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Abstract Background Long-term outcomes from autologous stem cell transplant (ASCT) in patients (pts) with relapsed/refractory (R/R) Hodgkin lymphoma (HL) are significantly better in patients who achieve a complete remission (CR) from salvage chemotherapy prior to ASCT. However, standard salvage therapy produces variable CR rates (19%-60%) and is associated with significant toxicity. Brentuximab vedotin and bendamustine are highly active when administered as single agents to pts with R/R HL (34% and 33% CR rates, respectively) and have manageable safety profiles. This phase 1/2, single-arm, 2-stage, open-label study was designed to evaluate the safety and efficacy of brentuximab vedotin in combination with bendamustine for the treatment of pts with primary refractory disease or in first relapse (ClinicalTrials.gov #NCT01874054). Methods Pts received an outpatient IV infusion of 1.8 mg/kg brentuximab vedotin on Day 1 with bendamustine on Days 1 and 2 of 3-week cycles for up to 6 cycles. Pts could undergo ASCT any time after Cycle 2 and post-transplant resume treatment with brentuximab vedotin as monotherapy for up to 16 total doses. Phase 1 was designed to determine the recommended dose of bendamustine, with an initial dose of 90 mg/m2 and a de-escalation scheme to be implemented if it exceeded the maximum tolerated dose. During phase 2, bendamustine was administered at the recommended dose in order to assess the CR rate of the combination. Response was assessed by the investigator per Cheson 2007. Enrollment is complete and long-term follow-up for PFS and OS continues. Results Fifty-five pts (56% female) with a median age of 36 yrs (range, 19-79) were enrolled. Fifty-one percent of pts had relapsed disease and 49% of pts had primary refractory disease after frontline therapy. A median of 13.8 mos (range, 3-98) had elapsed since initial diagnosis. No dose-limiting toxicities were observed in the safety cohort, thus the recommended dose of bendamustine in combination with brentuximab vedotin was 90 mg/m2. Pts received a median of 2 cycles (range, 1-6) of the combination and a median of 9 cycles (range, 1-14) of single-agent brentuximab vedotin. The main toxicity observed with the combination was infusion-related reactions (56% overall). The most common symptoms (≥10%) were pyrexia (26%), chills (20%), dyspnea and nausea (15% each), flushing (13%), and hypotension (11%). Premedication with corticosteroids and antihistamines was instituted with a protocol amendment and appeared effective. Before the amendment, 6 pts (24% of treated pts) discontinued treatment prematurely because of IRRs; post-amendment, IRRs led to treatment discontinuation for 2 pts (7%). The CR rate of the combination was 74% (39/53 pts evaluable for response) and the overall objective response rate (CR and partial remission) was 93% (49/53 pts). The CR rate was 64% and 84% for refractory and relapsed pts, respectively. Stem cell collection after first-line mobilization (G-CSF± plerixafor) was successful in 93% of pts (37/40). Median number of CD34+ cells collected was 4.1 x106 (Q1, Q3: 3.0, 5.4) in a median of 2 (range, 1-5) apheresis sessions. Median time to neutrophil and platelet engraftment was 11 days (range, 9-21) and 13 days (range, 9-39), respectively. Pts have been followed for a median of approximately 1 year from first dose (median = 418 days; range, 118-635) and approximately 10 mos (314 days; range, 13-553) from ASCT. To date, 12 progression events have been observed: 7 in the 40 pts who underwent transplant and 5 in the 13 pts who did not undergo transplant. The estimated 12-mos PFS is 80% for both the transplanted population (95% CI: 70%, 90%) and the overall population (95% CI: 60%, 90%). Three of the 12 progression events were deaths; 2 pts died from progression of their HL and 1 pt died from septic shock after transplant. Conclusions The outpatient regimen of brentuximab vedotin 1.8 mg/kg on Day 1 in combination with bendamustine 90 mg/m2 on Days 1 and 2 of 3-week cycles induced a very high CR rate that compares favorably with historical data. The regimen has a manageable safety profile, with the most significant side effect being IRRs that can be successfully managed by premedication. The estimated 12-mos PFS rate of 80% demonstrates response durability, making the combination a promising salvage regimen for pts with HL in the first relapse setting. Progression-Free Survival Figure 1. Figure 1. Disclosures Off Label Use: Brentuximab vedotin is indicated in the US for treatment of patients with Hodgkin lymphoma after failure of autologous stem cell transplant or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not ASCT candidates and for the treatment of patients with systemic anaplastic large cell lymphoma after failure of at least one prior multi-agent chemotherapy regimen. This study evaluates brentuximab vedotin in HL patients with primary refractory disease or in first relapse. . Sawas:Seattle Genetics, Inc.: Research Funding. Agura:Seattle Genetics, Inc.: Research Funding. Matous:Takeda Pharmaceuticals International Co.: Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Seattle Genetics, Inc.: Research Funding, Speakers Bureau. Ansell:Bristol-Myers Squibb: Research Funding; Celldex: Research Funding. Crosswell:KIYATEC (employment); Gilead (common stock ownership and research funding): Employment, Equity Ownership, Research Funding. Islas-Ohlmayer:Seattle Genetics, Inc.: Research Funding. Behler:Seattle Genetics, Inc.: Research Funding; Onyx Pharmaceuticals: Speakers Bureau. Cheung:Seattle Genetics, Inc.: Research Funding. Forero-Torres:Seattle Genetics, Inc.: Research Funding. Vose:Seattle Genetics, Inc.: Honoraria, Research Funding. Josephson:Seattle Genetics, Inc.: Employment, Equity Ownership. Advani:Seattle Genetics, Inc.: Research Funding; Genetech: Consultancy.

Abstract INTRODUCTION: mTOR inhibitors have been associated with responses in Mantle cell lymphoma and other lymphomas (J Clin Oncol23; 5347, 2005). Phase I and II trials with the oral everolimus (RAD001, Novartis Pharmaceuticals) have demonstrated a favorable side effect profile. This phase II study tested everolimus in patients with relapsed/refractory Waldenstrom Macroglobulinemia (WM). METHODS: Patients who had at least one previous therapy for WM and who had relapsed or refractory disease were eligible. Other eligibility criteria included symptomatic disease, > 2 weeks from last therapeutic agent used, >10% involvement with lymphoplasmacytic cells in the bone marrow, IgM paraprotein > 2x upper limit of normal, absolute neutrophil count >1000/mm3 and platelet count >75,000/mm3, serum creatinine of < 2 x upper limit of normal. NCI CTCAE v3.0 was used for toxicity assessment. Response was assessed by criteria established at the second consensus panel for WM. All patients received 10mg RAD001 daily for 28 days per cycle for 6 cycles; response was assessed after 2 cycles. RESULTS: 10pts (8 men and 2 women, median age is 62 years, range 52–71) have been treated to date. The median number of lines of prior treatment was 3 (range 1 – 5). The median IgM at baseline was 3970 mg/dL (range 3120– 7410); median M-spike at baseline was 2.07 gm/dL (range 1.41 – 4.02); and median hemoglobin was 11.3 g/dL (9.4–13.3). The median follow up was 4 months (range 1 – 7 months). Prior therapy included rituximab, nucleoside analogues (fludarabine and 2-CDA), combination chemotherapy (e.g CHOP, CVP), chlorambucil. and bortezomib. Seven patients are currently evaluable for response. The best response to single agent RAD001 after 2 cycles is presented in Table 1. Median duration of response has not been reached. Patients tolerated RAD001 well without significant toxicities. The main toxicities observed were apthous ulcers in 4 patients. One patient required dose reduction due to mucositis. One patient stopped therapy within the first month of treatment and went on to hospice care before succumbing to his disease after one month. Attributable toxicities otherwise proved manageable with appropriate supportive care and RAD001 was generally well tolerated, with no peripheral neuropathy. CONCLUSIONS: Oral RAD001 as monotherapy has been well tolerated and demonstrates exciting activity achieving PR + MR in 57%, and/or stabilization of disease in 43% of evaluable patients with relapsed WM. Accrual of a total of 30 patients is rapidly ongoing. Updated data will be presented at the meeting. Table 1 Response N=7; ORR (CR+PR+MR)= 57% Median time to best response (months) Partial Response 1 (14%) 5 Minimal Response 3 (43%) 4 (3–6) Stable Disease (SD) 3 (43%) NA Progressive Disease 0

AbstractObjectiveWe evaluated the accuracy of molecular breast imaging (MBI)—a nuclear medicine technique that employs dedicated dual-detector, cadmium zinc telluride gamma cameras to image the functional uptake of a radiopharmaceutical (typically Tc-99m sestamibi) in the breast—in patients with suspicious calcifications on mammography.MethodsWomen scheduled for stereotactic biopsy of calcifications detected on 2D digital mammography were prospectively enrolled to undergo MBI before biopsy. Molecular breast imaging was performed with injection of Tc-99m sestamibi and a dual-detector, cadmium zinc telluride gamma camera. Positive findings on either modality were biopsied. High-risk and malignant biopsy findings were excised.ResultsIn 71 participants, 76 areas of calcifications were recommended for biopsy after mammography, and 24 (32%) were malignant, including 20 cases of ductal carcinoma in situ (DCIS) and 4 cases of invasive ductal cancer. Prebiopsy MBI was positive in 17 of the 76 (22%) calcifications, including 10 of 20 (50%) DCISs and 2 of 4 (50%) invasive cancers. The median pathologic size for MBI–positive cancers was 1.5 cm (range 0.5–3.2 cm) compared with 0.9 cm (range 0.1–2.0 cm) for MBI–negative cancers (P = 0.09).Non-mass uptake on MBI led to additional biopsies of 6 sites in 6 patients, and 2 of 6 (33%) MBI–detected incidental lesions showed malignancy; both DCIS contralateral to the mammographically detected calcifications. The overall per-lesion positive and negative predictive values of MBI in this prebiopsy setting were 61% (14 of 23) and 80% (47 of 59), respectively.ConclusionMolecular breast imaging has insufficient negative predictive value to identify calcifications in which biopsy could be avoided. However, among women presenting for biopsy of suspicious calcifications, MBI revealed additional sites of mammographically occult breast cancer.To avoid biopsy of suspicious calcifications on mammography, negative findings on MBI should not be used.

Abstract Introduction: Carfilzomib (CFZ) is a structurally- and mechanistically-novel proteasome inhibitor (PI) of the peptide epoxyketone class that exhibits a high level of selectivity for the unique N-terminal threonine active sites within the proteasome. CFZ is similar to bortezomib (BTZ; VELCADE®), in that it is a potent inhibitor of the chymotrypsin-like activity, but unlike BTZ, CFZ has shown minimal cross-reactivity with the other catalytic sites within the proteasome or across other protease classes. Preclinical human tumor xenograft models indicate that consecutive day (D1, D2) dosing resulting in 48 hours of proteasome suppression was superior to split dosing (D1, D4). Methods: This phase 1 sequential dose escalation trial tested an intensive proteasome inhibition schedule with CFZ administered as an intravenous push (IVP) daily (QD) for 5 consecutive days on a 14 day cycle. The doses administered ranged from 1.2 mg/m2 to 20 mg/m2. Multiple myeloma (MM), non-Hodgkin’s lymphoma (NHL) that included mantle cell lymphoma (MCL), Hodgkin’s disease (HD), or Waldenström’s macroglobulinemia (WM) were eligible if they had relapsed after 2 or more prior therapies. Results: A total of 29 subjects have been treated. The minimal effective dose (MED) was 11 mg/m2. A maximum of 80% proteasome inhibition was achieved in peripheral blood and mononuclear cells at ≥15 mg/m2. Five responses have occurred in 14 patients (6 MM, 3 MCL, 1 WM, 4 NHL) enrolled at ≥ the MED: 1 MM partial response (PR), 2 MM minimal responses (MR), 1 WM MR and one macroscopic CR in a patient with gastrointestinal MCL. Responses occurred in patients whose disease had failed therapy with BTZ, immunomodulatory agents, and stem cell transplant. Four NHL patients have had stable disease and remained on treatment for up to 7 months. Dose limiting toxicity reported at 20 mg/m2 included febrile neutropenia (reversible) and grade 4 thrombocytopenia. Grade 3 (25%) or grade 4 events (8%) were primarily hematologic events. Most withdrawals occurred due to the inconvenience of frequent visits, or progressive disease. Conclusions: This study demonstrates that intensive CFZ dosing leading to sustained proteasome inhibition is well tolerated. The selectivity of the epoxyketone class of PI may promote a favorable safety profile. Furthermore, antitumor responses in heavily pretreated patients suggest non-cross resistant activity. Phase 2 trials in MM and solid tumors are proceeding with an alternate IV schedule. An oral agent suitable for frequent dosing schedules is under development.

Abstract Numerous cardiology groups are actively pursuing the use of hematopoietic stem cells for myocardial delivery. Most published studies have used a manual ficoll density separation procedure to enrich the Mononuclear Cell (MNC) population thus enriching the stem cell content in the final therapeutic cell product. Manual ficoll procedures have certain intrinsic limitations including technologist variability, training time, and risk of contamination due to its open nature. Most open and manual cell processing procedures have been supplanted by recent technology developments in automated and closed devices. The BioSafe SEPAX is a closed system-automated ficoll density separation device that currently has FDA 510k clearance for the processing of umbilical cord blood products. In support of multi-center clinical studies being conducted by the NHLBI Cardiovascular Cell Therapy Research Network (CCTRN), the MD Anderson Cell Therapy Laboratory has evaluated bone marrow derived, MNC enriched, stem cells for their cardiovascular therapeutic potential. Traditional transplantation immunophenotyping was performed on these cells to evaluate hematopoietic stem cells (CD34+ and CD133+), T-Cell subsets, B-Cells, and NK-Cells. Colony Forming Units (CFU) as wells as surrogates used in cardiac regeneration studies including endothelial invasion assays and CXCR4 immunophenotyping (a chemokine receptor involved in cell migration) were also performed. Our data suggests the cells produced using the automated ficoll BioSafe SEPAX device are equivalent to cells produced using a manual ficoll procedure with respect to TNC, MNC, viability, and CD34+ recoveries. Cell subsets and function including invasion and CXCR4 analysis were also similar between the two procedures. The automated method produced a product with statistically higher CFU potential than the manual method suggesting the SEPAX isolates a more potent subset of the mononuclear fraction. These studies support the use of the SEPAX device as for enriching BM-MNCs for the CCTRN. Additional benefits might include the use of a closed system, ease of training, speed of cell manufacturing, and product consistency.

Abstract Background: Reactive oxygen species cause DNA damage and altered immunologic responses, and have been linked to the development of NHL. Diets rich in fruits and vegetables are excellent sources of antioxidants, and vitamins C, E, polyphenols, and carotenoids, along with selected micronutrients such as zinc are thought to be responsible for most of the antioxidant activity in foods. We evaluated the hypothesis that vegetables, fruits and nutrients involved in antioxidant activity would protect against developing NHL. In a secondary analysis, we also assessed heterogeneity of this hypothesis for the most common subtypes of NHL: chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), follicular lymphoma, and diffuse large B cell lymphoma (DLBCL). Methods: We evaluated dietary antioxidant intake and NHL risk in a clinic-based study of 416 newly diagnosed NHL cases and 926 frequency-matched controls enrolled at the Mayo Clinic from 2002–2007. Usual diet two years before diagnosis/enrollment was assessed using a self-administered, 128-item food frequency questionnaire. Dietary intake of antioxidants was estimated using the Food Processor SQL system, further supplemented with data from US Department of Agriculture nutrient databases. Unconditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CI), adjusted for age, sex, residence, and total energy. NHL subtypes were centrally reviewed, and subtype-specific risks were estimated using polychotomous logistic regression. Results: The mean age at diagnosis was 60.8 years for cases and 57% were male; for controls, the mean age at enrollment was 60.8 years and 54% were men. NHL risk was inversely associated with intake of total vegetables (OR for highest compared to lowest quartile, 0.46; 95% CI 0.32–0.68; p-trend<0.001), and specifically green leafy (OR=0.54; 95% CI 0.39–0.76; p-trend<0.001) and cruciferous (OR=0.62; 95% CI 0.43–0.88; p-trend=0.02) vegetables, but not legumes or red/yellow/orange vegetables. There was no association with total fruit intake or intake of citrus fruits in particular. When modeled together, the association for green leafy vegetables was unchanged while the association for cruciferous vegetables attenuated (OR=0.75; 95% CI 0.50–1.13; p-trend=0.3). Higher intake of total vitamin A (OR=0.60; 95% CI 0.41–0.88; p-trend<0.001) and vitamin E (OR=0.53; 95% CI 0.34–0.82; p-trend<0.001), but not vitamin C, were associated with lower NHL risk. For vitamin A, there was no association with preformed Vitamin A, but there was an inverse association with beta-carotene (OR=0.56; 95% CI 0.39–0.81; p-trend<0.001); only weak inverse associations were observed for other carotenoids (lutein/zeaxanthin, lycopene, and cryptoxanthin). When modeled together, the inverse association for vitamin E was unchanged while the association for beta-carotene attenuated. For micronutrients, there were inverse associations for manganese (OR=0.60; 95% CI 0.40–0.90; p-trend=0.02), selenium (OR=0.47; 95% CI 0.27–0.80; p-trend=0.01), and zinc (OR=0.46; 95% CI 0.27–0.80; p-trend<0.001) but not copper; when modeled simultaneously, both manganese (p-trend=0.03) and zinc (p-trend=0.02) remained significantly and inversely associated with NHL risk. Further adjustment for education, family history of NHL, smoking, alcohol use, and body mass index did not alter these results. There was no NHL subtype heterogeneity for the associations with total vegetables, green leafy vegetables or vitamin E, while inverse associations were not observed for manganese and follicular lymphoma or zinc and CLL/SLL. Conclusion: Higher intakes of vegetables, particularly green leafy vegetables, vitamin E, manganese, and zinc were associated with lower risk of NHL. These finding extend a growing literature from case-control and cohort studies that support a protective role of foods and nutrients that function in antioxidant related pathways against development of NHL, and therefore may represent one of the few known modifiable risk factors for this cancer.

Abstract Introduction The phagocytic activity of macrophages is regulated by activating ("eat") and inhibitory ("do not eat") signals. Under normal physiologic conditions, the ubiquitously expressed cell surface antigen CD47 suppresses phagocytosis by binding to signal regulatory protein alpha (SIRPα) on macrophages. It is hypothesized that overexpression of CD47 by cancer cells enables immune evasion. Blockade of CD47 results in phagocytosis of cells bearing "eat" signals and primes effective anti-tumor T cell responses. TTI-621(SIRPαFc)is a soluble recombinant fusion proteinconsisting of the CD47 binding domain of human SIRPα linked to the Fc region of human IgG1designed to both: 1) block the CD47 "do not eat" signal, and 2) engagemacrophage Fcγ receptors with IgG1 Fc to enhance phagocytosis and antitumor activity.In vitro, TTI-621 binds to normal human cells, platelets, a wide range of human primary tumor cells and cell lines, but only minimally to human erythrocytes. TTI-621 selectively promotes macrophage-mediated phagocytosis of hematologic and solid tumors over that observed with normal monocytes, and exhibits antitumor activity in xenograft mouse models. Methods A first-in-human, phase 1, open label, multicenter study (NCT02663518) is ongoing to evaluate the safety and tolerability, and to identify the maximum tolerated dose of TTI-621 in patients (pts) with relapsed/refractory lymphomas using a 3+3 dose-escalation design. Once the optimal dose has been determined in the dose-escalation phase, multiple expansion cohorts will be enrolled comprising pts with various relapsed/refractory hematologic malignancies. Assessments include peripheral receptor occupancy, serum cytokine levels, pharmacokinetics, and immunogenicity. Eligible pts are adults with advanced, measurable, hematologic malignancies, who have progressed on standard anticancer therapy or for whom no other approved therapy exists. Pts are required to have baseline hemoglobin ≥10 g/dL, platelets ≥75 x 109/L, and be transfusion- and growth factor-independent. Pts with cutaneous T-cell lymphoma, high-grade lymphoma, and acute promyelocytic leukemia are excluded. TTI-621 is administered IV once weekly at protocol-defined doses. Treatment may continue until disease progression or unacceptable toxicity. Results Eleven pts (6M/5F, age 21-72 years) have been enrolled as of the data cut-off date of 28 July 2016. Lymphoma diagnoses included Hodgkin (N=4), diffuse large B cell (DLBCL) (N=4), follicular (N=2), and mantle cell (N=1). Treatment has been reasonably well tolerated by pts in the 0.05 mg/kg (N=3), 0.1 mg/kg (N=3), and 0.3 mg/kg (N=5) dose cohorts. The majority of pts experienced mild to moderate infusion-related events. Hemoglobin levels have remained stable or improved with treatment. Transient, dose-dependent decreases in platelets and leukocytes occurred in the hours following infusion in all pts without clinical sequelae. The 0.3 mg/kg dose was associated with reversible, dose-limiting toxicity (DLT) in 2 of 5 pts: one pt with G3 elevated ALT/AST and G4 platelet count, and a second pt with G4 platelet count who was transfused. Dosing at 0.2 mg/kg is now being explored. Aside from the DLTs and 2 non-DLT G3 platelet count (all in 0.3 mg/kg cohort), treatment-related adverse events have been ≤G2. CD47 receptor occupancy increased with each cohort, peaking at the end of infusion and remaining detectable 24 hrs after the 1st infusion in Cohort 3. Macrophage-associated cytokines, including MIP-1α and MIP-1β, increased during the 4 hrs after infusion. Six pts continue to receive weekly infusions of TTI-621; one pt with DLBCL and another with FL have experienced progression-free intervals of 161 and 70 days, respectively. Conclusions TTI-621 has been reasonably well tolerated. Pts retained stable hemoglobin levels consistent with minimal drug binding to erythrocytes. Manageable, dose-dependent thrombocytopenia was likely due to increased phagocytic clearance of platelets. TTI-621 binds to CD47+ cells in a dose-dependent manner, potently yielding increases in cytokines associated with augmented phagocytic activity. Enrollment continues at the 0.2 mg/kg dose level; updated data will be provided at the meeting. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Ansell: BMS, Seattle Genetics, Merck, Celldex and Affimed: Research Funding. Chen:Seattle Genetics: Consultancy, Honoraria, Research Funding, Speakers Bureau; Millenium: Consultancy, Research Funding, Speakers Bureau; Genentech: Consultancy, Speakers Bureau; Merck: Consultancy, Research Funding. Flinn:Janssen: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Gilead Sciences: Research Funding; ARIAD: Research Funding; RainTree Oncology Services: Equity Ownership. O'Connor:Bristol Myers Squibb: Research Funding; Spectrum: Research Funding; TG Therapeutics: Research Funding; Mundipharma: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Seattle Genetics: Research Funding; Bristol Myers Squibb: Research Funding; Mundipharma: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; TG Therapeutics: Research Funding. Johnson:Trillium Therapeutics: Employment. Irwin:Hoffmann La Roche: Employment, Equity Ownership; Trillium Therapeutics: Employment, Equity Ownership. Petrova:Trillium Therapeutics Inc: Employment, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Uger:Trillium Therapeutics: Employment, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Sievers:Seattle Genetics: Employment, Equity Ownership; Trillium Therapeutics: Employment, Equity Ownership; MEI Pharma: Consultancy.

Abstract INTRODUCTION: PR-171 is a novel, irreversible proteasome inhibitor under investigation for the treatment of hematological malignancies. In preclinical studies, PR-171 was well tolerated in rats and monkeys when given daily × 5 (QDx5), every two weeks. Proteasome inhibition determined in blood and other tissues one hour after dosing at the maximum tolerated dose (MTD) was >80%. Despite the irreversible mechanism of action, the half-life of recovery of proteasome inhibition in tissues was approximately 24 hours. PR-171 was effective in suppression of tumor growth in xenograft studies in mice when administered QDx2 every week for three weeks. Two phase I dose-escalation studies have been initiated, aimed at determining the safety, tolerability, and clinical response to PR-171. METHODS: Two different dose-intensive schedules were employed in these phase I studies. In PX-171-001, PR-171 was administered on a two week cycle, QDx5 with nine days rest, while in PX-171-002, PR-171 was administered on a four week cycle, QDx2 weekly for three weeks with 12 days rest. The objective of these studies was to evaluate the safety and effectiveness of single-agent PR-171 administered according to a modified Fibonacci dose escalation scheme in cohorts of three. Patients with multiple myeloma (MM), non-Hodgkin Lymphoma (NHL), Hodgkin disease, or Waldenstrom’s Macroglobulinemia who received two or more prior treatments were eligible. RESULTS: Both studies were initiated with a dose of 1.2 mg/m2. Thus far, a total of 15 and 23 subjects have been enrolled in PX-171–001 and -002, respectively. PR-171 has been well tolerated at the highest doses thus far, 8.4 and 15 mg/m2, respectively. Proteasome inhibition in whole blood at the highest dose levels exceeded 75%, and in peripheral blood mononuclear cells inhibition exceeded 65%, one hour after the first dose. There have been no dose-limiting toxicities, no adverse events (AEs) considered probably related to study medication, no dose-related increases in the incidence or severity of AEs, and no incidence of painful peripheral neuropathy on either study. Although the MTD has not yet been identified on either study, preliminary evidence of efficacy has been observed with reduction in myeloma paraprotein levels and symptomatic improvement in patients on both protocols. Eleven subjects remain on study with stable disease (SD), which has been observed in MM and NHL patients on both studies, lasting up to eight months. CONCLUSION: PR-171 is well-tolerated in relapsed and refractory MM and NHL patients at proteasome inhibition levels of more than 75%. Several subjects have achieved long-lasting SD, reduction in paraprotein levels or symptomatic improvement. Further data from these ongoing trials will be discussed at the meeting.