Preliminary Toxicity Data Research Articles

Consolidation Therapy with Subcutaneous (SC) Alemtuzumab After Fludarabine and Rituximab (FR) Induction Therapy Improves the Complete Response (CR) Rate in Chronic Lymphocytic Leukemia (CLL) and Eradicates Minimal Residual Disease (MRD) but Is Associated with Severe Infectious Toxicity: Final Analysis of CALGB Study 10101.

Abstract 210 Background:Alemtuzumab (Campath-1H) is approved for the treatment of CLL. CALGB sought to determine whether alemtuzumab can improve the CR rate and eradicate MRD after induction chemoimmunotherapy by performing a phase II study administering FR followed by alemtuzumab consolidation to previously untreated, symptomatic CLL patients (pts). We previously reported preliminary toxicity data (Lin et al. ASH 2007) and now report final toxicity and response data. Methods:Pts received fludarabine 25 mg/m2 IV on days 1–5, and rituximab 50 mg/m2 IV on day 1, 325 mg/m2 on day 3, and 375 mg/m2 on day 5 of cycle 1 and then only on day 1 of cycles 2–6, repeated every 28 days for up to 6 cycles. Four months after the last fludarabine dose, pts with stable (SD) or responsive disease by NCI 96 criteria received SC alemtuzumab 3 mg on day 1, 10 mg on day 3, and 30 mg on day 5, and then thrice weekly thereafter for 6 weeks (18 total doses). Pts received standard Pneumocystis (PCP) and Varicella zoster virus prophylaxis and were monitored weekly by PCR for Cytomegalovirus (CMV) viremia. When unacceptable serious infectious toxicity was noted in pts who received alemtuzumab after achieving CR from FR induction, the study was amended so that only PR or SD pts received alemtuzumab after FR. Results:Median age of pts (n=102) was 61 years (range, 23–82), 74% were male, and 30% were Rai stage III/IV. FR was well tolerated; 93% of pts received at least 3 cycles, and 77% completed all 6 cycles. Overall, complete and partial response (OR, CR, PR) rates after FR induction were 90%, 29% and 61%, and 15% were MRD negative by flow cytometry. Fifty-eight pts received alemtuzumab, and 42 (72%) completed the planned 6 weeks of therapy. OR, CR, and PR rates after alemtuzumab (n=58) were 91%, 66% and 26%, and 50% were MRD negative. Twenty-eight of 45 pts (62%) in PR after FR who received alemtuzumab attained CR. Of 11 pts in CR after FR who received alemtuzumab, 5 were MRD negative prior to consolidation and 3 of the other 6 converted to MRD negative afterwards. By intent-to-treat for all patients enrolled, OR, CR, and MRD negativity were attained by 90%, 57% and 42% of pts. With a median follow up of 34 months, median progression free survival (PFS) was 37 months (95% CI, 33–43 months); PFS was 73% and overall survival (OS) 86% at 2 years. Two-year PFS (76% vs 70%, p=0.54) and OS (84% vs 88%, p=0.89) were similar for pts who did and did not receive alemtuzumab. Similarly, there were no differences in PFS or OS among the 30 pts in CR after FR whether or not they received alemtuzumab, although the numbers were small. Grade 3–4 neutropenia and thrombocytopenia were observed in 43% and 19% of pts during alemtuzumab therapy. Grade 3–4 non-hematologic toxicity was observed in 41% of pts, including 19% infections and 19% febrile neutropenia, during alemtuzumab therapy. As we previously reported, 5 pts in CR after FR who received alemtuzumab died from infections (viral meningitis, Listeria meningitis, Legionella pneumonia, CMV and PCP pneumonia), and one pt in PR after FR who received alemtuzumab died of Epstein-Barr (EBV) viremia without evidence of EBV lymphoma. These grade 5 toxicities occurred both during and for up to 7 months after alemtuzumab therapy. Conclusions:Alemtuzumab consolidation improved the CR and MRD negative rates after FR induction. However, alemtuzumab consolidation resulted in significant toxicity, particularly severe infections in pts who achieved a CR after FR induction. Longer follow up is needed to determine if the improved CR and MRD negative rates following alemtuzumab consolidation will eventually result in improved PFS or OS, especially among pts who achieved a PR after FR induction. Disclosures:Lin:GlaxoSmithkline: Consultancy, Employment; Genentech: Consultancy; Bayer: Consultancy. Off Label Use: Use of alemtuzumab as consolidation therapy. Byrd:Genentech: Consultancy, Research Funding. Link:Genentech: Consultancy. Rai:Genentech: Consultancy; Bayer: Consultancy.

High-dose-rate brachytherapy as monotherapy delivered in two fractions over one day for favorable-risk prostate cancer. Preliminary toxicity data

High-dose-rate brachytherapy as monotherapy delivered in two fractions over one day for favorable-risk prostate cancer. Preliminary toxicity data

Toxicity associated with combination oxaliplatin plus fluoropyrimidine with or without cetuximab in the MRC COIN trial experience

We present the preliminary toxicity data from the MRC COIN trial, a phase III randomised controlled trial of first-line therapy in advanced colorectal cancer, with particular reference to the addition of cetuximab to an oxaliplatin–fluoropyrimidine combination. A total of 804 patients were randomised between March 2005 and July 2006 from 78 centres throughout the United Kingdom. Patients were allocated to oxaliplatin plus fluoropyrimidine chemotherapy with or without the addition of weekly cetuximab. The choice of fluoropyrimidine (either 5-fluorouracil (5FU) or capecitabine) was decided by the treating physician and patient before randomisation. Toxicity data were collected from all patients. Two hundred and three patients received 5FU plus oxaliplatin (OxMdG, 25%), 333 oxaliplatin+capecitabine (Xelox, 41%), 102 received OxMdG+cetuximab (OxMdG+C, 13%) and 166 Xelox+cetuximab (21%). Percent grade 3/4 toxicities included diarrhoea 6, 15, 13 and 25%, nausea/vomiting 3, 7, 7 and 14% for OxMdG, Xelox, OxMdG+C and Xelox+C, respectively. Sixty-day all-cause mortality was 6, 5, 5 and 7%. Statistically significant differences were evident for patients receiving Xelox+cetuximab vs Xelox alone: diarrhoea relative risk (RR) 1.69 (1.17, 2.43, P=0.005) and nausea/vomiting RR 2.01 (1.16, 3.47, P=0.012). The excess toxicity observed in the oxaliplatin-, capecitabine-, cetuximab-treated patients led the trial management group to conclude that a capecitabine dose adjustment was required to maintain safety levels when using this regimen.

Dosimetry and Acute Toxicity in IG-IMRT using a Consensus Prostate Bed CTV Following Prostatectomy

Recently published institutional guidelines for anatomic boundaries of the prostate bed clinical target volume (CTV) have raised concerns regarding the feasibility of high-dose delivery to the planning target volume (PTV) while respecting rectal and bladder dose-volume constraints. This study describes the prospective use of daily image guided intensity modulated radiation therapy (IG-IMRT), and reports the preliminary measures of acute toxicity in this group of patients. Between August 2007 and March 2008, 25 patients were enrolled on a prospective research ethics board approved clinical trial. All were CT-simulated with a full bladder and empty rectum, immobilized in a customized vacuum device. Seven field step-and-shoot IMRT plans were generated, prescribing 6600cGy in 33 fractions to the ICRU reference point. Dose planning objectives were as follows, in the order of priority: PTV D99 ≥ 5400cGy, posterior half of rectal wall (PostRW) 1cm3 ≤ 5500cGy, rectal wall 1cm3 ≤ 6600cGy, bladder wall 2 cm3 ≤ 6730cGy, penile bulb 0.5 cm3 ≤ 6600cGy, femur 1 cm3 ≤ 5500cGy and PTV V95 ≥ 95%. Dosimetry endpoints were measured using dose-volume histograms. Patient-reported acute radiation-induced toxicity was assessed weekly during treatment, and graded using the CTCAE v3.0 toxicity scale. PTV D99 ≥ 5400cGy was achievable in all cases with a mean dose of 5827cGy. PTV coverage was compromised to achieve the PostRW constraint, resulting an average V95 of 95.3% (range, 92 - 99% and SD = 2.0). Among the 25 patients, 60% had PTV V95 ≥ 95%. Dose constraints for other normal tissue were met. Grade 2 GU and GI toxicities were experienced by 8% and 32% of patients, respectively. One patient reported grade 3 GU toxicity due to voiding more frequently than once per hour, which resolved during the course of treatment. For patients who reported experiencing GI 2 toxicity, 4 of them required the use of medication for symptom management. The use of IG-IMRT technique is feasible in delivering high-dose to the PTV with minimal compromise to coverage while respecting normal tissue dose constraints. Preliminary acute toxicity data is considered acceptable. Ongoing investigation will continue to evaluate biochemical control and late toxicity.

A phase II study of pemetrexed, carboplatin and thoracic radiation with or without cetuximab in patients with locally advanced unresectable non-small cell lung cancer: CALGB 30407—Early evaluation of feasibility and toxicity

7518 Background: Less than one-third of patients with unresectable stage III non-small cell lung cancer (NSCLC) are cured with concurrent chemoradiation. Administering systemic doses of novel chemotherapy agents along with thoracic radiation, adding molecularly targeted agents and increasing the dose of thoracic radiation are current investigational approaches to improve outcomes. Methods: The Cancer and Leukemia Group B (CALGB) conducted a randomized phase II study of thoracic radiation (70 Gy) along with carboplatin (AUC 5) and pemetrexed 500 mg/m2 on days 1 administered intravenously every 21 days for 4 cycles (arm A) or the same chemotherapy regimen along with cetuximab with a loading dose of 400 mg/m2 followed a week later by 250 mg/m2 weekly for additional 6 weeks (arm B). Subsequently all patients received four additional cycles of pemetrexed (500 mg/m2 every 21 days) as consolidation therapy. Eligibility criteria: previously untreated stage III NSCLC performance status 0–1, no significant weight loss and adequate organ functions. The primary endpoint was the percentage of patients who lived longer than 18 months after initial treatment. Secondary endpoints were failure free survival and response rates. We planned to study the regimen (s) further if the 18 month survival rates equaled or exceeded 55%. Results: Characteristics of the 106 eligible pts (54 in arm A and 52 arm B) enrolled from 09/05 to 12/07: male 61%, median age 64.5 years (range 32–81). The most common histological type was adenocarcinoma (39%). Preliminary toxicity data (grade 3 or greater, %) by arms (arm A/arm B) for 106 pts: neutropenia 36/37; febrile neutropenia 5/7, thrombocytopenia 30/34, nausea/vomiting 10/12, esophagitis 35/22, skin rash 3/23 and fatigue 22/18. One patient died of fatal hemoptysis. Updated data on treatment delivery and toxicity will be available in May 2008. Conclusions: The combination of thoracic radiation with pemetrexed, carboplatin with or without cetuximab is feasible and is fairly well tolerated. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Lilly Oncology

Phase II single arm trial of aflibercept in patients with recurrent temozolomide-resistant glioblastoma: NABTC 0601

2020 Background: Anti-vascular endothelial growth factor (VEGF) therapy is a promising treatment approach for patients with recurrent glioblastoma. Aflibercept (VEGF Trap) is a recombinantly-produced fusion protein which scavenges both VEGF and placental growth factor (PlGF) removing important ligands for the VEGF family receptors expressed on tumor endothelium. Methods: We report the results of a phase II trial of aflibercept monotherapy for patients with temozolomide-resistant recurrent glioblastoma and anaplastic glioma at first relapse. Patients received 4 mg/kg aflibercept IV every 2 weeks. The primary endpoint was 6-month progression free survival (PFS) and secondary endpoints include radiographic response rate (RR), PFS, overall survival and toxicity. Response was assessed using Macdonald's criteria. At this time, we provide preliminary response and toxicity data but complete information will be available at the time of presentation. Results: A total of 48 patients have been enrolled; 32 patients with glioblastoma and 16 patients with anaplastic glioma (median age 54; median KPS 90%). Investigator assessment of RR demonstrated a 50% response rate for the anaplastic glioma cohort (4 SD, 5 PR, 2 CR of 14 evaluable patients) and a 30% response rate for patients with glioblastoma (14 SD, 8 PR of 27 evaluable patients). The primary endpoint assessment of 6-month PFS will be presented. The main treatment-related NCI CTC grade 3 adverse events (18 total) included fatigue, hypertension, hand-foot syndrome, lymphopenia, thrombosis and proteinuria. One CNS ischemia and one systemic hemorrhage grade 4 toxicities were reported. A total of 12 patients (25%) discontinued therapy due to toxicity, on average less than 2 months into treatment. In conjunction with a decrease in permeability on DCE-MRI, aflibercept therapy induced a rapid and prolonged decrease in free levels of VEGF and PlGF confirming sequestration of target growth factors. Analysis of growth factors mediating angiogenic escape is ongoing. Conclusions: Aflibercept was moderately well tolerated and has evidence of single agent activity in patients with recurrent glioblastoma and anaplastic glioma. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Novartis, Schering-Plough, Semafore Johnson and Johnson, Pfizer Genentech, Novartis, Schering-Plough Genentech, Novartis, Regeneron

Phase I dose escalation study of fludarabine, bortezomib, and rituximab for relapsed/refractory indolent and mantle cell non- Hodgkin lymphoma

8553 Background: Fludarabine (F) and bortezomib (B) have each demonstrated tolerability and efficacy in patients with non- Hodgkin lymphoma (NHL). Despite potential synergy between these agents, the combination remains untested. This phase I study was designed to obtain preliminary toxicity data and to determine the maximum tolerated dose (MTD) of the regimen. Methods: Relapsed or refractory indolent and mantle cell NHL and patients with chronic lymphocytic leukemia (CLL) were eligible. Dose levels of F and B were escalated as per the schema below with rituximab (R) being added to the 5th cohort. Due to unanticipated hematologic toxicity at dose level 5, cohorts 5a and 5b were subsequently added. Cycles were repeated every 21 days for a maximum of 8 cycles. Dose escalation occurred in cohorts of 3 patients. Cohorts were expanded to 6 patients if a dose limiting toxicity (DLT) was observed. The MTD was defined as one dose level below the cohort at which 1/3 of the patients experienced a DLT. Results: 23 patients have been enrolled to date. Patient histologies include 11 with grade 1/2 follicular, 4 with marginal zone, 3 with lymphoplasmacytic, 2 with CLL/small lymphocytic, 2 with mantle cell and 1 with grade 3 follicular NHL. No dose limiting toxicities were observed in cohorts 1 through 4. The addition of R in cohort 5 resulted in dose limiting hematologic toxicity. An additional DLT, grade 3 neuropathy, occurred in 1 patient. At dose levels 5a and 5b, no further grade 3 or 4 hematologic toxicity has been observed with cycle 1. Of the 17 patients currently evaluable for a response, 3 have achieved a complete response, 4 have achieved a partial response, 8 had stable disease, and 2 patients progressed on therapy. The median time of stable disease for the 8 patients was 9 months (range 3–30+). Conclusions: FBR is a well-tolerated and active regimen for patients with relapsed or refractory NHL. R may worsen the hematologic toxicity of a nucleoside analog and proteasome inhibitor containing regimen. Dose escalation of fludarabine, bortezomib, and rituximab Dose Level Fludarabine (25 mg/m2) Bortezomib (mg/m2 on days 1,4,8,11) Rituximab (mg/m2 on day 1) 1 days 1-3 0.7 - 2 days 1-3 1.0 - 3 days 1- 3 1.3 - 4 days 1-5 1.3 - 5 days 1-5 1.3 375 5a days 1-3 1.0 375 5b days 1- 3 1.3 375 No significant financial relationships to disclose.

Randomized phase II study of concomitant chemoradiotherapy with 5-fluorouracil-hydroxyurea (FHX) compared to FHX and bevazicumab (BFHX) in intermediate stage head and neck cancer (HNC)

6034 Background: Preclinical data supports inhibition of vascular endothelial growth factor (VEGF) to improve tumor radiosensitivity. Phase I data demonstates that BFHX was tolerable in HNC (Seiwert, pASCO2006). Here we present preliminary toxicity data from a randomized phase II trial in pts with PS 0–2, stage II-IV (T2–4 N0–1 M0) HNC. Methods: Pts were randomized (2:1) to receive either BFHX or FHX. Planned sample size is 72pts. Chemotherapy consists of 5- FU (600 mg/m2/day continuous infusion for 120 hrs), hydroxyurea (500 mg PO q12 hours for 11 doses) with or without bevacizumab (10 mg/kg IV on day 1), concurrently with twice daily RT on a week on-week off schedule. Results: 21pts (BFHX 14pt and FHX 7pt) have completed therapy and are evaluable for toxicity. Pt characteristics in the BFHX and FHX arms are: median age 61 vs. 55 yrs, males 78% vs. 85%, stage II-III 57% vs. 86% and IV 43% vs. 14%. All pts have PS 0–1. 20 pts are evaluable for toxicity. Two episodes of gr3 leukopenia and one episode of gr 3 neutropenia were observed in the BFHX arm; whereas no gr3 hematologic toxicities were seen in the FHX arm. Mucositis (Gr3 - BFHX 85% vs. FHX 86%) and dermatitis (Gr3 - 0% vs. 14%) were observed in every pt. Other common non- hematologic toxicities were pain (100% vs. 86%), fatigue (77% vs. 86%) and anorexia (62% vs. 51%). No hemorrhagic events were observed. In the BFHX arm, one episode of deep venous thrombosis and one non-neutropenic death from sepsis were observed. Pathologic complete response rates were 92% and 100% in the BFHX and FHX arms, respectively. Conclusions: Preliminary results support the tolerability of BFHX. Toxicity appears to be similar to FHX with an apparent increase in leukopenia consistent with prior reports. Bleeding complications were not increased with BFHX. No significant financial relationships to disclose.

Cetuximab (C), oxaliplatin (Ox) and fluoropyrimidine (Fp): Toxicity during the first 12 weeks of treatment for the first 804 patients entered into the MRC COIN (CR10) trial

4070 Background: COIN is a 3-arm trial comparing continuous chemotherapy (CT) plus C or intermittent CT with standard continuous CT (OxFp) in the first-line treatment of advanced colorectal cancer (ACRC). Methods: Eligible patients have measurable, inoperable ACRC; no prior CT for metastases; PS 0–2; GFR >50; ALP <5 xULN; bili <1.25 xULN. Patients and/or clinicians choose the OxFp regimen, either FOLFOX (Braun,M BJC 89:1155f, 2003) or capecitabine (Cap) with Ox. Thereafter, randomization is 1:1:1 between: (A) OxFp; (B) OxFp plus weekly C; or (C) Intermittent OxFp. In Arms A and B treatment is given until progression, cumulative toxicity or patient choice, in Arm C it is stopped at 12 wks in stable/responding patients and reintroduced following progression off treatment. Primary endpoint is Overall Survival (OS). The trial aims to recruit 2,421 patients over 3.5 years. Release of this preliminary toxicity data has been approved by the independent Data Monitoring Committee (DMC). Results: 804 patients were randomised between 03/05 and 07/06 and 12 week toxicity is available on approx. 85% of patients. 62% of patients received Ox + cap and 38% received FOLFOX. Grade 3 /4 toxicities (%) in the first 12 weeks by regimen are reported below. Conclusions: The addition of cetuximab to OxFp combinations results in increased grade 3/4 toxicities overall and specifically in GI, skin rash and lethargy. Cap combination is associated with more GI toxicity but less neutropenia. Unexpectedly, no hypersensitivity reactions have yet been seen on FOLFOX (with or without C). [Table: see text] [Table: see text]

Plasma kinetics, uptake by neoplastic breast tissue and preliminary toxicity data of a cholesterol-rich microemulsion (LDE) associated to a paclitaxel (PCT) derivative

12038 Background: Previously we described the association of PCT to a cholesterol-rich microemulsion (LDE) that binds to low-density lipoprotein (LDL) receptors and concentrates in neoplastic tissues. The association is stable, preserves the anti-proliferative activity and reduces the toxicity to animals. The present study was designed to provide preliminary toxicity data on the LDE-PCT oleate formulation, to determine its plasma kinetics compared to that of commercial PCT and to verify the complex ability to concentrate in malignant breast tissue. Methods: To determine the plasma kinetics [3H]-PCT oleate associated to LDE labeled with [14C]-Cholesteryl oleate was intravenously injected into 3 pts and [3H]-commercial PCT into 2 pts 24 h before surgery. Blood samples were collected over the 24 h to quantified radioactivity and the pharmacokinetic parameters. Tumoral and normal breast tissue were excised during the surgery. Other 3 heavily pretreated pts with breast cancer were included in this study to assess toxicity. LDE-PCT (175 mg/m2) was administered as a 1-hour infusion at 3 week interval, without pre medication. Results: Fractional clearance rate (FCR) of LDE and of the drug were similar (0.030 ± 0.026 e 0.018 ± 0.018, respectively, P = 0.5742). The uptake of both [14C]-LDE and [3H]-paclitaxel oleate by breast malignant tissue was 2 and 3 fold greater than that of the normal breast tissue. The PCT oleate T1/2 (h) was greater than the commercial PCT (T½ = 18.97 ± 7.7 and 7.34 ± 0.40) and the clearence (L/h) of PCT oleate was lesser than the commercial (CL = 1.51 ± 0.18 and 7.95 ± 4.32). No hematological or neurotoxicity was found. Nausea and anorexia grade 1 was found only in one patient. Conclusion: Most of the drug is retained in the microemulsion until its removal from the circulation. The complex is stable and has greater plasma half life and lesser clearance than those for commercial one and can be concentrated in malignant breast tissue. Furthermore, LDE-PCT showed no considerable toxicity events in the 3 patients. Although data regarding response rates were not assessed, our preliminary results suggest that LDE-PCT may be a suitable and powerful weapon to treat breast cancer patients. No significant financial relationships to disclose.

Preliminary toxicity analysis of intraperitoneal carboplatin in combination with intravenous paclitaxel chemotherapy for patients with carcinoma of the ovary, peritoneum, or fallopian tube

The objective of this study was to provide preliminary toxicity data of multiple-cycle combination chemotherapy with intraperitoneal (IP) carboplatin and intravenous (IV) paclitaxel for further clinical trials. The toxicity data of 42 patients with müllerian carcinoma who underwent IP carboplatin therapy in combination with IV paclitaxel were retrospectively analyzed. Chemotherapy was repeated through the Bard IP port placed at initial surgery using IV paclitaxel at 175 mg/m2followed by IP carboplatin. The doses of carboplatin were either at area under the curve (AUC) = 5, 6, 6.5, 7, or 7.5. The toxicity data in a total of 237 cycles were analyzed. The median number of cycles for IP chemotherapy was 6 (range: 3–12). The incidences of maximal grade toxicities in all cycles were: grade (G)2/3 nausea/vomiting, 23.8%; G2/3 constipation, 42.9%; G2 abdominal pain, 28.6%; G2/3 sensory neuropathy, 14.3%; motor neuropathy, 4.8%; myalgia/arthralgia 33.4%; G3/4 neutrocytopenia, 85.4%; and G3/4 anemia, 35.4%. These were not related to the dose of carboplatin. The incidences of G3 thrombocytopenia in relation to the dose of carboplatin were AUC = 5, 0%; 6, 31.6%; 6.5, 44.4%; 7, 25.0%; and 7.5, 80%. G4 thrombocytopenia did not occur. A dose of carboplatin between AUC = 6 and 7 with IV paclitaxel at 175 mg/m2is warranted for further evaluation.

Preliminary toxicity analysis of intraperitoneal carboplatin in combination with intravenous paclitaxel chemotherapy for patients with carcinoma of the ovary, peritoneum, or fallopian tube

The objective of this study was to provide preliminary toxicity data of multiple-cycle combination chemotherapy with intraperitoneal (IP) carboplatin and intravenous (IV) paclitaxel for further clinical trials. The toxicity data of 42 patients with mullerian carcinoma who underwent IP carboplatin therapy in combination with IV paclitaxel were retrospectively analyzed. Chemotherapy was repeated through the Bard IP port placed at initial surgery using IV paclitaxel at 175 mg/m2 followed by IP carboplatin. The doses of carboplatin were either at area under the curve (AUC) = 5, 6, 6.5, 7, or 7.5. The toxicity data in a total of 237 cycles were analyzed. The median number of cycles for IP chemotherapy was 6 (range: 3-12). The incidences of maximal grade toxicities in all cycles were: grade (G)2/3 nausea/vomiting, 23.8%; G2/3 constipation, 42.9%; G2 abdominal pain, 28.6%; G2/3 sensory neuropathy, 14.3%; motor neuropathy, 4.8%; myalgia/arthralgia 33.4%; G3/4 neutrocytopenia, 85.4%; and G3/4 anemia, 35.4%. These were not related to the dose of carboplatin. The incidences of G3 thrombocytopenia in relation to the dose of carboplatin were AUC = 5, 0%; 6, 31.6%; 6.5, 44.4%; 7, 25.0%; and 7.5, 80%. G4 thrombocytopenia did not occur. A dose of carboplatin between AUC = 6 and 7 with IV paclitaxel at 175 mg/m2 is warranted for further evaluation.

Pemetrexed (Pem)/gemcitabine (Gem) as front-line therapy for advanced NSCLC: A randomized, phase II trial of three schedules

7070 Background : The combination of the novel multitargeted antifolate, Pem and Gem is broadly active, and is in phase III trials. Conflicting pre-clinical sequence-dependent synergy data prompted further investigation of the optimal schedule of administration. Purpose: A randomized phase II study was undertaken to assess tumor response rates and compare toxicities among pts receiving 3 different schedules of Pem 500 mg/m2 plus Gem 1250 mg/m2. Method: Pts with stage IV (88%) or stage IIIB (12%) NSCLC and a PS ≤ 1 received 3 schedules of Pem and Gem administered 90 minutes apart, on a q21 day cycle as follows: Schedule A: Pem followed by Gem on d1, Gem on d8; Schedule B : Gem followed by Pem on d1, Gem on d8; Schedule C: Gem on d1, Pem followed by Gem on d8. Results: 148 eligible pts (58 arm A, median age 66; 30 Arm B, median age 59.5; 60 Arm C, median age 65) were treated. Median number of treatment cycles was 5 (arm A), 2.5 (arm B) and 4 (arm C). Arm B was permanently closed at interim analysis for inferior efficacy (< 3 responses in first 19 pts). Overall, 74% pts experienced grade 3+ hematologic toxicity and 62% pts experienced grade 3+ non hematologic toxicity of which fatigue (17.6%), dyspnea (11.5%) and rash ( 8.1%) were the most common. There were significant differences in the rate of grade 3+ febrile neutropenia (A = 5%, B = 20%, C = 5%, p = 0.03). Pts on arm A had less severe toxicity than arm C (grade 3+ events: 86% vs. 93%; grade 4+ event: 40% vs. 50%). All patients were evaluable for response. Arm A with a PR of 29% (95% CI 18–42%) met the protocol defined efficacy criteria, whereas arm C with PR of 17% (95% CI 10–32%) did not. Survival data will be presented (current median follow up ∼ 7 months). Conclusion: Sequence and schedule of administration is a critical determinant of the efficacy and toxicity of Pem and Gem combinations. Preliminary efficacy and toxicity data indicate that schedule A is optimal, and should be tested in future studies. No significant financial relationships to disclose.

Gemcitabine/Anthracycline Combinations in Metastatic Breast Cancer

Gemcitabine has demonstrated single-agent efficacy in the treatment of advanced breast cancer, with response rates of up to 42%. The agent is well tolerated, with relatively mild side effects, and has limited overlapping toxicities with other drugs used in combination chemotherapy for breast cancer. It is, therefore, a good candidate for inclusion in multidrug regimens for the treatment of this disease. This article reviews results of gemcitabine/anthracycline-containing double- and triple-drug combinations used to treat patients with early-stage and advanced breast cancer. Results from phase I and II trials were promising, with good tolerability and overall response rates ranging from 33%–89% in advanced disease and up to 95% in the neoadjuvant treatment of early-stage disease. A phase III trial is currently comparing gemcitabine/epirubicin/paclitaxel and 5-fluorouracil/epirubicin/cyclophosphamide in patients with advanced breast cancer. Preliminary toxicity data on 78 patients show that both regimens were well tolerated, with similar incidences of treatmentrelated effects. Additional comparative studies of gemcitabine-containing drug regimens in breast cancer are warranted.

Synthesis of 1-Amino-3-{2-[7-(6-deoxy-α/β-D-galactopyranos-6-yl)-1,7-dicarba-closo-dodecaboran(12)-1-yl]ethyl}cyclobutanecarboxylic Acid Hydrochloride

1-Amino-3-{2-[7-(6-deoxy-α/β-D-galactopyranos-6-yl)-1,7-dicarba-closo-dodecaboran(12)-1-yl]ethyl}cyclobutanecarboxylic acid was synthesized as a potential new agent for boron neutron capture therapy. The key step in the synthesis is the alkylation of 3-{2-[1,7-dicarba-closo-dodecaboran(12)-1-yl]ethyl}cyclobutanone ethylene monothioketal with 1,2:3,4-di-O-isopropylidene-6-O-triflyl-α-D-galactopyranose which gave the precursor ketone that was then converted to the title amino acid via a Bücherer-Strecker synthesis followed by removal of isopropylidene groups in HCl. Preliminary toxicity data in A 435 cancer cells were obtained.

Reduced ovulation rate and cytogenetic analysis following tyrosine phosphatase inhibition in mouse oocytes.

Objective: To investigate the effects of sodium orthovanadate (NaV)-induced tyrosine phosphatase inhibition on ovulation rate and aneuploidy during mouse oocyte maturation (OM). Design: A controlled NaV dose response cytogenetic study involving ovulated mouse oocytes. Materials/Methods: ICR female mice were superovulated with intraperitoneal injections of 10.0 IU PMSG and 5.0 IU hCG 48 hrs later. NaV was given immediately after hCG. Ovulated oocytes were collected and counted 16 hrs after hCG and processed for cytogenetic analysis. Based on preliminary cell and animal toxicity data, NaV doses of 5, 15, and 25 mg/kg were selected. Controls received the solvent distilled water. Chromosomes were C-banded to distinguish between complete dyads (chromosomes) and those separated into two chromatids. Data were analyzed by Chi-square and Fisher’s Exact tests. Results: NaV-induced tyrosine phosphatase inhibition led to a significant reduction in the number of oocytes ovulated but did not increase the frequencies of cytogenetic aberrations. The number of oocytes ovulated per number of females for the control group (535/20, 26.8%) was significantly (p < 0.01) greater than that in the 5 mg/kg NaV group (372/20, 18.6%), the 15 mg/kg NaV group (365/20, 18.3%), and the 25 mg/kg NaV group (537/30, 17.9%). The frequencies of hypoploidy (n = 10–19), hyperploidy (n = 20–29), premature centromere separation, premature anaphase, and single chromatids were neither significantly (p 0.05) different between the controls and each of the NaV groups nor among the NaV groups. Ovulated MI oocytes, diploid oocytes, and structural chromosome aberrations were not found. Conclusions: These in vivo oocyte data appear unique in the literature. Although phosphatase and kinase activities are essential for oocyte maturation, the tyrosine phosphatase inhibitor, NaV, did not alter the temporal sequence of OM and increase the frequency of numerical or structural chromosome aberrations. However, NaV-inhibition of tyrosine phosphatase activity resulted in a significant decrease in the number of mouse ovulated oocytes. Supported by: Department of Obstetrics and Gynecology, Louisiana State University Health Sciences Center, Shreveport, LA.

Preliminary observations of single-agent docetaxel as neoadjuvant therapy for locally advanced prostate cancer

Patients with locally advanced prostate cancer present a significant therapeutic dilemma. Despite aggressive local therapies, including radical prostatectomy (RP), these patients are at high risk for biochemical failure. Several research groups have recently demonstrated the feasibility of hormonal and chemohormonal therapy before RP, but limited published data are available regarding the usefulness of chemotherapy without hormonal therapy in the neoadjuvant setting. At Cleveland Clinic Foundation, a phase II trial was initiated to evaluate a 6-week course of docetaxel, 40 mg/m 2 intravenously every 7 days, followed by RP in patients with locally advanced prostate cancer. RP was to be performed within 3 weeks of completion of neoadjuvant chemotherapy. The primary endpoint of this study is pathologic complete response. Preliminary toxicity data suggest that weekly docetaxel is well tolerated and does not increase the risk of perioperative or post-operative complications. Reductions in prostate-specific antigen levels were noted in seven of 10 patients who completed the 6-week course of neoadjuvant docetaxel. The neoadjuvant use of investigational cancer therapies may allow for relatively rapid assessment of their antitumor activity.

Gemcitabine/Carboplatin Versus Cisplatin/Etoposide for Patients With Poor-Prognosis Small Cell Lung Cancer: A Phase III Randomized Trial With Quality-of-Life Evaluation

Small cell lung cancer is a chemosensitive disease; however, patients with extensive-stage disease or adverse prognostic factors are rarely cured. Gemcitabine (Gemzar; Eli Lilly and Company, Indianapolis, IN), a new agent with good tolerability, interacts synergistically with platinum agents. Carboplatin is as effective as cisplatin, but is less toxic. The London Lung Cancer Group is conducting a multicenter, open-label, randomized, phase III trial in patients with histologically or cytologically proven small cell lung cancer and extensive-stage, limited-stage but locally-advanced, or limited-stage disease with poor prognostic factors. Chemotherapy consists of 21-day cycles of gemcitabine 1,200 mg/m(2) intravenous (IV) on days 1 and 8, plus carboplatin area under the curve of 5 IV on day 1, or cisplatin 60 mg/m(2) IV on day 1 plus etoposide 120 mg/m(2) IV on day 1 and 100 mg orally on days 2 and 3. Thirty-nine patients have been randomized to gemcitabine/carboplatin and 38 to cisplatin/etoposide (23 and 22 completed treatment, with 96 and 84 cycles, respectively). Preliminary toxicity data indicate hematologic toxicity in 25% of cycles for gemcitabine/carboplatin and 16% for cisplatin/etoposide, although cisplatin/etoposide-treated patients experienced significant alopecia, nephrotoxicity, nausea and vomiting, and neutropenia. This London Lung Cancer Group trial of gemcitabine/carboplatin may define an active, safe, and acceptable treatment for patients with extensive-stage and poor-prognosis small cell lung cancer. Semin Oncol 28 (suppl 10):15-18.

1,3,5-Trialkyl-2,4,6-triiodobenzenes: novel X-ray contrast agents for gastrointestinal imaging.

Examination of the gastrointestinal (GI) tract has been performed for decades using barium sulfate. Although this agent has many recognized limitations including extreme radiopacity, poor intrinsic affinity for the GI mucosa, and very high density, no alternative contrast agents have emerged which produce comparable or better contrast visualization. In fact, the various techniques of the GI radiologic examination (i.e., single contrast, double contrast, biphasic) were developed to compensate for its limitations. Each of these techniques requires complex patient manipulation to achieve adequate mucosal coating or compression to overcome the marked radiopacity of barium sulfate in order to obtain a diagnostically useful examination. A series of novel radiopaque oils, the 1,3, 5-trialkyl-2,4,6-triiodobenzenes, was designed to improve the efficacy, stability, and safety of barium formulations. These substances were prepared in two steps from 1,3,5-trichlorobenzene. Compound 17 (1,3,5-tri-n-hexyl-2,4,6-triiodobenzene), formulated as an oil-in-water emulsion, was found to be well-tolerated in rodents (mice, hamsters, rats) following acute oral and/or intraperitoneal administrations at 4 times the anticipated human clinical dose. No metabolism of 17 was detected in rat, hamster, dog, monkey, or human hepatic microsomes, suggesting the lack of oral toxicity was a consequence of poor absorption. In imaging experiments in dogs, emulsions of 17 have demonstrated excellent mucosal coating and improved radiodensity relative to barium sulfate suspensions. On the basis of the preliminary imaging and toxicity data, compound 17 was selected as a potential development candidate.

Evaluation of mitoxantrone-loaded albumin microspheres following intraperitoneal administration to rats

Mitoxantrone has demonstrated therapeutic efficacy in the regional treatment of intraperitoneal malignancies. However, severe local toxicity was dose limiting. Consequently, a new injectable sustained delivery formulation of mitoxantrone has been developed: the drug was incorporated (8.2 w/w%) in highly hydrophilic albumin microspheres. In vitro drug release profile was modified by matrix crosslinking extent. The extractable amount of residual crosslinking agent (glutaraldehyde) in the microspheres was lower than 6 ppm. Mitoxantrone concentration in peritoneal fluid and plasma was determined up to 72 h after intraperitoneal administration of 30, 60 and 120 mg mitoxantrone per m 2 body surface area as solution and in the form of a dispersion containing mitoxantrone-loaded microspheres to rats. Data analysis revealed sustained release of mitoxantrone from microspheres into peritoneal fluid in all dosage groups. The initial high drug levels in peritoneal fluid and plasma observed after application of mitoxantrone in the solution form were prevented by administration of the drug incorporated in microspheres. However, tumoricidal drug levels in peritoneal fluid were maintained over a comparable time span. In addition, preliminary toxicity data suggest a superior local tolerability of mitoxantrone-loaded microspheres. The dose of intraperitoneally administered mitoxantrone might be increased from 30 to 60 mg per m 2 body surface area using the slow release formulation. In conclusion, the described microsphere drug delivery system for mitoxantrone might overcome dose-limiting drug toxicity.