Standard Eligibility Criteria Research Articles

Phase I/II study of TH-302 in combination with gemcitabine in patients with solid tumors including advanced pancreatic cancer.

e13519 Background: TH-302 is a 2-nitroimidazole hypoxia-activated prodrug of the DNA alkylator, bromo-isophosphoramide mustard. In preclinical models, TH-302 was active alone and enhanced the activity of gemcitabine (Gem). A phase I/II study was conducted to investigate TH-302 in combination with full dose Gem. Methods: This study used standard solid tumor eligibility criteria except patients (pts) must not have received prior Gem. Pts received IV TH-302 followed by Gem (1,000 mg/m2) on Days 1, 8 and 15 of a 28 day cycle. A standard 3+3 pts design was used with a TH-302 starting dose of 240 mg/m2. An expansion component was planned for first-line pancreatic cancer pts at the MTD. The objectives of the study were to determine the MTD/RP2D of TH-302 and Gem and to evaluate the safety, pharmacokinetics (PK) and preliminary efficacy of the combination. Results: 38 pts [20M/18F, median age: 62y (range 41-82), ECOG PS 0/1: 31/7] were enrolled at 8 sites and treated at TH-302 dose of 240 (7 pts), 340 (16), 400 (...

Phase I/II study of TH-302 in combination with docetaxel in patients with solid tumors including NSCLC and castrate-resistant prostate cancer (CRPC).

e13527 Background: TH-302 is a 2-nitroimidazole hypoxia-activated prodrug of the DNA alkylator, bromo-isophosphoramide mustard. In preclinical models, TH-302 was active alone and enhanced the activity of docetaxel (D). A phase I/II study was conducted to evaluate the safety and tolerability and investigate the activity of TH-302 in combination with D. Methods: This study used standard solid tumor eligibility criteria except patients (pts) could not have received prior D. Pts received IV TH-302 on days 1 and 8 and docetaxel 75 mg/m2 on day 1 of a 21 day cycle. A standard 3+3 pts design was used with a TH-302 starting dose of 240 mg/m2. Following the determination of the MTD, a dose expansion component enrolled subjects with CRPC and second-line NSCLC. The objectives of the study were to determine the MTD/RP2D of TH-302 and D and to evaluate the pharmacokinetics (PK) and preliminary efficacy. Results: 26 pts [16M/10F, median age 62y (range 39-76y), ECOG PS 0/1: 17/9] were enrolled at 7 sites and treated at ...

Allogeneic Hematopoietic Stem-Cell Transplantation Using Fludarabine/Treosulfan Conditioning Regimen Compared with Busulfan-Based Myeloablative and Reduced-Intensity Conditioning in Patients with AML and Mds; Relative Outcomes Depend On Disease Status at Transplantation.

Abstract 3358Poster Board III-246Allogeneic stem-cell transplantation (SCT) with both myeloablative (MAC) and reduced-intensity conditioning (RIC) is effective therapy in AML and MDS. However, the relative merits of each may differ in different settings. We have previously reported on the role of dose intensity in a group of 112 patients (pts) with AML/MDS given allogeneic SCT with different busulfan (Bu)- based regimens (Leukemia 2006). We showed that survival was similar with MAC and RIC in pts given SCT in remission, but was inferior in pts given RIC in active disease due to high post transplant relapse rates. The combination of fludarabine and treosulfan (FT) has been reported as an effective regimen in AML/MDS with limited toxicity. However, the relative dose intensity and expected outcomes with FT in the different SCT settings, compared with Bu-based regimens is not well defined. We now extend the analysis to a group of 298 pts with AML/MDS, given allogneic SCT from sibling (n=153) or unrelated/mismatched donors (n=145) and included the more recently introduced FT regimen. Pts meeting standard eligibility criteria for myeloablative conditioning were given high dose iv Bu and cyclophosphamide (BuCy, n=81). Pts with a risk factor for MAC, mainly due to advanced age, were given fludarabine (F) and reduced doses of Bu (6.4 mg/kg, FB2, n=91), F with high dose Bu (12.8 mg/kg, FB4,n=63) or FT (treosulfan 30-36 gr/m2). Protocol allocation was not randomized, resulting in a younger age for pts in the BuCy group; median age 37 years compared with 60, 50, and 58 for FB2, FB4 and FT, respectively. BuCy and FT groups included more pts with active disease at SCT, while the BuCy group had less unrelated donors. Non-relapse mortality (NRM) was 17%,18%,18% and 20% with FB2,FB4,FT and BuCy, respectively (p=NS). However, pts were selected to regimens other than BuCy based on a high estimated risk for NRM. With a median follow-up of 38 months (range, 1-115), estimated 5-yr overall survival (OS) was 38% (95%CI, 31-44). OS rates were 36%,33%,43% and 41% after FB2, FB4, FT and BuCy, respectively (p=NS). Multivariate analysis (MVA) defined age>50 [HR 1.5 (1-2.2), p=0.05)], active disease at SCT [HR 2.3 (1.6-3.2), p<0.001)] and unrelated donor [HR 1.5 (1-2.0), p=0.02)], as risk factors for shorter OS. The conditioning regimen used was not predictive in the entire group. When the analysis was limited to pts in first or subsequent remission (n=126), OS was 51%,43%,58%, and 43%, respectively. MVA identified age>50 as an adverse factor, while SCT using FB2 or FT was associated with prolonged OS [HR 0.3 (0.2-0.7), p=0.002)]. When the analysis was limited to pts with active disease (n=172) either chemo-refractory to induction or subsequent therapy (n=93) or untreated [n=79; untreated relapsed AML (n=15) or MDS with excess of blasts (n=64)], OS was 12%,25%,32%, and 36%, respectively. MVA identified chemo-refractory disease as the major adverse factor; OS [HR 2.2 (1.5-3.3), p=0.001), while SCT using BuCy or FT was associated with prolonged OS [HR 0.7 (0.5-1.0), p=0.06)]. The advantage of FT was observed mainly in pts with active untreated disease (mostly MDS). OS was 57% (95%CI, 32-82) in a group of 25 pts given FT for advanced, previously untreated MDS. Only BuCy and to a lesser degree FB4 (OS 27%) were effective in the truly refractory pts. FB2 and FT, were associated with a grim outcome in this setting (OS 6%, p=0.04). In conclusion, dose intensity is associated with different outcomes in the different transplant setting. In pts in remission at SCT, outcome is mostly related to SCT toxicity, thus there is an advantage to less intensive regimens, such as FB2, while FT shares this characteristic. When outcome is dominated by the risk for relapse, such as in pts with active disease at SCT, there is an advantage to a more intensive regimen, such as BuCy. FT shares this characteristic mainly in pts with no true chemo-refractoriness, and has an advantage over FB2 in this setting. FT should be considered as a reduced toxicity myeloablative conditioning, that is feasible in pts ineligible for MAC, rather than a reduced-intensity regimen. In pts in CR toxicity is comparable to FB2 while in pts with active untreated MDS its anti leukemic activity is comparable to BuCy. Disclosures:No relevant conflicts of interest to declare.

Long-Term Survival and Late Events After Allogeneic Stem-Cell Transplantation with Reduced-Intensity Conditioning (RIC) for AML and Mds; Comparable Results with Myeloablative Conditioning.

Abstract 518Allogeneic stem cell transplantation (SCT) is a potentially curative therapy for patients (pts) with AML and MDS. SCT is associated with substantial mortality during the first 2 years after treatment due to relapse and non-relapse causes, whereas after 2 years survival curves often reach a plateau. However, late mortality and late events continue to cause treatment failures through the late post-transplant course. The pattern of late events has been reported following myeloablative conditioning (MAC) but is not well defined in the RIC setting. To explore late outcomes we retrospectively analyzed SCT results in a cohort of 298 pts with AML/MDS given allogeneic SCT with various regimens. As a general role, pts meeting standard eligibility criteria were given MAC, consisting of high dose intravenous busulfan (Bu) and cyclophosphamide (BuCy). Pts considered at excessive risk for non-relapse mortality (NRM), mostly due to advanced age, were given a reduced toxicity regimen such as fludarabine with high-dose Bu (FB4) or treosulfan (FT) or a RIC regimen of fludarabine and reduced doses of Bu (FB2). The 2-year and 5-year overall survival (OS) for this cohort was 48% (95CI, 42-54) and 38% (95CI, 31-44), respectively. We identified 93 pts who were alive and leukemia-free 2 years after SCT. The median age at SCT was 52 years (17-72), 52 male, 41 female. The donors were HLA-matched siblings (n=57) or unrelated donors (n=36. The conditioning regimen was FB2 (n=28), FB4 (n=21, FT (n=15) or BuCy (n=29). At the 2-year time-point, 28 pts had a history of acute GVHD, 68 had a history of chronic GVHD, 43 had active chronic GVHD which still required immune suppressive therapy (IST) in 37. Among pts surviving leukemia-free 2 years after SCT, the probability of remaining alive and leukemia-free, for the next 5 years, was 81% (95CI, 71-91) and 79% (95CI, 69-88), respectively. The probability of OS was 75%, 84%, 92% and 79%, after the various regimens, respectively (p=NS). There were 14 deaths beyond 2 years, 8 deaths due to relapse and 6 due to NRM. NRM included 3 deaths due to solid cancers, 2 due to breast cancer (both in pts transplanted for therapy related AML relapsing with the primary malignancy) and one due to colon cancer. There were 3 additional secondary cancers; breast cancer, squamous cell skin cancer and Kaposi sarcoma (1 pt each; all currently alive). Two pts died of myocardial infarction and one of chronic GVHD. In all, the cumulative incidence of late NRM was 10% (4-24). Interestingly, unlike the early post-transplant period, with current supportive care regimens, late deaths from GVHD and infections are rare. Twelve pts relapsed, 24-59 months after SCT, cumulative incidence 12% (6-23); 8 died, 4 are alive following further therapies, 3 long-term. The kinetics of late relapses was similar with MAC and RIC. Advanced age (>50) was the most significant predicting factor for shortened survival. OS was 64% and 92%, in the older and younger groups, respectively (p=0.03). All deaths due to NRM, and all secondary cancers occurred in the older group (p=0.01). Multivariate analysis (MVA) identified advanced age as the only independent predicting factor for OS; HR 3.1 (1-11.3). The conditioning regimen, disease status at SCT and donor type were not predictive. A history of acute or chronic GVHD predicted improved leukemia-free survival. Age was the most important predicting factor for NRM Active chronic GVHD was the most important factor predicting for reduced relapse risk. The cumulative probability of stopping IST by 7 years post SCT, for the entire cohort, was 73% (63-82). This probability was related to the conditioning regimen and was 80%,76%,80% and 63%, after FB2,FB4,FT and BuCy, respectively (p=0.06 for BuCy versus others). MVA identified conditioning with BuCy (HR 1.8, p=0.06) and male gender (HR 1.7, p=0.04) as predicting for prolonged need for IST. Among the 37 pts who were still on IST 2 years after SCT, the cumulative probability of stopping IST during the following 5 years was only 35%. It was higher in younger pts (59% Vs 15%, p=0.05) and in pts given FB2 (42% Vs. 31%, p=NS). In conclusion the pattern of late outcome is similar after MAC and RIC. Younger pts with AML/MDS who are leukemia-free 2 years after SCT can expect a very good outcome, while older pts are at higher risk for NRM and second cancers, which may not always relate directly to SCT. Pts given RIC are more likely to be able to stop IST, which may be associated with a better quality of life. Disclosures:No relevant conflicts of interest to declare.

A phase II clinical and biological study of lithium carbonate (Li) in patients with low-grade neuroendocrine tumors

e15662 Background: Low-grade neuroendocrine tumors (NETs), such as carcinoid, islet cell tumors, and medullary thyroid carcinomas, respond poorly to chemotherapy, and effective, less toxic therapies are needed. Glycogen Synthase Kinase (GSK)-3β, a multifunctional protein kinase, has been shown to regulate growth and hormone production in NETs. Use of lithium carbonate (Li) in murine models suppressed carcinoid cell growth, reduced GSK-3β levels and reduced expression of chromogranin A. This study assessed the efficacy of Li in patients with NETs. Methods: Eligible pts had pathologically-proven, measurable low-grade NETs. Prior treatment was allowed if completed &gt;4wks prior to registration. Standard eligibility criteria were used, and use of medications affecting Li metabolism or levels were prohibited. A single-arm, open-label, two-stage Phase II design was used. Li was dosed at 300mg orally TID with meals, titrated to a target serum level of 0.8–1.0mmol/L. The primary endpoint was objective tumor response by RECIST. Secondary endpoints included overall survival, progression-free survival, decrease of serum tumor markers, toxicity, and quality of life. Results: 15 pts were enrolled between 10/3/07and 7/17/08; 6 men, 9 women. The median age was 58 (range 47–74). Patients’ diagnoses were carcinoid tumor for 8 subjects, islet cell tumor for 5 subjects, and 2 unknown primary sites. ECOG PS was 0 (6 patients) or 1 (9 patients). Two pts came off study due to side effects (tremor, dizziness/abdominal pain). There were no radiographic responses. Due to an early stopping rule requiring at least 1 objective response in the first 13 evaluable pts, the study was closed to further accrual. 13 patients had pre- and post-therapy biopsies. Evaluation of quality of life and GSK-3β levels in tumor tissue is ongoing. Conclusions: Li was ineffective at obtaining a radiographic response in our 13 evaluable patients who were treated as part of this study. We will determine from tumor biopsies whether Li was effective at phosphorylating GSK-3β in order to make conclusions about GSK-3β as a therapeutic target for future NET treatment strategies. Funded through NIH grant R21CA117117- 01A2 and CTRC grant 1ULRR025011. No significant financial relationships to disclose.

A phase I study of vorinostat in combination with bortezomib in refractory solid tumors

2531 Background: Vorinostat (suberoylanilide hydroxamic acid, SAHA) is an oral histone deacytlase (HDAC) inhibitor that has anti-tumor activity in hematologic malignancies and advanced solid tumors. Vorinostat has been postulated to act synergistically with bortezomib at the level of aggresome inhibition with creation of reactive oxygen species. We previously conducted a study of this combination with once-daily dosing of vorinostat with bortezomib (Step A). This study (Step B) was conducted to evaluate twice daily dosing of vorinostat during administration of bortezomib to determine safety and efficacy, pharmacokinetics, and activity this combination. Methods: This study used standard eligibility criteria except patients must have had no prior bortezomib. The treatment plan initially consisted of vorinostat given orally twice daily on days 1–14 with bortezomib IV on days 1, 4, 8, and 11 of a 21 day cycle. Two DLTs (elevated ALT and fatigue) were observed at level 1, and the protocol was amended to administer vorinostat twice daily on days 1–4 and 8–11. Starting dose was vorinostat 200 mg and bortezomib 1 mg/m2. RECIST was used to measure response. Results: 29 pts have been enrolled; 13 men and 16 women. Tumor types include: Prostate (1), Colorectal (3), Pancreatic (6), Sarcoma (7), Biliary (1), Thymus (1), GIST (2), Mesothelioma (1), ovarian (1), Neuroendocrine (1), Lung (1), Head and Neck (1), Breast (2), and Cervical (1). Grade 3–4 toxicities possibly related to SAHA at any dose level were as follows: thrombocytopenia (5), fatigue (3), increased ALT (1), elevated INR (1), anemia, (1), hypotension (1), diarrhea (3), anorexia (1), dizziness (1), nausea/vomiting (1), and hypoalbuminemia (1). The only dose limiting toxicities included elevated ALT (1), fatigue (1). There were two deaths but neither was felt to be related to the drug. The MTD for Step B was established at vorinostat 300 mg BID and bortezomib 1.3 mg/m2. Conclusions: The MTD for Step B was established at vorinostat 300 mg BID and bortezomib 1.3 mg/m2. Subjective evidence of clinical activity has been observed in patients with refractory solid tumors. These studies were supported by NCI, UO1, CA062491, SAIC 25XS097, and 1ULRR025011. No significant financial relationships to disclose.

A phase I study of R-(-)-gossypol (AT-101) in combination with cisplatin (P) and etoposide (E) in patients with advanced solid tumors and extensive-stage small cell lung cancer (ES-SCLC)

e13502 Background: AT-101 [R-(-)-gossypol acetic acid] (AT) is an orally-administered BH3 mimetic that lowers the threshold for apoptosis by direct binding to Bcl-2, Bcl-xL, Mc1–1, Bcl-W, and through upregulation of the proapoptotic proteins Noxa and Puma. Bcl- 2 is over-expressed in &gt;80% of SCLC. In vitro study using SCLC cells showed that treatment with EP had synergistic cytotoxic effects in suppression of Bcl-2. This is a phase I dose-escalation study of AT in combination with EP with an expanded cohort of patients with ES-SCLC. This study is being conducted to determine the maximum tolerated dose (MTD), pharmacokinetics and activity of AT with EP ± pegfilgrastim (F) in patients with advanced, refractory solid tumors and/or ES-SCLC. Methods: This study used standard eligibility criteria except patients must not have received prior therapy that inhibits the Bcl-2 family. At dose level 1, patients received P 60 mg/m2 on day 1 and E 100 mg/m2 on days 1, 2, and 3 every 21 days. AT was administered 30 mg orally BID on days 1, 2 and 3 of each cycle. Results: 10 patients have been enrolled; 7 men, 3 women. Tumor types: 6 lung; 2 prostate; 1 head &amp; neck; 1 unknown primary. 2 of 5 patients enrolled at dose level 1 experienced a DLT of neutropenic fever in cycle 1. Three subsequent patients were enrolled to dose level -1 (20 mg BID x 3 days, d1–3) which was well tolerated. Additional patients are being enrolled at dose level 1a (EP+AT with F). Grade 3/4 toxicities related to AT without F at dose level 1 and -1 were as follows: ANC (8), leucopenia (7), febrile neutropenia (2), low hemoglobin (1), thrombocytopenia (1), elevated AST (1), cardiac ischemia/MI (1), diarrhea (1). There were no reported grade 3/4 toxicities in two patients at level 1a. Four patients had stable disease; two progressive disease and four patients were unevaluable. Conclusions: The MTD without F was established at AT 20mg orally BID, P 60 mg/m2 on day 1, and E 100 mg/m2 on days 1, 2, and 3 every 21 days. The MTD with F has not yet been established. Accrual continues at dose level 1a. Subjective and objective evidence of clinical activity has been observed in patients with refractory solid tumors. This study was supported by NCI, UO1 CA062491, SAIC 25XS097 and 1ULRR025011. No significant financial relationships to disclose.

Randomized clinical trial eligibility rates for chemotherapy (CT) and antiangiogenic therapy (AAT) in a population-based cohort of newly diagnosed non-small cell lung cancer (NSCLC) patients

6538 Background: NSCLC leads the US in cancer deaths, but randomized clinical trials (RCT) of CT with/without antiangiogenic therapy (AAT) are relatively slow to accrue. Treatment guidelines for NSCLC are based on RCTs that enroll patients with a mean age of 62–64 without serious comorbidities. SEER mean age of NSCLC diagnosis in the US is 70. Methods: 326 consecutively diagnosed (from January 1, 2006) NSCLC patients from a large prepaid health care delivery system (Kaiser Permanente Northern California-KPNC), were retrospectively evaluated by manual chart and electronic medical record review for eligibility criteria (EC) to enter treatment defining RCTs, i.e. E4599, S0023. The KPNC members are representative of the regional population. Ineligibility, the main endpoint, was determined on imaging and laboratory tests and history in the medical record. This may overestimate eligibility. Results: Age at diagnosis:&lt;60years-18%, &lt;65–28%, &lt;70–50%, &gt;75–34%, &gt;80–18%; mean (SD)age- 69.3 (10.6). Male:Female 51:49%. Adeno-49%; Squamous-22%; LargeCell-2.5%; NSC NOS-27%. Current/former smokers-90%. Staging: IA-14%; IB-13%; IIA+B-4%; IIIA-17%; IIIB+IV-52%. Surgical resection-26%. When standard RCT eligibility criteria were applied to the entire cohort, 34% (CI 29%-39%) were eligible. Only 23% (CI 19%-28%) were both eligible and &lt;75yo. stage IIIB+IV patients were 29% (CI 24%-36%) eligible at all ages, 20% (15%-26%) were both eligible and &lt;75yo. When AAT EC were added, 21% (17%-26%) were eligible for all ages, 14% (CI 10%-18%) eligible and &lt;75yo., and 9%(CI 6%-13%) eligible and &lt;70yo. Conclusions: Treatment guidelines for NSCLC are based on RCTs enrolling the healthiest quartile of the youngest half of patients. The majority of NSCLC patients are excluded by trial eligibility criteria or subjective age criteria from entering CT and/or AAT RCTs. Toxicities in these older and more comorbid NSCLC patients likely alter the risk:benefit ratio. RCTs specific for the 70+yo and comorbid NSCLC patients are needed to help define the best therapy for this understudied majority of lung cancer patients. No significant financial relationships to disclose.

Phase III study of standard triweekly versus dose-dense biweekly capecitabine (C) + oxaliplatin (O) + bevacizumab (B) as first-line treatment for metastatic colorectal cancer (mCRC): XELOX-A-DVS (dense versus standard): Interim analysis

4078 Background: Every 3 week (Q3W) COB has been shown to be highly active and non-inferior to FOLFOX+B in first-line mCRC. Phase II data suggest that dose-dense every 2 week (Q2W) COB may be significantly more active and better tolerated than Q3W COB. Methods: XELOXA-DVS was a phase III, open-label study of 435 patients with chemonaive mCRC who met standard eligibility criteria. Patients were randomized to Q3W: C 850 mg/m2 BID d1–14 + O 130 mg/m2 d1 + B 7.5 mg/kg d1 or Q2W: C 1500 mg/m2 BID d1–7 + O 85 mg/m2 d1 + B 5 mg/kg d1 for up to 72 weeks. Complete surgical resection was allowed using pre-defined criteria. The primary endpoint, progression-free survival (PFS), was estimated using the Kaplan- Meier method, while the hazard ratio and 95% CI were estimated using Cox regression analysis, based on the intent-to-treat population. No formal statistical testing was conducted. Results: The median PFS was 8.4 months (Q2W) and 9.7 months (Q3W) (hazard ratio [HR]=0.84; 95% CI=0.62–1.13). The median PFS (on-treatment) was 9.1 months and 10.2 months, respectively (HR=0.81). Of the 72 and 73 patients with disease progression (DP), the median time to DP was 9.4 and 10.8 months, respectively (HR=0.86). The objective response rates were 21.7% vs 29.4%, respectively (HR=1.05). Patients in the Q2W vs Q3W group experienced higher rates of grade 3/4 diarrhea (29% vs 24%), hand-foot syndrome (12% vs 8%), and treatment discontinuation rates (40% vs 20%), respectively. Other grade 3/4 toxicities (&gt;5%, Q2W vs Q3W) included fatigue (13% vs 13%), dehydration (12% vs 10%), nausea (8% vs 9%), peripheral neuropathy (5% vs 9%), anorexia (5% vs 7%), and abdominal pain (5% vs 7%). Conclusions: At the dose and schedule used, dose-dense Q2W COB was not superior to standard Q3W COB. These data further confirm the activity and tolerability of Q3W COB. The activity and tolerability of a lower C dose Q2W, with more aggressive dose reduction, combined with B and O or irinotecan is currently being evaluated (X-BIO). [Table: see text]

Initiation of Assertive Community Treatment Among Veterans With Serious Mental Illness: Client and Program Factors

Initiation of Assertive Community Treatment Among Veterans With Serious Mental Illness: Client and Program Factors

Conditioning Regimens Prior to Allogeneic Stem-Cell Transplantation (SCT) In Acute Leukemia: The Role Of Dose Intensity

Allogeneic SCT with both myeloablative and reduced-intensity conditioning (RIC) is effective therapy in acute leukemia. To better define the role of dose intensity in SCT, we retrospectively analyzed SCT outcomes in 356 consecutive adult patients (pts) with MDS/AML (n = 277) and ALL (n = 79) given SCT over an 8-year period in a single institution. The median age was 51 (range, 17–75). The donors were HLA-matched siblings (n = 191), matched unrelated (n = 139) and alternative (n = 26). Pts meeting standard eligibility criteria were routinely given myeloablative conditioning (MAC, Cy/TBI or BuCy, n = 141). Pts non-eligible for MAC were given either RIC (fludarabine and reduced doses of busulfan or melphalan, n = 116) or modified myeloablative conditioning (modMAC, fludarabine with myeloablative doses of busulfan or treosulfan, n = 99). Disease status at SCT was CR1/ CR2 (n = 176), previously untreated or untreated relapse (n = 63) and chemo-refractory (n = 117). With a median follow-up of 30 months (range 1–103), 159 pts are alive and 197 died; 75 of treatment-related causes and 122 of relapse. The estimated 5-yr overall survival (OS) in this relatively high-risk pt group was 34% (95%CI, 27–41). The status of disease at SCT was the most important factor predicting OS; 48, 31 and 16% for pts in CR, untreated or chemo-refractory leukemia, respectively (p<0.001). Multivariable analysis (MVA) identified SCT not in CR, SCT from unrelated and alternative donors as adverse prognostic signs with hazard ratios (HR) of 2.7, 1.5, and 2.2, respectively. The conditioning regimen used was not a significant factor in the whole pt group with 5-yr OS of 38, 35 and 31% after MAC, modMAC and RIC, respectively (p = NS). However, RIC was associated with reduced OS in 2 subgroups. Among pts with MDS/AML given SCT not in CR, 5-yr OS was 34, 24 and 13% after MAC, modMAC and RIC, respectively (p = 0.03) with HR of 1.6 for RIC in MVA. In the group of ALL pts, MVA identified RIC and SCT not in CR1 as adverse prognostic signs with HR of 2.0 (p = 0.04) and 2.0 (p = 0.03), respectively. In conclusion, MAC should still be considered the standard of care for SCT in acute leukemia in eligible pts. RIC is associated with inferior outcome in pts with ALL and pts not in CR at SCT. Randomized studies are needed to determine the role of RIC in MDS/AML pts in CR at SCT. The novel modMAC regimens are relatively well tolerated even in pts not eligible for MAC and may be more effective than standard RIC in refractory disease.

Dosage Escalation Study of S-1 and Irinotecan in Metronomic Chemotherapy against Advanced Colorectal Cancer

The anti-angiogenic efficacy of chemotherapy would seem to be optimized by administering comparatively lower doses of drugs on a more frequent (daily, several times a week, or weekly) or continuous schedule, with no extended interruptions - sometimes referred to as 'metronomic' chemotherapy. This phase I study was performed to determine the recommended dosage (RD) of metronomic chemotherapy using oral fluoropyrimidine S-1 plus weekly irinotecan (CPT-11) in patients with previously untreated advanced or recurrent colorectal cancer. Patients received first-line chemotherapy consisting of 80 mg/m(2) of S-1 given on days 3 to 7, 10 to 14, and 17 to 21 with escalating dosages of CPT-11 (from 40 mg/m(2)) administered intravenously on day 1, 8, and 15 of a 28-day cycle. Standard patient eligibility criteria were used. Based on the concept of metronomic chemotherapy, dose limiting toxicity (DLT) was defined any toxicity that resulted in skipping of CPT-11 administration, or more than 5 days suspension in S-1 administration, in addition to the conventional criteria. If the maximum tolerated dosage (MTD) was defined as the maximum dosage at which no suspension of CPT-11 or S-1 administration occurred, the RD was considered to be the dosage one rank lower than the MTD. On the other hand, in the present study the MTD was defined as the dosage at which at least one suspension of CPT-11 or S-1 administration occurred, the MTD was considered to be the RD. Two of the first 3 patients at level 4 received 60 mg/m(2) of CPT-11 and 80 mg/m(2) of S-1 experienced a suspension in CPT-11 administration, thus level 4 was defined as the MTD and RD. Sixty mg/m(2) of CPT-11 and 80 mg/m(2) of S-1 were the indicated RD for the following phase II study of metronomic chemotherapy.

BuCy Provides Equivalent Outcomes to VCyTBI as Conditioning Prior to Auto-SCT in Patients with Relapsed/Refractory NHL and Is a Valuable Option in Older (≥60 years) Patients.

Cyclophosphamide+total body irradiation +/− etoposide (CyTBI+/−V) is a standard conditioning regimen prior to auto-SCT for NHL patients. However, TBI-based dose intensive therapy is often contraindicated in older patients, or those with prior radiation. We performed a single-institution Phase II non-randomized prospective study of VCyTBI vs. Busulfan+Cy (BuCy) to determine if BuCy provides comparable disease control to standard dose intensive therapy with VCyTBI. BuCy was used in patients ≥60 years and when TBI was contraindicated. Seventy-five relapsed or refractory NHL patients underwent auto-SCT at Roswell Park Cancer Institute from 8/92 to 7/05. All patients were treated on a single IRB-approved protocol with standard eligibility criteria including age ≥18 and ≤70, adequate cardiac, pulmonary, hepatic and renal function and KPS ≥70. All patients signed informed consent and were followed prospectively. All data have been de-identified. Survival status for all patients was updated through 8/1/08. VCyTBI (N=47) consisted of V 1800 mg/m2 26-hour continuous iv infusion on day -5, Cy 60 mg/kg day -4 (12 patients received 180 mg/kg total dose), and TBI 200 cGy on days -3, -2, and -1 for total dose of 1000 cGy (8 patients received 1200 cGy). BuCy (N=28) consisted of iv Bu 0.8 mg/kg every 6 hours on days -7, -6, -5, -4 (total 12.8mg, one patient received oral Bu total dose 16 mg/kg) and Cy 60 mg/kg on days -3 and -2 (total 120 mg/kg, one patient received total dose 200 mg/kg). Eight patients received iv Bu without dose adjustment and 19 received iv Bu with dose adjusted to maintain a steady state level between 600– 900 ng/ml. Stem cells were re-infused on day 0. Patients received peripheral blood stem cells (n=53), bone marrow (n=14) or both (n=8). The median age was significantly higher in the BuCy compared to the VCyTBI group (61.5 vs 53 years, p=0.0002), and there were fewer patients with a KPS of 90–100 in the VCyTBI group (75% vs 93%, p=0.07). There were no significant differences on the following patient characteristics by BuCy vs VCyTBI: gender, disease risk, stem cell source, histology (diffuse, follicular, mantle, other), or remission status at SCT. Treatment-related mortality at day+100 post-auto SCT was very low in both groups: 0% in BuCy and 2% in VCyTBI. However, 3 patients in the VCyTBI group and none in the BuCy group developed AML at 1.3, 1.8 and 6.5 years post-auto-SCT. At a median follow-up of 4.6 years, the 5-year progression-free survival for BuCy and VCyTBI was 32% (95% CI 14–50%) and 24% (95% CI, 11–39%, P>0.8), respectively. The 5-year overall survival for BuCy and VCyTBI was 46% (95% CI 25– 64%) and 49% (95% CI 33–64%, P>0.7), respectively. Multivariate analysis controlling for age and KPS at BMT also demonstrated no significant difference between BuCy and VCyTBI for either progression-free (RR=0.9, 95% CI 0.5–1.8) or overall (RR=0.7, 95% CI 0.3–1.6) survival. This is the largest reported study evaluating the efficacy of BuCy as alternative conditioning for auto-SCT in relapsed/refractory NHL. BuCy provides equivalent survival outcomes to VCyTBI as conditioning for auto-SCT in NHL patients. Based on these results, our practice continues to use BuCy for NHL patients ≥60 years.

The maximum tolerated dose and biologic effects of 3-amino-pyridine-2-carboxaldehyde thiosemicarbazone (T) in combination with irinotecan (I) for patients with refractory solid tumors

2527 Background: T is a small molecule inhibitor of ribonucleotide reductase (RR) and has been postulated to act synergistically with I. This study was conducted to determine the toxicity and antitumor activity of T with I. Correlative studies included pharmacokinetics, ABCB1 polymorphisms, and the effects of T on cell cycle and electron paramagnetic resonance (EPR). Methods: This study used standard eligibility criteria; in addition, patients (pts) must have had no prior I and no G6PD deficiency. The treatment plan consisted of I on day 1 with T on days 1–3 of a 21-day cycle. Starting dose (level 1) was I 150 mg/m2 and T 85 mg/m2/d. Polymorphisms in ABCB1 were evaluated by pyrosequencing, T concentrations were evaluated in plasma and erythrocytes by HPLC, and Fe-T, Cu-T and cytochrome c release were evaluated by EPR. Results: 23 pts were enrolled, 10 men, 13 women. Tumor types: 7 pancreatic, 4 lung, 2 cholangio, 2 mesothelioma, 2 ovarian, and 1 each of esophageal, sarcoma, gastric, lymphoma, cervical, an...

How Many Forensic Assertive Community Treatment Teams Do We Need?

Despite the growing interest in forensic assertive community treatment (FACT), there is no standardized definition of FACT eligibility and no guidelines for how many FACT teams communities may need. In this brief report a definition for FACT eligibility is proposed-severe and persistent mental illness and three jail detentions in a one-year period-and modeled by using 5.5 years of administrative data (July 1, 1993, through December 31, 1998) from a large, urban county in the western United States. Findings suggest that large, urban communities should develop enough FACT teams to serve approximately 44% of their populations of persons with severe mental illness, or roughly .05% of their adult populations. Developing standardized eligibility criteria for FACT is an important first step toward developing its evidence base.

How Many Forensic Assertive Community Treatment Teams Do We Need?

Despite the growing interest in forensic assertive community treatment (FACT), there is no standardized definition of FACT eligibility and no guidelines for how many FACT teams communities may need. In this brief report a definition for FACT eligibility is proposed-severe and persistent mental illness and three jail detentions in a one-year period-and modeled by using 5.5 years of administrative data (July 1, 1993, through December 31, 1998) from a large, urban county in the western United States. Findings suggest that large, urban communities should develop enough FACT teams to serve approximately 44% of their populations of persons with severe mental illness, or roughly .05% of their adult populations. Developing standardized eligibility criteria for FACT is an important first step toward developing its evidence base.

A phase I study of vorinostat in combination with bortezomib in refractory solid tumors

3573 Background: Vorinostat (suberoylanilide hydroxamic acid, SAHA) is a histone deacetylase (HDAC) inhibitor that has anti- tumor activity in hematologic malignancies and advanced solid tumors. Based on studies showing that HDAC inhibitors increase the activity of the 26S proteasome, vorinostat has been postulated to act synergistically with bortezomib. This study was conducted to determine the toxicities and efficacy of vorinostat with bortezomib. Correlative studies included pharmacokinetics and the effects of vorinostat/bortezomib on cell cycle, proteasome inhibition, histone acetylation, gene expression and apoptosis. Methods: This study used standard eligibility criteria except pts must have had no prior bortezomib. The treatment plan consisted of vorinostat given orally on days 1–14 with bortezomib IV on days 1, 4, 8 and 11 of a 21-day cycle. Starting dose (Step A, level 1) was once-daily vorinostat (400 mg) and bortezomib (0.7 mg/m2). Step B consisted of twice-daily dosing of vorinostat (200mg) with bortezomib at MTD established in Step A. RECIST was used to measure response. Effects on G2/M-phase arrest in buccal mucosa cells (BMC) were measured using flow cytometry. Samples were collected on days 1 and 9, at 0, 2 and 4 hr following treatment. Results: 22 pts have been enrolled; 14 men, 8 women. Tumor types: 5 sarcoma, 5 colorectal, 3 pancreatic, 2 lung, 1 breast, 1 ovarian, 1 bladder, 1 gastric, 1 germ cell, 1 mesothelioma, 1 GIST. Grade 3–4 toxicities at least possibly related to vorinostat at any dose level were as follows: fatigue (3), n/v (1), thrombocytopenia (1), and hyponatremia (1). One pt was unevaluable. DLTs included fatigue (3), hyponatremia (1) and elevated ALT (1). The MTD for Step A was established at vorinostat 400mg daily and bortezomib 1.3 mg/m2. One pt with refractory soft tissue sarcoma had a PR &gt; 9 mo. There was no effect on cell cycle arrest observed with vorinostat in BMCs. Conclusions: The MTD for Step A was established at vorinostat 400mg daily and bortezomib 1.3 mg/m2. Accrual continues at Step B, dose level 1. Subjective and objective evidence of clinical activity has been observed in pts with refractory solid tumors. (Supported by NCI grant UO1 CA062491, NCI SAIC contract 25XS097 and GCRC M01 RR03186.) No significant financial relationships to disclose.

Impact of Femoropopliteal Bypass Surgery on the Survival and Amputation Rate of End-Stage Renal Disease Patients with Critical Limb Ischemia

The appropriate medical approach to treat patients with end-stage renal disease (ESRD) and critical limb ischemia (CLI) is still controversial. The goal of this study was to investigate the survival rate of ESRD patients with foot ulcers who underwent femoropopliteal bypass surgery versus patients who did not receive any major surgical interventions. A 5-year Kaplan-Meier survival analysis of 99 ESRD subjects with foot ulcers, stage IV, recruited in the authors' single-center study between 1997 and 2005, was performed. 27 patients underwent bypass surgery because of meeting standard eligibility criteria for this procedure, and 72 patients received only conventional treatment due to their poorer vascular condition. Patients were censored upon major amputation during the observation period. Start of the observation was date of ulcer diagnosis. Survival rate was 16.2% (standard error [SE], 0.08) in the bypass group versus 18.6% (SE, 0.06) in the non-bypass group (p = 0.92; log-rank test). Median time to bypass surgery was 0.36 years (range, 0-2.65 years) after ulcer diagnosis. Six patients of 27 (22.2%) were censored due to major amputation in the bypass group versus 25 patients of 72 (34.7%) in the non-bypass group. These results may suggest that bypass surgery in ESRD patients with foot ulcers as treatment of CLI is not the appropriate surgical approach, since this procedure does not seem to cause a better survival than in patients who could not undergo revascularization surgery because of their poorer overall vascular condition.

Clofarabine Is Active in Myelodysplastic Syndrome (MDS).

Background. Clofarabine, an adenosine nucleoside analog, is active in acute myeloid leukemia (AML) and acute lymphoid leukemia (ALL). Its anti-MDS activity is not well defined. Study Aims. To evaluate the safety and efficacy of clofarabine in MDS in two studies, one with intravenous administration and one with oral, using lower doses than those for leukemia (40–52 mg/m2 IV daily x 5). Study Group and Results. The first study randomized patients in a Bayesian design to receive clofarabine 15 or 30 mg/m2 IV daily x 5 every 4–6 weeks. The second study used clofarabine 40 mg/m2 orally daily x 5 every 4–6 weeks (assuming oral bioavailability about 50%). Standard eligibility criteria for MDS were used; only high risk MDS patients (IPSS intermediate or high) were eligible. So far, 16 patients have been treated, 10 on IV clofarabine and 6 on oral clofarabine. Age ≥60 yr in 13 (81%); prior therapy with decitabine/azacitidine 11 (69%); cytogenetic abnormalities 12 (75%). Responses were graded according to International Working Group criteria (IWG). Results are shown in the table below. Myelosuppression was significant resulting in febrile episodes and hospitalization in 4/6 patients on oral clofarabine and in 4/10 patients on IV clofarabine. Rash grade 3 was noted in 1 patient on oral clofarabine. Summary. Clofarabine is active in MDS. The oral dose of 40 mg/m2 daily x 5 may be too high for MDS; lower dose of oral clofarabine 30 mg/m2 orally daily x 5 will be tested with PK studies. The 2 IV schedules (15 vs. 30 mg/m2) are ongoing. Oral Clofarabine IV Clofarabine • Treated/evaluable to date 6/3 10/6 • Response - CR 2 (67%) 3 (50%) - Other IWG response -- 1 (17%)

A phase I study of triapine in combination with irinotecan in refractory tumors

12011 Background: Triapine is a small molecule inhibitor of ribonucleotide reductase and has anti-tumor activity alone and in combination with other agents in advanced solid tumors. Based on its ability to limit DNA repair, Triapine has been postulated to act synergistically with irinotecan. This study was conducted to determine the toxicities and efficacy of Triapine with irinotecan. Correlative studies included: pharmacokinetics, MDR polymorphisms, and the effects of Triapine on cell cycle and electron paramagnetic resonance spectroscopy. Methods: This study used standard eligibility criteria with the following exceptions: patients must have had no prior irinotecan and no G6PD deficiency. The treatment plan consisted of irinotecan on day 1 with Triapine on days 1- 3 of a 21-day cycle. Starting dose (level 1) was irinotecan (150 mg/m2) and Triapine (85 mg/m2/day). RECIST was used to measure response. Results: 10 patients have been enrolled; 5 men, 5 women. Tumor types: 4 pancreatic, 2 cholangio, 1 esophageal, 1 sarcoma, 1 lung, 1 ovarian. Grade 3–4 toxicities at least possibly related to Triapine at any dose level were as follows: neutropenia (3), leukopenia (2), fatigue, hypoxia, nausea, vomiting, thrombocytopenia, abdominal cramping, hypocalcemia, and thrombosis. The first patient enrolled at level 1 developed a DLT (Grade 3 hypoxia). Consequently, irinotecan and Triapine doses were reduced to 100 mg/m2 and 60 mg/m2/day, respectively (level -1). One of 6 patients experienced a DLT at this dose level. Further patients were then enrolled at level 1. There were 2 DLTs of 4 patients at level 1. One partial response (NSCLC) was seen. Conclusions: Unacceptable toxicities were seen at dose level 1; however, dose level -1 was well tolerated. The trial has therefore been amended in order to evaluate a higher dose of irinotecan (150 mg/m2) with the level -1 dose of Triapine (60 mg/m2/day). Accrual continues at this dose level. Antitumor activity in NSCLC was noted at level 1. [Table: see text]