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Introduction: Diffuse large B-cell lymphomas (DLBCL) transformed from indolent B-cell non-Hodgkin lymphomas (B-NHL) or Richter transformation (RT) from chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) are associated with a poor prognosis, particularly in patients (pts) with relapsed/refractory (RR) disease. PD-1/PD-L1 blockade has produced anti-tumor responses in pts with lymphoma; however, the response rate in pts with DLBCL is low. Preclinical data suggest that some "immunogenic" chemotherapies alter the tumor microenvironment and act synergistically with checkpoint blockade to improve anti-tumor responses. We evaluated the addition of the PD-L1 inhibitor, atezolizumab, to immunogenic chemoimmunotherapy, rituximab with gemcitabine and oxaliplatin (R-GEMOX) in pts with RR transformed DLBCL. Methods: Pts with DLBCL transformed from indolent B-NHL or RT from CLL that had received ≥ 1 prior regimen with ECOG performance status ≤ 2, and adequate organ and hematologic function were eligible for this phase 1 study. Two cohorts were enrolled, one for pts with DLBCL transformed from follicular lymphoma (FL) and another for pts with non-FL transformed DLBCL, including RT. R-GEMOX was administered without atezolizumab on C1D1, R-GEMOX+Atezo was given subsequently (Days 1+15 of 28 day cycles) for a maximum of 6 doses. Pts in CR could proceed to R+atezo q3w maintenance for up to 2 years. Pts could proceed to hematopoietic cell transplantation (HCT) without subsequent maintenance at the discretion of the treating MD. A safety lead-in (6 pts, any cohort) with dose-limiting toxicity (DLT) evaluation (28-day period, after 1 st dose of atezo) at dose level (DL) 1 (rituximab 375mg/m2, gemcitabine 1000mg/m2, oxaliplatin 100mg/m2, atezolizumab 840mg, with de-escalation dose level available) was enrolled to confirm the recommended phase 2 dose (RP2D). After confirmation of the RP2D, expansion will continue until enrollment of n=14 transformed FL and n=10 non-FL transformed DLBCL. Responses were assessed by investigators by PET-CT (after C2, C4, and then q12weeks) according to the 2014 Lugano Classification. The primary endpoint was safety and determination of the RP2D. Results: 23 pts were enrolled, 22 were evaluable for response and adverse events (AEs), 1 is too early. Baseline characteristics are summarized in Table 1. 1/6 pts had a DLT related to atezolizumab during safety lead-in: grade (G) 4 Stevens-Johnson syndrome leading to death. DL1 was the RP2D. 2 pts were replaced during safety lead-in due to progressive disease (PD) prior to completing DLT evaluation. The most common AEs with R-GEMOX+Atezo (n=22) were fatigue (50%), elevated transaminases (45%), thrombocytopenia (45%), nausea/vomiting (41%), diarrhea (32%), fever (32%), hypertension (HTN) (27%), and neutropenia (27%). Common G3-4 AEs included lymphopenia (n=4), neutropenia (n=4), HTN (n=3), leukopenia (n=3), thrombocytopenia (n=3). Among 7 pts who proceeded to maintenance R-atezo, the most common AEs were fatigue (n=4) and HTN (n=3). There were 2 deaths related to study therapy, the pt with SJS and 1 pt with infusion reaction leading to respiratory failure who also had PD with both factors likely contributing to death. In addition, 1 pt had both sepsis and PD and died during maintenance, considered possibly related to treatment. 7 deaths were unrelated to treatment, including 1 from complications after autologous HCT, and 6 after PD. 5 pts remain on treatment; 17 pts are off treatment. Reasons for study discontinuation include: insufficient response/PD (n=12), HCT (n=2), death due to toxicity (n=2), and G3 neuropathy during maintenance (n=1). Among the 22 pts, the ORR was 50% and CR rate was 29%. The 9 pts with transformed FL had an ORR of 67% and CR rate of 33%. The 13 pts with non-FL transformed DLBCL/RT had an ORR of 38% and CR rate of 23%. Of 9 pts with RT there was 1 CR and 1 PR while all 3 pts with transformed marginal zone lymphoma responded (2 CR, 1 PR). Among responders (n=11), the median duration of response was not reached (Figure 1). Of the 6 pts with CR, 2 proceeded to HCT, and 4 had ongoing CR lasting 30.7+ months (mo), 13.9+ mo, 6.8+ mo, 5.0+ mo. Of the 5 patients with PR, 1 pt died of SJS without PD, PR lasted 3 and 4 mo in 2 patients (PD), and 2 pts have ongoing response (0.5+ and 2.0+ mo). Conclusions: R-GemOx+Atezo was tolerable and produced objective responses in patients with transformed DLBCL/RT, with all pts in CR having ongoing response. Figure 1 Figure 1. Disclosures Herrera: Gilead Sciences: Research Funding; ADC Therapeutics: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Tubulis: Consultancy; Takeda: Consultancy; Merck: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Kite, a Gilead Company: Research Funding; AstraZeneca: Consultancy, Research Funding; Karyopharm: Consultancy; Seagen: Consultancy, Research Funding. Allen: Epizyme: Consultancy; Kyowa Kirin: Consultancy; Secure Bio: Consultancy; ADC Therapeutics: Consultancy; MorphoSys: Consultancy. Popplewell: Hoffman La Roche: Other: Food; Novartis: Other: Travel; Pfizer: Other: Travel. Shouse: Beigene: Honoraria; Kite Pharma: Speakers Bureau. Siddiqi: AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Oncternal: Research Funding; BeiGene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Juno Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Kite Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Speakers Bureau; TG Therapeutics: Research Funding. Danilov: Gilead Sciences: Research Funding; Pharmacyclics: Consultancy, Honoraria; Beigene: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; TG Therapeutics: Consultancy, Research Funding; Takeda Oncology: Research Funding; Genentech: Consultancy, Honoraria, Research Funding; SecuraBio: Research Funding; Bayer Oncology: Consultancy, Honoraria, Research Funding; Astra Zeneca: Consultancy, Honoraria, Research Funding; Bristol-Meyers-Squibb: Honoraria, Research Funding; Rigel Pharm: Honoraria. Tuscano: Seattle Genetics: Research Funding; Bristol Myers Squibb: Research Funding; Takeda: Research Funding; Acrotech: Research Funding; Genentech: Research Funding; Pharmacyclics: Research Funding; Abbvie: Research Funding. OffLabel Disclosure: Atezolizumab is not approved for the treatment of aggressive B-cell non-Hodgkin lymphoma

Introduction Both blinatumomab and lenalidomide have proven, but limited, efficacy in relapsed/refractory (R/R) non-Hodgkin's lymphoma (NHL). Failure of blinatumomab to mediate durable responses is due to its inability to recruit competent cytotoxic T cells which leads to eventual T cell exhaustion. Lenalidomide has been shown to improve efficacy of rituximab through T and NK cell activation even in patients who have previously failed rituximab containing regimens. Based on this, we hypothesized that lenalidomide, when combined with blinatumomab, will enhance its efficacy. We report safety, efficacy and correlative analysis of blinatumomab and lenalidomide in R/R NHL. Methods We conducted a phase I, open-label trial involving patients 18 years and older with R/R CD19+ NHL who have received at least two prior chemotherapeutic or biologic regimens and were not eligible for standard curative options at time of enrollment. Previous CD19-targeted therapy was allowed. Study consisted of a dose escalation followed by a dose expansion phase once the maximum tolerated dose (MTD)/ recommended phase II dose (RP2D) was established using a Phase I Queue modified 3+3 design. The escalation phase has been completed and consisted of blinatumomab continuous infusion (level 1 and 2: 9 mcg/day to 112 mcg/day) from days 1-56 and lenalidomide (level 1: 10 mg and level 2: 20 mg daily) days 29-49 of a 56-day induction cycle. Patients who responded underwent consolidation with blinatumomab continuous infusion days 1-7 and lenalidomide days 1-21 of a 28-day cycle for a maximum of 6 cycles followed by lenalidomide maintenance for 2 years or until unacceptable toxicity or disease progression. Dose limiting toxicities (DLT) included any grade 3/4 drug related adverse events (AE) observed during and up to 7 days after blinatumomab/lenalidomide simultaneous administration. Additional patients were accrued to replace patients who had grade 3/4 AE or progressed before receiving lenalidomide for dose-finding purposes. Primary endpoints included toxicity and determination of the MTD/RP2D during the first 8 weeks of blinatumomab/ lenalidomide induction. Secondary endpoints included overall response rate (ORR), complete response (CR) rate, progression free survival (PFS) which was censored at time of transplant and immune response biomarkers. Results As of July 17, 2019, 18 patients initiated therapy; 7 with diffuse large B cell lymphoma, 3 with mantle cell lymphoma, 3 with follicular lymphoma, 2 with nonspecified B cell lymphoma and 1 each with marginal zone lymphoma, Burkitt's lymphoma and small lymphocytic lymphoma. Median age was 58 (range 30-84) years and the median number of prior regimens was 2.5 (range 2-5); 5 patients had previous stem cell transplant (SCT). 6 patients had disease progression prior to starting lenalidomide. 3 patients received blinatumomab/lenalidomide at dose level 1 with no DLT noted. 9 patients received blinatumomab/lenalidomide at dose level 2 with 4 requiring blinatumomab dose reduction prior to starting lenalidomide. Due to favorable safety profiles with the combination using the MTD/RP2D of lenalidomide 20 daily, upfront doublet therapy was initiated as part of the planned expansion phase. Most common grade 3/4 adverse events were lymphopenia (39%), hypophosphatemia (22%) and hyponatremia (11%). 1 patient (5.5%) experienced grade 3 neurotoxicity. No grade 3/4 cytokine release syndrome or treatment related deaths were seen. At time of data cutoff, three patients remain on active treatment. At a median follow-up time of 14.3 months, ORR was 56% for all patients and 83% (50% CR) for those who received blinatumomab/lenalidomide combination therapy. Median PFS was 3.8 months (95% CI, 1.1 to NR) for all patients and 8.3 months (95% CI, 2.2 to NR) for those who received blinatumomab/lenalidomide combination therapy. 3 patients who achieved response underwent allogeneic SCT and remained in remission for 14.2 to 22.3 months thereafter. Correlative studies are pending and will be reported at time of presentation. Conclusions The combination of blinatumomab and lenalidomide, given at the RP2D dose of 20 mg daily, is safe and well tolerated. This regimen demonstrates encouraging efficacy in this heavily pretreated patient population and is a promising alternative treatment option for R/R NHL patients who are not candidates for aggressive cytotoxic chemotherapy or as a bridge to allogeneic SCT. Disclosures Abedi: Abbie: Speakers Bureau; Takeda: Speakers Bureau; BMS: Speakers Bureau; Celgene: Speakers Bureau; Gilead: Speakers Bureau. Costello:Takeda: Honoraria, Research Funding; Janssen: Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Zain:Seattle Genetics: Consultancy; Spectrum: Consultancy. Budde:F. Hoffmann-La Roche Ltd: Consultancy. William:Defined Health: Consultancy; Techspert: Consultancy; Celgene Corporation: Consultancy; Kyowa Kirin, Inc.: Consultancy; Guidepoint Global: Consultancy. Foss:Spectrum: Other: fees for non-CME/CE services ; Acrotech: Consultancy; miRagen: Consultancy; Eisai: Consultancy; Mallinckrodt: Consultancy; Seattle Genetics: Consultancy, Other: fees for non-CME/CE services . Jonas:AbbVie, Accelerated Medical Diagnostics, AROG, Celgene, Daiichi Sankyo, Esanex, Forma, Genentech/Roche, GlycoMimetics, Incyte, LP Therapeutics, Pharmacyclics: Research Funding; AbbVie, Amgen, Celgene, GlycoMimetics, Jazz, Pharmacyclics, Tolero: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie, Amgen, GlycoMimetics: Other: Travel expenses. Rosenberg:Amgen: Consultancy, Research Funding. Tuscano:Seattle Genetics: Honoraria; Amgen: Honoraria; Celgene: Honoraria, Research Funding; Novartis: Research Funding; Spectrum: Research Funding; Takada: Research Funding; Abbvie: Research Funding; Genentech: Research Funding; Pharmacyclics: Research Funding. OffLabel Disclosure: The use of blinatumomab and lenalidomide in patients with aggressive lymphoma

Background MLN8237 is an oral inhibitor of aurora kinase A (AURKA) that causes mitotic spindle defects, mitotic delay, and apoptosis in lymphoma cell lines and mouse models. Human studies have shown promising responses in hematologic malignancies. Vorinostat is an oral HDAC inhibitor that is FDA-approved for cutaneous T-cell lymphoma, and is under study in other lymphomas. AURKA inhibitors in combination with vorinostat show synergistic pro-apoptotic effects in vitro in Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) cell lines (Kretzner 2011, Cancer Res 71:3912). Our phase I multicenter study assessed the safety and tolerability of MLN8237 combined with vorinostat in patients with lymphoid malignancies [[NCT01567709][1]] and determined the maximum tolerated dose (MTD) to be 20 mg twice daily (BID) of MLN8237 and 200 mg BID of vorinostat orally in an interrupted dosing schedule (Schedule II). We have recently completed accrual to an expanded cohort at MTD and report preliminary data on our secondary endpoints among patients treated on Schedule II of this study. Methods Eligible patients were ≥18 years old with relapsed or refractory (r/r) lymphoid malignancies (HL, B-NHL, T-NHL), measureable disease, ECOG performance status 0-2, neutrophils ≥1500/µL, platelets ≥100,000/µL, and adequate kidney and liver function. Secondary endpoints were toxicities, clinical response, pharmacokinetic (PK) analysis, and correlative studies. A 3+2 modified rolling-6 design was employed to determine the MTD. Enrollment was initiated on a continuous dosing schedule (Schedule I) that was poorly tolerated, with adverse events (AEs) on dose levels 1 and 2 leading to many dose delays primarily due to gastrointestinal intolerance and myelosuppression. The protocol was amended to the interrupted dosing Schedule II: MLN8237 escalated from 20 to 50 mg BID on days 1-3 and 8-10, and vorinostat given at 200 mg BID on days 1-5 and 8-12 of a 21-day cycle. Results We treated 25 patients (11 DLBCL, 7 HL, 3 FL, 2 MCL, 1 PTCL, 1 NK/T cell) on the interrupted dosing Schedule II. Median age was 59 years (range 26-78). Mediannumber of prior therapies was 4 (range 1-10); 9 patients (36%) underwent prior stem cell transplantation. See Table for treatment summary. MTD of the combination is 20 mg BID for MLN8237 and 200 mg BID for vorinostat on the interrupted schedule. The commonest (>5%) ≥ grade 3 drug-related AEs were neutropenia (52%), thrombocytopenia (44%), leukopenia (44%), anemia (28%), lymphopenia (24%), febrile neutropenia (12%), oral mucositis (8%), diarrhea (8%), and lung infection (8%). There were no study-related deaths. 4 patients stopped treatment due to AEs and 13 due to progressive disease (PD). 2 patients achieved complete remission (CR); both had DLBCL, and both halted therapy after completing 2 further cycles of treatment post-CR. They both remain in CR (18 months and 1 month at data lock). 1 patient had a partial response (PR), and 8 patients maintained stable disease (SD). PKs demonstrated a clearance of 230 L/h (sd=495) and 2.94 L/h (sd=1.57) for vorinostat and MLN8237, respectively. Archived baseline biopsies are being analyzed to determine AURKA expression. Six fresh paired tumor biopsies were obtained before and on-treatment in the expanded cohort at MTD for correlative studies. Conclusions MLN8237 when given in combination with vorinostat is safe and tolerable in an interrupted dosing schedule among heavily pre-treated patients with r/r lymphoid malignancies. The MTD for MLN8237 is 20 mg BID on days 1-3 and 8-10, combined with vorinostat at 200 mg BID on days 1-5 and 8-12, of 21 day cycles. The commonest AEs were hematologic and gastrointestinal. Promising responses were seen in several patients, especially those with DLBCL, which support phase 2 exploration of this therapy in patients with intermediate-high grade NHL. PK analysis suggests that combination therapy exposures are similar to single agent exposure. Correlative studies done in a 12-patient expanded cohort will be presented. [Trial supported in part by UM1CA186717] | Schedule II: MLN8237 (mg)/ Vorinostat (mg) | # of patients treated | # of cycles completed Median (range) | # of dose limiting toxicities (DLT) | DLT Description | Best response | | ------------------------------------------------- | --------------------- | -------------------------------------------- | ----------------------------------- | --------------------------------------------------------------------------------------------- | --------------------------------------------- | | Dose level 1 (30/200) | 7 | 3 (0-18) | 2 | 1 pt had grade 3 febrile neutropenia; 1 pt had grade 3 thrombocytopenia requiring transfusion | 1 CR, 3 SD, 2 PD, 1 N/A | | Dose level -1 (20/200) | 18 | 2 (0-14) | | | 1 CR, 1 PR, 5 SD, 8 PD, 3 too early to assess | Table 1. Disclosures Siddiqi: Kite pharma: Other: attended advisory board meeting; Seattle Genetics: Speakers Bureau; Pharmacyclics/Jannsen: Speakers Bureau. Off Label Use: Vorinostat is only FDA-approved for CTCL but in this study it is being used in conjunction with MLN8237 (not FDA-approved) for all lymphomas.. Beumer: Millenium: Other: Research support. Forman: Mustang Therapeutics: Research Funding. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01567709&atom=%2Fbloodjournal%2F126%2F23%2F2731.atom

Background: Amplification or overexpression of AURKA, a key mitotic regulator, is seen in various tumors and is associated with poor outcome in relapsed/refractory (r/r) lymphoma patients. MLN8237 is an oral inhibitor of AURKA, leading to mitotic spindle defects, mitotic delay, and apoptosis in lymphoma cell lines and mouse models. Human studies have shown promising responses in hematologic malignancies. Vorinostat is an oral HDAC inhibitor FDA-approved for cutaneous T cell lymphoma, and is under study in other lymphomas. AURKA inhibitors, MK0457 and MK5108, when combined with vorinostat and applied to Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) cell lines, convincingly showed synergistic pro-apoptotic effects compared with the AURKA inhibitor alone (Kretzner 2011, Cancer Res 71:3912). Our phase I multicenter study assessed the safety and tolerability of MLN8237 combined with vorinostat in patients with lymphoid malignancies [NCT01567709]. Methods: Patients ³18 years old with r/r mature lymphoid malignancies (HL, B-NHL, T-NHL), measureable disease, ECOG performance status 0-2, neutrophils ³1500/µL, platelets ³100,000/µL, and adequate kidney and liver functions were eligible. The primary endpoints were maximum tolerated dose (MTD) of MLN8237 when combined with vorinostat and description of adverse events (AEs). Secondary endpoints were toxicity, clinical response, pharmacokinetic (PK) analysis and correlative studies. A 3+2 modified rolling design was employed. Enrollment was initiated on Schedule I: MLN8237 escalated from 30-50 mg twice daily (BID) on days 1-7 and vorinostat given at 200 mg BID on days 1-14 of a 21-day cycle*. AEs in patients treated on Schedule I dose levels 1 and 2 led to many dose delays, primarily due to gastrointestinal intolerance and myelosuppression. The protocol was amended to the interrupted dosing Schedule II: MLN8237 escalated from 20-50 mg BID on days 1-3 and 8-10, and vorinostat given at 200 mg BID on days 1-5 and 8-12 of a 21-day cycle. Results: As of August 1 2014, 23 patients have been treated (3 HL, 6 DLBCL, 7 FL, 1 MCL, 1 MZL, 2 B-CLL/SLL, 2 ALCL, 1 NK/T cell). Median age was 61 years (range 28-82). Median number of prior therapies was 4 (range 1-8); 9 patients (39%) underwent prior stem cell transplantation. See Table for treatment summary. MTD of the combination is 20mg BID for MLN8237 and 200mg BID for vorinostat in an interrupted schedule. The most common grade 1-2 AEs (>/=30%) were fatigue (78%), nausea (65%), diarrhea (65%), vomiting (56%), hypokalemia (48%), hypertension (47%), anemia (43%) high alkaline phosphatase (39%), hyponatremia (39%), thrombocytopenia (35%), anorexia (31%), alopecia (31%), constipation (30%), high ALT (30%), high AST (30%), high creatinine (30%), leukopenia (30%). Commonest (>5%) >/= grade 3 drug-related AEs were thrombocytopenia (66%), neutropenia (60%), leukopenia (52%), lymphopenia (43%), anemia (34%), febrile neutropenia (13%), and oral mucositis (8%). There were no study-related deaths. 6 patients stopped protocol treatment due to AEs/intolerance and 7 due to progressive disease (PD). Most patients (8) had stable disease (SD) and 1 patient achieved a complete remission (CR). Conclusions: MLN8237 when given in combination with vorinostat is safe and tolerable in an interrupted schedule among heavily pre-treated patients with r/r lymphoid malignancies. The MTD for MLN8237 is 20mg BID on days 1-3 and 8-10, combined with vorinostat at 200mg BID on days 1-5 and 8-12, of 21 day cycles. The commonest AEs are hematologic and gastrointestinal. PK analysis, correlative studies and response assessments are ongoing in a 12-patient expansion cohort. [Trial supported in part by UM1CA186717] Abstract 4483. TableMLN8237 (mg)/ Vorinostat (mg)# treated# completed cyclesMedian (range)# DLTsDLT DescriptionBest responsesSCHEDULE I (continuous)Dose level 1 (30/400*)62 (1-3)1Grade 3 thrombocytopenia requiring a plt transfusion2 SD, 2 PD, 2 N/ADose level 2 (20/200)32 (2-13)2Both pts had grade 4 thrombocytopenia2 SD, 1 PDSCHEDULE II (interrupted)Dose level 1 (30/200)73 (0-18)21 pt had grade 3 febrile neutropenia; 1 pt had grade 3 thrombocytopenia requiring a plt transfusion1 CR, 3 SD, 2 PD, 1 N/ADose level -1 (20/200)71 (1-3)01 SD, 2 PD, 4 too early *Initial vorinostat dosing was 400mg daily but subsequent cohorts were switched to 200mg BID for better tolerance. Disclosures Off Label Use: MLN8237 and vorinostat have not been FDA-approved for all lymphoid malignancies..

Background Follicular (FL), marginal zone (MZL), mantle cell (MCL) lymphomas, and lymphoplasmacytic lymphomas are indolent non-Hodgkin's lymphomas (NHL) that tend to recur multiple times with decreasing intervals of remissions. Vorinostat is an orally administered histone deacetylase inhibitor. Previously, we observed a single agent overall response rate (ORR) of 29% for vorinostat and a complete remission rate (CR) rate of 14% in indolent lymphomas (Kirschbaum 2009). Preclinical data suggests enhanced activity for the combination of vorinostat plus rituximab. We report the final results of a phase II study of the combination of vorinostat plus rituximab with correlative assays. Methods This is a two-stage phase II study in patients with newly diagnosed, relapsed or refractory indolent NHL. Vorinostat was given at 200 mg PO twice daily for 14 consecutive days on a 21 day cycle. Rituximab was given on day 1 of each cycle. CT scanning and/or FDG-PET were performed after every three cycles. The primary endpoint was the overall response rate according to Revised Cheson Criteria. Immune cytokine analysis was performed on serum samples drawn on day 0 and day 14 of treatment using Luminex X-MAP bead array. Results 30 patients were accrued with 28 eligible (2 ineligible tumor types). See Table 1 for baseline characteristics. The overall response (CR+PR) rate was 46% (13/28), and CR rate was 39% (11/28). The ORR and CR for previously untreated patients was 67% (4/6, all CR). The ORR for relapsed/refractory patients was 41% (9/22), with a CR rate of 32% (7/22). By histology, the ORR was 50% (11/22) and CR was 45% (10/22) for FL, 33.3% (1/3) for MCL (PR), 50% (1/2) for MZL (CR), and 0/1 for lymphoplasmacytic lymphoma. The median PFS was 38.2 months (95% CI: 14.4, 51.0) for all patients, 21.1 months (95% CI: 8.5, 51.0) for previously treated patients, and not-reached for untreated patients. Figure 1 shows the PFS of patients in CR and PR versus others. Patients who achieved CR were allowed to discontinue treatment and return to treatment upon progression. 10/13 CRs were progression-free with a median follow-up of 14.4 months (range 4-48 months). 2/3 patients who relapsed achieved CR again after resuming therapy. Of non-responders, 8 patients achieved stable disease for at least 9 cycles with one SD for 69 cycles. The disease control rate for >9 cycles (CR+PR+SD>9 cycles) was 75% (21/28). Five patients were taken off study for reasons other than progression (2 patient's choice, 1 to transplant, 1 for violation, and 1 physician choice). The median time to treatment failure for all patients was 17.8 months, 95% CI: (6.2, 51). Treatment was well tolerated. Grade 4 toxicities possibly attributable to study drug included neutropenia (n=1), incidental asymptomatic thrombosis (n=4), and thrombocytopenia (n=2). Grade 3 possibly related toxicities >20% included fatigue (n=9, 32%) and lymphopenia (n=7, 25%). The thromboses were asymptomatic pulmonary embolism discovered incidentally on CT scan, and resulted in amending the study to include 40 mg enoxaparin as prophylaxis, resulting in no further thromboses identified. Vorinostat plus rituximab reduced the levels of pro-inflammatory cytokines such as IL-2, INF-g, TNF-a, and IL-6. 8 of the 16 cytokine markers showed statistical decrease (p Conclusions The combination of vorinostat with rituximab is well tolerated, and showed encouraging activity against newly diagnosed and relapsed/refractory indolent NHL. Durable responses can be achieved and retreatment can lead to 2nd CR. The activity observed warrants multicenter evaluation of vorinostat with rituximab in patients with indolent lymphoma. Disclosures: Off Label Use: use of vorinostat and rituximab to treat indolent NHL.

Abstract 3151 Background: Ablative dose total body irradiation (TBI) of 800 cGy in combination with high-dose melphalan (MEL) as part of single cycle autologous transplantation (AT) was found to be too toxic, and therefore inferior, in comparison to MEL. We set out to test total marrow irradiation, (TMI), a “sculpted” form of targeted total body irradiation using image-guided intensity modulated helical tomotherapy, given as the sole ablative regimen during the second cycle of tandem AT (TAT) as consolidation in patients with stable/responsive myeloma. Patients and Methods: Patients with Durie-Salmon stages I-III multiple myeloma in response or with stable disease, who were ≤ 70 years old and within 18 months from diagnosis, were enrolled. Patients received MEL 200 mg/m2 and AT (cycle 1), and, following recovery, TMI and AT were administered (cycle 2) at a median of approximately 2 months after the first AT. During the phase I part, TMI was tested between 1000 cGy and 1800 cGy given twice daily × 5 days. The maximum tolerated dose (MTD) –as previously reported- was established at 1600 cGy [Somlo et al. Clin Cancer Res. 2011; 17 (1):174–82]. Following cycle 2 of TAT, maintenance therapy consisted of dexamethasone 40 mg/day × 4 days and an IMiD (first thalidomide, and during the phase II portion, lenalidomide) in a 28-day cycle, administered for 6 cycles for patients in complete response (CR), or for a minimum of 12 cycles for pts not in CR. Results: 54 patients were enrolled (23 females, 31 males). The median age was 54.2 years (range 31.5–66.9). All patients with stage I (7), II (14), III (n=33) multiple myeloma received MEL. Forty-three patients (79.6%) received TMI, 30 at the MTD (6 enrolled at the MTD did not receive TMI). Reversible grade 3 non-hematologic toxicities following TMI at the MTD included febrile neutropenia (5/30), electrolyte abnormalities (7/30), sepsis/infection (5/30), anorexia (2/30), nausea/vomiting (2), fatigue (1), syncope (1). Grade 3 late toxicities include 1 case each of fatigue, nausea, 1 myositis and transaminitis. There were no primary or secondary graft failures, or second malignancies. Of the entire cohort of 54 patients, by intent to treat analysis best responses following TAT included CR (n: 20), very good partial response (VGPR, n:11), partial response (PR, n:16). At a median follow-up of 39 months from first AT, progression-free survival is 55% (95% CI 42–73%) and overall survival is 81% (95% CI 70–94%). For patients treated at the MTD of TMI 1600 cGy, at a median follow-up of 39 months from the first AT, progression-free survival (PFS) is 66% (50–88%), and overall survival (OS) is 80% (65–99%). Conclusion: TMI of 1600 cGy is feasible as ablative therapy following recovery from high-dose melphalan and AT. CR and VGPR rates are expected to improve with time on maintenance therapy and such data as well as progresion-free and overall survival will be updated. Safety and progression-free and overall survival data are encouraging, and further assessment of the role of TMI is warranted in combination with MEL as part of either single AT, part of TAT, or in comparison of tandem versus single ablative therapy, both in the upfront, and salvage settings. Disclosures: Off Label Use: IMiDs as maintenance.

Abstract 2399 The quality and depth of response particularly achievement of complete remission (CR) have been associated with significant improvement in progression free survival (PFS) and overall survival in multiple myeloma patients undergoing autologous stem cell transplant. Achievement of CR is considered a valid surrogate endpoint for survival in clinical trials for patients with multiple myeloma. We performed a phase II study investigating the role of sequential bortezomib/dexamethasone followed by thalidomide/dexamethasone as maintenance therapy post single autologous PSCT. The objectives were to examine the feasibility, toxicities, CR, PFS and overall survival rates. Within 4–8 weeks of autologous PSCT using melphalan 200mg/m2, pts received weekly bortezomib (bor) at 1.3mg/m2 /wk × 3 weeks with 1 week rest and dexamethasone (dex) at 40mg/d × 4 d for 6 months, followed by thalidomide (thal) at 50 –200mg/d and dexamethasone (dex) at 40mg/dx4 d for 6 more months. Single agent thalidomide was then continued until disease progression. Between March 2008 and June 2010, forty-five pts were enrolled. Median age was 54 years (29-71). Median time from diagnosis was 6.1 mo. (3.5 – 145.9). Disease stage at diagnosis; by Salmon-Durie (I/II/III 2/8/34/1 not available) and by ISS (I/II/III 18/14/8/ 5 not available). Pts received prior induction treatment with thal/dex (15), bortezomib based (27) and lenalidomide based regimens (10). Median B2M at enrollment was 1.8 mg/L (1.05 -5.3). Disease status at enrollment included complete remission (CR) (11), very good partial response (VGPR) (11), partial response (PR) (23). Six pts had chromosome 13 abnormalities (1 pt by karyotype and 5 pts by FISH), 2 pts had t 4;14 (one with concurrent ch 17 p del) and 3 pts had complex cytogenetic abnormalities. Results: Forty-five pts have been enrolled and undergone transplant. Five pts were unable to start planned maintenance therapy due to development of grade II or more neuro toxicities (4), and persistent thrombocytopenia (1) after PSCT. Thirty nine pts started maintenance bor/dex within 4–8 weeks of PSCT. One pt is too early for maintenance therapy. Twenty-five pts have completed the planned 6 months of bor/dex. Ten pts stopped bor/dex because of low WBC (2), PN (4), diagnosis of adrenal cancer (1), myocardial infarction (MI) (1), and relapse (2). Six pts are still receiving maintenance bortezomib. With a median F/U of 8.5 mo. (0.2 -24.0) twelve of 44 evaluable pts (27%) have achieved CR post PSCT and 17 of 33 evaluable pts (51%) have achieved CR after bor/dex on an intention to treat (ITT) analysis. Fifteen of 25 pts (60%) who have completed 6 months of bor/dex have achieved CR. Nine of 25 pts (36%) have upgraded their response with bor/dex. Eight pts (24%) could not complete bortezomib due to toxicities. At one year post PSCT fourteen of 28 evaluable pts (50%) remain in CR. Six pts have relapsed of whom 2 died of relapsed myeloma (leptomeningeal disease 1 pt). One pt experienced MI while receiving bortezomib (grade IV). Grade III toxicities have occurred in 17 pts; low platelet (1), asthenia (2), mood alteration (1), GI (severe constipation due to partial bowel obstruction on thalidomide) (1), skin rash (1), hyperglycemia (1), lymphopenia (10), sinus bradycardia (1), elevated triglyceride (1), DVT (1), low phosphate (3), leukopenia (1), edema (1). Sixteen pts had peripheral neuropathy (PN) grade I prior to start of bortezomib. Only 8 pts have developed new PN on the study and all are grade I-II. No patient has experienced grade III-IV PN. Median bortezomib dose is 1.3 mg /m2 per week. Conclusion: Prolonged weekly bortezomib maintenance therapy is well tolerated and can upgrade response post single autologous PSCT with no severe peripheral neuropathy. Fifty one percent of pts have achieved CR and 36% have upgraded their response after six months of bortezomib/dexamethasone therapy suggesting this is an active maintenance strategy post PSCT. Disclosures: No relevant conflicts of interest to declare.

Abstract 3698 Background: Follicular, marginal zone and mantle cell lymphomas are indolent lymphomas that tend to recur with decreasing intervals of remissions. Vorinostat (SAHA) is an orally administered hydroxamic acid histone deacetylase inhibitor with activity against class I and II deacetylases. Single agent vorinostat has an overall response rate of 29% in all indolent lymphomas (47% in follicular lymphoma) with prolonged disease free survival. (Kirschbaum, JCO 2009) Preclinical data suggests enhanced activity for the combination of vorinostat plus rituximab. We report the clinical results of a phase II study of the combination of vorinostat plus rituximab. Methods: These are the updated results of our two-stage phase II study in patients with newly diagnosed, relapsed or refractory follicular, marginal zone, or mantle cell lymphoma. Vorinostat is given at 200 mg PO twice daily for 14 consecutive days on a 21 day cycle. Rituximab is given on day 1 of each cycle. CT scanning and/or FDG-PET are performed after every three cycles. Patients may have received up to four prior chemotherapy regimens including tositumomab or ibritumomab; previous autologous transplant is allowed. The primary endpoint was the overall response rate according to Revised Response Criteria for Malignant Lymphoma (Cheson 2007). Results: 26 eligible patients were accrued thus far. See Table 1 for baseline characteristics. Outcomes are available on 23 patients: the overall response (CR+PR) rate thus far is 35% (8/23) The CR rate for all patients is 30% (7/23). The response rate for untreated patients (5 FL, 1 MZL) is 66.6% (4/6, all CR). The other two patients remain on study with prolonged stable disease. The formal response rate thus far for relapsed/refractory patients is 23.5% (4/17). By histology, the response rate is 35% (7/19) for FL, 0/2 for mantle cell, 1/1 for MZL, and 0/1 for lymphoplasmacytic lymphoma. The median time to achieve CR is 12 months. Of the 7 patients who achieved CR, 3 have relapsed while off treatment and were retreated with vorinostat plus rituximab. 1 achieved CR and is 13 months into treatment, 1 achieved PR and is 23 months into treatment, while 1 transformed both to Hodgkin lymphoma and diffuse large B cell lymphoma (biopsy proven). The median time to treatment failure for patients achieving CR is 38 months, with 6 ongoing, including the two retreated patients (14, 27, 29, 29, 31, and 35 months). Of non-responders, 8 patients achieved stable disease for at least 9 cycles with one SD for 63+ cycles. The disease control rate for > 9 cycles (CR+PR+SD) is 69.6% (16/23). Five patients were taken off study for reasons other than progression (2 patients choice, 1 to transplant, 1 for concomitant medication violation, and 1 physician choice). The median time to treatment failure for all patients was 9 months (95% CI, 6 months, NR). Treatment was well tolerated. Grade 4 toxicities possibly attributable to study drug include neutropenia (n=1), asymptomatic thrombosis (n=4), and thrombocytopenia (n=2). Grade 3 possibly related toxicities include fatigue (n=7), hyperglycemia (n=3), dehydration (n=2), and one each of thrombocytopenia, neutropenia, anemia, hypophosphatemia, hypotension, pneumonia, diarrhea, diverticulitis, and syncope. The thromboses were nonclinical pulmonary embolism discovered incidentally on CT scan, and resulted in amending the study to include 40 mg enoxaparin as prophylaxis, resulting in no further thromboses identified. Conclusions: The combination of vorinostat with rituximab is well tolerated, and shows encouraging activity against newly diagnosed, as well as relapsed/refractory indolent lymphoma. Durable responses can be achieved. Extended treatment with this combination is feasible and well tolerated, and retreatment with this regimen is efficacious in previous responders who relapsed. Disclosures: Off Label Use: Use of vorinostat in combination with rituxan for indolent B cell lymphomas.

Abstract 528 Background: Allogeneic Stem Cell transplantation remains the only curative treatment modality for hematologic malignancies such as AML, ALL, and MDS. Reduced intensity regimens were designed which replaced the alkylating agent cyclophosphamide with the purine nucleoside antimetabolite, fludarabine, a potent immunosuppressive with a substantially milder toxicity profile. Clofarabine is a purine nucleoside analogue designed to exploit a double halogen strategy which confers resistance to adenosine deaminase, increases stability and bioavailability and makes the drug more efficient than fludarabine at inhibiting ribonucleotide reductase (RNR) and disrupting mitochondrial function, leading to apoptosis. Clofarabine is potentially a superior antileukemic agent as compared with fludarabine, thus enhancing the activity of the conditioning regimen. Aims: To evaluate a novel clofarabine containing regimen as conditioning for adult fully matched allogeneic stem cell transplant. Methods: phase I dose escalation: clofarabine (dose level 1 = 30 mg/m2, dose level 2 and 3 =40 mg/m2) IV daily days –7 to day –3 infused over 30 minutes IV, plus Melphalan (dose level 1 and 2, 100mg/m2, dose level 3, 140 mg/m2) administered over 30 minutes IV on day –2. Related or unrelated allogeneic stem cells were infused on day 0. GVHD prophylaxis: initially cyclosporine plus mycophenolate, then tacrolimus plus sirolimus was adopted as per City of Hope standard of care. Patients (pts) age ≥ 18 years with AML, ALL, MDS in either CR1, CR2 or in relapse (up to 50% marrow blasts), not deemed eligible for standard transplant regimens by the attending physician, or at high risk for relapse, are eligible. Results: 16 eligible pts, all with AML, have been treated thus far, 7,males, 9 females, with a median age of 63 years (30 – 66). Seven pts were in CR1, 2 pts were in CR2, 4 pts where induction failures, and 3 pts were in first relapse. Grade 3 non-hematologic toxicities included elevation of transaminases, diarrhea, and hyponatremia. No dose limiting toxicities (DLT) were seen in the 3 pts treated at dose level 1. One patient in dose level 2 died prior to engraftment due to hepatic, renal, and infectious toxicities; that dose level has been expanded to 12 patients and no further DLTs were seen. The first patient treated at dose level 3 developed multiorgan failure and died prior to engraftment. Given the excellent results seen in the two previous cohorts we opted not to dose escalate any further patients beyond clofarabine 40 mg/m2 and melphalan 100 mg/m2. Three patients with primary induction failure received an unrelated donor graft and had complete engraftment and obtained remission. The median time to ANC recovery is 14 days and to platelet recovery is 16 days (see table). Mild acute skin graft versus host disease (GvHD) was seen in five patients, mild chronic GvHD in four patients, one patient developed severe chronic GVHD of the liver and died at day 201 from CNS bleed due to tacrolimus-sirolimus related TTP-HUS. Of the 14 patients that successfully completed transplant (no DLT or engraftment difficulty), only one patient has relapsed, with median follow-up of 10.5 months (range 4–24). Conclusion: The combination of clofarabine and melphalan is a well tolerated reduced intensity conditioning regimen with enhanced anti-leukemia activity leading to complete engraftment of related and unrelated fully matched allogeneic stem cells. Complete engraftment with prolonged disease free survival was seen at both dose levels 1 and 2. Disclosures: Off Label Use: clofarabine as a component of the conditioning regimen for allogeneic transplant.

Abstract 3403 Poster Board III-291 Autologous PSCT remains standard treatment in younger patients (pts) with multiple myeloma. However, relapse is the major cause of treatment failure. Several studies have reported improved progression-free survival (PFS) and possibly overall survival with thalidomide alone or in combination with steroid and chemotherapy as maintenance/consolidation therapy post autologous PSCT. We performed a phase II study investigating the role of sequential velcade/thalidomide/dexamethasone (VTD) as maintenance therapy post single PSCT. The objectives were to examine the toxicities of prolonged course of sequential VTD, CR rate, PFS and overall survival following single autologous PSCT. Within 4-8 weeks of autologous PSCT using melphalan 200mg/m2, pts received weekly velcade (vel) at 1.3mg/m2 /wk x 3 weeks with 1 week rest and dexamethasone (dex) at 40mg/d x 4 d for 6 months, followed by thalidomide (thal) at 50 -200mg/d and dexamethasone (dex) at 40mg/dx4 d for 6 more months. Single agent thalidomide was then continued until disease progression. Twenty-eight pts have been enrolled. Median age is 54 years (29-66). Median time from diagnosis is 7.9 mo. (4.2 – 145). Disease stage at diagnosis; by Salmon-Durie (II/III 6/22) and by ISS (I/II/III 11/9/7/missing data in 1 pt). Pts received induction treatment with thal/dex (14), velcade based (15) and revlimid based regimens (7). Median B2M at enrollment is 1.75 mg/L (1.14 -5.3). Disease status at enrollment; CR (7) VGPR (9), PR (11), SD (1). Three pts have chromosome 13 abnormalities (1 pt by karyotype and 2 pts by FISH). Results: All pts have undergone transplant. Four pts were unable to start planned maintenance therapy due to development of grade II or more neuro toxicities (3), and persistent thrombocytopenia (1) after PSCT. Twenty-four pts started maintenance vel/dex within 4-8 weeks of PSCT. Nine pts have completed 6 months of vel/dex. Two pts stopped vel/dex because of low WBC (1) or PN (1). With a median F/U of 5.2 mo. (1.2 -17.3) nine of 28 pts (33%) have achieved CR post PSCT and six out of 11 evaluable pts (55%) have achieved CR after vel/dex. Six out of 9 pts (66%) who have completed 6 mo. of vel/dex achieved CR. Two out of 9 pts (22%) have upgraded their response with vel/dex. Four pts have completed 6 month of thal/dex and are beyond 1 year post PSCT. Two out of 4 pts remain in CR at one year post PSCT. One pt is in PR and 1 pt has progressed. Two pts could not complete thal/dex phase of therapy because of relapse (1) and grade III GI toxicity (1). Three pts have relapsed of whom 1 pt died of relapsed myeloma (leptomeningeal disease). No grade IV toxicity has been noted. Grade III toxicities have occurred in 4 pts; low platelet (1), fatigue (1), mood alteration (1), GI (severe constipation) (1). Thirteen pts have peripheral neuropathy (PN). Ten pts had PN grade I at enrollment. Only 3 pts have developed PN on the study and all are grade I - II. Median velcade dose is 1.3 mg /m2/wk and thalidomide dose is 100mg /d. Conclusion: Prolonged sequential velcade/thalidomide/dexamethasone maintenance therapy post single autologous PSCT is well tolerated with no severe peripheral neuropathy. Fifty-five percent of pts have achieved CR and 22% have upgraded their response after six months of velcade/dexamethasone therapy suggesting this is an active and well tolerated maintenance strategy post PSCT. Disclosures: Sahebi: Celgene: Honoraria; Millennium Pharmaceutical: Research Funding. Off Label Use: The use of bortezomib(Velcade)in combination with thalidomide and dexamethasone is investigated as maintenance therapy post autologuous stem cell transplant in patients with multiple myeloma.

Abstract 1682 Poster Board I-708 Background The outlook for patients with relapsed or primary progressive intermediate to high grade Non Hodgkin's Lymphoma (NHL) remains problematic. The current best strategy is to to identify potential chemosensitive patients who may respond to autologous transplant, by use of high dose chemotherapy protocols However, approximately fifty percent of those who undergo high-dose therapy, and the majority of patients treated with standard salvage regimens alone, will ultimately show progression or relapse; newer regimens are necessary. In-vitro data in a number of tumor cell types shows enhanced activity of gemcitabine (gem) when combined with the proteasome inhibitor bortezomib (B). Methods Patients with intermediate to high grade relapsed or refractory B cell NHL or mantle cell lymphoma who had been treated with up to 4 prior regimens including autologous transplant were eligible. Starting dose of gemcitabine was 1000 mg/m2 on days 1 and 8 of a 21 day cycle, with bortezomib starting at 1 mg/m2 on days 1, 4, 8, 11. CT (and PET when possible) were performed after cycle 4 and after cycle 6. Patients were allowed to continue therapy in the event of clinical benefit. Results 28 patients were enrolled overall, of whom 24 are evaluable for response. 3 of the patients had mantle cell lymphoma. Median Age was 63 (range 34-77). 20 were male, 8 female. Four patients were enrolled on dose level 1, of whom three were evaluable for toxicity. All 3 showed DLT (neutropenia and thrombocytopenia) so enrollment continued at dose level -1 (gem 800 days 1 and 8, B 1.0 mg/m2 d1, 4, 8, 11). One DLT was seen in the five patients treated. In order to make the regimen more easily tolerable, the regimen was changed to increase the time between doses so that dose escalations would begin from gem 800 given on days 1 and 15 and B 1.0 given on days 1 and 15 only, on a 28 day cycle. Dose escalation to the target dose of gem 1000 mg/m2 and B 1.3 mg/m2 was achieved without DLT, and this level was expanded to six patients. A second group of six patient was treated on this dose level with the addition of rituxan 375 mg/m2 given on days 1 and 15 with no DLT seen. Grade 4 toxicities seen on the study were neutropenia (4 pts), and thrombocytopenia (2). Grade 3 toxicities were neutropenia (6) thrombocytopenia (5) and febrile neutropenia (1). Other toxicities of grade 2 or less included elevated transaminases, fatigue, diarrhea, and peripheral neuropathy (grade 2: 3 pts grade 1: 3 patients). 24 patients were evaluable for response. Complete Remission was seen in 3 patients, one at dose level 1, one at dose level 5B (gem 1000 mg/m2 d1 and 15, B 1.3 mg/m2 d1 and 15) and one at dose level 5B1 (5B plus rituxan 375 mg/m2 d1 and 15). Conclusion The combination of gemcitabine 1000 mg/m2 combined with bortezomib 1.3 mg/m2 with or without rituxan 375 mg/m2 on a day 1, 15 schedule shows activity in patients with relapsed/refractory B cell NHL, and was well tolerated. A phase II study of this combination is ongoing. Disclosures Off Label Use: bortezomib in lymphoma.

Background: Radiation therapy has been used primarily for palliation in pts with MM. Ablative dose total body irradiation (TBI) of 800 cGy in combination with high-dose melphalan (MEL) as part of single cycle AT was found to be too toxic, and therefore inferior, in comparison to MEL. TMI, a form of image-guided targeted TBI using intensity modulated helical tomotherapy, when given as the sole ablative regimen during the second cycle of TAT, may improve the efficacy of MEL without unacceptable toxicities. Patients and Methods: We designed a phase I-II TAT study in pts with Durie-Salmon stages I–III MM in response or with stable disease (SD), who were ≤ 70 years old. Pts received MEL 200 mg/m2 and AT (cycle 1), and, following recovery, TMI and AT was administered (cycle 2). The dose of TMI started at 1000 cGy, and was to be escalated by an increment of 200 cGy per cohort, up to 200 cGy twice daily x 5 days. Following cycle 2 of TAT, maintenance therapy consisted of dexamethasone 40 mg/day x 4 days and thalidomide (Thal) 50–200 mg daily on a 28-day cycle, administered for 6 cycles for pts in complete response (CR), or for a minimum of 12 cycles for pts not in CR. Results: The median age was 53.5 years (35–66). Twenty three pts (13 female, 10 male) with stages I (1), II (6), III (16) MM received MEL at a median time of 10 mos (7–18) from diagnosis; 22 pts received TMI (1000 cGy through 1800 cGy); 1 pt did not receive TMI due to post-MEL toxicities. The median time between MEL and TMI was 63.5 days (range, 44–119). Granulocyte recovery to >1000/microliter following Mel was 14 days (13–15) versus 15 days after TMI (range; 13–19). Platelet recovery to >20,000/microliter was identical: 13 days (range: 0–16 versus 0–17). Reversible grade 3 non-hematologic toxicities by TMI dose levels included febrile neutropenia (levels 1 and 2: 1 pt each); none (level 3); fatigue (level 4: 1 pt). Dose limiting toxicities (DLT) at level 5 (1800 cGy) were reversible, and included grade 3 radiation pneumonitis/congestive heart failure necessitating administration of oxygen, steroids, and oral cardiac medications, and abdominal pain/enteritis requiring parenteral feeding (n: 1), and grade 3 hypotension requiring pressor support (n: 1), defining the maximum tolerated dose (MTD) at 1600 cGy (200 cGy twice daily x 4 days). The estimated median radiation dose to normal organs was 14–64% of the targeted bone marrow dose in the 6 pts each treated at doses 1600 and 1800 cGy. Late toxicities included reversible enteritis in the pt previously experiencing the same symptom as DLT after receiving 1800 cGy of TMI, and lower extremity deep venous thrombosis (DVT) during maintenance therapy in 2 pts. We observed neither primary nor secondary engraftment failure. Best responses included CR (n: 12), very good partial response (VGPR, n: 4) PR or stable disease (n: 6). At a median follow-up of 22 months (range, 10–39+ months) 5 pts progressed (at 7.5, 8, 16, 21, and 22 months) and 8 pts continue on maintenance. Conclusion: We defined the MTD of TMI as 1600 cGy. Delayed toxicities are limited so far, but underline the need for careful long-term monitoring and DVT prophylaxis during Thal-based maintenance. Phase II of this trial at the MTD of 1600 cGy of TMI is ongoing.

Background: The indolent (follicular, marginal zone and mantle cell) lymphomas tend to recur with decreasing intervals of remission after standard chemotherapy. New modalities of treatment are necessary. Vorinostat (SAHA) is an orally administered hydroxamic acid histone deacetylase inhibitor with activity against class I and II deacetylases with preclinical and clinical activity against various forms of lymphoma. Methods: We report the results of a phase II study of oral vorinostat in patients with relapsed or refractory (to chemotherapy and/or rituximab) follicular, marginal zone, or mantle cell lymphoma. Vorinostat is given at 200 mg PO twice daily for 14 consecutive days on a 21 day cycle. CT scanning and/or FDG-PET are performed after every three cycles, as is marrow biopsy for those with marrow involvement at time of entry into study. Patients may have received up to four prior chemotherapy regimens including tositumomab or ibritumomab; previous transplant is allowed. Results: 37 patients (14 female, 23 male) were accrued (2 ineligible patient due to wrong histology are excluded from the analysis). The median age for evaluable patients at treatment was 65 (32–79) years. Histologies represented: follicular lymphoma (FL)-20, mantle cell (MC)-8, marginal zone (MZL)- 7. Treatment was well tolerated. Grade 3–4 toxicities possibly attributable to study drug were thrombocytopenia, neutropenia, anemia, diarrhea, anorexia, myalgia, hypokalemia, hypophosphatemia, thrombus (1 patient) and fatigue. 18 patients were taken off study due to progression. Three pts came off study due to toxicities (fatigue and diarrhea after 10 cycles, diarrhea and dizziness after 2 cycles, DVT after 5 cycles), 1 stopped therapy due to intercurrent illness, 1 came off for alternate therapy. By the current Cheson criteria, 6 patients achieved complete remission (CR), and 4 patients achieved partial remission (PR), for an overall response rate (CR+PR) of 29%. By histology, 10 formal responses were seen in patients with follicular (8) or marginal zone lymphoma (2), thus for patients with FL and MZL the response rate is 37%, whereas no responses were seen in mantle cell lymphoma. Two patients with PR as best response subsequently progressed (one at 6 months, one after 16 months), the other two remain on therapy. One CR was achieved after 2 years of stable disease on therapy. At a median follow up of 12 months, median progression-free survival for the 35 eligible patients is 7 months; 5 patients are progression-free for more than 18 months. Eleven patients remain on therapy. Conclusions: The histone deacetylase inhibitor vorinostat is well tolerated over long durations of therapy, and shows promising activity (10 CR+PR out of 27 patients) against relapsed/refractory follicular and marginal zone lymphoma.

Tipifarnib (R115777, Zarnestra) is a methylquinolone analogue that is a potent inhibitor of farnesylation. The initial phase I study in leukemia by Karp and Lancet (Blood, 2001) showed clinical responses in 10/34 evaluable patients with AML on a 21 day schedule, with 600 mg bid identified as the MTD. Preclinical work shows that farnesyltransferase remains inhibited for seven days after tipifarnib, suggesting an alternate week dosing schedule. We report the results of a tipifarnib phase I dose escalation trial in AML on a week on week off schedule. Dose levels were 400, 600, 800, 1200, 1400, and 1600 mg BID on a standard 3+3 design. Eligibility was defined as relapsed or refractory AML after one to three prior induction regimens. A total of 37 patients were accrued, with 32 evaluable for toxicity. Median age at treatment is 62 (range 33–77), with 15 F, 22 M. RESULTS: The MTD on this schedule was 1200 mg B.I.D., with the major dose limiting toxicity determined by course one being creatinine elevation. At the 6 pts treated at the MTD there was one DLT (grade 3 creatinine), one grade 3 nausea (not a DLT), and grade 2 toxicities including liver enzyme abnormalities, nausea/vomiting, and rash. At dose level 1, metabolic acidosis and hepatic failure in a patient with progressive leukemia who had previous hepatic toxicity during chemotherapy was observed. Two patients treated at the MTD had a complete remission: a 69-yr old male who relapsed after 231 days, and a 66-yr old male who relapsed after 258 days, but who responded to re-treatment with tipifarnib and is disease-free 548 days (18 months) since enrolling in the study. At 1000mg BID dose, a 69-yr old woman with relapsed AML after autologous transplant had a CR after 2 cycles and went on receive a successful allogeneic transplant and is in remission 2yrs from her first cycle of tipifarnib. One patient with AML evolving out of CMMoL had disappearance of the AML blasts but persistence of the CMMoL after two cycles at the 800 mg bid level, and one patient at the 1400 dose had a platelet rise to 140 from a starting platelet count below 40 despite continued presence of blasts. Higher doses resulted in a higher incidence of dose limiting renal toxicity, fewer courses, and no complete remissions. Additional patients are accruing at the MTD to further understand the toxicities on this schedule. In AML patients, a two-fold increase in tipifarnib dosing can be tolerated on this dosing schedule with responses seen at the higher doses. A monotherapy phase 2 or tipifarnib combination study in AML using this schedule appears warranted.

Tipifarnib (R115777, Zarnestra) is a methylquinolone analogue that is a potent inhibitor of farnesylation. The initial phase I study in leukemia by Karp and Lancet (Blood, 2001) showed clinical responses in 10/34 evaluable patients with AML on a 21 day schedule, with 600 mg bid identified as the MTD. Preclinical work shows that farnesyltransferase remains inhibited for seven days after tipifarnib, suggesting an alternate week dosing schedule. We report the results of a tipifarnib phase I dose escalation trial in AML on a week on week off schedule. Dose levels were 400, 600, 800, 1200, 1400, and 1600 mg BID on a standard 3+3 design. Eligibility was defined as relapsed or refractory AML after one to three prior induction regimens. A total of 37 patients were accrued, with 32 evaluable for toxicity. Median age at treatment is 62 (range 33–77), with 15 F, 22 M. RESULTS: The MTD on this schedule was 1200 mg B.I.D., with the major dose limiting toxicity determined by course one being creatinine elevation. At the 6 pts treated at the MTD there was one DLT (grade 3 creatinine), one grade 3 nausea (not a DLT), and grade 2 toxicities including liver enzyme abnormalities, nausea/vomiting, and rash. At dose level 1, metabolic acidosis and hepatic failure in a patient with progressive leukemia who had previous hepatic toxicity during chemotherapy was observed. Two patients treated at the MTD had a complete remission: a 69-yr old male who relapsed after 231 days, and a 66-yr old male who relapsed after 258 days, but who responded to re-treatment with tipifarnib and is disease-free 548 days (18 months) since enrolling in the study. At 1000mg BID dose, a 69-yr old woman with relapsed AML after autologous transplant had a CR after 2 cycles and went on receive a successful allogeneic transplant and is in remission 2yrs from her first cycle of tipifarnib. One patient with AML evolving out of CMMoL had disappearance of the AML blasts but persistence of the CMMoL after two cycles at the 800 mg bid level, and one patient at the 1400 dose had a platelet rise to 140 from a starting platelet count below 40 despite continued presence of blasts. Higher doses resulted in a higher incidence of dose limiting renal toxicity, fewer courses, and no complete remissions. Additional patients are accruing at the MTD to further understand the toxicities on this schedule. In AML patients, a two-fold increase in tipifarnib dosing can be tolerated on this dosing schedule with responses seen at the higher doses. A monotherapy phase 2 or tipifarnib combination study in AML using this schedule appears warranted.

Vascular endothelial growth factor (VEGF) plays a seminal role in neo-angiogenesis. VEGF is present on myeloma cells, and its receptors, VEGFR1 (Flt-1) and VEGFR2 (KDR) are detectable on the surface of neighboring myeloid and monocytic elements. Hence, VEGF is implicated in the pathogenesis of multiple myeloma (MM). Thalidomide, an important agent in the treatment of MM, among its many postulated mechanisms of actions also inhibits VEGF-mediated neo-angiogenesis. We set out to test the feasibility and explore the efficacy of combining an anti-VEGF agent with thalidomide. With the availability of the anti-VEGF antibody rhuMAB bevacizumab, a trial of bevacizumab 10 mg/kg given intravenously every 2 weeks alone (in thalidomide-exposed patients) versus a randomized comparison of bevacizumab +/− thalidomide 50–400 mg/day (in thalidomide naive patients) was initiated by the California Cancer Consortium. Twelve patients (median age:58 years; range:50–75) with initial stages of I (n:2), II (n:2) and III (n: 8), all with refractory MM have been enrolled. Patients received a median of 1 prior regimen (range:0–5). Six patients had failed an autologous stem cell transplant prior to enrollment. In patients who have received bevacizumab alone, grade 3 toxicities included fatigue and neutropenia (1), hypertension (1), and hyponatremia (1). In the group receiving bevacizumab and thalidomide, grade 3 lymphopenia was observed in 1 patient during cycle 3, and one patient was taken off study due to exacerbation of pre-exisiting (diet pill induced) pulmonary hypertension and was considered inevaluable. Median time to progression for the 6 patients treated with bevacizumab alone was 2 (range 1–4) months. Progression-free survival for the 5 evaluable patients treated with bevacizumab and thalidomide is 6 +, 7, 8 +, 10, and 30 + months, with 2 patients still on study and in response. Two of these patients did not progress but were taken off study (one for patient’s choice, and one due to the physician’s choice to pursue a stem cell transplant at 7.5 months, this patient is listed above as in response at 30 + months). Immunohistochemical staining (IHC) revealed 2 + to 4 + expression of VEGF on myeloma cells in 7 cases of the available 8 pre-treatment bone marrow samples. Weak staining (1+) of VEGFR1 was observed on the surface of myeloma cells in 5 cases. VEGFR2 expression was also observed on plasma cells by IHC (1+ to 2+) in 5 cases. Myeloma cells from a patient treated with bevacizumab alone for a duration of 4 months, and from a patient receiving bevacizumab and thalidomide for 7.5 months before going on to transplant, demonstrated the strongest staining intensity for VEGF. Due to slow accrual the study had been closed to accrual, although 2 patients continue on the bevacizumab and thalidomide arm. However, in light of our findings further testing of bevacizumab, preferably in combination with other active agents is warranted. Supported by NO1 CM 17101.

Tandem high-dose therapy (HDT) followed by peripheral blood progenitor cell reinfusion (PBPC) improves survival for patients with MM, but 80% of patients relapse within 7 years after HDCT. Attempts to treat all areas of skeletal involvement by combining total body irradiation (TBI) with high-dose melphalan (Mel) resulted in substantial organ toxicities and precluded optimal dosing of Mel. Helical tomotherapy allows for 3D CT image guided intensity modulated radiation therapy to large target regions. Radiation beams can be shaped and directed at disease sites from multiple directions. This technology may allow delivery of total marrow irradiation (TMI) at high doses in order to treat MM, while avoiding collateral toxicities. We had performed pre-clinical simulation studies for an adult female patient generating dose volume histograms (DVH) which demonstrated a 2–7 fold reduction in median dose to critical organs and which predicted for the ability to deliver up to 2.0 Gy to the marrow compartment with comparable or reduced risks of mucositis, espohagitis, enteritis, pneumonitis, nephropathy, and cardiomyopathy as it would be expected with TBI of 1.2 Gy. We then designed a phase I/II study for patients with responding or stable stage I-III MM who undergo PBPC mobilization with cyclophosphamide 1.5 gm/kg and G-CSF 10 microgram/kg, and than receive tandem HDT first with melphalan 200 mg/m2 and PBPC, and a minimum of 6 weeks later they are treated with escalating doses of TMI (starting dose: 200 cGy daily x 5, to be escalated up to 200 cGy twice daily x 5 days), and PBPC. Subsequent maintenance therapy consists of dexamethasone 40 mg/day x 4 days every 28 days and thalidomide 50-200 mg/day. The first patient treated with 1 Gy of TMI was a 53 year old woman with stage I IgGκ MM in complete remission after thalidomide and dexamethasone induction. Neutrophil (ANC) and platelet nadirs were observed on days 5 and 9 after melphalan and PBPC; ANC recovery to > 500/uL occured by day 13 and the patient became platelet transfusion independent by day 9. TMI and PBPC were administered 12 weeks later. ANC and platelet nadirs occurred on days 3 and 5; ANC recovered in 10 days and platelet transfusion independence was accomplished by day 11. The patient experienced partial alopecia, grade 2 nausea and grade 1 emesis on the second day of TMI, but she was completely devoid of erythema, mucositis, or diarrhea. The actual DVHs were comparable to those seen in the preclinical studies/simulations and reflected an estimated 2.5 fold median decrease in the amount of radiation delivered to non-target organs in comparison to the target: bone marrow. Figure Figure Accrual to the first dose level is completed. Details of toxicities and DVH curves from additional patients/cohorts who will have completed their TMI cycles will be presented.