Allogeneic hematopoietic cell transplantation (HCT) is a potentially curative approach in patients with multiple myeloma, but its use for consolidation of first remission has not yet been fully explored. Twenty-two myeloma patients with very good partial response (VGPR) or CR received allogeneic peripheral blood grafts as consolidation from HLA-matched donors between 2007 and 2012. Conditioning regimens were fludarabine (30 mg/m2 i.v. if with bortezomib and 40 mg/m2 i.v. when without bortezomib, × 4 days) plus melphalan (70 mg/m2 intravenously × 2 days) with (n=13) or without (n=9) bortezomib (1.3 mg/m2). The cumulative incidence of grades II – IV acute GVHD at day 100 was 45% (95% CI: 24–65%) and moderate-to-severe chronic GVHD at 2 years was 46% (95% CI: 19–69%). With a median follow-up of 18 (range, 2–61) months, the 2-year PFS estimate is 74.8% (95% CI: 45–90%), which compares favorably with the 52% (95% CI: 35–66%) after autologous HCT for similar patients (a median follow-up of 30 (range, 9–55) months). We are conducting a phase 2 study to assess the efficacy of allogeneic HCT as post-remission therapy.

Abstract 4158 Background: High-dose chemotherapy followed by autologous hematopoietic cell transplantation (HCT) is a preferred primary treatment approach for those patients who have adequate organ function and performance status. We previously reported the use of melphalan + bortezomib conditioning regimen for tandem transplants in a different group of patients with refractory myeloma (Alekshun, et al. ASH 2007). In this study, we examine the effects of adding bortezomib to standard high-dose melphalan in patients with newly diagnosed myeloma who have chemosensitive disease. Methods: Thirty five newly diagnosed multiple myeloma patients with responsive disease (partial response (PR) or better) to induction therapy were enrolled to the study from January 2010 to June 2011. Patients received high-dose melphalan conditioning at 100 mg/m 2 IV for 2 days, immediately followed by 1 dose of bortezomib at 1.3 mg/m 2 (Mel/Vel). Those patients who achieved PR post induction were considered for tandem autologous transplant with Mel/Vel conditioning. Results: To date, 35 patients received autologous HCT conditioned with Mel/Vel, and 32 are evaluable for response. Median age is 56 years (range, 25 – 72) with the following disease characteristics: IgG (n=21), IgA (n=8), IgD (n=1), light chain (n=5). High-risk cytogenetics/FISH were seen in 13 patients (37%). Median beta-2 microglobulin was 3.5 (range, 1.3 – 34.8). Sixteen patients received bortezomib-based induction, 9 patients received lenalidomide-based therapy and 10 received both bortezomib and lenalidomide. Median time from initiation of induction to transplant was 221 days (range, 134 – 664). Responses to induction therapy were stringent CR (n=10), CR (n=4), very good partial response (VGPR) (n=13), and PR (n=8). Median CD34 cell dose is 4.86 × 10 6 /kg (range, 2 – 20.08). Neutrophil engraftment was achieved after a median of 11 days (range, 10 – 14) and platelet engraftment occurred after a median of 16 days (range, 11 – 19). Two patients received tandem HCT. Best responses post transplant were sCR (n=19), CR (n=3), VGPR (n=7), PR (n=1) and progressive disease (n=2). The one year progression-free survival (PFS) estimate is 77% (95% CI 0.59 – 0.95) and one year overall survival (OS) estimate is 96% (95% CI 0.88 – 1.00) with a median follow-up of 279 days (range, 47 – 515). We did not detect significant differences in OS (p=0.69) stratified by cytogenetic/FISH risk status. Conclusions: The combination of bortezomib and high-dose melphalan (Mel/Vel) as conditioning regimen for autologous HCT is well tolerated and appears to improve responses post transplant. This early result is encouraging and the regimen will be examined in expanded cohort of patients. Disclosures: Baz: Millenium: Research Funding, Speakers Bureau; Celgene: Research Funding. Alsina: Millennium: Consultancy, Membership on an entity9s Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity9s Board of Directors or advisory committees; Allergan: Research Funding.

Relapse remains a leading cause for treatment failure after hematopoietic cell transplantation (HCT) in patients with intermediate- or high-risk myelodysplastic syndrome (MDS). To discern the impact of 5-azacitine treatment pretransplant on the risk for relapse after HCT, we analyzed the post transplant outcomes of all 54 consecutive patients with MDS or chronic myelomonocytic leukemia who received HCT from HLA-compatible donors according to pretransplant 5-azacitidine exposure. Thirty patients received a median of four (1–7) cycles of 5-azacitidine, and 24 patients did not receive 5-azacitidine before HCT. The 1-year estimates of overall survival, relapse-free survival and cumulative incidence of relapse were 47, 41 and 20%, for 5-azacitidine patients and 60, 51 and 32%, respectively, for non-5-azacytidine patients. These observations suggest that outcomes are similar in both groups with a trend toward decreased early relapse in patients receiving 5-azacitidine. 5-Azacitidine may be of value in stabilizing the disease, thereby allowing time for patients to reach transplant and does not appear to affect transplant outcomes.

Abstract Abstract 3347 Poster Board III-235 We report here our experience with 145 consecutive patients (pts) treated with IV busulfan and fludarabine (BuFlu) as conditioning prior to allogeneic hematopoietic cell transplant (HCT). Bu was dosed at 130mg/m2/day on days 1 and 2 with pharmacokinetic (PK) targeting for days 3 and 4; the dose of Flu was 40mg/m2/day for 4 days. The median age was 48 (range 22-68) years. Median HCT Comorbidity Index (HCT-CI) was 3 (range 0-9) and median Karnofsky performance status (KPS) was 100% (60-100%). Sixty-two pts received grafts from HLA matched siblings, 61 from matched unrelated donors (MUD), and 22 from 1 antigen/allele mismatched MUD (mMUD). Disease status was categorized in 50 pts as standard risk (acute leukemia in CR1 or CML in CP1) and in 91 pts as high risk (including acute leukemias > CR1, CML.>.CP1, MDS, MPD, lymphoma, myeloma, and CLL). 4 pts had aplastic anemia. Bu doses were targeted to a daily area under the concentration time curve (AUC) value of 5300 uM*min. Median actual AUC after the first dose was 5002 uM*min (range 3609-8190 uM*min) and doses 3 and 4 were adjusted in 92 pts (63%) to achieve the overall target AUC. Median total Bu dose to achieve AUC target was 520 mg/m2 (range 332-1040 mg/m2). Median Bu clearance (Cl) was 2.7 ml/min/kg (range 1.5-5.2 ml/min/kg). Maximum Bu concentrations (Cmax) after the first dose was 3315 ng/ml (range 1135-4848 ng/ml). First dose Bu AUC, Cmax, and Cl were not correlated with age, race, ethnicity, KPS, or HCT-CI. Women had significantly higher Cl than men (median 2.9 vs 2.6 ml/min/kg; p=0.001). Grade 3 or 4 elevations in hepatic transaminases occurred in 15 pts (10%), hepatic VOD/SOS in 6 pts (4%), and interstitial pneumonitis in 4 pts (3%). None of these toxicities were associated with any of the PK parameters measured. 100 day and 1 year non-relapse mortality (NRM) were 7% and 23% respectively. In multivariable analyses, neither first dose Bu AUC nor Bu Cl were associated with NRM. Having an unrelated donor (MUD: HR 2.68; p=0.025 and mMUD: HR 3.64; p=0.009) and a diagnosis of CML (HR 3.82; p<0.001) or lymphoma (HR 5.15; p=0.005) were associated with increased NRM. In multivariable analyses of relapse, only first dose AUC was significantly associated, with >6000 uM*min predictive of an increased risk of relapse (HR 2.66; p=0.007). The only significant predictor of overall and progression-free survival in multivariable analysis was disease risk. Overall and progression -free survivals at 2 years for the standard risk vs high risk groups were 61% and 57% vs 39% and 32% (p=0.04 and p=0.03, respectively). The increased risk of relapse in the high first dose AUC group may be related to an association between Bu Cl and uptake into malignant cells or the presence of a larger proportion of patients in this group with high risk features other than the predefined disease risk. We conclude that PK targeting of Bu provides a safe method of delivering high doses given that increased toxicity and NRM were not seen in pts with high first dose AUC due to dose adjustment. Disclosures: Perkins: PDL BioPharma: Research Funding. Off Label Use: IV Busulfan and Fludarabine for pre-transplant conditioning. Fernandez:Otsuka: Consultancy. Field:PDL BioPharma: Research Funding.

Introduction: Allo SCT offers long term control and in some cases cure in patients with MM. In this study we reviewed our experience at H. Lee Moffitt Cancer Center, of Allo SCT for MM and examined indicators of long term survival.Patient and Methods: A retrospective analysis was performed on patients with MM who underwent allo SCT between 1996 to 2008 at our institution. Kaplan-Meier estimates were used to determine overall and progression free survival.Results: Thirty-one patients(18 males and 13 females) underwent AlloSCT for MM between 1996 and 2008. The median age was 45 years(range 29–63). The majority (64%) were Durie-Salmon stage III at diagnosis. Most patients(74%) received at least 2 lines of prior treatment and 16 received prior autologous transplant including 4 who received 2 autotransplants(2 out 4 were tandem).Disease status prior to Allo SCT included 4 CR, 3 VGPR, 11 PR and 5 100 months) did get TBI containing regimens in this analysis. However the melphalan-fludarabine patients look promising, but require longer follow up. A multivariate analysis of the prognostic factors is ongoing. Introduction: Allo SCT offers long term control and in some cases cure in patients with MM. In this study we reviewed our experience at H. Lee Moffitt Cancer Center, of Allo SCT for MM and examined indicators of long term survival. Patient and Methods: A retrospective analysis was performed on patients with MM who underwent allo SCT between 1996 to 2008 at our institution. Kaplan-Meier estimates were used to determine overall and progression free survival. Results: Thirty-one patients(18 males and 13 females) underwent AlloSCT for MM between 1996 and 2008. The median age was 45 years(range 29–63). The majority (64%) were Durie-Salmon stage III at diagnosis. Most patients(74%) received at least 2 lines of prior treatment and 16 received prior autologous transplant including 4 who received 2 autotransplants(2 out 4 were tandem).Disease status prior to Allo SCT included 4 CR, 3 VGPR, 11 PR and 5 100 months) did get TBI containing regimens in this analysis. However the melphalan-fludarabine patients look promising, but require longer follow up. A multivariate analysis of the prognostic factors is ongoing.

Histone deacetylase inhibitors (HDACi) can sensitise cancer cells to topoisomerase inhibitors by increasing their access and binding to DNA. This phase I trial was designed to determine the toxicity profile, tolerability, and recommended phase II dose of escalating doses of the HDACi vorinostat, with weekly doxorubicin. In total, 32 patients were treated; vorinostat was dosed at 400, 600, 800, or 1000 mg day−1 on days 1–3, followed by doxorubicin (20 mg m−2) on day 3 for 3 of 4 weeks. Maximal tolerated dose was determined to be 800 mg day−1 of vorinostat. Dose-limiting toxicities were grade 3 nausea/vomiting (two out of six) and fatigue (one out of six) at 1000 mg day−1. Non-dose-limiting grade 3/4 toxicities included haematological toxicity and venous thromboembolism. Antitumor activity in 24 evaluable patients included two partial responses (breast and prostate cancer). Two patients with melanoma had stable disease for ⩾8 months. Histone hyperacetylation changes in peripheral blood mononuclear and tumour cells were comparable. Histone hyperacetylation seemed to correlate with pre-treatment HDAC2 expression. These findings suggest that vorinostat can be combined with weekly doxorubicin in this schedule at a dose of 800 mg day−1. The HDAC2 expression may be a marker predictive of HDAC inhibition. Antitumor activity of this regimen in breast cancer, prostate cancer, and melanoma seems interesting.

Tabled 1Multivariable Regression Analysis for OS and NRS† Post-transplant variables at day 90 (±7) post-allo HCT §OSNRSHospital stay (≤5 vs. >5 days)∗from hematopoietic engraftment until day 90 (±7).NSNSDays of TPN (>0 vs. 0)∗NSNSPRBC transfusion (>0 vs. 0)∗from hematopoietic engraftment until day 90 (±7).NSNSPlatelets transfusion (>0 vs. 0)∗from hematopoietic engraftment until day 90 (±7).NSNSPneumonia episodes (>0 vs. 0)∗from hematopoietic engraftment until day 90 (±7)., ¥development of infiltrates requiring additional/alternative antimicrobials.NSp=0.0008; 2.8 (1.5, 5.1)Episodes of CMV reactivation (>0 vs. 0)∗from hematopoietic engraftment until day 90 (±7).NSNSCumulative dose of steroids (<2,650mg vs. ≥ 2,650mg)∗from hematopoietic engraftment until day 90 (±7).NSp=0.001; 0.4 (0.2, 0.7)Total days of steroids (<60 vs. ≥60)∗from hematopoietic engraftment until day 90 (±7).NSNSDose of steroid at day 90 (±7) (<20 vs. ≥20mg/day)NSNS% weight loss (≤10% vs. >10%)from initiation of conditioning chemotherapy (baseline) until day 90 (±7).NSNSAcute GVHD (max grade) 0-I vs. II vs. III-IVNSNSKPS at day 90 (±7) (<80 vs. ≥80)p<0.0001; 4.7 (3.0, 7.4)p<0.0001; 3.9 (2.0, 7.5)Total bilirubin at day 90 (±7) (<1.1 vs. ≥1.1mg/dl)NSNS% Creatinine change (≥30 vs. <30)∗from hematopoietic engraftment until day 90 (±7).p=0.0002; 2.2 (1.5, 3.3)NSAlbumin at day 90 (±7) < 3.0 g/dl vs. > 3.5 g/dl; 3.0-3.5 g/dl vs. > 3.5 g/dlp=0.006; 2.5 (1.4, 4.5); 1.5 (0.9, 2.3)p=0.01; 3.2 (1.4, 7.1); 1.2 (0.6, 2.3)Additional immunosuppressive therapy (ies) (>0 vs. 0)^additional anti-GVHD therapy(ies) apart from standard GVHD prophylaxis and glucocorticoids until day 90 (±7).NSNSAdditional anti-microbial(s) (>0 vs. 0)additional antimicrobials apart from acyclovir, fluconazole or voriconazole (whenever used for primary prohylaxis) and trimethoprin-sulfamethoxazole (or equivalents).p=0.002; 2.8 (1.5, 5.3)NS†Table entry: p-value (p) for the covariate effect;Hazard ratio (HR) (95% CI).§The effects of post-transplant variables were adjusted for baseline variables such as age, KPS and patient/donor CMV statuses in this regression, whenever appropriate/necessary. Statistical significance defined as <0.05; NS: not significant (p≥0.05). TPN: total parenteral nutrition.∗ from hematopoietic engraftment until day 90 (±7).∗∗ from initiation of conditioning chemotherapy (baseline) until day 90 (±7).^ additional anti-GVHD therapy(ies) apart from standard GVHD prophylaxis and glucocorticoids until day 90 (±7).^^ additional antimicrobials apart from acyclovir, fluconazole or voriconazole (whenever used for primary prohylaxis) and trimethoprin-sulfamethoxazole (or equivalents).¥ development of infiltrates requiring additional/alternative antimicrobials. Open table in a new tab †Table entry: p-value (p) for the covariate effect;Hazard ratio (HR) (95% CI). §The effects of post-transplant variables were adjusted for baseline variables such as age, KPS and patient/donor CMV statuses in this regression, whenever appropriate/necessary. Statistical significance defined as <0.05; NS: not significant (p≥0.05). TPN: total parenteral nutrition.

Remission consolidation with allogeneic blood or marrow transplantation improves survival of young patients with acute lymphoid leukemia (ALL), but the potential benefit of transplantation in older patients is offset by regimen toxicity and non-relapse mortality. Busulfan is not thought to be an effective drug for ALL, presumably because of intrinsic resistance of ALL to alkylating agents, or perhaps because of the large variability in busulfan pharmacokinetics and erratic drug exposure. Here we report results of treatment with a PK-targeted intravenous busulfan regimen in 25 adults with ALL. Patient age was 23–55 (median 40) years, 13 were treated in first complete remission, 10 in second remission, and 2 with resistant disease. Treatment was with 4 consecutive daily doses of fludarabine 40 mg/m2, followed by intravenous busulfan, administered on days 1 and 2 at 130–145 mg/m2 daily over 4 hours with PK-sampling and mass spectrometry assay. On days 3 and 4 busulfan dose was adjusted to target an average area under the concentration curve of 5300 ± 530 mMol∗min/L for each of the four days. Donors were siblings (14), or unrelated (11). Grafts were T-replete, filgrastim-mobilized hematopoietic blood cells. GVHD prophylaxis was tacrolimus plus methotrexate or mycophenolate mofetil. Mortality from all non-relapse causes was 4% at 100 days, and 8% at one year. The one-year overall survival (OS) was 66%, and relapse-free survival (RFS) was 62%, with a median follow-up of 1.3 years for live patients. For patients transplanted in CR1, one-year OS was 77% and RFS 70%; in CR2, OS and RFS were 58%; and with resistant disease, OS and RFS were 0%. OS was 56% in patients up to 40 years, and 67% in patients 41–55 years old, with disease status and stage similarly distributed in younger and older cohorts. With this treatment protocol, the one-year non-relapse mortality is identical to what is observed with non-transplant therapies. When compared to irradiation-containing regimens, fludarabine and PK-targeted busulfan appear much safer and similarly effective in controlling ALL, providing a treatment option for all adult patients with ALL. A multicenter study comparing this transplant protocol against post-remission chemotherapy for adult ALL is warranted.

The proto-oncogene Ras requires localization to the intracellular surface of the cellular membrane to exert its mitogenic effects. This subcellular localization is dependent on post-translational modification of the Ras protein, which results in the covalent addition of a lipid hydrophobic moiety to the carboxy-terminal. This post-translational processing is catalyzed by the enzyme farnesyltransferase. This enzyme adds a 15-carbon farnesyl group to the sulfur atom of the cysteine residue in the carboxy-terminal end of the Ras protein. Specific inhibitors of farnesyltransferase have been generated to block the mitogenic function of Ras. These inhibitors can also prevent the post-translational modification and function of many other farnesylated proteins. These include the centromere-associated proteins CENP-E and CENP-F, RhoB and E, the nuclear lamins, and Rap2. Preclinical studies indicate that these agents have a broad spectrum of antitumor activity, blocking proliferation and inducing apoptosis. The lead compounds currently in clinical development are R115,777 and SCH66336. Clinical trials have shown that these compounds can be safely administered, with favorable therapeutic indices, allowing the administration of biologically active doses of drug. Recent phase II clinical trials in patients with metastatic breast carcinoma have shown that R115,777 has reproducible single-agent activity, with activity being predominantly seen in patients with HER2-positive disease. Studies evaluating combined signal transduction blockade with trastuzumab and R115,777 are therefore being pursued, with a phase I study indicating that full-dose R115,777 can be safely administered with full-dose trastuzumab. Efficacy studies of this combination in patients with metastatic breast carcinoma are ongoing. Taxane and farnesyltransferase inhibitor combinations are also being evaluated because preclinical studies suggest that these classes of anticancer agents may be synergistic. Randomized clinical studies investigating the clinical benefits of farnesyltransferase inhibition, with or without a taxane and trastuzumab, in patients with treatment-naive HER2-positive metastatic breast carcinoma are now warranted.

There is limited data evaluating the feasibility of combining rituximab with conditioning chemotherapy (or chemo-radiotherapy) for patients undergoing allogeneic hematopoietic cell transplantation (allo-HCT). Twelve patients (M = 7; F = 5), with median age of 54.5 (41–66) years, underwent allo-HCT for the following diagnoses (disease-status at transplantation) [chronic lymphocytic leukemia (CLL)= 7 (CR2 = 2; PR2 = 3; ≥PR3 = 2); mantle cell lymphoma (MCL)= 3 (CR1 = 1; ≥PR2 = 2); follicular NHL = 1 (CR3 = 1), diffuse large B-cell (DLBC) NHL = 1 (>PR3 = 1)]. Donors were as follows: matched-related donors (MRD) = 7; matched-unrelated donors (MUD) =3; mismatched donor (MMD)= 2. Fludarabine-based regimens comprised fludarabine plus targeted doses of intravenous busulfan (FLU-BU = 8), or total-body irradiation (FLU-TBI = 3), or cyclophosphamide (FLU-CY = 1). Anti-thymocyte glogulin (ATG) was administered in MMD cases. GVHD prophylaxis consisted of tacrolimus plus mycophenolate mofetil = 8, or methotrexate = 4. Nine (75%) patients received rituximab 375 mg/m2 on days +1 (±3 days) and all (100%) received rituximab 375 mg/m2 on day +8 (±3 days) without serious infusion reactions. All patients engrafted. Median time to neutrophil engraftment for entire cohort was 15.5 (12–21) days. Median time to platelet engraftment in 8 patients was 13.5 (10–18) days. Four patients never dropped their platelet counts below 20,000/uL. Median donor chimerism at day +90 (±10 days) for unsorted BM, CD3 and CD33 by PCR/STR were 95% (70–100%), 87.5% (59–100%) and 100%, respectively. At a median follow-up of 6 (2.2–32) months, the 100-day non-relapse mortality in 11 evaluable patients was 10%. Acute GVHD, grades II, III, IV, developed in 58%, 8.3% and 8.3%, respectively, at a median of 28 (16–77) days. Response rates, at day +100 (±10 days), according to diagnosis, in 10 evaluable patients were as follows: CLL (CR = 4/5; PR = 1/5); MCL: (CR = 3/3); follicular NHL (CR = 1/1); DLBC: (progressive disease = 1/1). Administration of rituximab is feasible and does not affect timely hematopoietic engraftment in allo-HCT recipients with advanced CD20+ malignancies. There is limited data evaluating the feasibility of combining rituximab with conditioning chemotherapy (or chemo-radiotherapy) for patients undergoing allogeneic hematopoietic cell transplantation (allo-HCT). Twelve patients (M = 7; F = 5), with median age of 54.5 (41–66) years, underwent allo-HCT for the following diagnoses (disease-status at transplantation) [chronic lymphocytic leukemia (CLL)= 7 (CR2 = 2; PR2 = 3; ≥PR3 = 2); mantle cell lymphoma (MCL)= 3 (CR1 = 1; ≥PR2 = 2); follicular NHL = 1 (CR3 = 1), diffuse large B-cell (DLBC) NHL = 1 (>PR3 = 1)]. Donors were as follows: matched-related donors (MRD) = 7; matched-unrelated donors (MUD) =3; mismatched donor (MMD)= 2. Fludarabine-based regimens comprised fludarabine plus targeted doses of intravenous busulfan (FLU-BU = 8), or total-body irradiation (FLU-TBI = 3), or cyclophosphamide (FLU-CY = 1). Anti-thymocyte glogulin (ATG) was administered in MMD cases. GVHD prophylaxis consisted of tacrolimus plus mycophenolate mofetil = 8, or methotrexate = 4. Nine (75%) patients received rituximab 375 mg/m2 on days +1 (±3 days) and all (100%) received rituximab 375 mg/m2 on day +8 (±3 days) without serious infusion reactions. All patients engrafted. Median time to neutrophil engraftment for entire cohort was 15.5 (12–21) days. Median time to platelet engraftment in 8 patients was 13.5 (10–18) days. Four patients never dropped their platelet counts below 20,000/uL. Median donor chimerism at day +90 (±10 days) for unsorted BM, CD3 and CD33 by PCR/STR were 95% (70–100%), 87.5% (59–100%) and 100%, respectively. At a median follow-up of 6 (2.2–32) months, the 100-day non-relapse mortality in 11 evaluable patients was 10%. Acute GVHD, grades II, III, IV, developed in 58%, 8.3% and 8.3%, respectively, at a median of 28 (16–77) days. Response rates, at day +100 (±10 days), according to diagnosis, in 10 evaluable patients were as follows: CLL (CR = 4/5; PR = 1/5); MCL: (CR = 3/3); follicular NHL (CR = 1/1); DLBC: (progressive disease = 1/1). Administration of rituximab is feasible and does not affect timely hematopoietic engraftment in allo-HCT recipients with advanced CD20+ malignancies.

3502 Background: Preclinical cell culture and xenograft studies suggest that pre-exposure of cancer cells to a histone deacetylase inhibitor (HDACi) may potentiate topoisomerase (topo) inhibitors. The HDACi-induced histone acetylation and chromatin modulation facilitates DNA access and target recruitment for topo II inhibitors. Methods: This Phase I trial explores the safety, tolerability and maximum tolerated dose (MTD) of a weekly schedule of escalating vorinostat doses (twice daily days 1–3) followed by doxorubicin (20 mg/m2) on day 3 (3 out of 4 weeks). Histone acetylation and topo II expression are evaluated in pre-and post-vorinostat peripheral blood mononuclear cells and in tumor cells of the 30 patients treated at the MTD. Results: To date, 15 patients [median age 54 (38–73)] have been treated in 4 vorinostat cohorts: 200, 300, 400, 500 mg bid. Tumor types included: breast (3), melanoma (3), pancreatic (2) and one each of SCLC, sarcoma, endometrial, colon, prostate, renal cell and bladder cancer. Dose-limiting toxicities included a grade 3 thrombocytopenia (1/6) at the 400 mg bid dose. Non-dose limiting Grade 3 and 4 toxicities include neutropenia, thrombocytopenia, fatigue, pulmonary embolus, and anemia (1 pt each). Currently, vorinostat doses of 500 mg bid are being evaluated. One confirmed partial response in a breast cancer patient, as well as minor responses in a melanoma and a prostate cancer patient were seen in 10 evaluable patients. Patients received a median number of 2 (1–9+) treatment cycles. Doxorubicin is stopped after 6 cycles and patients continue on vorinostat alone. H3 and H4 histone acetylation and topo II expression will be correlated with vorinostat dose, plasma concentration and response. Conclusion: A sequence-specific combination of vorinostat and doxorubicin is active without exacerbation of doxorubicin toxicity. The tolerated vorinostat dose exceeds the proposed single agent dose for vorinostat derived from patients with hematological malignancies. Histone hyperacetylation occurs in peripheral blood mononuclear cells at all levels. The anti-tumor activity in breast cancer and melanoma will be further explored. No significant financial relationships to disclose.

661 Background: The incorporation of G into DNA enhances cleavage complexes in vitro when combined with a topo I inhibitor. Topo I poisons require enzyme interaction with DNA to exert activity. Methods: Two stage accrual design, primary endpoint: response (RR) using RECIST criteria. Inclusion criteria: male and female patients (pts) with MBC, prior anthracycline therapy, measurable disease, ECOG PS of ≤ 2, adequate organ function, and ≤ 3 prior chemotherapy regimens for MBC. 51 eligible pts received therapy with G at 1000mg/m2 and I at 100mg/m2 on days 1 and 8 of a 21-day cycle. Optional tumor biopsies were obtained in 9 pts (18%) prior to therapy to determine localization of topo I using immunofluorescence. PK: Irinotecan: A validated limited sampling strategy was used. Gemcitabine: Serial blood samples were collected over 24 hrs following the first dose. Intracellular nucleotides were quantitated in PBMCs. Results: 45 pts have been evaluated with a RR of 27% (CR=0, PR=12; 95% CI 13–37%). 4 pts had SD for ≥6 months for a clinical benefit rate (PR+SD) of 36%. 3 pts received < 1 cycle of therapy before protocol withdrawal and were not evaluable for RR. RR for the final 3 patients will be available at the time of presentation. 7/9 tissue biopsies were assessable for topo I with results listed below. PK and toxicity data will be available at presentation.Conclusion: GI is active in MBC. Topo I localization can be measured in MBC. In this limited data set, the two lowest nuclear to cytoplasmic (N/C) ratios were associated with lack of response to irinotecan. Further validation is needed. [Table: see text] [Table: see text]

Myeloablative doses of intravenous busulfan in combination with fludarabine have been employed as conditioning before hematopoietic cell allografts with reduced treatment-related toxicity and mortality. In this report, we describe the early results of a targeted busulfan pharmacokinetic dosing strategy (tBuFlu) used in combination with fludarabine before either related or unrelated grafts We treated 61 pts with tBuFlu prior to allogeneic peripheral blood stem cell transplantation. The median patient age was 48 (range 22-68) years.

3746 Background: Combination chemotherapy for pts with advanced crc has led to an improved overall survival (os) when compared to monotherapy. Retrospective review of phase III studies demonstrates that pts who are exposed to all three cytotoxic agents (oxaliplatin, 5-fluorouracil and irinotecan) have the longest median os (Grothey A et al: J Clin Oncol. 2004 Apr 1;22(7):1209–14). Current chemotherapy regimens for advanced crc are cumbersome and involve prolonged infusion times. Methods: We propose a phase II study of OCI (oxaliplatin 130mg/m2 day 1 intravenously (iv), irinotecan 180 mg/m2 day 21 iv, and capecitabine 825 mg/m2 by mouth days 1–14, and days 21–35, every 42 days) in pts with advanced, surgically unresectable crc. Results: Eight pts have been enrolled to date: median age 60 years, five females and three males. Three pts have been withdrawn from the study (one for recurrent bowel obstructions due to adhesions, two due to withdrawal of consent due to toxicity). Of four pts evaluable for response, two confirmed partial responses and two unconfirmed partial responses have been observed. Conclusions: This preliminary data show tolerance and encouraging radiographic activity, suggesting that this combination is worthy of further study. Accrual is ongoing, and updated results will be presented at the meeting. No significant financial relationships to disclose.

Myeloablative doses of intravenous busulfan in combination with fludarabine have been employed as conditioning before hematopoietic cell allografts with reduced treatment-related toxicity and mortality. In this report, we describe the early results of a targeted busulfan pharmacokinetic dosing strategy (tBuFlu) used in combination with fludarabine before either related or unrelated grafts We treated 43 pts with tBuFlu prior to allogeneic peripheral blood stem cell transplantation. The median patient age was 48 (range 22–67) years. Patient diagnoses included AML (8 de novo, 6 with prior MDS, and 2 treatment related), MDS (6 pts), MF (5), NHL (5 pts), ALL (4 pts), CML (3 pts), CLL (2), MM (1) and PNH (1). Three patients had received a prior autologous HCT. Donors were HLA-A, B, C, DRB1, DQB1 matched siblings (24), matched unrelated donors (13), or unrelated donors mismatched for one HLA antigen (3), one HLA allele (2), or two HLA alleles (1). Fludarabine 40 mg/m2 was given intravenously daily for four days, with each infusion followed immediately by intravenous busulfan. The dose of busulfan for days 1 and 2 was 130 mg/m2. Pharmacokinetic analysis was performed after the first infusion of busulfan; in 41 pts, the goal was to adjust busulfan doses for days 3 and 4 to achieve an average targeted Css level of 800–1000 ng/ml. Levels were drawn incorrectly in 4 of these pts and doses were not changed. Twenty-five (61%) pts had their doses adjusted, increased by 42% (± 28%) in 18 and decreased by 27% (± 14%) in 7, while 12 pts had Css within the desired range without adjustment. Patients received tacrolimus and standard doses of methotrexate for GVHD prophylaxis, with the exception of three patients treated with tacrolimus and mycophenolate mofetil or cyclosporine and prednisone. Engraftment occurred in 41 (95%) pts. Median day to ANC > 500/uL was 16 days, range (range 12–28); median day to platelet count > 20,000/uL untransfused was 18 days (range 8–45). Thirteen (52%) of 25 pts followed for at least 100 days experienced acute GVHD requiring treatment. Two pts have died of transplant-related complications (aplasia and suspected fungal pneumonitis), and 4 pts have failed to achieve remission or have relapsed. Median follow-up is 115 days (range 17–361 days). The 100-day K-M estimate of survival for the whole cohort is 94%, and event-free survival 86%. The 100-day mortality in this study compares well with the 100-day mortality reported to the IBMTR for patients with AML, ALL, MDS, and CML transplanted from either HLA-matched siblings or unrelated donors. These preliminary results indicate that tBuFlu is a promising myeloablative regimen that can be utilized in older patients with low early treatment-related mortality. We plan to escalate the busulfan dose based on targeted Css to explore a potential dose-response relationship and improve control of malignancy.