Non-neutropenic Fever Research Articles

Phase I Trial of the Combination of Lenalidomide, Thalidomide and Dexamethasone In Relapsed/Refractory Multiple Myeloma

AbstractAbstract 1948 Background:The combination of lenalidomide (Len) and dexamethasone(D) have demonstrated overall response rates (ORR) of 60% in relapsed/refractory multiple myeloma (RRMM). The three drug combination of Len/Thalidomide/D has not previously been evaluated in RRMM. The ORR with LenD with prior Thalidomide(Thal) is 40–50%, while the ORR with ThalD after prior Len is < 20%. Preclinical studies have demonstrated Len resistance is mediated via the wnt-β-catenin pathway which is modulated by Thal. The minimal overlapping side effect profile and differing mechanism of action of Len and Thal and preclinical data provided the rationale for the combination of Len/Thal/D in an attempt to improve RR and overcome lenalidomide resistance. The aim of this study was to determine the tolerability, maximum tolerated dose (MTD) and evaluate preliminary activity. Methods:Patients(pts) with relapsed/refractory myeloma with ≥ 1 line of therapy were eligible with adequate hematology, cardiac, pulmonary, and renal function. Patient were eligible regardless of prior Imid exposure or Imid refractory disease, enrolled in 3 dose cohorts(C), C1: Len 15 mg/Thal 100 mg/Dex, C2:Len 25 mg/Thal 100 mg/Dex, and C3: Len 25 mg/Thal 200/Dex. Dexamethasone was dosed in pulse dose fashion cycles 1–2 and reduced to weekly Dex in cycles 3 and beyond. Pts were treated until disease progression or toxicity. All patients received anticoagulation with warfarin or low molecular weight heparin. Results:18 patients with median 3 prior lines of therapy (range: 1–6) were enrolled, age 67 (range: 52–81), male/female: 13/5; 3 in cohort 1, 6 in cohort 2 and 9 in cohort 3. There were no dose limiting toxicity (DLT) in cohort 1 (0/3), 1/6 DLT in cohort 2 and 2/8 DLT in cohort 3 (1 pt was unevaluable for DLT due to disease progression within cycle 1 and removed prior to completing cycle 1). The DLT in cohort 2 was due to steroid induced toxicity, requiring reduction in dex dosing in cycle 1. The DLT in cohort 3 included one patient with G3 rash due to thalidomide and asymptomatic G2 atrial fibrillation (a. fib) and a second patient with G3 hypertensive crisis and volume overload due to dexamethasone. Other toxicity included a patient with new onset symptomatic a fib in Cohort 3 (during cycle 2, therefore not a DLT) with concurrent newly diagnosed cardiac amyloidosis, and non-neutropenic fever and pneumonia in patient in Cohort 2. Among the 8 patients in C3 who received > 1 cycle, 5 required dose reduction of Thal to 100 mg. No DVT/PE were observed with use of anticoagulation. No G3/4 peripheral neuropathy has been observed.13 patients were evaluable for efficacy (6 unevaluable: 1 withdrew consent after cycle 1, 4 patients in cycle 2 currently and responses not repeated/confirmed). Among the 13 evaluable patients the ORR (> PR) was 92%, 2 nCr, 3 VGPR, 7 PR and 1 with PD in cycle1. Among the 13 evaluable, 6/13 patients had prior thal, 10/13 autologous stem cell transplant, 9/13 prior Len and 8 patients were lenalidomide refractory. Among the 8 patients with Len refractory disease (4 had prior thal), the ORR was 88%, with 1 VGPR, 6 PR, and 1 PD in cycle 1. 4 pts, all with Len refractory disease, have discontinued therapy due to progressive disease after cycle 1, 4, 4, 6 (after initial PR to therapy), the other 4 remain on trial on cycle 3, 5, 7 and 9. Conclusions:The maximum recommended dose is lenalidomide 25 mg/thalidomide 100 mg/dex due to the DLT observed and need for dose reductions in thalidomide. The combination is well tolerated with only 1 pt discontinued therapy due to toxicity (a fib) and 4 pts discontinued secondary to PD. The very high ORR of 92% was much higher than seen with two drug regimen of Len/Dex. The preserved superior activity in lenalidomide refractory disease, supports the modulation of lenalidomide resistance with thalidomide, however a phase 2 trial is open and additional pts at cohort 2 will be enrolled to further evaluate the activity of this combination. Disclosures:Shah:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millenium: Research Funding; Novartis: Research Funding. Orlowski:Celgene: Consultancy, Research Funding; Millennium Pharmaceuticals, Inc.: Consultancy, Research Funding. Wang:Celgene: Research Funding; Onyx: Research Funding; Millenium: Research Funding; Novartis: Research Funding. Weber:novartis-unpaid consultant: Consultancy; Merck- unpaid consultant: Consultancy; celgene- none for at least 2 years: Honoraria; millenium-none for 2 years: Honoraria; celgene, Millenium, Merck: Research Funding.

Definitive concurrent chemoradiation (CRT) with weekly paclitaxel and carboplatin for patients (pts) with irresectable esophageal cancer: A phase II study.

e14508 Background: This multicenter phase II study investigated the efficacy and feasibility of a non-cisplatin based definitive CRT regimen consisting of carboplatin and paclitaxel and concurrent radiotherapy for pts with irresectable esophageal carcinoma. Methods: Patients with locally irresectable (T4N0-1M0) carcinoma of the esophagus received CRT consisting of RT (50.4 Gy in 28 fractions, 5 days/week) and concurrent paclitaxel 50 mg/m2 and carboplatin AUC = 2 on days 1, 8, 15, 22, 29 and 35. Results: From December 2003 to November 2007 52 patients: male/female 34/18, median age 63 (42-76), squamous/adeno/undifferentiated carcinoma 36/14/2, lymph node involvement yes/no 44/8 were enrolled. Forty-two pts completed CRT without delay or dose-reduction, 6 pts received less than 6 courses chemotherapy but completed radiotherapy, and 4 pts received less than 46 Gy radiotherapy and less than 6 courses of chemotherapy. Major toxicities (grade ≥ 3): neutropenia 16%, thrombocytopenia 4%, esophagitis 12%, fatigue 8%, pulmonary 2% and 2 pts died because of a fatal bleeding. Five pts needed to be hospitalized during CRT for bleeding (2 pts), pneumonia (2 pts), or esophagitis and non-neutropenic fever (1 pt). During CRT dysphagia improved in 23 pts and worsened in 7 pts. Five pts underwent surgery after CRT, 2 pts showed complete pathological response. The median overall survival was 17 months (1-49+). One-, two- and three-year overall survival was 64%, 32%, and 16%, respectively. The median disease-free survival was 9 months (8 pts local recurrence, 9 pts distant metastases, 13 pts both). The median time to local progression was 14 months. Conclusions: Radiotherapy with concurrent weekly paclitaxel and carboplatin as definitive treatment for irresectable esophageal carcinoma is a tolerable regimen, which can be given on an outpatient basis and leads to durable locoregional control and palliation in about half of the patients. No significant financial relationships to disclose.

NCCAM/NCI phase I study of mistletoe extract and gemcitabine in patients with advanced solid tumors.

2559 Background: European mistletoe (viscum album L.) extracts (EMEX) are used for cancer treatment in Europe. Clinical efficacy remains controversial. Controlled safety and toxicity data are lacking. Objectives of this novel phase I dose-escalation study of an EMEX/gemcitabine (GEM) combination were 1) safety, toxicity, and MTD in patients with advanced solid cancers (ASC), 2) neutrophil count recovery, 3) formation of mistletoe lectin antibodies (ML ab), 4) plasma concentrations of IL-6, IL-12, IFNg, and TNF-a, 5) clinical response. Methods: ASC patients (n=44, breast 12, pancreas 10, colorectal 17, NSCLC 5, f:m=21:23, average age 55 years) received escalating doses of EMEX (HELIXOR A, Helixor GmbH, Rosenfeld, Germany) during stage 1 (20-250 mg s.c. daily) and increasing doses of GEM during stage 2 (750 - 1680 mg/m2 over 30 minutes i.v. on day 1 and 8, 3-week cycle) for 3 cycles. GEM plasma concentrations (Cp, baseline and week 8 (stable EMEX dose for 7 days) were determined during stage 1 by HPLC with UV detection. Plasma cytokine and MLab concentrations were measured by ELISA. Results: Five dose-limiting toxicities were observed: grade 4 neutropenia (2), grade 4 thrombocytopenia, grade 3 cellulitis, and grade 4 acute renal failure. GEM 1380 mg/m2 and EMEX 250 mg were the MTD. Of 44 patients 24 developed Non-neutropenic fever and flu-like syndrome. GEM pharmacokinetics were unaffected by EMEX. All patients developed ML3 IgG antibodies. Plasma cytokine concentrations were minimally affected. ANC values showed a trend to increase between baseline and C2 in stage I. Partial response and stable disease were found in 6% and 42% of patients, respectively. All partial responses occurred in patients with pancreatic cancer. Median survival was 190 days. Compliance with EMEX injections varied from 78.6-100%. Conclusions: The EMEX/GEM combination demonstrated limited toxicity, no alterations of GEM Cp during infusion of EMEX, clinical benefit in 48% of patients, good tolerability and excellent EMEX compliance. Addition of EMEX may allow for use of higher doses of GEM and increase the ANC nadir. No effects on the measured cytokines were observed. The long-term utility, safety, and tolerability of EMEX plus GEM warrant further study. No significant financial relationships to disclose.

Efficacy of Nilotinib in Patients (Pts) with Newly Diagnosed, Previously Untreated Philadelphia Chromosome (Ph)-Positive Chronic Myelogenous Leukemia in Early Chronic Phase (CML-CP).

Abstract 341▪▪This icon denotes an abstract that is clinically relevant. Background:Nilotinib, an oral tyrosine kinase inhibitor with increased selectivity against Bcr-Abl and approximately 30-fold more potent than imatinib, is effective in CML after imatinib failure. We initiated a phase II study to evaluate the efficacy of nilotinib as 1st line therapy in pts with newly diagnosed CML-CP. Aims:To investigate the efficacy and safety of nilotinib as first-line therapy for pts with CML-CP. Methods:The primary objective was to estimate the proportion of pts attaining major molecular response (MMR) at 12 months (mo). Pts with untreated CML-CP within 6 mo from diagnosis were eligible and received nilotinib 400 mg twice daily. A cohort of patients with previously untreated CML in accelerated phase (AP) was also included. Results:Sixty-five pts (61 CP, 4 AP) have been treated for a median of 17 mo (range 1 to 43). The median age was 46 years (range 19 to 86). Among 48 pts who were not in CHR at the start, 47 (98%) achieved CHR (one discontinued after 2 weeks without adverse events). Among 51 pts followed for at least 3 mo, 50 (98%) achieved a complete cytogenetic response (CCyR). MMR has been achieved in 32 (63%) pts, including 12 (24%) with a complete molecular response. The rate of CCyR at different time points (intention-to-treat) for pts in CP compares favorably to that observed in historical controls treated with imatinib 400 mg or 800 mg daily:Months on therapyPercent with CCyRNilotinibImatinib 400mgImatinib 800mg3903763696548512976589189367892493678830926789MMR was achieved by 55% at 12 mo and 53% at 24 mo (corresponding rates with imatinib 400 mg 34 and 55%, and with imatinib 800 mg 58% and 66%, respectively). Grade 3-4 hematologic toxicity (transient) included thrombocytopenia 11%, neutropenia 12%, and anemia 5%. Grade 3-4 non-hematologic adverse events (regardless of causality) included elevation of bilirubin in 8% and lipase in 6%, and non-neutropenic fever in 6%. 24 (37%) pts had transient treatment interruptions and 11 (17%) had dose reductions. The actual median dose is 800 mg daily. Ten pts have discontinued therapy: 4 pts for toxicity, 2 because of transformation to accelerated or blast phase, and 4 for other reasons. 24 mo EFS (event = loss of CHR, loss of MCyR, AP/BP, death, or off because of toxicity) is 90%. All patients are alive. Among pts in AP, 3 achieved CCyR (all of them sustained); one patient progressed to blast phase and died. Conclusion:Nilotinib 400 mg twice daily induces a CCyR in nearly all patients as early as 3 mo after the start of therapy and MMR in more than 50% at 12 months with a favorable toxicity profile. Disclosures:Cortes:BMS: Research Funding; Novartis: Research Funding; Wyeth: Research Funding. Off Label Use: Presentation will include use of nilotinib as initial therapy for CML, and indication for which nilotinib is not approved.. O'Brien:Novartis: Research Funding. Jones:Novartis: Research Funding, Speakers Bureau. Jabbour:Novartis: Speakers Bureau; BMS: Speakers Bureau. Borthakur:Novartis: Speakers Bureau. Kantarjian:Novartis: Research Funding; MGI Pharma (Eisai): Research Funding; Genzyme: Research Funding; BMS: Research Funding.

A Phase I/II Study of Lenalidomide in Combination with Rituximab in Relapsed/Refractory Mantle Cell Lymphoma.

Abstract 2719Poster Board II-695 Background:Rituximab directly targets CD20 positive lymphoma cells while lenalidomide targets the microenvironment. This combination was proven effective in vitro and in vivo in mantle cell lymphoma (Wu et al, Clin Cancer Res 2008; Zhang et al, Am J Hematol 2009). Clinically, lenalidomide (Habermann et al, Br J Haematol 2009) and rituximab have single-agent activity in mantle cell lymphoma (MCL) and may be an effective combination. The goal of our study was to determine the maximum tolerated dose (MTD) in phase 1 and evaluate the efficacy and safety of lenalidomide plus rituximab in patients with relapsed/refractory MCL in phase 2. Methods:Patients with relapsed/refractory MCL received lenalidomide on days 1–21 of every 28-day cycle, and rituximab (375 mg/m2) weekly during cycle 1. Dose escalation was used to determine the MTD with lenalidomide (10 mg, 15 mg, 20 mg, and 25 mg). Dose-limiting toxicity (DLT) was defined as grade 3 or 4 non-hematologic, or grade 4 hematologic adverse events in cycle 1. Phase 2 has reached targeted enrolment with 45 patients treated at MTD. Kaplan-Meier method was used to estimate progression free survival rate and response duration. Median time to event in months with 95% confidence interval was calculated. Of 45 patients treated at the MTD, the median age was 66 (46–85), 91% were males. All patients had received prior rituximab and were enrolled regardless of prior rituximab sensitivity or resistance. Results:The median follow-up time for the censored observations was 11.4 months. Two DLTs occurred at 25 mg in phase 1 (hypercalcemia, non-neutropenic fever); therefore, the MTD was 20 mg. The grade 3–4 non-hematologic events included elevated AST, elevated ALT, fatigue, myalgia, tremors, ataxia, cough, deep vein thrombosis, dyspnea, edema (facial), infection, neuropathy sensory, rash, and respiratory failure. Grade 3–4 hematologic adverse events included neutropenia (37 events), neutropenic fever (4 events), and thrombocytopenia (16 events). There were no responses in patients treated at 10 mg or 15 mg. Thirty six patients (36) were evaluable for response. Nine (9) patients are too early in their treatment and are not yet eligible for response evaluation. Among the 36 evaluable patients, 11 (31%) patients achieved CR, 8 (22%) patients achieved PR, 3 (8%) patients had minor response, 6 (17%) patients had stable disease and 8 (22%) patients had progressive mantle cell lymphoma. The overall response rate (CR + PR) was 53%. Seventy eight (78%) patients achieved stable disease or better and benefited from oral Lenalidomide plus 4 doses of rituximab. The median time to response was 2 months (2–8), and the median duration of response for the 19 patients with CR or PR was 18 months (95% CI: 10.6, NA) (range1–30 months). The median progression free survival for all patients on phase 2 was 14 months (95% CI: 9.8, NA) (ranging from 1–32 months). Conclusion:Oral lenalidomide plus rituximab resulted in durable responses in relapsed/refractory MCL with a favourable toxicity profile. Disclosures:Wang:Celgene: Honoraria, Research Funding. Hagemeister:Celgene Corporation: Consultancy. Samaniego:Celgene Corporation: Research Funding. Yi:Celgene Corporation: Research Funding. Shah:Celgene Corporation: Consultancy, Research Funding, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Elan: Consultancy; Millennium: Research Funding, Speakers Bureau. Bell:Celgene Corporation: Employment, Equity Ownership. Knight:Celgene Corporation: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Zeldis:Celgene: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

Phase I Trial of Weekly Topotecan and Gemcitabine in Patients With Solid Tumors

This phase I trial was designed to determine the maximal tolerated dose (MTD) of the combination of topotecan and gemcitabine given in a weekly schedule. In this single-arm, open label, dose-escalation study, we administered topotecan (0.75-1.5 mg/m) and gemcitabine (1000 mg/m) on days 1, 8, and 15 every 4 weeks to 25 patients with advanced solid tumors. The topotecan MTD, when combined with gemcitabine, was 1.25 mg/m/wk. Dose-limiting toxicities consisted of febrile granulocytopenia in 2 patients at the highest dose level. At the MTD, no episodes of granulocytopenia were observed, whereas 2/9 patients exhibited grade 3 thrombocytopenia. Other common grades 3-4 adverse events across all cohorts included non-neutropenic infections, fatigue, skin reactions, vomiting, and fever. One partial response and 2 stable diseases were observed in patients with nasopharyngeal carcinoma. Disease stabilization was also observed in patients with squamous cell carcinoma of the head and neck (3), nonsmall cell lung cancer (1), and thymoma (1). Topotecan and gemcitabine combined in a weekly schedule exhibit a favorable toxicity profile. Efficacy results support the further evaluation of this regimen in patients with head and neck cancer (particularly nasopharyngeal carcinoma).

Lenalidomide and Rituximab Are a Promising Combination in Vitro, in Vivo Preclinically and in a Phase I/II Clinical Trial in Relapsed/Refractory Mantle Cell Lymphoma

Relapsed/refractory mantle cell lymphoma (MCL) is difficult to treat. Rituximab (R) targets CD20 antigen on the surface of MCL cells while lenalidomide (Len) may target the microenvironment of MCL cells and enhance the antibody-dependent cellular cytotoxicity (ADCC) activity of R. To test this hypothesis, we initiated preclinical studies and a phase I/II clinical trial. In the preclinical study we found that Len and R induced growth inhibition and apoptosis of both cultured and fresh primary MCL cells. Len enhanced R-induced apoptosis via upregulating phosphorylation of c-Jun N-terminal protein kinases (JNK), Bcl-2, Bad; increasing release of cytochrome-c; enhancing activation of caspase-3, -8, -9 and cleavage of PARP. Daily treatment with Len increased NK cells by 10 times in SCID mice. The combination of Len and R decreased tumor burden and prolonged survival of MCL-bearing SCID mice. In the phase I/II clinical trial, Eligible patients (pts) with MCL had 1–4 lines of prior therapies. Treatment consisted of Len given orally daily on days 1–21 of a 28-day cycle and R 375 mg/m2 by IV infusion weekly for 4 weeks only during the first cycle with the first dose on Day 1 in Cycle 1. A standard 3+3 dose escalation was used to determine MTD with Len doses at 10 mg, 15 mg, 20 mg, and 25 mg. Detailed toxicity profile in phase I was reported previously (Wang et al, ASH 2007). Two DLT s occurred at 25 mg including 1 grade 3 hypercalcemia and 1 grade 4 non-neutropenic fever during the first cycle. Six patients from phase 1 were at 20 mg dosage level. One patient from phase 1 was initially at 25 mg dosage level and was subsequently reduced to 20 mg dosage level due to DLT. Eight patients have been enrolled in the phase II trial at MTD. In the 14 patients evaluated at 20 mg dosage level in phase II, median age was 68 (51–77); median prior therapies were 2 (1–4); median cycles received to date were 4 (range 2–26). Grade 3/4 hematologic toxic events included neutropenia (35), febrile neutropenia (2), and thrombocytopenia (11). There was no grade 3–4 anemia. Grade 3 non-hematologic toxic events included fatigue (2) and myalgia (1). Fourteen pts at MTD (20 mg) including 7 in phase I plus 7 in phase II were evaluable for response. Eight out of 14 pts achieved responses including 4 CRs, 4 PR s, 2 SD and 4 PD s.Conclusions: Lenalidomide in combination with rituximab provided a synergistically therapeutic effect on mantle cell lymphoma cells by enhancement of apoptosis and R-dependent NK cell-mediated cytotoxicity preclinically. Lenalidomide plus rituximab showed early evidence of response with a very favorable toxicity profile in a phase I/II clinical trial. Updated information will be presented at the conference.

Phase II study of intraperitoneal recombinant interleukin-12 (rhIL-12) in patients with peritoneal carcinomatosis (residual disease &lt; 1 cm) associated with ovarian cancer or primary peritoneal carcinoma

BackgroundPharmacokinetic advantages of intraperitoneal (IP) rhIL-12, tumor response to IP delivery of other cytokines as well as its potential anti-angiogenic effect provided the rationale for further evaluation of IPrhIL-12 in patients with persistent ovarian or peritoneal carcinoma.MethodsA phase 2 multi-institutional trial (NCI Study #2251) of IP rIL-12 (300 nanogram/Kg weekly) was conducted in patients with ovarian carcinoma or primary peritoneal carcinoma.Patients treated with primary therapy for ovarian cancer who had no extraabdominal/parenchymal disease or bulky peritoneal disease were eligible. Four to 8 weeks from last chemotherapy, eligible patients underwent a laparotomy/laparoscopy. Patients with residual disease ≤ 1 cm were registered for the treatment phase 2–5 weeks post surgery. The effect of IP rIL-12 on the expression of TNFα , INFα , IL-10, IP-10, IL-8, FGF, VEGF was also studied.ResultsThirty-four patients were registered for the first screening phase of the study. Median age was 56.6 years (range: 31–71); 12 completed the second phase and were evaluable for response/toxicity. Performance scores of IL-12 treated patients were 0 (11 pts) and 1 (1 pt). There were no treatment related deaths, peritonitis or significant catheter related complications. Toxicities included grade 4 neutropenia (1), grade 3 fatigue (4), headache (2), myalgia (2), non-neutropenic fever (1), drug fever (1), back pain (1), and dizziness (1). The best response observed was SD. Two patients had SD and 9 had PD, and 1 was evaluable for toxicity only.Peritoneal fluid cytokine measurements demonstrated a ≥ 3 fold relative increase post-rhIL-12: IFN-γ, 5/5 pts; TNF-α , 1/5; IL-10, 4/5; IL-8, 5/5; and VEGF, 3/5. IP10 levels were increased in 5/5 patients. Cytokine response profiles suggest either NK or T-cell mediated effects of IP rhIL-12. Cytokine/chemokine results also suggest a pleiotropic response since proteins with potential for either anti-tumor (IFN-γ , IP-10) or pro-tumor growth effects (VEGF, IL-8) were detected.ConclusionIP IL-12 can safely be administered at this dose and schedule to patients after first line chemotherapy for ovarian/peritoneal carcinoma. The maximum response was stable disease. Future IP therapies with rhIL-12 will require better understanding and control of pleiotropic effects of IL-12.

Lenalidomide (Len) in Combination with Rituximab (R) Demonstrated Early Evidence of Efficacy in a Phase I/II Study in Relapsed/Refractory Mantle Cell Lymphoma (MCL).

Background: Relapsed/refractory MCL is difficult to treat. R targets CD20 antigen on the surface of MCL cells while Len may target the microenvironment of MCL cells and enhance the ADCC activity of R. To test this hypothesis, we initiated a single-center, phase I/II study. We now report the data from the completed phase I trial and the ongoing phase II trial.Methods: Eighteen eligible patients (pts) with MCL had 1–4 lines of prior therapies. None had prior thalidomide and all received R. Treatment consisted of Len given orally daily on days 1–21 of a 28-day cycle and R 375 mg/m2 by IV infusion weekly for 4 weeks only during the first cycle with the first dose on Day 1 in Cycle 1. A standard 3+3 dose escalation was used to determine MTD with Len doses at 10 mg, 15 mg, 20 mg, and 25 mg. DLT was defined as grade (G) 3 or 4 non-hematologic or G4 hematologic toxicity during the first cycle. Phase I has been completed with 15 pts. Phase II is ongoing with 3 pts enrolled at MTD. Total 80 cycles of therapy were given to 18 pts. In addition to the regular radiology evaluation, a separate radiology evaluation was performed independently. EGD and colonoscopy with random biopsies were performed to confirm all CRs.Results: In the phase I study, median age was 73 (62–84); median prior therapies were 3 (1–4); median cycles received to date (August 18, 2007) were 4 (range 1–14). Two DLT's occurred at 25 mg. One G3 hypercalcemia and 1 G 4 non-neutropenic fever during the first cycle. After total 80 cycles of therapy in 18 patients, except for the 2 DLT's, common non-hematologic toxic events included fatigue (23 G1-2), pruritis (18 G1-2), myalgias (5 G1-2, 1 G3) and rash (5 G1-2). There was no DVT/PE. Grade 3 hematologic toxic events included neutropenia (11), febrile neutropenia (2), and thrombocytopenia (2). The only grade 4 hematologic toxic events were neutropenia (5). There was no grade 3–4 anemia. There were no responses at 10 mg or 15 mg. Ten pts at MTD (20 mg) including 7 in phase I plus 3 in phase II were evaluable for response. Seven out of 10 pts achieved responses including 3 CRs (30%), 4 PR's (40%), 1 SD and 2 PD's. Therefore, the overall response rate was 70%. Media time to response was 2 cycles (range 2–4).Conclusions: The MTD for Len with R in relapsed/refractory MCL was 20 mg, orally daily on days 1–21 of a 28-day cycle. Early evidence of response is promising with a very favorable toxicity profile at 20 mg and is being further evaluated in the ongoing phase II trial.

A Single-Center Study To Evaluate the Safety and Efficacy of Intravenous/Oral Fludarabine in Untreated Gastric MALT Lymphoma. Impact of t(11;18)(q21;q21) in Molecular Response Rates.

Background: The treatment of gastric mucosa-associated lymphoid tissue (MALT) lymphoma in the absence of H. pylori infection or when the lymphoma fails to regress after adequate antibiotic treatment remains controversial. Fludarabine (F) is an active agent for indolent lymphoma, however, its clinical activity in gastric MALT lymphoma has not been studied. The aim of the study is to assess the efficacy and safety of single-agent fludarabine in gastric MALT lymphoma and to analyze the molecular response (MR) after this treatment.Methods: Treatment consisted of fludarabine (25 mg/m2 IV) given on days 1–5, every 4 weeks, for 6 cycles; after the first cycle, oral fludarabine was allowed to be given orally at 40 mg/m2 with the same schedule. Molecular response (MR) was assessed by RT-PCR analysis of t(11;18) or by PCR assays for analysis of IgH gene rearrangements analyzing FR1, FR2 and FR3 in endoscopic biopsies.Results: Eight consecutive patients were included. Median age: 60 years (range: 45–77); 3 pts were in stage I, 2 stage II-1 and 3 stage IV according to Lugano system. Four out of 5 (80%) pts achieved a CR after three cycles and all eight cases (100%) achieved a CR after six cycles, for an overall response rate of 100%. After a median follow-up of 44 months (range 14.5–58 mo) no patient has shown clinical or endoscopic relapse. Hematological toxicity occurred in 75% of pts, mainly mild neutropenia and generally after the third cycle. Three cases received G-CSF (after the 2nd, 3rd and 6th cycle) and three patients required dose modification or delay (3–7 days) in the delivery of the following cycle. No blood transfusions were required. Only one patient had to be admitted because of non-neutropenic fever. None case of myelodisplasia has been detected at last follow-up. Four out of 8 pts (50%) achieved MR during the study-period (see figure). Four out of 5 (80%) pts without t(11;18) achieved MR. In contrast, no patient carrying t(11;18) achieved MR. Sequencing analysis of monoclonal PCR products will be presented.Conclusions: Fludarabine, either intravenous or oral, is safe and achieve a high response rate when given in gastric MALT lymphoma, with many pts achieving MR. In those pts carrying t(11;18), residual disease can be detected by PCR but do not determine relapse at present follow-up. [Display omitted]

Systematic Review of Piperacillin-Induced Neutropenia

Because penicillin agents are implicated in granulopoiesis inhibition, healthcare professionals frequently consider discontinuation of such therapy in patients with decreasing white blood cell counts. No systematic review to date has described piperacillin and the patient population at risk for this adverse drug reaction (ADR). This review sought to assess the occurrence of piperacillin-induced neutropenia, describe characteristics of affected patients and assess the reporting modalities that most accurately classify this ADR. Case reports, cohort studies and clinical trials identified by comprehensive searches of PubMed and the US FDA Adverse Event Reporting System (AERS) database were reviewed for patient demographics, duration and dose of piperacillin or piperacillin-tazobactam treatment and the occurrence of neutropenia. Causality assessments were performed. Six published case reports, three cohort studies, 178 clinical trials and two compilations of phase I-III trials were reviewed. Review of case reports was notable in that the duration of beta-lactam therapy prior to the noting of leukopenia always exceeded 15 days. No deaths were recorded in this group. Among 13,816 patients enrolled in non-neutropenic fever studies, the occurrence of piperacillin-induced neutropenia was rare: five patients (0.04%) developed neutropenia; none died. The demographics for this group were poorly documented. Through the AERS database, we identified 366 unique cases of piperacillin or piperacillin-tazobactam-induced haematological abnormalities, including neutropenia (n = 183, 50.0%), leukopenia, (n = 99, 27%), agranulocytosis (n = 58, 15.8%) and others. In 62 cases, patients received between 1 and 14 days of therapy (mean 7.7 + 4.1 days). Overall, there were 82 (22.4%) deaths. Reports of haematological ADRs among patients receiving piperacillin or piperacillin-tazobactam are rare. Report of neutropenia associated with piperacillin usage prior to 15 days of therapy is a novel finding that requires further evaluation. Current reporting methods poorly characterise patient groups at risk.

Phase II Study of Yttrium 90 (90Y) Ibritumomab Tiuxetan (Zevalin®) in Patients with Relapsed and Refractory Mantle Cell Lymphoma (MCL).

Background: Mantle cell lymphoma (MCL) has poor clinical outcome and is a significant therapeutic challenge in patients with relapsed or refractory disease due to its resistance to salvage chemotherapy. Although recent studies have shown the clinical utility of radioimmunotherapy (RIT) in relapsed and transformed indolent B-cell lymphoma, the clinical efficacy of this treatment modality in patients with MCL is not well described. We report the results of a completed phase II clinical trial of yttrium 90 ibritumomab tiuxetan (Zevalin) in patients with relapsed and refractory MCL.Patients and Methods: Patients with relapsed or refractory MCL with measurable disease, age ≥18 years, and performance status <3 were eligible. Patients were required to have adequate function of the bone marrow (ANC ≥1,500/mm3, platelets ≥100,000/mm3), liver, and kidneys. Patients were excluded if they had prior stem cell transplantation, RIT, CNS lymphoma, HIV infection, pleural effusion, HAMA reactivity, or circulating lymphoma cell count ≥5,000/mm3. Patients with pretreatment platelet counts ≥150,000/mm3 received a dose of Zevalin at 0.4 mCi 90Y/kg (maximum dose 32 mCi), whereas those with platelet counts <150,000/mm3 received 0.3 mCi 90Y/kg.Results: Thirty-five patients were enrolled at MDACC. The median age was 68 years (range 52–79), and 27 patients were men. All patients had an ECOG performance status of 0 or 1 and had been previously treated with rituximab with or without other chemotherapy. The median number of prior regimens was 3 (range 1–6). Twelve of the patients did not respond to their last regimen. Twenty-two patients were previously treated with Hyper-CVAD alternating with MTX/Ara-C, and 7 previously received bortezomib. Thirty-one of 35 patients are eligible for evaluation of treatment response and toxicity. There were no grade 3 or 4 non-hematologic toxic events. Grade 1 non-hematologic toxic events included fatigue in 7 and nausea in 3. Grade 2 non-hematologic toxic events included non-neutropenic fever in 1 and melana in 1. Grade 3 or 4 hematologic toxic events included thrombocytopenia in 8, neutropenia in 2 and anemia in 1. Objective responses were observed in 13/31 patients for an overall response rate (ORR) of 42% including 8 CR/CRu's (26%) and 5 PR's (16%). Three patients had stable disease. Among the 4 patients who received a Zevalin dose of 0.3 mCi 90Y/kg, 1 achieved a CRu while the 3 others had progressive disease. Eight of the 13 responding patients were previously treated with 3 or more regimens; two patients achieved CR after having received 4 prior lines of therapy. Median progression free survival for the responded patients was 6 months after a median follow up time of 16 months.Conclusion: Zevalin treatment was generally well tolerated; with the most common toxicity being hematological. The observed responses to Zevalin in heavily pretreated patients with MCL are promising and warrant further investigation of its activity after first or second relapse, and in conjunction with front-line therapy.

A phase II trial of oxaliplatin plus capecitabine (xelox) as second line therapy for patients with advanced pancreatic cancer

4119 Background: There is no established chemotherapy for patients with pancreatic cancer who have progressed on gemcitabine. This trial was designed to explore the efficacy of xelox as second line therapy in patients with pancreatic cancer. Methods: The primary objective was to determine overall survival at 6 months. It was estimated that 40 patients would be needed to detect 50% 6-month survival with 90% credible interval between 37%-62%. Eligibity criteria included biopsy-confirmed diagnosis of adenocarcinoma of the pancreas, one prior systemic chemotherapy, ECOG performance status (PS) 0–2, and adequate hepatic, renal, and bone marrow functions. Oxaliplatin was administered at 130 mg/m2 and capecitabine at 1000 mg/m2 twice daily for 14 days for patients who were younger than 65 and had ECOG PS score 0–1. For patients older than 65 or PS 2, the oxaliplatin dose was decreased to 110 mg/m2 and capecitabine to 750 mg/m2/twice daily. The treatment was repeated every 3 weeks. Tumor measurements were performed every 9 weeks (3 cycles) in patients who had measurable disease by RECIST criteria, although measurable disease was not required. Results: A total of 41 patients were enrolled into the study, 2 were never treated. Among 39 evaluable patients, 17 were female, median age 62 years (45–75), and 8 had ECOG PS 2. For the 36 patients who have completed therapy, the median number of treatment cycle was 3 (range, 1–6). Grade 3 or 4 toxicities included: abdominal pain (2 patients), dehydration (3), diarrhea (2), fatigue (6), gastrointestinal syndrome (including diarrhea and colitis) (4), hand-foot syndrome (1), hematemesis (1), mastitis (1), myocardial infarction (1), nausea/vomiting (2), neuropathy (1), non-neutropenic fever (1), pneumonia (1). One patient had a partial response and 8 others had stable disease. Median survival duration was 5.8 months (95% confidence interval [CI] 3.2–12.1 months). The six month and 1 year survival rate was 48% (95% CI 33%-70%) and 22% (95% CI 9%-51%), respectively. Conclusions: When used in the second line setting, the xelox has promising activity in pancreatic cancer. [Table: see text]

Prospective evaluation of procalcitonin in adults with non-neutropenic fever after allogeneic hematopoietic stem cell transplantation

The aim of this study was to analyze whether procalcitonin (PCT) is a diagnostic marker of infectious diseases during the non-neutropenic period in patients who have received an allogeneic hematopoietic stem cell transplant (HSCT). We included 65 patients in whom an allogeneic HSCT was performed in a 2-year period (April 2002-July 2004). PCT levels were monitored in every febrile episode by an immunoluminometric assay. Febrile episodes were classified according to the final diagnosis in: fever of unknown origin, microbiologically or clinically documented infection and non-infectious fever. Fifty-two febrile episodes in the non-neutropenic period were included in the study. Out of these 52, 26 had an infectious etiology: 11 fulfilled criteria for probable or proven invasive aspergillosis (IA), three were classified as possible invasive fungal infection (IFI) and 12 episodes were caused by other infections. Mean values of PCT on the first day of admission were: 8.0 (+/- 4.9) in probable-proven IA (P = 0.013, Kruskall-Wallis), 4.5 (+/- 3.4) in possible IFI and 1.5 (+/- 0.9) in infections other than IFI. Therefore, we could conclude that during the non-neutropenic phases of allogeneic HSCT, a high PCT value is associated significantly with IA.

Phase II study of oblimersen sodium and rituximab in patients with recurrent B-cell non-Hodgkin’s lymphoma

6611 Background: Oblimersen sodium (Genasense;GNS) is an 18-mer oligonucleotide that targets the mRNA of Bcl-2, a protein that inhibits apoptosis and confers treatment resistance. GNS has shown marked activity in xenograft models of non-Hodgkin’s lymphoma (NHL) and enhances the antitumor activity of rituximab (RIT). We are conducting a phase II study to determine the efficacy and toxicity of GNS + RIT in patients (pts) with recurrent B-cell NHL. Methods: GNS (3mg/kg/d) was administered as continuous IV infusion for seven days in weeks 1,3, and 5 (d1–7,15–21,29–35). RIT (375 mg/m2) was given weekly for 6 doses (d3,8,15,22,29,36). Patients whose disease did not progress were allowed to receive one additional cycle. Prior exposure to rituximab was permitted. Results: To date 29 have been enrolled. Thirteen pts had follicular lymphoma (FL), 5 large cell lymphoma (LCL), 5 small lymphocytic lymphoma (SLL), 3 mantle cell lymphoma (MCL), 2 mucosa-associated lymphoid tissue (MALT) lymphoma, and one B-cell lymphoma not further classified (NOS). Median number of prior treatments was 2 (range 1–3). Twenty-one pts are evaluable for response and toxicity. Eight pts (38%) responded to the combination therapy, 2 pts achieved a CR (1 MALT, 1 FL), 1 pt achieved an unconfirmed CR (FL), 5 pts achieved a PR (1 MCL, 2 FLCL, 1 SLL, 1FL). Two of the responses (1 CR,1 PR) were observed in rituximab-refractory pts. Common grade 3–4 toxicities included: reversible neutropenia in 7 pts (33%), thrombocytopenia in 2 pts (9%), non-neutropenic fever in 4 pts (19%). Conclusions: GNS can be safely combined with RIT and appears to be an active combination in recurrent B-cell lymphomas. Patients accrual is ongoing. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech Genentech

Phase I study of topotecan continuous infusion and weekly cisplatin with radiation therapy for locally advanced/recurrent cervical cancer

5129 Background: Topotecan is a topoisomerase -1 inhibitor with radiosensitizing effects. The combination of topotecan with cisplatin has shown clinical activity against cervical cancer. Methods: Patients with stages IB2- IVA or recurrent cervical cancer who had not received prior radiation or chemotherapy were eligible. Topotecan was administered as a continuous I.V. infusion for 5 days each week through a central venous catheter. Dose levels evaluated were 0.05 (n= 7), 0.1 (n=7) and 0.15 (n= 5) mg/m2 / day. Cisplatin was administered I.V. weekly at 20 mg/m2. Conventional doses of pelvic and para-aortic radiation were administered. Results: Ninety seven, 92 and 96% of all cycles for each dose level were administered on schedule. Onlythree patients did not complete the full treatment course: one due to noncompliance and two due to grade 4 thromboembolic complications (one patient in dose level 1 with a septic superior vena cava thrombus leading to death and another in dose level 3 with a pulmonary embolus). The most common hematologic toxicity was grade 3 lymphopenia (n=9). Only one patient experienced grade 3 neutropenia. Of 3 delayed weekly cycles, none were due to hematologic toxicity. Other main toxicities included: grade 3 leukopenia (n=6), grade 3 coagulation (n=1), grade 3 fatigue (n=2), grade 3 G.I. (n=3), lymphocysts (n=2), non-neutropenic fever (n=2). Six patients required blood transfusion during therapy. Only 3 patients required r-erythropoetin. Only one patient had persistent disease diagnosed within the six months following completion of treatment while the rest had complete responses. Conclusions: The administration of 0.15 mg/m2/day topotecan as a continuous infusion in conjunction with cisplatin and radiation is reasonably well tolerated and appears clinically active in advanced cervical cancer. Thromboembolic complications, frequent in cervical cancer patients, may lead to alternative delivery methods in future clinical trials. No significant financial relationships to disclose.

Oblimersen sodium (Bcl-2 antisense) plus rituximab in patients with recurrent B-cell non-Hodgkin's lymphoma: Preliminary phase II results

6572 Background: Oblimersen sodium (Genasense;GNS), a phosphorothioate 18-mer antisense oligonucleotide directed against the first 6 codons of Bcl-2 mRNA, enhances the anti-tumor activity of rituximab (RIT) in NHL cell lines and lymphoma xenografts. We are conducting a phase II study to determine the efficacy and toxicity of GNS plus RIT in recurrent B-cell NHL and to evaluate the effects of this combination on the level of Bcl-2 expression, correlating this with clinical and molecular response. Methods: Pts are required to have recurrent B-cell NHL, absolute neutrophil count of ≥ 1000, platelet count of ≥ 75,000, and serum creatinine ≤ 1.8 mg/dL. GNS (3mg/kg/d) is administered as continuous IV infusion for 7 days in weeks 1, 3, and 5 (days1–7, 15–21, 29–35). Rituximab (375mg/m2) is given weekly for 6 doses (days 3,8,15,22,29). Results: Twenty-one pts have been entered to date (median age: 63 y, range 37–82; median no. prior treatments: 2, range 1–3). Eight pts had follicular lymphoma (FL), 6 small lymphocytic lymphoma (SLL), 2 mucosa- associated lymphoid tissue (MALT) lymphoma, 3 mantle cell lymphoma (MCL), and 2 large cell lymphoma (LCL). Fifteen pts are evaluable. The overall response rate is 33%. One pt with MALT achieved a CR (6%), four pts (3 FL, 1 MCL) achieved a PR (26%), one pt (FL) had minimal response (6%), and 7 had stable disease (46%). Two responders had a relapse within 6 months of the prior therapy and one response occurred in a RIT-refractory patient. Common grade 3–4 toxicities included: reversible neutropenia in 7 pts (36%), thrombocytopenia in 2 pts (10%), and non-neutropenic fever in 4 pts (21%), Conclusions: Combined therapy with GNS and RIT is feasible and has clinical activity in both aggressive and indolent recurrent NHL. Accrual is ongoing and additional data is needed to better define the activity of this regimen. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genta Genta Genta

A phase II trial of temozolomide in patients with unresectable or metastatic soft tissue sarcoma

The objective of this study was to assess the efficacy and toxicity of the imidazotetrazine derivative temozolomide for patients with unresectable or metastatic soft tissue sarcoma. Twenty-five of 26 patients were eligible and assessable for toxicity and response. Temozolomide was administered twice daily on a 12-hour schedule for 5 days as an oral bolus dose of 200 mg/m(2) followed by 9 doses of 90 mg/m(2) every 4 weeks. There were 2 partial responses, 2 mixed responses, and 3 patients with stable disease that lasted > 6 months, for an overall objective response rate of 8%. At a median follow-up of 13.2 months, the median progression-free survival and the median overall survival were 2.0 months (95% confidence interval [95% CI], 1.7-2.3) and 13.2 months (95% CI, 4.7-31.1), respectively. All responding patients had leiomyosarcoma of uterine or nonuterine origin; and, in a subset analysis of these patients, the objective response rate was 18% (2 of 11 patients), with disease stabilization occurring in 3 of 11 patients (27%). For this subgroup, at a median follow-up of 24.4 months, the median progression-free survival and the median overall survival were 3.9 months (95% CI, 1.9-21.9) and 30.8 months (lower-bound 95% CI, 7.8), respectively. There were no treatment-related deaths or National Cancer Institute Grade 4 toxicities. Grade 3 toxicities included nausea, anemia, fatigue, elevated alkaline phosphatase levels and nonneutropenic fever (1 patient each). Temozolomide at the dose schedule employed in the current study was tolerated well and had modest activity against previously treated unresectable or metastatic leiomyosarcoma of both uterine and nonuterine origin.

Catheter-related bacteremia caused by the nocardioform actinomycete Gordonia terrae.

Five cases of catheter-related bacteremia caused by Gordonia terrae are reported. All patients who also had the primary diagnosis of cancer experienced nonneutropenic fever as a result of G. terrae infection. All patients were treated successfully with antibiotics, with the requirement of catheter removal for 2 patients who had systemic infections.

Phase II Study of Fludarabine, Cytarabine (Ara-C), Cyclophosphamide, Cisplatin and GM-CSF (FACPGM) in Patients With Richter's Syndrome or Refractory Lymphoproliferative Disorders

A phase II study was conducted to evaluate the safety and efficacy of fludarabine, cytarabine (ara-C), cyclophosphamide, cisplatin and GM-CSF (FACPGM) treatment in patients with Richter's syndrome (RS), refractory prolymphocytic leukemia (PLL) or refractory non-Hodgkin's lymphoma (NHL). Twenty-two patients with RS, refractory PLL, or refractory NHL were entered into this trial between March 1997 and February 2001. Median age was 62 years (42-74); 77% were over 60 years of age. Histologic diagnosis was large cell NHL transformation in 15 patients with CLL, immunoblastic transformation of CLL in one, refractory PLL in three, and refractory NHL in three patients. Treatment consisted of fludarabine 30 mg/m 2 (days 1-3), ara-C 0.5 g/m 2 (days 3-4), cyclophosphamide 250 mg/m 2 (days 2-4), cisplatin 15 mg/m 2 IV CI (days 1-4) with GM-CSF 250 µ g/m 2 from day 5 to recovery of neutrophils and antibiotic prophylaxis. Patients with response were to receive a maximum of six cycles of therapy. Eighteen patients were evaluable for response; one patient achieved a complete remission (5%), 12 stable disease/no response (67%) and five patients had progressive disease (28%). The median survival was 2.2 months (range, 1-19); the median failure-free survival was 1.5 months (range, 0.5-18.6). Grade III/IV toxicities were as follows: anemia in 62% of cycles; leucopoenia in 66%; granulocytopenia in 90%; thrombocytopenia in 83%; hyperbilirubinemia in 14%; hyperuricemia in 17%; hyponatremia in 17%; hypokalemia in 14%; hypophosphatemia in 10%; hypoalbulinemia in 14%; hypocalcemia in 7%; and hypercalcemia in 3%. One (3%) patient developed cardiac failure. Forty-one percent of the cycles were complicated with fever, 34% with non-neutropenic fever, and 55% cycles with infections (fungal 31%; bacterial 57%; HSV 6%; VZV 6%). FACPGM had very limited activity and significant toxicity in a cohort of patients with heavily pretreated refractory lymphoproliferative disorders.