Infusion Schedule Research Articles

Phase II study of TAS‐106 in patients with platinum‐failure recurrent or metastatic head and neck cancer and nasopharyngeal cancer

TAS-106, a RNA polymerase inhibitor, was studied in solid tumors with potential clinical benefit and reasonable tolerability. We conducted a multicenter, international phase II trial of TAS-106 in salvage metastatic or recurrent head and neck squamous cell cancer (HNSCC) and nasopharyngeal cancer (NPC) patients. TAS-106 monotherapy was given at 6.5 mg/m2 over 24-h continuous infusion every 3 weeks. Translational studies for blood and tissue were included. Twenty-seven enrolled patients experienced the most common drug-related adverse events of neutropenia, fatigue, non-neutropenic fever, injection site reaction, and skin rash/dermatitis. The greater than or equal to grade 3 adverse events included neutropenia (14.8%), febrile neutropenia (7.4%), pneumonia (7.4%), and peripheral neuropathy (3.7%). The overall response rate was 0% in both subgroups; five HNSCC patients had stable disease (median duration 99 days) and four NPC patients had stable disease (median duration of 92.5 days). Median progression-free survival (PFS) for HNSCC patients was 52 days (95% CI 43.0–99.0 days) and 48 days (95% CI 41.0–83.0 days) for NPC. Median overall survival (OS) for HNSCC patients was 175 days (95% CI 92.0–234.0 days) and 280 days (95% CI 107.0–462.0 days) for NPC. The TAS-106 plasma levels were equivalent between Asian and Caucasian patients. There was no significant correlation of tumor UCK2 protein expression levels to TAS-106 efficacy. TAS-106 was reasonably tolerated in patients with platinum-failure HNSCC and NPC. The administration schedule of 24-h continuous infusion prevented neurologic toxicity, but had myelosuppression as its main toxicity. There was no anti-tumor efficacy seen with TAS-106 monotherapy. Future studies will focus on TAS-106 combinations and mechanisms of drug resistance.

A phase I pharmacokinetic study of PM00104 (Zalypsis®) administered as a 24-h intravenous infusion every 3 weeks in patients with advanced solid tumors

PM00104 (Zalypsis) is a synthetic tetrahydroisoquinoline alkaloid with potent antiproliferative activity against tumor cell lines. This phase I study evaluated the safety, dose-limiting toxicities (DLTs), recommended dose for phase II trials (RD), pharmacokinetics (PK) and preliminary antitumor activity of PM00104 as a 24-h intravenous (i.v.) infusion every 3 weeks (q3wk). Thirty-seven patients with refractory advanced solid tumors received PM00104 in a toxicity-guided dose escalation study design (3 + 3 patients per cohort). Plasma samples were collected for PK analysis. DLTs comprised severe neutropenia lasting >5 days (n = 4 patients), vomiting, thrombocytopenia, transaminase increases (n = 2 each), fatigue, tumor pain, myalgia, muscle stiffness, creatine phosphokinase increase and dosing delay >2 weeks due to moderate fatigue (n = 1 each). The RD was 4.0 mg/m(2). Most PM00104-related adverse events at the RD were mild or moderate; the most common were nausea, vomiting and fatigue. Myelosuppression and transaminase increases were transient and manageable. PK parameters increased linearly with dose. Higher PM00104 PK exposure was related to a decrease in hemoglobin, neutrophils, platelets and white blood cells. Area under the curve was directly correlated with both incidence and severity of nausea and vomiting. Three patients with hepatocellular carcinoma, esophageal adenocarcinoma and prostate adenocarcinoma had response evaluation criteria in solid tumors stable disease ≥3 months. PM00104 given as 24-h i.v. infusion q3wk has predictable and manageable toxicity, but resulted in more myelotoxicity (because of the higher dose level achieved as the RD) and a similar drug clearance compared to 1-h infusion schedules. Preliminary evidence of antitumor activity was observed.

PHC-020 Pharmacokinetically Guided Dose Adjustment of 5-Fluorouracil (5-FU) in Gastrointestinal Cancer Patients

BackgroundAppropriate dosing of chemotherapeutic drugs is critical to reducing mortality and increasing progression-free survival. 5-fluorouracil (5-FU) is a widely used chemotherapeutic drug in gastrointestinal cancer. The standard approach to dosing...

Rituximab Treatment for the Patients with Refractory Inflammatory Myopathy

Objective. To assess the efficacy and safety of rituximab (RTX) on disease activity and muscle strength in patients with inflammatory myopathies refractory to conventional therapy. Methods. Four inflammatory myopathy patients who had been refractory to glucocorticoids, one or more immunosuppressive therapies and intravenous immunoglobulin were treated on an open-label basis. Each patient received two 500 mg doses of RTX 2 weeks apart in one cycle. In one patient who did not respond after the first cycle of RTX, the infusion schedule was modified by the physician. We measured muscle enzyme including CPK, LDH and assessed muscle strength individually to evaluate RTX response. Additionally anti-CD19 antibody was measured. Results. Three patients responded to the first cycle of RTX treatment with improvements in muscle enzyme and muscle strength, and then maintained physical function over the duration of several infusion cycles. In one patient, muscle enzyme did not decrease after the first cycle of RTX, and a high dose glucocorticoid was given. After modifying the treatment schedule with monthly RTX infusion, his muscle enzyme level and muscle strength improved. Anti-CD19 antibody decreased after RTX generally, but responses were variable. Herpes zoster infection occurred in two patients. Conclusion. Rituximab may be a therapeutic choice in refractory inflammatory myopathy. However a further trial is needed to confirm the efficacy and prove the safety.

Chemotherapeutic Options for Gastroesophageal Junction Tumors

A doublet of a fluoropyrimidine and a platinum compound remains the reference regimen in palliative chemotherapy for esophagogastric cancers. Newer regimens involve the substitution of infusional 5-fluorouracil (FU) for a shorter infusional schedule or oral 5-FU prodrugs and the replacement of cisplatin with oxaliplatin. Although the addition of epirubicin to the standard 2-drug regimen is part of routine practice, there are no randomized data to support a benefit. In contrast, the docetaxel-based docetaxel/cisplatin/5-FU regimen has been shown to modestly improve survival compared with 5-FU/cisplatin alone but at the expense of significant additional toxicity, which has hindered widespread acceptance of this regimen. Irinotecan-containing regimens have also been evaluated in a few phase III evaluations but are not clearly superior to 5-FU/cisplatin or even infusional 5-FU alone. Nevertheless, their favorable toxicity profile indicates that infusional 5-FU/irinotecan regimens also represent a first-line therapy option. In addition to its primary role in palliative therapy, there are also now established peri- or postoperative chemotherapy strategies that increase survival rates by approximately 10-15% compared with surgery alone. Preoperative chemoradiation in esophageal and gastroesophageal junction tumors has also been shown to improve outcomes.

Phase I Trial of Bortezomib (PS-341; NSC 681239) and Alvocidib (Flavopiridol; NSC 649890) in Patients with Recurrent or Refractory Indolent B-Cell Neoplasms - Update of the “Bolus” Infusion Schedule of Alvocidib.

Abstract 2959Preclinical studies suggest that neoplastic cells may be particularly sensitive to simultaneous interruption of cell cycle and survival signaling pathways. We have previously reported that the cyclin-dependent kinase inhibitor alvocidib interacts with bortezomib, a proteasome inhibitor, to induce mitochondrial injury and apoptosis in human leukemia, myeloma, and lymphoma cells (Dai et al, Oncogene 22:7108, 2003; Dai et al, Blood 104:509, 2004). These actions were associated with inhibition of NF-κB DNA binding, increased expression of pJNK, and down-regulation of XIAP and Mcl-1. Based on these findings, a phase I trial was initiated in which bortezomib was administered in conjunction with alvocidib on the same days, according to 2 separate schedules: a “hybrid” infusion schedule (half the dose over 30 minutes and half over a 4-hour infusion); and a bolus infusion schedule in which alvocidib was administered over 1 hour. Results of the hybrid infusion schedule have recently been reported (Holkova et al, Clin Cancer Res 17:3388, 2011). The primary objective was to identify the maximum tolerated doses (MTDs) for the combination in the treatment of recurrent or refractory indolent B-cell neoplasms.Eligible patients included those with multiple myeloma (MM) or non-Hodgkin’s lymphoma (NHL), with recurrent or refractory disease following at least 1 prior systemic therapy. To date, 43 patients have been treated at 9 dose levels. Patients with the following disease types have been treated: MM n=25 (Waldenstrom’s macroglobulinemia n=2), NHL n=18 (mantle cell lymphoma n=5). The male:female ratio was n = 31 (72%):12 (28%); the median age was 65 (range: 40–79) years; ECOG performance scores ranged from 0–1; and the median number of prior therapies was 3 (range: 1–10). The schedule of administration was bortezomib via intravenous push over 3–5 seconds followed by alvocidib via intravenous 1-hour infusion on days 1, 4, 8, and 11; on a 21-day cycle, with indefinite continuation for responding patients and those with stable disease.Adverse events (AEs) were evaluated using CTCAE version 4. Dose limiting toxicities (DLTs) observed to date are shown in Table 1. Grade 3 and 4 AEs possibly, probably, or definitely related to study treatment tht occurred in ≥ 5% of patients were dehydration (7%), diarrhea (19%), fatigue (16%), febrile neutropenia (5%), leukopenia (37%), lymphopenia (28%), neutropenia (58%), peripheral neuropathy (12%), and thrombocytopenia (44%). No grade 5 events were observed. One patient developed tumor lysis syndrome and required hospitalization for 48 hours with complete recovery. Common grade 2 AEs possibly, probably or definitely related to treatment were anemia (30%), anorexia (28%), diarrhea (47%), fatigue (60%), leukopenia (47%), lymphopenia (28%), and thrombocytopenia (56%).Of the 43 patients treated, 38 have been evaluable for response. Patient responses are shown in Table 2. Correlative studies examining expression of pJNK, Mcl-1, XIAP, PARP, and NFκB are being collected for processing at the end of the study.Collectively, these findings indicate that the combination of bortezomib and alvocidib, the latter administered as a 1-hour infusion, is tolerable. The regimen appears active in patients with relapsed and/or refractory MM or NHL, justifying phase II studies to determine the activity of this regimen more definitively. The MTD has not yet been reached.Table 1Dose levels and DLTsDose LevelBortezomib (mg/m2)Alvocidib (mg/m2)Patients treated/# DLTsDLT11.0153/021.3155/031.3223/041.3303/051.3407/1Grade 3 back pain6*1.3505/1Grade 3 fatigue7**1.3608/2Grade 3 febrile neutropeniaGrade 3 tumor lysis syndrome8**1.3756/2Grade 3 diarrheaGrade 3 esophagitis/oral mucositis9**1.3903/2Grade 3 febrile neutropeniaGrade 4 absolute neutrophil count decrease*Study is currently enrolling to dose level 6**Exceeded MTDTable 2Response by diagnosisNHLMMTotal(n = 15)(n = 23)(n = 38)Complete Remission2b,c1a3Partial Remission37d,e10Complete + Partial Remission N(%)5 (33)8 (35)13 (34)aIncludes 1 patient with prior bortezomibbIncludes 1 patient with prior autologous SCTcIncludes 1 patient with mantle cell lymphomadIncludes 1 patient with Waldenstrom's macroglobulinemiaeIncludes 1 patient still under active treatment Disclosures:Baz:Celgene: Research Funding; Millennium: Research Funding; Bristol Myers Squibb: Research Funding; Novartis: Research Funding.

Does Faster Rituximab Infusion for Patients with NHL Lower Cancer Care Costs?

AbstractAbstract 2063 IntroductionRituximab in combination with chemotherapy is a recommended regimen for non-Hodgkin’s lymphoma (NHL), which has been shown in randomized trials and real-world studies to provide a survival benefit compared with chemotherapy alone. Per the US Prescribing Information (USPI), rituximab is typically administered over 4–6 hours for the first infusion and 3–4 hours for subsequent infusions. A 90-minute infusion schedule for rituximab has been found to be safe and feasible in NHL patients who tolerate their first infusion administered at the standard rate and who do not have significant cardiovascular disease or high circulating lymphocytes. This study’s primary objective was to assess the cost from a US societal perspective of faster 90-minute rituximab infusion vs the conventional 4–6 hour rituximab infusion. MethodsAnalyses were performed in accordance with best research guidelines of the International Society of Pharmacoeconomic Outcomes and Research. The target population was patients with previously untreated diffuse large B-cell lymphoma (DLBCL) or follicular lymphoma (FL) who were scheduled to receive rituximab 375 mg/m2plus CHOP or CVP chemotherapy. Medical resources assessed were: chemotherapy administration, chemotherapy and pre-treatment drugs, and Grade 3/4 adverse events. Indirect costs include societal resources such as income foregone by patients and informal caregivers/spouses as a result of visit duration for infusion. Trial data were used to extract event rates of adverse events and duration of infusions, and patient drop-out rate by cycle. Prices for medical resources were obtained from publicly available Medicare Fee Schedules. Per capita hourly wage rates were extracted from statistics of the US Labor Department. Outcomes were costs per year for patients treated in the US and cost per infusion and per course of therapy in 2012 US dollars. ResultsA projected 23,519 newly diagnosed DLBCL and FL patients comprise the target population. Estimated total direct medical cost for conventional infusion is $925,318,162 and $9,855,416 in foregone income for patients and caregivers. The 90-minute infusion reduced direct medical costs by $22,362,397 (2%) and foregone income for patients and caregivers by $5,115,629 (52%). The average cost savings were $359 per infusion and $2,119 per course. The most influential parameters were administration cost and patient foregone income due to time for infusions. The savings per course may be greater if infusion centers are able to spread fixed costs, e.g., overhead, among a greater number of patients resulting from increased capacity to schedule more patients. ConclusionThe 90-minute rituximab infusion has been found to be a safe and feasible alternative to conventional rituximab infusion for patients with untreated DBLCL or FL. In an era of landmark legislation (The Patient Protection and Affordable Care Act of 2010) designed to address concerns about rising costs of healthcare and place more emphasis on patient-centered research, the faster rituximab infusion regimen offers direct medical savings and reduces foregone income to patients and caregivers. Disclosures:Hornberger:Cedar Associates LLC: Employment; Genentech, A Member of the Roche Group: Research Funding. Off Label Use: Rituxan (Rituximab) - faster infusion is off-label. Dai:Cedar Associates: Employment; Genentech, Inc, A Member of the Roche Group: Research Funding. Goertz:Genentech, Inc, A Member of the Roche Group: Employment, Equity Ownership. Dawson:Genentech, A Member of the Roche Group: Employment, Equity Ownership. Reyes:Genentech, Inc, A Member of the Roche Group: Employment, Equity Ownership.

Collision Sports and Risk of Bleeding in Children With Hemophilia

IN THIS ISSUE OF JAMA, BRODERICK AND COLLEAGUES 1 report results of their study of the association of vigorous sports with bleeding rate in 104 children and adolescents with moderate or severe hemophilia. Most participants were receiving prophylactic infusions of replacement clotting factor, which has been established as the standard of care for children and adolescents with hemophilia. Activities were scored as category 1, 2, or 3, depending on the expected trauma related to frequency and severity of collisions associated with the activity; category 2 and 3 activities can be referred to as collision sports. The study results indicate that the risk of bleeding events requiring acute factor replacement was increased following collision sports, with an odds ratio of 2.7 for category 2 activities (such as basketball or baseball) and 3.7 for category 3 activities (such as wrestling or US football). However, because exposure time to the higher-risk activities was a small percentage of total life hours and because the annual rate of bleeding was low, the absolute increase in risk was low. Additional statistical modeling, in which factor level was inferred from infusion schedule and known recovery and half-life, revealed that each 1% increase in plasma factor activity was associated with a 2% lower bleeding risk, thus suggesting therapeutic strategies that might further reduce the bleeding risk associated with collision sports. The study was strengthened by a novel and robust prospective case-crossover design. Data were acquired for each bleeding event from the 24-hour period preceding the event, as well as the 2 preceding 24-hour periods that served as control time periods during which exposure to sports and factor infusions were compared. To evaluate the accuracy of activity estimates during the control periods, participants were also asked to report their physical activity during randomly chosen times without bleeding events, along with the 2 preceding 24-hour intervals. This accuracy check found activity levels that were comparable with the control periods. The study by Broderick et al expands previous data on injury and bleeding rates related to sports participation in children with severe hemophilia. A study of school-aged children by Ross et al comparing 299 high-impact-sports seasons in 27 children and 46 low-impact-sports seasons in 10 children (92% using clotting factor prophylaxis) found a very low rate and no between-group differences for joint hemorrhage, injuries, or new target joint development related to high-impact sports. Similar bleeding outcomes were found in a study by Tiktinsky et al of 44 children with hemophilia not using prophylaxis. Both studies suggested that bleeding events related to sports in children with severe hemophilia represent a small proportion of total bleeding episodes. Evidence that participation in collision sports does not worsen the outcome of severe hemophilia may seem counterintuitive and inconsistent with conventional wisdom. However, the study by Broderick et al suggests that a factor level below a critical threshold is a more important determinant of bleeding risk than modest exposure to vigorous activities. All children need to feel part of their peer group. The label of a rare disorder, requirements for frequent intravenous infusions, and exclusion from sports intensify a painful sense of being different for children with hemophilia. Hemophilia almost exclusively affects males and peer participation of boys in many societies is centered around competitive sports. Participation in a popular sport can be important to reduce the sense of isolation experienced by many boys with hemophilia. Participation in desired but possibly higher-risk sports may be a strong motivator for positive health-promoting activities such as self-infusion of prophylactic factor replacement, year-round conduct of strengthening exercises, and increased body awareness with early bleed recognition. In the study by Ross et al, all participants, with their parents, underwent counseling regarding the risks and benefits of the sports in question as well as techniques to minimize risks and maximize health benefits. In addition, prophylaxis regimens were carefully reviewed and optimized. The analyses by Broderick et al suggest that higher factor level at the time of collision was preventive for tempo-

A Tale of a Patient with Two Autoimmune Disorders

Purpose: Wegener's granulomatosis (WG) is a rare clinical disorder affecting individuals with an underlying genetic susceptibility. The incidence of concurrent WG and Crohn's Disease (CD) is unknown. The diagnosis of both autoimmune disorders is challenging and requires a high level of suspicion. We describe a patient with a known history of CD presenting with persistent fevers, bloody diarrhea, and diffuse arthralgias despite treatment for a CD flare. The patient was ultimately diagnosed with WG based on positive serine protease 3 antibody (PR3). Case: A 36-year-old Pacific Islander male with a known history of diffuse CD presented with bloody diarrhea, skin blisters, fevers, and diffuse arthralgias. The patient was admitted to the medical service for treatment for a CD flare with IV steroids, mesalamine, and antibiotics. Comprehensive infectious disease evaluation was negative for bacterial, fungal and viral infections. Subsequently, the patient was transferred to the MICU for hypotension, persistent fevers up to 104.7, and tachycardia (HR=140's). An echo showed RV enlargement consistent with pulmonary hypertension. A CT scan of the abdomen and pelvis showed bilateral pulmonary nodules consistent with granulomatous disease and hypodensities in the splenic parenchyma concerning for splenic infarcts. Sarcoidosis was excluded by negative serum ACE; in addition, patient age and gender did not support this diagnosis. Colonoscopy with TI intubation showed erythema and friability from sigmoid to cecum consistent with CD. Biopsies showed active colitis and negative for AFB and CMV. Skin lesion biopsies were negative for infectious markers and positive for neutrophilic infiltrates. Significant lab findings included a marked PR3 positivity at 171 (cutoff for normal 19), highly specific for WG. The patient was started on treatment for WG including high-dose IV solumedrol and rituximab infusion with significant clinical improvement within 24 hours. He was ultimately discharged on prednisone taper and scheduled rituximab infusions. At his two-week follow-up clinic visit, the patient was doing well with complete resolution of his arthralgias, no further fevers and formed, non-bloody stools. We speculate that his CD flare may have been triggered by the onset of WG. Focused treatment for his WG also resulted in improvement in his CD flare. CD and WG are both autoimmune disorders with genetic susceptibilities that may overlap and may be triggered by infectious and environmental factors. The underlying mechanisms of WG and CD remain elusive. Future studies may help identify genes that overlap in both WG and CD but also provide ability to distinguish between these two autoimmune disorders.

Bacteriotherapy in Chronic Fatigue Syndrome (CFS): A Retrospective Review

Purpose: CFS is both difficult to diagnose and to treat due to its complex and multifactorial etiology. CFS is considered an exclusionary diagnosis in the absence of known etiological causes such as hyperthyroidism and anaemia, and is characterised by persistent (>6 months) disabling fatigue1. Bacterial and viral species have been known to trigger CFS symptoms such as EBV, B. burgdorferi, Coxiella and Brucella, species. Current inadequate symptom-specific therapies include cognitive behavioural therapy and graded exercises. We previously reported 40% improvement in a sub-group of constipation-predominant IBS patients with CFS2. These findings led to speculation of an enteric flora-derived bacterial etiology in CFS. Here we review a larger cohort who had undergone bacteriotherapy for CFS, with long-term follow up. Methods: A total of 60 patients presented with CFS (52 IBS-CFS, 4 Constipation-CFS, 4 CFS) (36F, 24M m: 55 ± 11.5yrs). 5/60 CFS patients received a single transcolonoscopic (TC) infusion of 300cc culture comprising 13 nonpathogenic enteric bacteria [Bacteroidetes, Clostridia, E coli]. 52/60 patients underwent 2 day infusion (TC and rectal infusion) while 3/60 underwent three day rectal infusion schedule (TC and 2 day rectal infusion). Response/non-response was defined as a resolution/return of CFS symptoms (sleep deprivation, lethargy/fatigue) at 4 week follow-up. Results: 35/60 patients responded to initial bacteriotherapy treatment. 10/15 patients who failed initial bacteriotherapy were offered a secondary TC infusion and either; follow up rectal infusion (n=4) or an oral course of cultured bacteria (n=6). Of these 7/10 responded to therapy. Hence a total of 42/60 (70%) patients achieved clinical response post bacteriotherapy and of this 37/42 also experienced resolution of associated gastrointestinal (GI) symptoms. Of 18 nonresponders, 10 attained associated GI symptom improvement despite persisting CFS symptoms. At 15-20yr follow-up 12/60 patients were contactable and 7/12 (58%) remains CFS-free. 5/12 experienced CFS recurrence approx 1.5-3 years post bacteriotherapy. Conclusion: Bacteriotherapy achieves initial success rate of 70% in CFS and 58% sustained response. This result is favourable when compared with current therapies where fewer than 10% recover fully and a further 10%-20% worsen during follow-up.1 Given that manipulation of the colonic microbiota improved CFS symptoms, bacteriotherapy for CFS warrants further investigation. Furthermore, the pathophysiology of CFS could be in part explained by enteric derived toxin-releasing bacteria capable of producing systemic effects.

T.P.45 An ongoing phase 2a study to investigate drug–drug interactions between escalating doses of AT2220 (duvoglustat hydrochloride) and acid alpha glucosidase in subjects with Pompe disease – Preliminary results

Pompe disease is an inherited lysosomal storage disease that results from a deficiency in acid alpha-glucosidase (GAA) activity, and is characterized by progressive accumulation of lysosomal glycogen primarily in heart and skeletal muscles. Recombinant human GAA (rhGAA, Genzyme) is the only approved enzyme replacement therapy for Pompe, and is administered biweekly via intravenous infusion. While rhGAA provides clinical benefit, drawbacks as low stability at neutral pH/body temperature, modest tissue uptake and glycogen reduction, and immune responses affect tolerability and efficacy. AT2220 (duvoglustat HCl) is a pharmacological chaperone which selectively and reversibly binds and stabilizes endogenous GAA, facilitating proper folding and trafficking to lysosomes. AT2220-010 is an open-label, single ascending dose, fixed-sequence, two-period, dose-finding study comprised of four cohorts of 4–6 subjects with Pompe disease. During the first period, subjects receive their regularly scheduled intravenous infusion of rhGAA 20mg/kg alone. During the second period they receive a single oral dose of AT2220 with rhGAA. The objectives of the study are (1) evaluate the safety of single ascending doses of AT2220 (50mg, 100mg, 250mg, and 600mg) and (2) characterize the pharmacokinetic interaction of AT2220 on rhGAA. Preliminary plasma, peripheral blood mononuclear cells, and muscle GAA activity, total GAA protein, and AT2220 concentrations as well as safety data including urine Hex 4 concentrations are available for the first and second cohorts. Anti-GAA antibodies are also being evaluated.

Can Capecitabine Replace 5-Fluorouracil for Locally Advanced Rectal Cancer?

The use of preoperative chemoradiotherapy is standard treatment for patients with T3 or node-positive rectal cancer. An infusional schedule of

Analysis of Hohn (HC) and porth-a-cath (PAC) central venous catheters (CVC) adverse events (AEs) and related costs in advanced soft tissue sarcomas (STS) treated with trabectedin (TR) 24-hour (24-h) infusion therapy.

e20512 Background: TR is registered as second line in STS. The 24-h infusion schedule showed a better activity profile but a CVC is mandatory to administer TR with related costs and possible complications. The HC (Bard Access System, USA) is a silicone, open-ended, non-tunneled CVC characterized by low cost and easy placement and removal. We performed a retrospective analysis of STS patients (pts) treated with TR through a CVC to evaluate the incidence of CVC AEs (malfunctioning, thrombosis, infection or extravasation) in pts carrying HC or PAC. Methods: Eligible criteria were: at least 1 course of TR via CVC, adequate premedication (steroid and 4000 units/die of low molecular weight heparin), absence of previous CVC alterations or any underlying coagulation disorder. All CVC were placed in our Institution under radiological control and full medical history was available for all pts included into the study. Average total costs (placement, hospital admission, device, and medications) are 255 and 560 $ for HC and PAC, respectively. Results: Between March 2008 and October 2011 42 pts, median age 58 (20-74) yrs, received TR after placement of a CVC: 14 (33%) HC and 28 (67%) PAC. At the time of TR administration, pts had received a median of 2 (range 1-4) chemotherapeutic lines. A total of 185 courses of TR (44 via HC / 141 via PAC) were administered at a median dose of 1.3 mg/m2 with a median of 3 (1-22) courses per pts. AEs occurred after a median of 2 (range 1-6) TR courses. We recorded 13 CVC-related AEs: 7 infection (2 HC / 5 PAC), 4 thrombosis (2 HC / 2 PAC), 2 malfunctioning (1 HC / 1 PAC,) no extravasation. CVC had to be removed and substituted in 10 pts (5 HC/5 PAC) with an estimated total cost of 280 and 680 $ for HC and PAC, respectively. In PAC pts, AEs determined 5 dose delays, only. Conclusions: CVC AEs should be considered in the management of pts treated with TR. HC showed a favorable safety profile and its AEs management is easier compared to implanted CVC. If disease does not progress after 2 cycles, HC can be converted in an implanted CVC. However, HC is also an adequate and cheaper device when best supportive care is the only useful therapy left.

Targeting EGFR and ERBB3 in lung cancer patients: Clinical outcomes in a phase I trial of MM-121 in combination with erlotinib.

7556 Background: Erlotinib is effective in NSCLCs with wild-type EGFR and shows enhanced benefit in EGFR mutation-positive cancers. However, resistance invariably develops, often involving persistent ErbB3 signaling and activation of the PI3K/AKT survival pathway. We present the full results of the Phase 1 study evaluating the safety and tolerability of erlotinib plus MM-121 a fully human IgG2 monoclonal antibody (mAb) to ErbB3. Methods: Eligible patients had advanced stage NSCLC, and ECOG 0-2. Seven cohorts were enrolled, evaluating varying levels of the MM-121 and erlotinib, as well as alternate MM-121 infusion schedules. Tumor response was assessed every 8 weeks. Dose levels were determined by safety and pharmacokinetic (PK) data, and immunogenicity, efficacy endpoints and exploratory biomarker evaluations were performed. Results: From February 2010 – July 2011 32pts entered the study (median age 63y; 45% male; 18% ECOG 0, 82% ECOG 1. 56% had adenocarcinoma and 30% pts received 3 or more lines of prior therapies (range 0-7) with 91% having had prior platinum. 65% had wild-type EGFR status and were never treated or never responded to EGFR-TKIs (EGFRwt) and 28% had acquired resistance to erlotinib treatment (EGFRresist). The most common toxicities (any grade) observed were diarrhea (82%), rash (64%), and fatigue (64%). DLTs observed in different cohorts were diarrhea, mucositis, rash and failure to thrive. Clinical activity was observed including 1 PR (an EGFR TKI naïve EGFR mutant) and 14 SD. Average duration of disease stabilization was 21.6 wks (range 7.1 -89.3 wks). Median PFS is 8.1 weeks and the 16 week PFS rate was 41% in the overall population. For EGFRwt and EGFRresist pts the median PFS were 7.7 weeks and 15.1 weeks, and the 16 week PFS rates were 32% and 44%, respectively. 7/20 EGFRwt pts and 5/9 EGFRresist pts achieved SD. Conclusions: This study suggests that the combination of erlotinib and MM-121 has an acceptable safety profile in heavily pre-treated NSCLC patients with and without EGFR mutations. Early signals of patient benefit were seen and a large randomized phase II study is ongoing.

Patent Highlights

Patent Highlights

P367 Compliance to the scheduled treatment with infliximab. Experience in a tertiary care hospital

Background: Scheduled infliximab infusions are effective inducing and maintaining remission in IBD. Compliance with the schedule is important to avoid infusional reactions and loss of response. The aim of this report is to assess the compliance to this treatment in our Unit. Methods: All infliximab infusions received in the IBD Day Care Centre of our hospital since its opening in March 2007 were recorded. Treatment schedule consists in an induction phase 0, 2, 6 weeks and maintenance every 8 weeks. Treatment intensification was prescribed following medical criteria. Infusion delay was defined when the interval between two maintenance doses exceeded 63 days (9 weeks) or when infusion was delayed more than 5 days from calculated date in the induction phase. Intervals when treatment was stopped due to pregnancy, “drug holidays” by medical criteria, etc were excluded. We define “non-adherent patient” when at least three doses and 25% of the total are delayed. Results: 128 patients received 1508 infliximab infusions in our hospital from March 2007 to October 2011. Mean number of infusions was 11.78 (SD 8.9). 60 patients (46.9%) were male and 68 (53.1%) female. The indication was Crohn’s disease in 98 patients (76.5%) and ulcerative colitis in 30 (23.4%). Age at start of the therapy was 39 years (SD 14.6 range 15 77). 74 patients (57.81%) had some dose delayed, being 1.73 the mean number of infusion delayed (SD 2.4). Mean delay was 11.97 days (SD 16.4 median 7 days). Only 19 (14.84%) patients had at least one interval between doses greater than 12 weeks. 13 patients were defined as non-adherent (10,15%) 8 male (53.3%) and 5 female. The type of disease was Crohn in 9 cases (69.2%) and ulcerative colitis in 4 (30.8%). Differences between adherent (AP) and non-adherent patients (NAP) were analyzed: there is no difference in gender or type of disease. Statistically significant differences were found in mean age at start of the therapy (39.44 SD 14.6 AP vs 25.67 SD 5.6 NAP, p < 0.001), number of doses received 11.78 SD 8.9 AP vs 19.15 SD 7.9, NAP p < 0.001), and time on therapy (202.25 SD 9.6 AP vs 99.3 SD 94.9 NAP, p < 0.001). There is no difference in treatment intensification need between both groups; 24 of 115 patients (20.8%) in adherent vs 3 of 13 (23%) in non-adherent (p =NS). Conclusions: Our patients have a good scheduled doses compliance on infliximab therapy in our Unit, even after years of treatment. Risk factors for poor compliance are young patients and need of prolonged therapy. P368 Routine practice of iron infusion therapy in IBD T. Iqbal1 *, G. Rogler2, C. Hoffman3, J. Stein4. 1University Hospital Birmingham, Gastroenterology, Birmingham, United Kingdom, 2University Hospital Zurich, Klinik fur Gastroenterologie und Hepatologie Department fur Innere Medizin, Zurich, Switzerland, 3Vifor Pharma Ltd., Glattbrugg, Switzerland, 4Interdisciplinary Crohn Colitis Centre Rhein Main, Frankfurt, Germany

ABI-007 in the treatment of unresectable or recurrent gastric cancer refractory to fluoropyrimidine-containing regimen: Updated data from the multicenter phase II study.

90 Background: ABI-007 is a novel Cremophor-free nanoparticle albumin-bound paclitaxel. Cremophor-free formulation allows administration using a shorter infusion schedule (30 minutes) and without the need for premedicaion to prevent solvent-based hypersensitivity reactions.This single arm phase II study evaluated the efficacy and safety of ABI-007 given every three weeks to unresectable or recurrent gastric cancer patients (pts) who had received one prior chemotherapy regimen containing fluoropyrimidine and developed disease progression (PD) or recurrence. Methods: Eligibility include: histologically or cytologically confirmed gastric adenocarcinoma , received one prior regimen containing fluoropyrimidine analogs and developed PD or recurrence, age: 20 - 74, at least one measurable lesion by RECIST(1.0), PS:0-2, adequate organ function and written informed consent. Study duration was until PD or unacceptable toxicity developed. Pts received ABI-007 260 mg/m2, i.v. on day 1 of each 21 day cycle) without premedication. The primary endpoint was overall objective response rate (ORR). Results: From April 2008 to July 2010, total of 56 pts were enrolled, 55 received the study treatment, and 54 pts were evaluable for response. Median age was 64, Male/Female was 43/12, PS:0/1/2 was 33/22/0 and number of sites of metastasis corresponding was 1/2/≥3:19/21/15. ORR was 27.8% (15/54; 95%CI, 16.5-41.6) and DCR (disease control rate:CR+PR+SD) was 59.3% (32/54, 95%CI, 45.0-72.4) for all evaluable patients. One confirmed CR was observed. Median progression–free survival was 2.9 months (95%CI, 2.4-3.6), and median overall survival was 9.0 months (95%CI, 6.6-11.5). The most common grade 3/4 toxicities were neutropenia (49.1%), leucopenia (20.0%), lymphopenia (10.9%); and peripheral sensory neuropathy (23.6%). Conclusions: These data demonstrate that ABI-007 showed promising activity with well-tolerated toxicities for previously treated unresectable or recurrent gastric cancer pts.

A comparison of traditional vs. Canadian tailored prophylaxis dosing of prophylactic factor infusions in children with haemophilia A and B in a single hemophilia treatment center

Prophylactic infusion of clotting factor concentrates is a developing standard of care for individuals with haemophilia. The ideal schedule and techniques of prophylactic infusions remain incompletely defined. Our aim was to determine the optimal techniques and schedules for factor prophylaxis in paediatric patients. A retrospective electronic medical record review of all children treated with prophylactic factor infusions in a single Haemophilia Treatment Center was conducted. Comparison of traditional vs. Canadian dosing regimens and primary vs. secondary prophylaxis was made. Failure of prophylaxis was defined as the first serious bleed. A total of 58 children were identified for review. Five cases were excluded (four due to high titre inhibitors and one due to repeated non-compliance), thus there were 53 total cases: 46 with severe haemophilia, 2 with moderate haemophilia, 5 with mild haemophilia, 44 with haemophilia A and 9 with haemophilia B; 32 Traditional dosing and 21 Canadian dosing regimens. Patients on primary prophylaxis had a decreased failure rate (25%) compared to children treated with secondary prophylaxis (67%) regardless of technique of prophylaxis. When compared to a 'Traditional' factor prophylaxis schedule, the 'Canadian' tailored prophylaxis protocol was comparable with the exception of a decreased use of implanted venous devices in the 'Canadian' group. Ongoing bleeding (primarily joint bleeds) occurs with all prophylactic regimens. The lowest incidence of treatment failure was noted in children who began primary prophylaxis at a young age and before initial joint bleeds. Primary prophylaxis is superior to secondary prophylaxis regardless of dosing regimen. Traditional and Canadian dosing regimens were equivalent in outcome when measured over several years of follow-up.

Management of paclitaxel-induced neurotoxicity

Paclitaxel exerts its antitumor activity by promoting microtubule assembly and stabilizing microtubules. Microtubules are important for the development and maintenance of neurons. As a consequence, neurotoxicity is one of the drug’s major side effects. The risk of neurotoxicity depends on dose, duration and schedule of paclitaxel. Risk increases for patients with pre-existing conditions that may cause neuropathy (such as alcohol consumption, diabetes, or renal disease) or with simultaneous or prior exposure to other neurotoxic chemotherapy such as platinum-based drugs, vinca alkaloids, immunomodulators, proteasome inhibitors, and epothilones. Patients with paclitaxel-induced neurotoxicity (PINT) experience a constellation of symptoms over the course of treatment and beyond, ranging from mild to severe. Typically, the clinical presentation reflects an axonal peripheral neuropathy with glove-and-stocking distribution sensory loss, combined with features suggestive of nerve hyperexcitability including paresthesia, dysesthesia, and pain. Proprioceptive and motor effects become apparent as neuropathy becomes more advanced. These symptoms may be prolonged, severe, disabling, relatively resistant to intervention and adversely affect activities of daily living and thereby quality of life. Management is mainly symptomatic and supportive. Despite attempts to minimize PINT with changes in dose, vehicle, delivery systems, infusion schedule and premedication or co-treatment with neuroprotective agents, PINT remains dose-limiting in many instances and is a barrier to achieving the desired clinical response.

A Phase II Study of Sequential Administration of DLI and Cytokine Induced Killer (CIK) Cells in Patients with Hematologic Malignancies Relapsing After Allogeneic Hematopoietic Stem Cell Transplantation: Preliminary Results

Abstract 657 Background:Cytokine Induced Killer (CIK) cells have been previously shown by us and others to possess non restricted, NK-like anti-tumoral cytotoxicity in vitro and in vivo, with little graft-versus host disease (GVHD), in vitro and in several animal models. We have previously performed a phase I study with donor derived CIK cells in 11 adult hematologic patients and shown that the infusions of CIK cells (median 12.4 × 106/kg, range 7.2 to 87.4) were well tolerated and no acute or late infusion related reactions were recorded. Acute GVHD (grade I and II) was observed in 4 patients and progressed into extensive chronic GVHD in two cases (Introna et al, Haematologica 92:952, 2007). Methods:This study is an open-labeled, multicenter, exploratory phase IIA study to evaluate the safety (dose-finding) and efficacy of a sequential administration of donor derived unmanipulated lymphocytes (DLI) plus in vitro expanded CIK cells to patients with hematologic malignancies relapsing after related or unrelated allogeneic hematopoietic stem cells transplantation. The protocol was formally approved by the italian competent national authority (Agenzia Italiana del Farmaco, AIFA) on 14/04/2009. Two infusions of unmanipulated DLI (1×106/kg each) were given with a minimum interval of 3 weeks. Three infusions of donor CIK cells were then administered according to a dose escalating program, starting 3 weeks after the second DLI. CIK administrations were separated by 3 weeks intervals. Up to 4 combinations of dose escalating levels were provided in sequential order until the maximal tolerated dose (MTD) was reached. Indeed the first triplet of patients was supposed to receive CIK cells at the doses of 1×106/kg, 1×106/kg and 5×106/kg, the second 1×106/kg, 5×106/kg, 5×106/kg, the third 1×106/kg, 5×106/kg,10×106/kg, the last triplet 5×106/kg, 5×106/kg, 10×106/kg. In case of grade II or more severe acute GVHD, the next scheduled infusion was planned to be suspended. Only grade IV acute GVHD was considered the dose limiting toxicity (DLT). Once identified the MTD, this same dose will be administered up to 24 patients in a two-stage Simon’s design. Results:So far 16 patients have been enrolled and 12 are evaluable. No DLT (grade IV acute GVHD) was observed at any dose. One patient suffered from grade III skin and gut acute GVHD in the group which received the highest dose and the therapy was stopped after the first administration of CIK cells (5×106/kg), while another patient showed grade I skin acute GVHD in this same group, but completed the 3 administrations program. So far, 7 patients have received the highest dose of CIK cells and they all completed the schedule without toxicity except one case. As per protocol, the best clinical response was evaluated 100 days after the end of the last CIK administration. We observed 3 CR (3 AML), 5 PR (3 AML, 1 MM and 1 HD) and 4 NR (2 AML, 1 NHL and 1 MM) in the 12 evaluable patients. Of the 12 evaluable patients, 5 required additional therapy at the end of the cell therapy program because of NR (3 patients) or to improve the PR (2 patients). Four patients died after a mean 63 days (3 due to relapse and 1 for infection), 6 patients are in PR and 2 patients remain in CR. Conclusions:These preliminary observations suggest that the sequential infusion of DLI and CIK cells is feasible with relatively minor toxicity, the MTD has not been achieved and the triplet of three CIK administrations of 5×106/kg, 5×106/kg and 10×106/kg will be further evaluated in 17 additional patients. This cell therapy program confirms the antineoplastic activity of this cell therapy schedule in some patients relapsing after allogeneic stem cell transplantation. Disclosures:No relevant conflicts of interest to declare.