression free survival (PFS) was 13 ± 4% and overall survival (OS) was 48 ± 5%. CONCLUSIONS: The low objective response rate and failure to prolong TTP indicate that ABT-751 is not sufficiently active to warrant further development for neuroblastoma. However, this trial demonstrates the utility of TTP as the primary endpoint in phase 2 trials in children and adolescents with neuroblastoma.

Preclinical discovery of candidate genes to guide pharmacogenetics during phase I development: the example of the novel anticancer agent ABT-751.

OBJECTIVE: ABT-751, a novel orally available antitubulin agent, is mainly eliminated as inactive glucuronide (ABT-751G) and sulfate (ABT-751S) conjugates. We performed a pharmacogenetic investigation of ABT-751 pharmacokinetics using in-vitro data to guide the selection of genes for genotyping in a phase I trial of ABT-751. METHODS: UDP-glucuronosyltransferase (UGT) and sulfotransferase (SULT) enzymes were screened for ABT-751 metabolite formation in vitro. Forty-seven cancer patients treated with ABT-751 were genotyped for 21 variants in these genes. RESULTS: UGT1A1, UGT1A4, UGT1A8, UGT2B7, and SULT1A1 were found to be involved in the formation of inactive ABT-751 glucuronide (ABT-751G) and sulfate (ABT-751S). SULT1A1 copy number (>2) was associated with an average 34% increase in ABT-751 clearance (P=0.044), an 18% reduction in ABT-751 AUC (P=0.045), and a 50% increase in sulfation metabolic ratios (P=0.025). UGT1A8 rs6431558 was associated with a 28% increase in glucuronidation metabolic ratios (P=0.022), and UGT1A4*2 was associated with a 65% decrease in ABT-751 C trough (P=0.009). CONCLUSION: These results might represent the first example of a clinical pharmacokinetic effect of the SULT1A1 copy number variant on the clearance of a SULT1A1 substrate. A-priori selection of candidate genes guided by in-vitro metabolic screening enhanced our ability to identify genetic determinants of interpatient pharmacokinetic variability.

A phase I trial and in vitro studies combining ABT-751 with carboplatin in previously treated non-small cell lung cancer patients.

BACKGROUND: ABT-751 is a novel antimitotic agent that exerted cytotoxic effects in preclinical studies. Carboplatin has efficacy in treating advanced non-small cell lung cancer (NSCLC) in combination with other drugs. METHODS: Lung cancer cell lines were treated with ABT-751 and/or carboplatin to investigate their impact on cell growth. A phase I study with an expansion cohort was conducted in previously treated NSCLC patients. The primary objective was the maximum tolerated dose (MTD); secondary objectives were objective response rates, median survival, time to tumor progression, dose-limiting toxicities (DLTs), and pharmacodynamic evaluation of buccal swabs. RESULTS: Combining ABT-751 with carboplatin significantly reduced growth and induced apoptosis of lung cancer cell lines. Twenty advanced NSCLC patients were enrolled. MTD was ABT-751 125 mg orally twice daily for 7 days with carboplatin AUC 6. DLTs included fatigue, ileus, neutropenia and pneumonitis. Two patients had confirmed partial responses. Median overall survival was 11.7 months (95% CI 5.9-27.0). Time to tumor progression was 2.8 months (95% CI 2.0-2.7). Four of 6 patients showed decreased cyclin D1 protein in posttreatment versus pretreatment buccal swabs. CONCLUSION: Combining ABT-751 with carboplatin suppressed growth of lung cancer cell lines and had modest clinical antitumor activity in advanced NSCLC previously treated predominantly with carboplatin. Further studies of this combination are not recommended while investigations of biomarkers in different patient populations, alternative schedules and combinations may be pursued.

A randomized, double-blind, placebo-controlled trial of misoprostol for oral mucositis secondary to high-dose chemotherapy.

PURPOSE: Misoprostol, a synthetic analog of prostaglandin E1, has anti-inflammatory and mucosa-protecting properties. The objective of this study was to evaluate the efficacy of misoprostol oral rinse in reducing the severity of oral mucosal injury caused by high-dose chemotherapy. METHODS: The study used a randomized, double-blind, placebo-controlled, parallel-group design. Oncology patients receiving myeloablative high-dose chemotherapy, in preparation for a hematopoietic stem cell transplant, were randomized to misoprostol or placebo rinse. The primary outcome measure was the severity of oral mucositis, measured using the modified Oral Mucositis Index. Additional outcome measures included the severity of mouth pain (measured using a Visual Analog Scale and the Pain Affect Faces Scale), duration of hospital stay, and days on total parenteral nutrition. RESULTS: This study was originally planned to accrue 160 subjects but was terminated early due to revised sponsor research priorities. The intent-to-treat population consisted of 22 subjects randomized to misoprostol rinse and 26 subjects randomized to placebo rinse. There was no significant difference between the two groups in mucositis or pain severity. In both groups, duration of hospital stay was approximately 19 days, and number of days on total parenteral nutrition was 17-18 days. There were no serious adverse events attributable to misoprostol rinse. CONCLUSIONS: Although this study did not find a beneficial effect of a misoprostol rinse in mucositis secondary to high-dose chemotherapy, the small sample size limits the strength of this conclusion. Given the proposed importance of the prostaglandin pathway in the pathogenesis of oral mucositis, additional studies are warranted.

Regulatory approval of cancer risk-reducing (chemopreventive) drugs: moving what we have learned into the clinic.

This article endeavors to clarify the current requirements and status of regulatory approval for chemoprevention (risk reduction) drugs and discusses possible improvements to the regulatory pathway for chemoprevention. Covering a wide range of topics in as much depth as space allows, this report is written in a style to facilitate the understanding of nonscientists and to serve as a framework for informing the directions of experts engaged more deeply with this issue. Key topics we cover here are as follows: a history of definitive cancer chemoprevention trials and their influence on the evolution of regulatory assessments; a brief review of the long-standing success of pharmacologic risk reduction of cardiovascular diseases and its relevance to approval for cancer risk reduction drugs; the use and limitations of biomarkers for developing and the approval of cancer risk reduction drugs; the identification of individuals at a high(er) risk for cancer and who are appropriate candidates for risk reduction drugs; business models that should incentivize pharmaceutical industry investment in cancer risk reduction; a summary of scientific and institutional barriers to development of cancer risk reduction drugs; and a summary of major recommendations that should help facilitate the pathway to regulatory approval for pharmacologic cancer risk reduction drugs.

Phase I/II study of pemetrexed with or without ABT-751 in advanced or metastatic non-small-cell lung cancer.

PURPOSE: ABT-751 is an antimitotic and vascular disrupting agent with potent preclinical anticancer activity. We conducted a phase I and randomized double-blind phase II study of pemetrexed with ABT-751 or placebo in patients with recurrent advanced or metastatic non-small-cell lung cancer (NSCLC). METHODS: One hundred seventy-one patients received intravenous pemetrexed 500 mg/m(2) day 1 and oral ABT-751 or placebo days 1 to 14 of 21-day cycles. The primary end point was progression-free survival (PFS). Secondary end point included overall survival (OS); pharmacokinetic and pharmacodynamic parameters were also analyzed. RESULTS: The recommended phase II dose of ABT-751 with pemetrexed is 200 mg. Fatigue, constipation, anemia, nausea, and diarrhea were the most common toxicities in both study arms. No pharmacokinetic interactions were observed. Median PFS in the ABT-751 arm was 2.3 months versus 1.9 for placebo (P = .819, log-rank) for the intention-to-treat population. However, differences in PFS (P = .112, log-rank) and OS (P = .034, log-rank; median 3.3 v 8.1 months) favoring ABT-751 were seen in the squamous NSCLC subgroup. Baseline circulating tumor cell concentrations were predictive of improved OS (P = .013). Changes from baseline of greater than 20% in plasma levels of placenta growth factor (P = .056), squamous cell carcinoma antigen (P = .03), and cytokeratin 19 fragment antigen 21-1 (P = .01) were markers best associated with improved OS. CONCLUSION: Addition of ABT-751 to pemetrexed is well-tolerated, but does not improve outcome in unselected patients with recurrent NSCLC. ABT-751 may have therapeutic potential in squamous NSCLC. Exploratory cellular and molecular analyses in this study identified biomarkers that may correlate with survival.

Chemoprevention of nonmelanoma skin cancer with celecoxib: a randomized, double-blind, placebo-controlled trial.

BACKGROUND: Preclinical studies indicate that the enzyme cyclooxygenase 2 plays an important role in ultraviolet-induced skin cancers. We evaluated the efficacy and safety of celecoxib, a cyclooxygenase 2 inhibitor, as a chemopreventive agent for actinic keratoses, the premalignant precursor of nonmelanoma skin cancers, and for nonmelanoma skin cancers, including cutaneous squamous cell carcinomas (SCCs) and basal cell carcinomas (BCCs). METHODS: A double-blind placebo-controlled randomized trial involving 240 subjects aged 37-87 years with 10-40 actinic keratoses was conducted at eight US academic medical centers. Patients were randomly assigned to receive 200 mg of celecoxib or placebo administered orally twice daily for 9 months. Subjects were evaluated at 3, 6, 9 (ie, completion of treatment), and 11 months after randomization. The primary endpoint was the number of new actinic keratoses at the 9-month visit as a percentage of the number at the time of randomization. In an intent-to-treat analysis, the incidence of actinic keratoses was compared between the two groups using t tests. In exploratory analyses, we evaluated the number of nonmelanoma skin cancers combined and SCCs and BCCs separately per patient at 11 months after randomization using Poisson regression, after adjustment for patient characteristics and time on study. The numbers of adverse events in the two treatment arms were compared using χ(2) or Fisher exact tests. All statistical tests were two-sided. RESULTS: There was no difference in the incidence of actinic keratoses between the two groups at 9 months after randomization. However, at 11 months after randomization, there were fewer nonmelanoma skin cancers in the celecoxib arm than in the placebo arm (mean cumulative tumor number per patient 0.14 vs 0.35; rate ratio [RR] = .43, 95% confidence interval [CI] = 0.24 to 0.75; P = .003). After adjusting for age, sex, Fitzpatrick skin type, history of actinic keratosis at randomization, nonmelanoma skin cancer history, and patient time on study, the number of nonmelanoma skin cancers was lower in the celecoxib arm than in the placebo arm (RR = 0.41, 95% CI = 0.23 to 0.72, P = .002) as were the numbers of BCCs (RR = 0.40, 95% CI = 0.18 to 0.93, P = .032) and SCCs (RR = 0.42, 95% CI = 0.19 to 0.93, P = .032). Serious and cardiovascular adverse events were similar in the two groups. CONCLUSIONS: Celecoxib may be effective for prevention of SCCs and BCCs in individuals who have extensive actinic damage and are at high risk for development of nonmelanoma skin cancers.

Phase 0 clinical trial of the poly (ADP-ribose) polymerase inhibitor ABT-888 in patients with advanced malignancies.

PURPOSE: We conducted the first phase 0 clinical trial in oncology of a therapeutic agent under the Exploratory Investigational New Drug Guidance of the US Food and Drug Administration. It was a first-in-human study of the poly (ADP-ribose) polymerase (PARP) inhibitor ABT-888 in patients with advanced malignancies. PATIENTS AND METHODS: ABT-888 was administered as a single oral dose of 10, 25, or 50 mg to determine the dose range and time course over which ABT-888 inhibits PARP activity in tumor samples and peripheral blood mononuclear cells, and to evaluate ABT-888 pharmacokinetics. Blood samples and tumor biopsies were obtained pre- and postdrug administration for evaluation of PARP activity and pharmacokinetics. A novel statistical approach was developed and utilized to study pharmacodynamic modulation as the primary end point for trials of limited sample size. RESULTS: Thirteen patients with advanced malignancies received the study drug; nine patients underwent paired tumor biopsies. ABT-888 demonstrated good oral bioavailability and was well tolerated. Statistically significant inhibition of poly (ADP-ribose) levels was observed in tumor biopsies and peripheral blood mononuclear cells at the 25-mg and 50-mg dose levels. CONCLUSION: Within 5 months of study activation, we obtained pivotal biochemical and pharmacokinetic data that have guided the design of subsequent phase I trials of ABT-888 in combination with DNA-damaging agents. In addition to accelerating the development of ABT-888, the rapid conclusion of this trial demonstrates the feasibility of conducting proof-of-principle phase 0 trials as part of an alternative paradigm for early drug development in oncology.

ABT-751, a novel tubulin-binding agent, decreases tumor perfusion and disrupts tumor vasculature.

ABT-751 is an orally bioavailable tubulin-binding agent that is currently under clinical development for cancer treatment. In preclinical studies, ABT-751 showed antitumor activity against a broad spectrum of tumor lines including those resistant to conventional chemotherapies. In this study, we investigated the antivascular properties of ABT-751 in a rat subcutaneous tumor model using dynamic contrast-enhanced magnetic resonance imaging. A single dose of ABT-751 (30 mg/kg, intravenously) induced a rapid, transient reduction in tumor perfusion. After 1 h, tumor perfusion decreased by 57% before recovering to near pretreatment levels within 6 h. In contrast, ABT-751 produced little change in muscle perfusion at either time point. To further elucidate mechanisms of drug action at the cellular level, we examined the effects of ABT-751 on endothelial cells using an in-vitro assay. ABT-751, at concentrations corresponding to plasma levels achieved in vivo, caused endothelial cell retraction and significant loss of microtubules within 1 h. The severity of these morphological changes was dose-dependent but reversible within 6 h after the discontinuation of the drug. Taken together, these results show that ABT-751 is a tubulin-binding agent with antivascular properties. Microtubule disruption and morphological changes in vascular endothelial cells may be responsible, at least in part, for the dysfunction of tumor blood vessels after ABT-751 treatment.

Effects of the end point adjudication process on the results of the Perindopril Protection Against Recurrent Stroke Study (PROGRESS).

BACKGROUND AND PURPOSE: End point adjudication committees (EPAC) are widely used in large-scale clinical trials to ensure the robustness of diagnosis for end points. METHODS: The Perindopril Protection Against Recurrent Stroke Study (PROGRESS) was a double-blind randomized trial of blood pressure lowering in 6105 participants with pre-existing cerebrovascular disease. Separate estimates of the effects of randomized treatment were determined using Cox regression models that were based on the unadjudicated events initially reported by the investigator and on the final events assigned by the EPAC. RESULTS: There were 992 strokes initially reported by the investigators and 894 (90%) retained these diagnoses after adjudication by the EPAC. The hazard ratios (95% CIs) for the effect of randomized treatment on stroke were 0.74 (0.64 to 0.85) based on the investigator diagnoses and 0.72 (0.62 to 0.83) based on the EPAC diagnoses (P homogeneity=0.7). For each stroke subtype reported, the corresponding numbers of diagnoses (investigators/EPAC) were ischemic (593/565), hemorrhagic (124/111), and unknown (124/93) with no impact of the EPAC review on the estimates of treatment effects (all P homogeneity >0.3). There was likewise no detectable effect of reclassification of diagnoses for the effect estimates calculated for myocardial infarction or the main causes of death (all P homogeneity >0.5). CONCLUSIONS: The EPAC process had no discernible impact on the trial conclusions. Very large trials powered to detect effects on stroke subtypes might obtain real scientific gain from an EPAC, but in the case of PROGRESS, the value of the EPAC was in the reassurance it provided.