Every Other Week Research Articles

Efficacy and safety of epratuzumab in patients with moderate/severe active systemic lupus erythematosus: results from EMBLEM, a phase IIb, randomised, double-blind, placebo-controlled, multicentre study

ObjectiveTo identify a suitable dosing regimen of the CD22-targeted monoclonal antibody epratuzumab in adults with moderately to severely active systemic lupus erythematosus (SLE).MethodsA phase IIb, multicentre, randomised controlled study (NCT00624351)...

Adalimumab for the Treatment of Moderate to Severe Hidradenitis Suppurativa

Hidradenitis suppurativa (HS) is a chronic, painful skin disease characterized by abscesses, nodules, and draining fistulas in the axilla and groin of young adults. To evaluate the efficacy and safety of adalimumab, an anti-tumor necrosis factor-α antibody, in patients with moderate to severe HS. Phase 2, parallel, randomized, placebo-controlled trial consisting of a blinded 16-week period (period 1) and an open-label 36-week period (period 2). All study personnel, investigators, and patients remained blinded to treatment group throughout the study. (ClinicalTrials.gov: NCT00918255) 26 academic and private practice medical centers in the United States and Europe. 154 adult patients with moderate to severe HS who were unresponsive or intolerant to oral antibiotics. Patients were assigned in a 1:1:1 ratio to adalimumab, 40 mg/wk; adalimumab, 40 mg every other week (EOW); or placebo. All patients received adalimumab, 40 mg EOW, at the beginning of period 2 but switched to weekly dosing if the response was suboptimal (HS Physician's Global Assessment [PGA] score of moderate or worse) at weeks 28 or 31. The primary outcome measure (clinical response) was the proportion of patients achieving an HS-PGA score of clear, minimal, or mild with at least a 2-grade improvement relative to baseline at week 16. At week 16, 3.9% of placebo patients (2 of 51), 9.6% of EOW patients (5 of 52), and 17.6% of weekly patients (9 of 51) achieved clinical response (EOW vs. placebo strata-adjusted difference, 5.6% [95% CI, -4.0% to 15.3%]; P = 0.25; weekly vs. placebo strata-adjusted difference, 13.7% [CI, 1.7% to 25.7%]; P = 0.025). Serious adverse event rates were 3.9%, 5.8%, and 7.8% for placebo, EOW, and weekly patients, respectively (EOW vs. placebo difference, 1.8% [CI, -6.4% to 10.1%]; weekly vs. placebo difference, 3.9% [CI, -5.2% to 13.0%]). Significantly greater improvements in patient-reported outcomes and pain were seen in the weekly dosing group than in the placebo group. A decrease in response was seen after the switch from weekly to EOW dosing in period 2. Weeks 16 to 52 of the study were open-label. The study was not powered to assess the risk for known serious adverse effects of adalimumab, such as tuberculosis, other serious infections, and demyelinating disorders. Adalimumab dosed once per week alleviates moderate to severe HS. Abbott Laboratories.

Report on the Safety of Velaglucerase Alfa Enzyme Replacement Therapy in Patients with Type 1 Gaucher Disease and the Transition From Clinic to Home Infusions During Treatment Protocol HGT-GCB-058

Abstract 1101▪▪This icon denotes a clinically relevant abstract BACKGROUND:Type 1 Gaucher disease (GD) is an inherited storage disease characterized by acid-β-glucosidase deficiency and the accumulation of glucosylceramide in the mononuclear phagocyte system. Hematologists are commonly the specialists to whom affected individuals present; findings may include anemia, thrombocytopenia, splenomegaly, hepatomegaly, and skeletal and bone marrow pathology. HGT-GCB-058 was a multicenter treatment protocol initiated at the request of the US Food and Drug Administration (FDA) in 2009 (ClinicalTrials.gov identifier NCT00954460). It provided velaglucerase alfa, then an investigational drug, to patients with type 1 GD who would otherwise have experienced a disruption or delay in receiving enzyme replacement therapy (ERT) due to a global supply shortage of imiglucerase at that time. OBJECTIVE:We report safety results in patients who received up to 12 months of velaglucerase alfa in protocol HGT-GCB-058, and the transition from administration at the clinical site to home infusions. METHODS:To enroll, patients had to be aged >2 years, with a documented diagnosis of type 1 GD and no history of an anaphylactic or anaphylactoid reaction to ERT. Patients who were treatment-naïve received 60 U/kg (body weight) of velaglucerase alfa as an intravenous infusion every other week (EOW). Patients who were previously treated with imiglucerase (switch patients) received the same EOW dose of velaglucerase alfa as their prior imiglucerase treatment. Each patient could continue in the protocol until commercial therapy was available to him or her. Adverse events (AEs) were monitored throughout the patient’s participation in the protocol. Switch patients were eligible for home therapy if they received their first 3 infusions, at the clinical site, in the absence of an infusion-related AE or treatment-related, serious AE (SAE). RESULTS:Across 23 centers, 211 patients were enrolled. The median age was 54 years (range 6–89 years); 8 patients were aged <18 years; 48% were male; 34% were splenectomized. There were 205 switch patients (the median prior imiglucerase exposure was 145 months [range 1–231 months]) and 6 treatment-naïve patients. All 211 patients received ≥1 infusion of velaglucerase alfa. By the end of 12 months, 203 patients had left the protocol; most patients transitioned to commercial velaglucerase alfa, which was approved by the FDA in 2010. The median duration of velaglucerase alfa treatment in the protocol was 182 days (range 1–365 days) for switch patients and 106 days (range 27–232 days) for treatment-naïve patients. Over 12 months, most AEs were mild or moderate in severity. Twenty severe AEs were reported in 11 patients, of which 5 – pain in extremity and fatigue in 1 patient, fatigue in 1 patient, and 2 instances of generalized pain in 1 patient – were considered treatment-related Table). Ten SAEs were reported in 7 patients, of which 1 (migraine) was considered treatment-related. The AEs leading to protocol discontinuation were: nausea, increased blood pressure (both treatment-related), and hip fracture (not treatment-related). The most common AEs were nasopharyngitis (n=15), headache (n=15), and nausea (n=12). After the first 3 infusions, 187 of the 205 switch patients were eligible for home therapy based on safety criteria. During the protocol, 54 patients received ≥1 home infusion. Home infusions were administered by qualified and trained medical personnel under the direction of the investigator. Patients’ and investigators’ preferences for home therapy were not captured in the protocol.Number of patients (n) experiencing AEs in 12 months of HGT-GCB-058Experiencen (% of total)Treatment-naïve (total N = 6)Switch (total N = 205)≥1 AE3 (50)89 (43)≥1 treatment-related AE1 (17)35 (17)≥1 infusion-related AE1 (17)27 (13)≥1 severe AE011 (5)Possibly or probably treatment-related03 (1)≥1 SAE07 (3)Possibly or probably treatment-related01 (0.5)≥1 life-threatening SAE00Discontinued protocol due to an AE03 (1) CONCLUSIONS:Velaglucerase alfa was generally well-tolerated in a large, clinically heterogeneous group of patients with type 1 GD. Of 205 patients in treatment protocol HGT-GCB-058 who switched from imiglucerase, 91% met the safety criteria for early transition to home infusions and 26% received ≥1 home infusion, which supports home therapy as a treatment option depending on the patient’s response and the recommendation of the treating physician. Disclosures:Pastores:Actelion: Research Funding; Amicus: Research Funding; Biomarin: Research Funding; Genzyme Corp: Research Funding; Protalix: Research Funding; Shire HGT: Research Funding. Rosenbloom:Genzyme Corporation: Educational Grant; Shire Pharmaceuticals: Research Funding, Speakers Bureau; Genzyme Corp: Research Funding, Speakers Bureau. Weinreb:Shire HGT: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amicus: Research Funding; Actelion: Speakers Bureau. Goker-Alpan:Shire HGT: Consultancy, Research Funding; Genzyme Corp: Research Funding, Speakers Bureau; Amicus: Research Funding; Pfizer-Protalix Biotherapeutics: Consultancy, Research Funding. Lipson:Kaiser-Permanente: Employment. Ibrahim:Shire HGT: Research Funding. Cohn:Shire HGT: Employment. Zahrieh:Shire HGT: Employment. Mistry:Shire: Research Funding.

Abstract A97: Final phase 1/2a results evaluating the cyclodextrin-containing nanoparticle CRLX101 in patients with advanced solid tumor malignancies.

Abstract Introduction: Topoisomerase-1-inhibiting camptothecin (CPT) and derivatives such as irinotecan (CPT-11) and topotecan demonstrate clinical utility across multiple cancer types. Use of these agents remains limited by insufficient tumor exposure and high systemic toxicity. A novel cyclodextrin-containing polymer conjugate of CPT that self-assembles into nanoparticles, CRLX101 delivers sustained levels of active CPT into cancer cells while substantially reducing systemic exposure. In vitro and in vivo data suggest superior activity of CRLX101 in multiple tumor models. Efforts are made now to demonstrate the safety and efficacy of CRLX101 in human patients with advanced solid tumor malignancies. Experimental Procedures: CRLX101 was administered intravenously over 1 hour every other week (EOW) to patients (pts.) with advanced and multiply pre-treated solid tumor malignancies. In phase 1, 24 pts. received CRLX101 at 5 escalating dose levels. Following identification of a maximum tolerated dose (MTD), a 38 patient phase 2a MTD-expansion cohort was enrolled at 3 clinical sites. Summary of Data: As of a data cut-off of 6/1/11, 62 total pts. (31 F; 31 M) received CRLX101 at doses ranging from 6 mg/m2 to 18 mg/m2 of CPT equivalent per dose. In phase 1, 2 pts. (18 mg/m2) experienced dose limiting toxicity of CTCAE v3.0 grade (G)4 thrombocytopenia with one of these pts. additionally experiencing G4 neutropenia. An MTD/recommended phase 2 dose (RP2D) of CRLX101 was established at 15 mg/m2 EOW. Among 44 phase 1 or 2a pts. receiving the MTD/RP2D, most common grade 3/4 adverse events considered by investigators to be at least possibly related to study drug included neutropenia (9 events observed among 6 pts.) and lymphopenia (3 events observed among 2 pts.). Phase 2a pts. received CRLX101 for periods of time ranging from 1 day to approximately 13 months (mos.) with an average duration of 3.3 mos. Among 36 evaluable phase 2a pts. receiving the MTD, mean plasma Cmax and AUCall were 306 μg./L. and 27.1 mg./L.*hr. (polymer-unconjugated) and 8260 μg./L. and 300 mg./L.*hr. (polymer-conjugated), respectively. Mean urinary clearance of polymer-conjugated and free CPT over the 0–8 hr., 8–24 hr., and 24–48 hr. collection intervals post CRLX101 dosing were 0.0299, 0.0074, and 0.0062 L./hr. (polymer-conjugated) and 0.0888, 0.0898, and 0.1010 L./hr. (free CPT), respectively. Among all phase 2a pts., overall median progression-free survival (mPFS) was 3.7 mos., with mPFS of 4.4 mos. observed among 21 NSCLC pts. (4.8 mos. excluding 6/21 pts. with squamous cell histology). At time of data cut-off, 6 pts. (incl. 3 NSCLC pts.) remain on therapy. Notably, of the 21 NSCLC pts. in phase 2a (with an average of 3 prior regimens of chemotherapy), 66.7% (14/21) achieved stable disease (SD) ≥ 3 mos. and 14.3% (3/21) achieved SD ≥ 6 mos. Conclusions: CRLX101 appears to be extremely well tolerated with an MTD/RP2D of 15 mg/m2 EOW. Pharmacokinetics are linear and suggest prolonged duration of CPT tumor exposure. Similarly, extended periods of stable disease observed across multiple tumor types are encouraging and merit further investigation. Patients are currently being enrolled into a multinational randomized clinical trial in 2nd/3rd line NSCLC and additional studies in renal cell cancer, small-cell lung cancer, ovarian cancer, and gastric cancer are being developed. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A97.

Adalimumab is effective in long-term real life clinical practice in both luminal and perianal Crohn's disease. The Madrid experience

Objective To evaluate effectiveness and safety of adalimumab in CD patients of the Madrid area and identify predictors of response. Methods Multicenter retrospective survey of all CD patients treated with adalimumab in 9 hospitals of the Madrid area (Spain). Univariate and multivariate analysis of predictors of response was performed. Results 174 patients included (50% males) with a median follow-up of 40 weeks. 30% had active perianal fistulizing disease at the beginning of the therapy with adalimumab. 59% had been previously treated with infliximab, being the lost of response (42.2%) the most frequent cause of withdrawal of the drug. 33% of patients needed dose escalation from every-other week to everyweek. The median time for this dose escalation was 33 weeks (range 2-120). The percentages of complete response at 4 weeks, 6 months and end of follow-up were 63, 70 and 63% in luminal disease and 49, 50 and 41% in perianal disease respectively. The prevalence of adverse events was 18% (most frequent was: 5 abscesses) causing the withdrawal of the drug in 21% of them. Conclusions Adalimumab is effective and safe for the management of CD, even in refractory cases to infliximab.

Dosage adjustment during long-term adalimumab treatment for Crohnʼs disease: Clinical efficacy and pharmacoeconomics

Data from CHARM, a 56-week, randomized controlled trial of adalimumab for patients with moderately to severely active Crohn's disease (CD), were used to evaluate outcomes of adalimumab dosage adjustment. Patients randomized to blinded adalimumab 40 mg every other week (EOW) in CHARM were the focus of the analysis. At ≥12 weeks, patients with flares or lack of response versus baseline (including patients who responded and then lost response) could move sequentially to open-label (OL) adalimumab EOW and then to OL adalimumab weekly. Of 260 patients randomized to adalimumab EOW, 140 (54%) continued blinded EOW therapy and 120 (46%) moved to OL therapy. Of patients on OL therapy, 49 (19%) continued EOW therapy and 71 (27%) moved to weekly therapy; 36 (14%) completed the trial on weekly therapy. Of 71 patients on weekly therapy, 37% achieved clinical remission (Crohn's Disease Activity Index [CDAI] <150), 58% achieved CR-100 (CDAI decreased ≥100 points), and 63% achieved CR-70 (CDAI decreased ≥70 points). Of the 49 patients who remained on OL EOW therapy, 39% achieved clinical remission, 59% achieved CR-100, and 63% achieved CR-70. In a logistic regression, greater baseline CDAI predicted changing to weekly therapy. A model of dosage-adjustment cost indicated a modest per-patient drug-acquisition cost increase ($574 over yearly EOW dosing cost [$22,518]). Of patients randomized to blinded EOW therapy, 19% moved to OL EOW therapy and 27% moved to OL weekly therapy for flares or lack of response versus baseline. Weekly therapy was associated with clear clinical benefits and a small cost increase.

A phase 2, 24-week, randomized, placebo-controlled, double-blind study examining the efficacy and safety of an anti-interleukin-12 and -23 monoclonal antibody in patients with relapsing–remitting or secondary progressive multiple sclerosis

Background: Interleukins 12 and 23 (IL-12/23) have been implicated in multiple sclerosis (MS) pathogenesis. This study assessed the efficacy and safety of ABT-874, a monoclonal anti-IL-12/23 antibody, in active relapsing–remitting MS (RRMS) or secondary progressive MS (SPMS). Methods: In this 24-week study, patients with RRMS or SPMS received ABT-874 200 mg every other week (EOW), ABT-874 200 mg every week (EW), or placebo. The cumulative number of gadolinium-enhanced lesions, relapse rate, disability progression, and adverse events were measured. Results: 215 patients were randomized (ABT-874 200 mg EOW, N = 76; ABT-874 200 mg EW, N = 70; placebo, N = 69). At week 24, gadolinium-enhanced lesions were statistically significantly reduced with ABT-874 200 mg EOW vs. placebo (mean number [SD]: 5.4 [8.1] vs. 7.6 [14.4], p = 0.003), but not with ABT-874 200 mg EW (6.8 [11.3], p = 0.134). Mean relapse rate (relapses/y) was significantly lower for ABT-874 200 mg EW vs. placebo (0.1 [95% CI −0.0, 0.3] vs. 0.5 [0.2, 0.8], p = 0.007). Changes from baseline in disability scores and incidences of adverse events were not significantly different across treatment groups, although a numerically greater percentage of serious adverse events was reported for ABT-874 treatment groups. Conclusions: Although rates of adverse events were not significantly different between ABT-874 treatment groups and placebo, the magnitude of ABT-874 efficacy was less than that observed with other agents currently in development for MS treatment. Anti-IL-12/23 monotherapy does not appear to warrant further testing as monotherapy treatment for MS.

Enzyme Replacement Therapy for Fabry Disease

Fabry disease is a progressive and life-threatening glycolipid storage disorder affecting both males and females. The primary driver of the disease is the accumulation of glycolipids (globotriaosylceramide [GL-3]) in a variety of cell types, including vascular endothelial cells, a range of renal cell types, cardiomyocytes and neurons, which is caused by deficient activity of the lysosomal enzyme, alpha-galactosidase. The disease typically presents during childhood or adolescence. First manifestations reflect involvement of small nerve fibres of the peripheral and autonomic nervous systems. With age, severe complications involving the kidneys, heart and brain cause considerable morbidity and premature death. Outside the US, enzyme replacement therapy (ERT) with agalsidase alfa 0.2 mg/kg every other week (EOW) and agalsidase beta 1.0 mg/kg EOW is available for the treatment of patients with Fabry disease, while agalsidase beta 1.0 mg/kg EOW is the only approved drug in the US. To analyse the evidence for ERT, a systematic review of the literature was performed to identify prospectively designed randomized, controlled trials (RCTs) and open-label studies on the efficacy of agalsidase alfa and agalsidase beta. MEDLINE and EMBASE databases were searched; inclusion criteria for the systematic review were prospectively designed clinical studies evaluating ERT with quantifiable endpoints: double-blind and open-label studies were eligible. Exclusion criteria were review articles, case reports, case studies, letters to the editor and articles based on registry data (Fabry Outcome Survey or Fabry Registry). In addition, any studies with a retrospective design or data based on post hoc analyses were excluded. The evidence was reviewed with respect to the clinical benefits of ERT at the level of the end organ. A total of 9 RCTs and 23 open-label studies were identified for inclusion. The efficacy of ERT in Fabry disease has been measured against a variety of endpoints, the majority of which were subclinical parameters rather than clinical outcomes. Plasma levels of GL-3 together with accumulation in the kidney, heart and skin were the most commonly studied endpoints, followed by renal endpoints of proteinuria and glomerular filtration rate, whereas cardiac and neurological endpoints were not commonly studied. To date, only one RCT with ERT defined hard clinical outcomes in the form of cardiac, renal or cerebrovascular events, or death as its primary endpoint. The currently available data from prospective RCTs and open-label studies in patients with Fabry disease are more robust for ERT at a dose of 1 mg/kg EOW than a dose of 0.2 mg/kg EOW, although the beneficial effects of ERT with either dose or preparation are variable.

A Multicenter Open-Label Experience on the Response of Psoriasis to Adalimumab and Effect of Dose Escalation in Non-Responders: The Aphrodite Project

There is much evidence to show the efficacy of adalimumab, a human monoclonal antibody targeting tumour necrosis factor-alpha, in the treatment of plaque psoriasis. In this open-label experience, 147 high-need patients suffering from plaque psoriasis, with a mean Psoriasis Area and Severity Index (PASI) of 18.8, and concomitant psoriatic arthritis (PsA) received subcutaneous injections of 40 mg of adalimumab every other week (EOW). This was actually the dosage regimen recommended for PsA, as the drug had not then been approved for psoriasis at the time of the patients enrolment. At week 12, an improvement of at least 50 percent of the PASI (PASI-50) was observed in 111 (77 percent) patients. Continuation of treatment in responders with adalimumab 40 mg EOW led to a sustained response, with the PASI-50 achieved by 97 percent of patients in the as-treated analysis at week 24 (PASI-75 in 82 percent and PASI-90 in 45 percent out of 109 patients who received EOW injections up to week 24). Thirty subjects who failed to attain the PASI-50 response at week 12 were treated with adalimumab 40 mg every week for a further 12 weeks. At week 24, 80 percent of these patients obtained a PASI-50 response after dose escalation. Tolerability was good in the majority of patients. Only two patients discontinued treatment because of an adverse event (repeated flu-like episodes and a pleuropericarditis of unknown origin, respectively).

Cost-Effectiveness of Natalizumab in Patients with Crohnʼs Disease Who Have Failed Anti-TNFα Therapy

Purpose: To compare the cost-effectiveness (CE) of natalizumab (NAT) to tumor-necrosis factor alpha inhibitors (anti-TNFα) in patients with Crohn's disease (CD) who failed previous anti-TNFα treatment. Methods: A decision analytic framework was used to model treatment for patients with moderate to severe CD (Crohn's Disease Activity Index scores ≥ 220 and < 450). Patients are assumed to have failed treatment with corticosteroids, immunomodulators, and an anti-TNFα agent. The model compared natalizumab (NAT) 300 mg, infliximab (INF) 5 mg/kg or 10 mg/kg, adalimumab (ADA) 40 mg dosed every other week (EOW) or weekly (QW), and certolizumab 400 mg. The model includes an induction period (induction dose and schedule as per product package insert) followed by a 2-year maintenance phase. At the end of induction and each of the four 6-month maintenance cycles, patients were assigned to 1 of 3 efficacy states (remission, response, nonresponse) based on estimates from the published literature and NAT clinical data. Patients entering the nonresponse health state at any point were assumed to remain in that state for the duration of the model. Medical costs associated with resource use—including hospitalizations, surgeries, physician visits, and laboratory tests—were estimated for patients in each health state from a database assembled by Health Benchmarks International. Wholesale acquisition drug costs were obtained from published price lists. The drug costs for INF and ADA were weighted by dose (maintenance phase) based upon the distribution observed in phase 4 studies. Results: Modeled estimates of total costs and efficacy (per person-year in remission) over the 2-year maintenance period and adjusted by dose for each comparator are presented in the table below. NAT had the lowest CE ratio using all of the following outcome measures of efficacy: remission, steroid-free remission, and response and remission. CE ratios were insensitive to increases in NAT costs (up to 100%) or decreases in NAT efficacy (up to −25%). Conclusion: This model, based on estimates from the available published literature, projected NAT to have the lowest cost-efficacy ratio among comparator biologics for patients who had failed prior anti-TNFα therapy.Table

Sustainability of Adalimumab in Fistula Healing and Response: 2-Year Data from CHARM and 12-Month Open-Label Extension Follow-Up Study

Purpose: Adalimumab (ADA), a fully human monoclonal antibody that targets tumor necrosis factor, has been shown to be efficacious in the induction and maintenance of remission in patients (pts) with Crohn's disease (CD). Fistulizing disease complicates the course of CD in 20–30% of pts, in many cases leading to surgical resection. The CHARM study has previously shown efficacy of ADA in fistula closure and response. We assessed long-term efficacy of ADA in fistula healing and response in CD pts from the CHARM trial in an open-label extension (OLE) follow-up study. Methods: Pts in CHARM were randomized to placebo (PBO), 40 mg every other week (EOW) or 40 mg weekly (EW). Pts with flare or non-response could receive OL ADA at/after Week 12. At the end of CHARM (56 weeks), pts were allowed to enroll into an open-label extension (OLE). In the OLE, pts received EOW OL or remained on EW OL, and could change from EOW to OL EW for flares or non-response. In this analysis, pts with fistulas at baseline (BL) of CHARM were studied, pooling the 2 doses, using an ITT, non-responder imputation analysis. Pts were analyzed for the percentage (%) of healed fistulas and% with ≥50% fistula response at 6 and 12 months in the blinded study and at 6 and 12 months of the OLE follow-up study (for a total of 24 months of therapy). Results: Results are in the table below.Table: Long-Term Efficacy of Fistula Healing and Response with ADA Through 2 YearsConclusion: Sustainable efficacy of ADA in fistula healing and response is evident after 2 years. ADA has shown sustained response in almost two-thirds of the patients in the OLE who had fistulas at baseline of CHARM and sustained closure in more than half of the ADA-treated patients.

Responses to the combination of the glycolytic inhibitor 2-deoxy-glucose (2DG) and docetaxel (DC) in patients with lung and head and neck (H/N) carcinomas

14025 Background: We demonstrated in mouse xenografts that the combination of docetaxel chemotherapy with 2DG is feasible and increases responses against tumors (CancerRes; 2004 64:31–4). Methods: To determine the maximum tolerated dose (MTD) of daily oral doses of 2DG given alone and in combination with weekly docetaxel (DC) in patients (pts) with advanced malignancies who had relapsed after chemotherapy, and to evaluate the pharmacokinetics (PK) of 2DG alone and in combination with weekly DC. 2DG was initially administered orally once daily for 7 days every other week starting at a dose of 2 mg/kg, and DC was administered at 30mg/m2 for 3 of every 4 weeks. A modified accelerated titration design was used. Following completion of the every other week (EOW) 2DG dosing regimen, 3 weeks on and 1 week off (3–1W) dosing; and then continuous (CW) 2DG dosing were investigated. Results: 21 pts were enrolled in the EOW dosing at 2DG doses up to 88 mg/kg/day; another 10 pts were enrolled in the other dosing regimens. 5 pts had lung cancer (4 NSCLC + 1 SCLC); and another 6 pts had H/N cancers. One pt discontinued for DC-related sensory neuropathy. Single cases of DLT occurred - asymptomatic (64mg/kg) and symptomatic (88 mg/kg) Grade 3 hyperglycemia. The MTD was not reached with the EOW regimen. 2DG is rapidly absorbed (Tmax 0.5–1h) with a half-life of 5–10h. 2DG exhibits linear PK following single and multiple doses with minimal accumulation after multiple doses at 63 and 88 mg/kg. 2DG PK and DC PK do not alter each other. One of 18 evaluable pts in the EOW dosing with breast cancer had a partial response (PR). Another 8 pts achieved disease stabilization (SD) among them: 2 of 4 pts with NSCLC, 2 of 6 pts with H/N cancers, 1 pt with thyroid cancer, and 1 of 3 pts with adenoidcystic carcinoma. The others were unknown primary and a breast lymphoma. Also the MTD was not reached at 63mg/kg (3–1W) dosing where one patient with H/N cancer achieved stabilization of his disease. Enrollment of pts in the CW regimen is ongoing now. Conclusions: The combination of 2DG and DC appears to be feasible and safe with no evidence of PK interactions. Evidence of anti-tumor activity was observed in patients with NSCLC and H/N cancers. No significant financial relationships to disclose.

Adalimumab Induces and Maintains Clinical Response and Remission in Patients With Active Crohn’s Disease: Results of the CHARM Trial

Adalimumab Induces and Maintains Clinical Response and Remission in Patients With Active Crohn’s Disease: Results of the CHARM Trial

Adalimumab Induced and Maintained Clinical Remission in Patients with Crohnʼs Disease Independent of Baseline CRP Concentration

Purpose: To evaluate the association of baseline CRP concentrations with induction and maintenance of clinical remission with anti-TNF adalimumab (ADA) therapy in patients with active Crohn's disease (CD) in the CHARM study. Methods: In CHARM, a Phase III, double-blind, placebo-controlled study of remission and safety of ADA therapy in patients with active moderate to severe CD (CDAI 220–450), all patients received open-label induction dosages of ADA, 80 mg at Wk 0 (BL) and 40 mg at Wk 2. At Wk 4, all patients were randomized to receive placebo (PBO) or 40 mg ADA sc, every other week (EOW) or weekly (W), through Week 56. Those randomized with a clinical response of ≥70 decrease from BL CDAI (CR70) at Wk 4 were classified as randomized responders. Patients in clinical remission (CDAI < 150) at Wks 26 and 56 were stratified by baseline CRP concentrations (< 1 mg/dL vs. ≥1 mg/dL). Results: Baseline characteristics were similar across treatment arms, with mean CDAI = 313 and median CRP = 0.9 mg/dL. Of 854 patients who received induction therapy, 778 were randomized. Of these, 449 (58%) had achieved CR70 at Wk 4. Clinical remission in randomized responders by baseline CRP concentration is presented in the table.Table: Remission Rates by Baseline CRP, n/N (%).Conclusions: Adalimumab induced and maintained remission over 1 year in patients with CD independent of CRP concentrations, with clear separation of adalimumab-treated groups from placebo. The small, nominal differences in absolute remission rates for adalimumab between the CRP-elevated and CRP-normal groups are without clinical significance.

Sustained Clinical Remission in Patients with Moderate to Severe Crohnʼs Disease with Adalimumab, Regardless of Anti-TNF History or Concomitant Immunosuppressant Therapy

Purpose: To evaluate the efficacy of adalimumab (ADA) in sustaining clinical remission in patients with CD with concomitant immunosuppressant (IMM) therapy or history of anti-TNF treatment. Methods: In CHARM, a Phase III, double-blind, placebo-controlled study of the maintenance of clinical remission (CDAI<150) and safety of ADA, pts with active CD (CDAI 220–450) received open-label induction ADA 80 mg at Wk 0 (BL) and 40 mg at Wk 2. At Wk 4, all pts were randomized to placebo (PBO) or 40 mg ADA, every other week (EOW) or weekly (W), through Wk 56. Patients with clinical response, a decrease in CDAI ≥70 from BL (CR70), when randomized at Wk 4 were classified as randomized responders (RR). The% of pts with CDAI<150, stratified by concomitant IMM use and anti-TNF history, were calculated at Wks 26 and 56. Results: Of 854 pts receiving induction therapy, 778 were randomized. Of these, 499 (58%) were RR. BL characteristics were similar across the 3 arms: mean CDAI = 313; concomitant IMM use (such as AZA, 6-MP, or MTX), 47%; history of anti-TNF therapy, 50%. The proportions of RR with CDAI<150 at Wks 26 and 56 by prior anti-TNF or concomitant IMM therapy are in the table.Table: Randomized Responders in Remission by Concomitant/Prior Therapy.Conclusions: Adalimumab was significantly superior to PBO for the long-term treatment of CD irrespective of concomitant IMM therapies. Prior anti-TNF therapy resulted in slightly lower remission rates, but ADA significance vs. PBO was maintained.

Every-other week capecitabine (C7) combinations: An active and well tolerated treatment in heavily pretreated patients (p) with advanced solid tumours

10649 Background: Standard C schedule is 14 days every 3 w (C14). However, data have shown that C7 schedule is as effective as and significantly less toxic than C14. The objective is to evaluate retrospectively the response rate and toxicity of C7 as single agent or in combination in heavily pretreated p with advanced solid tumours. Methods: p with advanced solid tumour, age ≤ 75 years, ECOG PS &lt;2 and adequate bone marrow, renal and hepatic functions were analyzed. p received C7: 1250 mg/m2/12 h x 7 days every-other week. The combination drugs doses were adjusted to be used days 1 and 15. Cycles every 28 days. Response was evaluated every 3 cycles according to RECIST criteria Results: 20 p received C7. Cancer type: 11 breast (BC), 7 colo-rectal (CRC), 1 H&amp;N and 1 gastric (GC). Median age 56 y (33–75). M/F: 8p/12p. ECOG 0/1: 39%/61%. 19 p stage IV and 1 (H&amp;N) stage III. The most frequent metastatic site was liver 42.2%. 90% p had been heavily pretreated with chemotherapy (CT): 55% p had received ≥ 2 CT lines. 15% p had been treated with taxanes, 45% p taxanes + anthracyclines, 10% p 5-FU, 15% p oxaliplatin (Oxa) and/or raltritexed. 2 BC p had also received herceptin (Her) and 2 p (1BC/1CRC) had been previously treated with C14. Median nº cycles: 6 (1–19). C7 combinations were: 5/7 CRC p Oxa or CPT-11 and 11/11 BC p docetaxel (1p) or gemcitabine (1 p) or carboplatin (9 p) ± Her. 4 p received C7 alone. Toxicity (20 p). Grade I/II: HFS 55%, diarrhoea 25%, nausea/vomiting 15%, mucositis 5%, skin 5% and parestesias 5%. Grade III/IV: diarrhoea in 2 p (1CRC and 1 BC). Response (20 p): 2 CR (10%) both CRC p; 6 PR (30%) 5 BC p and 1 CRC p; 4 SD (20%) and 8 PD (40%). 40% ORR rate and 60% TGC. Median response duration: 37 w (22–44 w). 2 p who achieved CR received C7 combined with CPT-11. C7 combination in p with PR were Oxa (1 CRC p) and carboplatin ± Her (5 BC p). Conclusions: C7 schedule is an active regimen in patients with advanced CRC and BC heavily pretreated with CT and it shows a very favourable toxicity profile. These results warrant a phase II trial of carboplatin-C7 in MBC as front line therapy that will by lauched by Feb-2006. No significant financial relationships to disclose.