Daily Continuous Infusion Research Articles

Adjuvant chemotherapy with 5-fluorouracil and cisplatin compared with surgery alone for gastric cancer: 7-year results of the FFCD randomized phase III trial (8801)

The aim of this study was to evaluate the efficacy of adjuvant chemotherapy after resection for gastric cancer in a randomized controlled trial. After curative resection, stage II-III-IVM0 gastric cancer patients were randomly assigned to postoperative chemotherapy or surgery alone. 5-Fluorouracil (5-FU) 800 mg/m(2) daily (5-day continuous infusion) was initiated before day 14 after resection. One month later, four 5-day cycles of 5-FU (1 g/m(2) per day) plus cisplatin (100 mg/m(2) on day 2) were administered every 4 weeks. The study was closed prematurely after enrollment of 260 patients (79.7% N+), owing to poor accrual. At 97.8 months median follow-up, 5- and 7-year overall survival were 41.9% and 34.9% in the control group versus 46.6% and 44.6% in the chemotherapy group (P=0.22). Cox model hazard ratios were 0.74 [95% confidence interval (CI) 0.54-1.02; P=0.063] for death and 0.70 (95% CI 0.51-0.97; P=0.032) for recurrence. An invaded/removed lymph nodes ratio >0.3 was the main independent poor prognostic factor identified by multivariate analysis (P=0.0001). Because of toxicity, only 48.8% of patients received more than 80% of the planned dose. There was no statistically significant survival benefit with this toxic cisplatin-based adjuvant chemotherapy, but a risk reduction in recurrence was observed.

Effect of Postoperative Epidural Analgesia on Rehabilitation and Pain after Hip Fracture Surgery

Hip fracture surgery usually carries a high demand for rehabilitation and a significant risk of perioperative morbidity and mortality. Postoperative epidural analgesia may reduce morbidity and has been shown to facilitate rehabilitation in elective orthopedic procedures. No studies exist on the effect of postoperative epidural analgesia on pain and rehabilitation after hip fracture surgery. Sixty elderly patients were included in a randomized, double-blind study comparing 4 days of continuous postoperative epidural infusion of 4 ml/h bupivacaine, 0.125%, and 50 mug/ml morphine versus placebo. Both patient groups received balanced analgesia and intravenous nurse-controlled analgesia with morphine. All patients followed a well-defined multimodal rehabilitation program. Pain, ability to participate in four basic physical functions, and any factors restricting participation were assessed on the first 4 postoperative days during physiotherapy. Epidural analgesia provided superior dynamic analgesia during all basic physical functions, and patients were significantly less restricted by pain, which was the dominating restricting factor in the placebo group. Motor blockade was not a restricting factor during epidural analgesia. Despite improved pain relief, scores for recovery of physical independence were not different between groups. Postoperative epidural analgesia after hip fracture surgery provides superior analgesia attenuating pain as a restricting factor during rehabilitation without motor dysfunction. However, superior analgesia did not translate into enhanced rehabilitation. Future studies with multimodal rehabilitation are required to establish whether superior analgesia can be translated into enhanced rehabilitation and reduced morbidity in hip fracture patients.

Phase I/II study of GTI-2040 plus docetaxel as 2nd-line treatment in non-small cell lung cancer (NSCLC) and other solid tumors

7253 Background: Median survival in advanced NSCLC with systemic therapy is 8 to 10 months, with modest benefits from 1st-, 2nd-, and 3rd-line therapy. GTI-2040 (Lorus Therapeutics, Canada), an antisense oligonucleotide complementary to mRNA encoding the RNR R2 subunit, demonstrates preclinical activity against lung cancer cell lines, synergy with taxanes, and disease stabilization as a single agent in a phase I trial. Objective: To determine the recommended phase 2 dose (RP2D) of GTI-2040 plus docetaxel, and the objective response rate and toxicity at RP2D as 2nd-line therapy in advanced NSCLC. Methods: Advanced solid tumor (phase I) and NSCLC (phase II) patients (pts) with performance status 0–2, adequate renal, hepatic, and hematologic function, and ≤ 1 prior chemotherapy regimen were treated with escalating doses of GTI-2040 by 14-day continuous venous infusion (CVI) plus IV docetaxel on one day every 21 days. Pts in Phase II were treated at RP2D. Results: 18 pts have been treated, 11 at RP2D (7 NSCLC). Dose escalation is shown below, with GTI-2040 5 mg/kg by CVI for 14 days plus docetaxel 75 mg/m2 IV q21days as the RP2D. Dose-limiting toxicity was not seen in cycle 1 at any dose level. Toxicities included neutropenia, sepsis, fatigue, and GI toxicity. Pts received a median of 2 cycles at RP2D (1–7); 2 pts at RP2D developed grade 4 or 5 febrile neutropenia; 3 developed grade 3 thrombosis related to central venous catheters; 2 experienced grade 3 hyperglycemia (likely dexamethasone-related); 1 developed grade 3 anemia after cycle 2. Stable disease (SD) was seen in 10 (6 NSCLC, 2 prostate, 1 SCLC, 1 H&N), including 4 minor responses (3 NSCLC, 1 prostate) and 1 minor PSA response (prostate). 15 patients have come off treatment, 1 after 6 cycles, 7 for progressive disease (PD), 2 for toxicity (including toxic death), 3 at investigator discretion and 2 pts withdrew; 3 remain on treatment, 1 on cycle 7. Accrual, response, survival and toxicity will be updated. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Aventis

Intracerebral and Intrathecal Infusion of the TGF-β2-Specific Antisense Phosphorothioate Oligonucleotide AP 12009 in Rabbits and Primates: Toxicology and Safety

Here, we provide first evidence that long-term continuous infusion of highly purified antisense phosphorothioate oligodeoxynucleotides (S-ODN) into brain parenchyma is well tolerated and thus highly suitable for in vivo application. AP 12009 is an S-ODN for the therapy of malignant glioma. It is directed against human transforming growth factor-beta (TGF-beta2) mRNA. In the clinical setting, AP 12009 is administered intratumorally by continuous infusion directly into the brain tumor. In view of this clinical application, the focus of our data is on local toxicology studies in rabbits and monkeys to evaluate the safety of AP 12009. AP 12009 was administered either by intrathecal bolus injection into the subarachnoidal space of the lumbar region of both cynomolgus monkeys and rabbits or by continuous intraparenchymatous infusion directly into the brain tissue of rabbits. Intrathecal bolus administration of 0.1 ml of 500 microM AP 12009 showed neither clinical signs of toxicity nor macroscopically visible or histomorphologic changes. After a 7-day intraparenchymatous continuous infusion of 500 microM AP 12009 at 1 microl/h in rabbits, there was no evidence of toxicity except for local mild to moderate lymphocytic leptomeningoencephalitis. Additionally, AP 12009 showed good tolerability in safety pharmacology as well as in acute toxicity studies and 4-week subchronic toxicity studies in mice, rats, and monkeys. This favorable safety profile proves the suitability of AP 12009 for local administration in brain tumor patients from the point of view of toxicology.

Chemoradiation using 5-fluorouracil given every other day 24hours continuous iv infusion and cisplatin combination for the patients with esophageal cancer

4217 Background: 5-fluorouracil(5-FU) and cisplatin(CDDP) are key drugs for esophageal cancer. We performed a single institution chemoradiation study using every other day dosing of 5-FU to improve dose intensity(DI) and evaluated the efficacy and tolerance data. Methods: : Aim of study: Evaluating feasibility, efficacy and safety. Inclusion criteria: age<80, ECOG PS 0–2, disease-stages II,III,IV assessed by CT scan and EUS. Treatment scheme: Radiation:40Gy over 4 weeks(2Gy/fr/day Monday through Friday). Chemotherapy:5-FU 750 mg/m2 24hours continuous iv infusion day(D)1,3,5,8,10,12,15,17,19,22,24,26 and CDDP4mg/m2 iv D1–5,8–12,15–19,22–26 were given concurrently over the 4 weeks resulting in more than twice in terms of 5-FU DI compared with the other commonly used chemoradiation regimens. Responded tumors were resected, while additional 20Gy and the same chemotherapy were also given over 2 weeks to rest of the patients and stage IV patients. Results: : 28 patients with locally advanced esophageal cancer were treated between 2002 May and 2004 November. 27 patients were evaluable. 3 female, 24 male, median age 65(range 40–78) All patients had ECOG PS2 or better and squamous cell cancer. Stage II:4,III:12,IV:11. Primary tumor site:Upper: 2, Middle: 17, Lower: 8, Tumor length: median 70mm(35–160). Compliance with radiation, doses and timing: almost 100%. CR: 21% at the completion of scheduled chemoradiation regimen. 1-year survival was 60%, 2years 38%. Pathological CR was 30%(3/10) among patients undergone surgery. Grade 3/4 toxicity: Neutropenia 44%, Esophagitis 11%, Nausea 11%, Anorexia 33%. Conclusions: Chemotherapy employing dose intensified 5-FU regimen is a safe and well tolerated regimen for concurrent chemoradiation of locally advanced esophageal cancer. Since active drugs are limited for this disease, explorative study searching for improved outcome and sustaining safety is further warranted. No significant financial relationships to disclose.

Randomized phase II evaluation of aprinocarsen in combination with gemcitabine and cisplatin for patients with advanced/metastatic non-small cell lung cancer

Aprinocarsen is a specific antisense oligonucleotide inhibitor of protein kinase C-alpha. This study aimed to evaluate the response rate to combination therapy with aprinocarsen, gemcitabine and cisplatin, in chemonaive patients with advanced/metastatic NSCLC. Secondary objectives included comparison of response rate, time to event efficacy parameters, and toxicities on the 2 treatment arms. Patients with stage IV, or stage IIIB disease (N3 and/or pleural/pericardial effusion), were randomized to either control or experimental arm. Patients on both arms received gemcitabine 1250 mg/m2 on days 1 and 8, and cisplatin 80 mg/m2 on day 1 of a 3-week cycle. Additionally, on the experimental arm, aprinocarsen was administered as 2 mg/kg continuous iv infusion on days 1-14, every 21 days. A total of 18 enrolled patients were randomized on the 2 arms. Further enrollment was terminated in March 2003 as a result of a phase III trial suggesting that aprinocarsen did not have an added survival benefit when combined with paclitaxel and carboplatin therapy in patients with NSCLC. Patients received a median of 4 cycles on control arm and 2.5 cycles on experimental arm. The response rate was 16.7% in the experimental arm and 44.4% in the control arm. Most frequent grade 3/4 toxicities were hematologic, with a higher incidence of thrombocytopenia in the experimental arm (87.5% vs. 33.3%). Despite the 14-day continuous infusion schedule, infection rate was not increased in the experimental arm. The present study did not show any advantage, in response rate or secondary endpoints, with aprinocarsen; however, the toxicity was not unduly increased, and aprinocarsen regimen was safely administered.

Randomized Phase III Evaluation of Cisplatin Plus Fluorouracil Versus Cisplatin Plus Paclitaxel in Advanced Head and Neck Cancer (E1395): An Intergroup Trial of the Eastern Cooperative Oncology Group

To determine the response rate, survival and toxicity of infusional cisplatin plus fluorouracil (CF) versus cisplatin plus paclitaxel (CP) in patients with incurable squamous cell cancer of the head and neck, with the hypothesis that CP is superior. Two hundred eighteen patients with locally advanced, recurrent, or metastatic disease were randomly assigned to CF (cisplatin 100 mg/m2 day 1 and fluorouracil 1,000 mg/m2/24 hours by continuous intravenous infusion day 1 through 4) or CP (cisplatin 75 mg/m2 day 1 and paclitaxel 175 mg/m2 over 3 hours on day 1). Cycles were repeated every 3 weeks until progression or a minimum of 6 cycles with complete response or stable disease. The primary outcome was overall survival. Secondary outcomes included response rate and toxicity. No significant difference in overall survival or response rate was seen. Estimated median survival was 8.7 months in the CF group and 8.1 month in the CP group. Objective response rate (complete response plus partial response) was 27% in the CF group and 26% in the CP group. Toxicity was similar between groups, with the most frequent including myelosuppression, thrombocytopenia, anemia, nausea, vomiting, and stomatitis. A total of 12 deaths occurred (CF, seven; CP, five) during treatment; eight from infection, two from hemorrhage, one from cardiac causes and one from unknown causes. Gastrointestinal and hematologic toxicities were more common in the CF group, whereas neurotoxicity was equivalent between groups. This phase III, randomized, multicenter trial showed no difference in survival between patients treated with CF or CP.

A Phase II Study of Docetaxel and Infusional Cisplatin in Advanced Non-Small-Cell Lung Cancer

Background: To evaluate the efficacy and safety of combination chemotherapy of cisplatin (5-day continuous infusion) and docetaxel for the treatment of previously untreated patients with advanced non-small-cell lung cancer (NSCLC). Materials and Methods: Eligible patients had an ECOG performance status of 0–2 with measurable NSCLC. Patients received continuous infusion cisplatin 20 mg/m²/day on 5 days and bolus docetaxel 60 mg/m²/day (day 1; PiD therapy) at a 4-week interval. Results: Forty-three patients were enrolled. The mean number of cycles administered per patient was 2, and ranged from 1 to 4. The response rate was 49% (95% confidence interval, 33.9–63.8%). The median survival time was 47 weeks and the 1-year survival rate was 47%. The major toxic effects were grade 3 or 4, neutropenia (88%), leukopenia (81%), thrombocytopenia (14%) and anemia (42%). There were no treatment-related deaths. Conclusion: PiD therapy was a well-tolerated and active regimen for patients with advanced NSCLC. The major toxicity was neutropenia.

A randomized phase III study of radiotherapy alone or with 5-fluorouracil and mitomycin-C in patients with locally advanced adenocarcinoma of the pancreas: Eastern Cooperative Oncology Group study E8282

The median survival time of patients with locally advanced adenocarcinoma of the pancreas is 8-10 months. Radiation therapy has been used to improve local control and palliate symptoms. This randomized study was undertaken to determine whether the addition of 5-fluorouracil (5-FU) and mitomycin-C (MMC) to radiation therapy improves outcome in this patient population. One hundred fourteen patients were randomized to receive 59.4 Gy external beam radiotherapy in 1.8 Gy fractions alone or in combination with 5-FU (1,000 mg/m2/day for 4 days by continuous infusion Days 2-5 and 28-31) and MMC (10 mg/m2 on Day 2). One hundred four patients were evaluable for efficacy. Hematologic and nonhematologic toxicities were more common in the combination arm. The response rates were 6% in the radiation therapy arm and 9% in the combination arm. There were no differences in median disease-free survival time (DFS) or overall survival time (OS) between the combination and radiation therapy alone arms: 5.1 vs. 5.0 months, respectively, for DFS (p = 0.19) and 8.4 vs. 7.1 months, respectively, for OS (p = 0.16). The addition of 5-FU and MMC to radiotherapy increased toxicity without improving DFS or OS in patients with locally advanced pancreatic cancer. Alternative drugs for radiosensitization may improve outcome.

Evaluation of a 7-Day Continuous Intravenous Infusion of Decitabine: Inhibition of Promoter-Specific and Global Genomic DNA Methylation

The nucleoside analog 5-aza-2'-deoxycytidine (5-aza-CdR, decitabine) is a potent inhibitor of DNA methylation in vitro. Cellular treatment with this agent induces the re-expression of methylation-silenced genes. It remains unclear to what extent this compound inhibits DNA methylation in vivo. A clinical study was designed to examine the molecular effects and toxicity of a continuous 1-week intravenous infusion of decitabine in solid tumor patients. Ten patients with refractory solid tumors were included in this study. Decitabine was administered at 2 mg/m(2)/d [DOSAGE ERROR CORRECTED] via continuous infusion for 168 hours. Quantitative polymerase chain reaction and high performance liquid chromatography were utilized to measure promoter-specific and global DNA methylation in peripheral-blood cells before and after treatment. Transient grade III/IV neutropenia (two patients) and grade II thrombocytopenia (one patient) was observed at the lowest planned dose step (2 mg/m2/d for 7 days). Nonhematologic toxicities were not observed. Quantitative polymerase chain reaction demonstrated significant MAGE-1 promoter hypomethylation by 14 days after the start of treatment in all 13 treatment cycles examined. Significant genomic DNA hypomethylation was also seen by day 14 in 11 of 13 treatment cycles analyzed. Genomic DNA methylation reverted to baseline levels by 28 to 35 days after the start of treatment, demonstrating that inhibition of DNA methylation by decitabine is transient. A 168-hour continuous infusion of decitabine is well tolerated and results in the inhibition of promoter-specific and genomic DNA methylation in vivo. This treatment schedule is suitable for evaluation of decitabine in combination with agents whose activity may be enhanced by the reversal of DNA methylation-mediated gene silencing.

Safety and Biologic Activity of Intravenous BCL-2 Antisense Oligonucleotide (G3139) and Taxane Chemotherapy in Patients With Advanced Cancer

G3139 is a BCL-2 antisense oligonucleotide whose antitumor effects in preclinical models are enhanced when combined with taxane-based chemotherapy. This trial determined the safety and biologic activity of G3139 given with paclitaxel and docetaxel for the treatment of progressive solid tumors. Three cohorts of patients received weekly paclitaxel 100 mg/m2 on days 1, 8, and 15 concurrently with a 21-day continuous infusion of G3139 at 4.1, 5.3, and 6.9 mg/kg/d, depending on the cohort. Two subsequent cohorts received docetaxel (75 mg/m2) on day 5 of a 5-day infusion of G3139 at 5 or 7 mg/kg/d. Bcl-2 protein levels in peripheral blood mononuclear cells (PBMCs) were assayed on an exploratory basis. Fifteen patients were treated. Eight received a total of 14 cycles of G3139 and paclitaxel; seven received a total of 22 cycles of G3139 and docetaxel. Eight patients required dose modifications for either grade 4 neutropenia (6 patients) or grade 1-2 reversible transaminitis (2 patients). No radiographic responses were seen, although two of the six taxane-naive prostate cancer patients exhibited a prostate-specific antigen decline greater than 50%. Bcl-2 protein levels in PBMCs declined with treatment as assessed by immunohistochemistry. The authors conclude that G3139, whether given as a 5- or 21-day infusion, is well tolerated with taxane chemotherapy and is biologically active by immunohistochemistry at doses up to and including 7 mg/kg/d, using weekly paclitaxel (100 mg/m2) or docetaxel every 3 weeks (75 mg/m2). These data support the dose selection of ongoing phase 2 studies of G3139 at 7 mg/kg/d and docetaxel 75 mg/m2.

Hyperfractionated Accelerated Chemoradiation With Concurrent Fluorouracil-Mitomycin Is More Effective Than Dose-Escalated Hyperfractionated Accelerated Radiation Therapy Alone in Locally Advanced Head and Neck Cancer: Final Results of the Radiotherapy Cooperative Clinical Trials Group of the German Cancer Society 95-06 Prospective Randomized Trial

To report the results and corresponding acute and late reactions of a prospective, randomized, clinical study in locally advanced head and neck cancer comparing concurrent fluorouracil (FU) and mitomycin (MMC) chemotherapy and hyperfractionated accelerated radiation therapy (C-HART; 70.6 Gy) to hyperfractionated accelerated radiation therapy alone (HART; 77.6 Gy). Three hundred eighty-four stage III (6%) and IV (94%) oropharyngeal (59.4%), hypopharyngeal (32.3%), and oral cavity (8.3%) cancer patients were randomly assigned to receive either 30 Gy (2 Gy every day) followed by 1.4 Gy bid to a total of 70.6 Gy concurrently with FU (600 mg/m(2), 120 hours continuous infusion) days 1 through 5 and MMC (10 mg/m(2)) on days 5 and 36 (C-HART) or 14 Gy (2 Gy every day) followed by 1.4 Gy bid to a total dose of 77.6 Gy (HART). The data were analyzed on an intent-to-treat basis. At 5 years, the locoregional control and overall survival rates were 49.9% and 28.6% for C-HART versus 37.4% and 23.7% for HART, respectively (P = .001 and P = .023, respectively). Progression-free and freedom from metastases rates were 29.3% and 51.9% for C-HART versus 26.6% and 54.7% for HART, respectively (P = .009 and P = .575, respectively). For C-HART, maximum acute reactions of mucositis, moist desquamation, and erythema were lower than with HART, whereas no differences in late reactions and overall rates of secondary neoplasms were observed. C-HART (70.6 Gy) is superior to dose-escalated HART (77.6 Gy) with comparable or less acute reactions and equivalent late reactions, indicating an improvement of the therapeutic ratio.

Remifentanil in neurosurgical patients in the intensive care unit

Remifentanil is a rapidly metabolized opioid analgesic that is being increasingly used in critically ill patients [1,2]. Our purpose was to evaluate the hemodynamic changes of sedated neurosurgery patients in the ICU caused by remifentanil as well as the time elapsed until the wakening in comparison with fentanyl and morphine. Patients received remifentanil for more than 5 days in continuous infusion.

Neoadjuvant and concomitant chemotherapy and radiation therapy in patients with advanced head and neck carcinoma

Our study evaluated the effectiveness of neoadjuvant chemotherapy and concomitant chemotherapy with radiotherapy compared to standard surgery and radiation therapy in patients with resectable stage III/IV head and neck squamous cell carcinoma. Forty-two eligible patients received neoadjuvant chemotherapy (cisplatin 100 mg/m2 intravenously day 1, and 5-fluorouracil 1 g/m2 /day continuous infusion days 1-5 every 3 weeks for 3 courses) followed by radiotherapy (65-70 Gy in 32-39 fractions to the primary site and lymph nodes; 50 Gy in 25-28 fractions to areas at risk) and concomitant chemotherapy (cisplatin 80 mg/m 2 intravenously every 3 weeks starting on day 1 of radiotherapy). Neoadjuvant therapy induced grade 4 cytopenias (12/42 patients) and grade 4 gastrointestinal toxicities (7/42 patients). Concomitant radiochemotherapy-induced grade 4 toxicities (6 patients). Neoadjuvant chemotherapy biopsy-proven complete responses were 15 of 42 patients (36%), partial responses in 23 of 42 patients (55%), and an overall response rate of 91%. Thirty-seven of 38 responders received concomitant radiochemotherapy. Complete responses in 35 of 42 patients (83%), partial response in 7 of 42 patients (7%), and overall response in 90%. The 3-year disease-free and overall survival for chemotherapy plus radiotherapy versus surgery plus radiotherapy: 61% versus 43% (P = 0.17) and 71% versus 43% (P = 0.02). These data suggest that a randomized trial of concomitant radiochemotherapy versus neoadjuvant plus concomitant radiochemotherapy should be considered. B-2.

Phase I Dose Escalating Trial of Bortezomib (Velcade®) in Combination with Idarubicin and Cytarabine in Patients with Acute Myeloid Leukemia.

Conventional therapy for acute myeloid leukemia (AML) consists of a combination of cytarabine and an anthracycline such as idarubicin. Currently, most patients ultimately fail treatment due to leukemia cell resistance to drug therapy. In vitro experiments have shown that the addition of a proteasome inhibitor to an anthracycline results in synergistic cytotoxicity to leukemia cells. Hence, we initiated this phase I trial in patients to see if bortezomib could be safely added to conventional treatment. Patients over age 60 with AML or any patient 18 or older with relapsed disease after a remission of at least 3 months (not refractory) were eligible. All patients received idarubicin 12 mg/m2 on days 1–3 and cytarabine 100 mg/m2 by continuous infusion days 1–7. In addition, patients received bortezomib by IV bolus on days 1, 4, 8, and 11. Cohorts of 3 to 6 patients were entered using increasing doses of bortezomib in order to determine the maximum tolerated dose (MTD). The first cohort received 0.7 mg/m2 of bortezomib with each bolus. If dose limiting toxicity (DLT) was encountered, then cohort advancement was restricted. DLTs included prolonged myelosuppression, neuropathy, and other grade 3 or 4 toxicities. Dose escalation would proceed to 1.0 mg/m2 and then to 1.3 mg/m2 if tolerated. No escalation was planned beyond 1.3 mg/m2. To date 14 patients have been entered on this study. In the first cohort of 3 patients with bortezomib at 0.7 mg/m2, a DLT due to prolonged neutropenia was encountered, so an additional 3 patients were entered at this dose level. No DLTs were encountered among these additional patients, so 3 more patients were entered with bortezomib at 1.0 mg/m2. One of these patients experienced prolonged thrombocytopenia and thus 3 additional patients were enrolled at 1.0 mg/m2. No DLTs were encountered among these additional patients, and thus the next cohort of patients with bortezomib at 1.3 mg/m2 was opened. To date, two patients have been enrolled at this dose level. The plan is to enroll a third patient at this level and to assess for possible DLTs. Among the 12 patients evaluable for response, there have been 4 patients achieving complete remission, 3 patients achieving remission without complete recovery of platelet count (CRp defined as having met criteria for CR but with 25,000–99,000 platelets/μl), 2 patients achieving a partial remission (CR but with 5–24% bone marrow blasts), and 3 patients failing to respond. In conclusion, bortezomib at 0.7 mg/m2 and 1.0 mg/m2 in the day 1, 4, 8, and 11 schedule can be added to idarubicin and cytarabine with acceptable toxicity. This study continues in an attempt to determine whether bortezomib can be escalated safely to 1.3 mg/m2 in this combination. Additional patients will be enrolled at the candidate MTD to gain confidence in the safety and activity at this level. Correlative science studies are planned.

A phase I and pharmacologic study of idarubicin, cytarabine, etoposide, and the multidrug resistance protein (MDR1/Pgp) inhibitor PSC-833 in patients with refractory leukemia

This study was conducted to define the maximum tolerated dose (MTD), dose limiting toxicity (DLT), and pharmacokinetics of idarubicin when administered with and without the P-glycoprotein inhibitor PSC-833 in combination with cytarabine, and etoposide. Fifteen patients with relapsed and refractory acute leukemia were enrolled and received cytarabine as a 7-day continuous infusion, with etoposide and idarubicin administered for any three consecutive days during the cytarabine infusion. Two hours prior to the second dose of idarubicin, PSC-833 administration was initiated. The pharmacokinetics of idarubicin alone and with PSC-833 was assessed at three idarubicin dose levels (6, 8 and 10 mg/m 2). The MTD of idarubicin in this combination was 8 mg/(m 2 day) with a DLT of oral mucositis. The complete remission rate (on an intent-to-treat basis) for this regimen was 33%, with a median duration of 6 months. The clearance of idarubicin was 140 ± 200 and 181 ± 94.3 l/h for idarubicin alone and with PSC-833, respectively. The volume of distribution of the central compartment was 423 ± 443 and 337 ± 394 l for idarubicin alone and in combination with PSC-833, respectively. This combination including PSC-833 was well tolerated. Although a pharmacokinetic interaction might have been expected, PSC-833 did not significantly alter the disposition of idarubicin.

SJG-136 (NSC 694501), a novel rationally designed DNA minor groove interstrand cross-linking agent with potent and broad spectrum antitumor activity: part 2: efficacy evaluations.

Pyrrolo[2,1-c][1,4]benzodiazepine dimer SJG-136 (NSC 694501) selectively cross-links guanine residues located on opposite strands of DNA, and exhibits potent in vitro cytotoxicity. In addition, SJG-136 is highly active in vivo in hollow fiber assays. In the current investigation, SJG-136 was evaluated for in vivo efficacy in 10 tumor models selected on the basis of sensitivity of cells grown in the hollow fiber and in vitro time course assays: LOX IMVI and UACC-62 (melanomas); OVCAR-3 and OVCAR-5 (ovarian carcinomas); MDA-MB-435 (breast carcinoma); SF-295 and C-6 (gliomas); LS-174T (colon carcinoma); HL-60 TB (promyelocytic leukemia); and NCI-H522 (lung carcinoma). SJG-136 was active against small (150 mg) and large (250-400 mg) xenografts with tumor mass reductions in all 10 models. In addition, significant growth delays occurred in nine models, cell kill in six models ranged between 1.9 and 7.2 logs, and there were 1 to 4/6 tumor-free responses in six models. SJG-136 is active following i.v. bolus injections, as well as by 5-day continuous infusions. Of all of the schedules tested, bolus administrations for 5 consecutive days (qd x 5) conferred the greatest efficacy. SJG-136 is active over a wide dosage range in athymic mouse xenografts: on a qd x 5 schedule, the maximum-tolerated dose was approximately 120 microg/kg/dose (total dose: 0.6 mg/kg = 1.8 mg/m2) and the minimum effective dose in the most sensitive model (SF-295) was approximately 16 microg/kg/dose (total dose: 0.08 mg/kg = 0.24 mg/m2). Results of this study extend the initial in vivo observations reported in the reference above and confirm the importance of expediting more detailed preclinical evaluations on this novel agent in support of phase I clinical trials in the United Kingdom and the United States, which are planned to commence shortly.

Continuous infusion of B-domain deleted recombinant factor VIII (ReFacto) in patients with haemophilia A undergoing surgery: clinical experience.

This retrospective, open-label, non-comparative study evaluated continuous infusion of recombinant factor VIII (ReFacto), B-domain deleted recombinant FVIII (BDDrFVIII), in patients with haemophilia A undergoing surgery and requiring >5 consecutive days of treatment. Sixteen patients from eight centres underwent a total of 20 procedures. Haemostatic outcome was assessed as 'excellent' or 'good' in 75% of procedures, and target FVIII:C levels were maintained throughout the continuous infusion period. The reported volume of blood loss during surgery was also within the normal range for non-haemophilic patients for the type of surgery performed. Red blood cell transfusions were required to balance excessive blood loss during BDDrFVIII continuous infusion in eight (40%) procedures (seven patients), five with bleeding or requiring volume replacement and three to treat anaemia secondary to blood loss. Non-serious adverse events considered by investigators as possibly or probably related to BDDrFVIII continuous infusion were infrequent (n = 5) considering the duration of treatment (n =239 cumulative days of continuous infusion), and all of these were mild-to-moderate in severity. No thromboembolic complications were reported except for one case of thrombophlebitis occurring at the infusion site. Only two patients (four events) experienced serious adverse bleeding; BDDrFVIII was otherwise well-tolerated. These data show that continuous infusion of BDDrFVIII provides reliable haemostasis and is an effective and well-tolerated regimen for patients with haemophilia A undergoing surgery.

Priming GM-CSF and low dose cytarabine (LODAC) in the treatment of high risk and elderly acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) patients

6612 Background: Priming of leukemic cells with cytokines may enhance the efficacy of cell cycle chemotherapy. We attempted to use GM-CSF to enhance the effects of low dose cytarabine to increase cell recruitment, and optimize cell cycle chemotherapy in patients who could not tolerate conventional induction chemotherapy. Methods: We evaluated the efficacy of GM-CSF priming with low-dose cytarabine and concomitant hydroxyurea in high risk, elderly AML and advanced MDS patients. Patients received induction chemotherapy with GM-CSF 250mcg/m2/d by continuous infusion days 1–7, hydroxyurea 500 mg po qid day 1 and 500mg po tid days 2–15, and cytarabine 20mg/m2/d by continuous infusion days 2–15. Results: Forty-nine patients (26F, 23M) were treated, median age 68.5 years (range 48–85); 78% had no previous treatment, and 22% of patients had a median of 2 prior treatments (range 1–7). All patients were not eligible for standard induction chemotherapy. Following treatment, 44% of the assessable patients had documen...

Priming GM-CSF and low dose cytarabine (LODAC) in the treatment of high risk and elderly acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) patients

6612 Background: Priming of leukemic cells with cytokines may enhance the efficacy of cell cycle chemotherapy. We attempted to use GM-CSF to enhance the effects of low dose cytarabine to increase cell recruitment, and optimize cell cycle chemotherapy in patients who could not tolerate conventional induction chemotherapy. Methods: We evaluated the efficacy of GM-CSF priming with low-dose cytarabine and concomitant hydroxyurea in high risk, elderly AML and advanced MDS patients. Patients received induction chemotherapy with GM-CSF 250mcg/m2/d by continuous infusion days 1–7, hydroxyurea 500 mg po qid day 1 and 500mg po tid days 2–15, and cytarabine 20mg/m2/d by continuous infusion days 2–15. Results: Forty-nine patients (26F, 23M) were treated, median age 68.5 years (range 48–85); 78% had no previous treatment, and 22% of patients had a median of 2 prior treatments (range 1–7). All patients were not eligible for standard induction chemotherapy. Following treatment, 44% of the assessable patients had documented aplastic bone marrows. The overall response rate was 49%; 33% with CR and 16% with PR. Median duration of CR was 251 days (range 36–842). The CR for secondary AML was 18%, for de novo AML 38%, and for MDS 67%. None of the patients developed mucositis or alopecia, and no patient had greater than grade I nausea and vomiting. The most common adverse effects were neutropenic fever (68%), atrial fibrillation (7%) and congestive heart failure (5%). Five patients died of treatment related toxicity (sepsis). The median survival for all patients was 150 days, for patients achieving CR was 290 days, and the 1 year survival rate was 24%. Conclusions: GM-CSF priming can enhance the cytoreductive effects of low doses of cytarabine. This combination therapy is well tolerated, and should be explored as an alternative regimen for high risk and elderly AML and advanced MDS patients. No significant financial relationships to disclose.