ALBERT

Description: Triplet regimens combining an immunomodulatory agent, a proteasome inhibitor (PI), and a steroid are used to treat newly diagnosed and relapsed multiple myeloma (MM). Although ixazomib (Ix), an oral PI with single agent activity, can be combined with lenalidomide (LEN), patients (pts) with relapsed/refractory (R/R) MM are often LEN-refractory. Pomalidomide (POM) has single agent activity in LEN-refractory disease, and both POM and Ix also show activity in poor cytogenetic risk pts. Methods: Primary objectives: 1) determine the maximum tolerated dose (MTD) of Ix in combination with standard dose POM and dexamethasone (DEX), and 2) evaluate the anti-tumor activity of the triplet. The treatment regimen included two dose levels (3 mg and 4 mg) of Ix on days 1, 8, 15; POM 4 mg days 1-21; and DEX 40 mg days 1, 8, 15, 22, of a 28 day cycle. Eligibility: R/R MM after 〉1 prior therapy, LEN-refractory, and ≤ grade(gr) 1 peripheral neuropathy (PN). Pts were treated until progression or unacceptable toxicity. Design: Phase I study utilizing a standard 3+3 design; dose limiting toxicities (DLTs) defined during cycle 1. Results: 32 pts treated, 31 evaluable for toxicity and response. Pts received a median 4 cycles (range 1-13); median follow-up is 5.5 months (range 1.8-21.1). Six pts treated on DL1, 25 treated on DL2, the MTD/Phase II dose (P2D). Median age: 62 years (range 38-84); median time from diagnosis: 3.7 years (range 1.0-8.9); median number prior therapies: 3 (range 1-5); prior transplant: n = 23 (74%); double (LEN/Bortezomib[BOR]) or triple (LEN/BOR/Carfilzomib[CFZ]) refractory: 19 (61%). Phase I: DL1 expanded to n=6 after 1/3 pts experienced DLT (gr3 lung infection); no further DLT seen on DL 1 or 2. Adverse events (AEs) related to POM and/or Ix: ANC decrease Gr1/2 n=11 (35%), Gr3/4 n=10 (32%), platelet decrease Gr1/2 n=9 (29%), lymphocyte decrease Gr1/2 n=8 (26%), Gr3/4 n=11 (35%), PN Gr1/2 n=9 (29%), no Gr3/4. Response: Phase I and II, n=31 pts treated. ORR: 45% (6 VGPR, 8 PR); Clinical Benefit Rate (CBR): 81% (6 VGPR, 8 PR, 3 MR, 8 SD). In the pts with high risk cytogenetics (7[23%] 1q, 3[10%] 17p, 2[6%] t(4;14)) an ORR of 58% (3 VGPR, 4 PR) was seen, and the CBR was 83%. In the double or triple refractory pts, an ORR of 26% and CBR of 79% (1 VGPR, 4 PR, 3 MR, 7 SD) were observed. Conclusions: Ix/POM/DEX is a well-tolerated oral combination therapy, and responses were seen even at DL1 and in high risk patients, including those with poor-risk cytogenetics or advanced refractory disease. Disclosures Kapoor: Celgene: Research Funding; Amgen: Research Funding; Takeda: Research Funding. Kumar:Millennium: Consultancy, Research Funding; AbbVie: Research Funding; Glycomimetics: Consultancy; Sanofi: Consultancy, Research Funding; Noxxon Pharma: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; BMS: Consultancy; Kesios: Consultancy; Onyx: Consultancy, Research Funding; Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Research Funding; Array BioPharma: Consultancy, Research Funding. Lonial:Novartis: Consultancy; BMS: Consultancy; Janssen: Consultancy; Merck: Consultancy; Celgene: Consultancy; Onyx: Consultancy; Novartis: Consultancy; BMS: Consultancy; Celgene: Consultancy; Millenium: Consultancy; Janssen: Consultancy; Onyx: Consultancy. Nathwani:Carevive Systems, Inc.: Research Funding. Forman:Mustang Therpapeutics: Other: Construct licensed by City of Hope. Berdeja:Abbvie, Acetylon, Amgen, Bluebird, BMS, Calithera, Celgene, Constellation, Curis, Epizyme, Janssen, Karyopharm, Kesios, Novartis, Onyx, Takeda, Tragara: Research Funding.

Description: Background MLN9708 (ixazomib citrate) is an oral proteasome inhibitor that is being investigated in phase 3 trials. MLN9708 rapidly hydrolyzes to the biologically active form, MLN2238 (ixazomib). Preliminary findings from studies using weekly and twice-weekly schedules in relapsed/refractory MM have suggested evidence of single-agent activity (Kumar et al, ASCO 2013; Lonial et al, ASCO 2012), and a phase 1/2 study has suggested the feasibility and activity of weekly oral MLN9708 plus len-dex in newly diagnosed MM (Kumar et al, ASH 2012). Here we report the results of a phase 1/2 study, conducted in collaboration with the Multiple Myeloma Research Consortium, of twice-weekly oral MLN9708 plus len-dex (NCT01383928). Methods Phase 1 primary objectives were to determine safety, tolerability, the MTD, and the recommended phase 2 dose (RP2D); secondary objectives included characterizing MLN2238 pharmacokinetics (PK). Phase 2 primary objectives were to determine the combined CR+VGPR rate and further evaluate safety and tolerability; secondary objectives included overall response rate (≥PR), time to response, and duration of response (DOR). Pts aged ≥18 yrs who had no grade ≥2 peripheral neuropathy (PN) and no prior/concurrent DVT/pulmonary embolism received MLN9708 3.0 or 3.7 mg (d 1, 4, 8, 11), len 25 mg (d 1–14), and dex 20/10 mg (cycles 1–8/9–16; d 1, 2, 4, 5, 8, 9, 11, 12) for up to 16 21-day cycles, followed by MLN9708 maintenance (same schedule) until progression or unacceptable toxicity. Transplant-eligible pts could undergo stem cell collection after ≥4 cycles and discontinue for ASCT after ≥8 cycles. Responses were assessed per IMWG uniform response criteria. Adverse events (AEs) were graded per NCI-CTCAE v4.03. Blood samples for PK analysis were taken at multiple time points during cycles 1 and 2. Results 64 pts were enrolled; median age was 64 yrs (range 34–82), 63% were male, and 31%/16% had ISS stage II/III MM. In phase 1, 14 pts received MLN9708 3.0 mg (n=7) and 3.7 mg (n=7). No DLTs were seen in cycle 1; based on overall tolerability and incidence of rash at 3.7 mg, the RP2D was chosen as 3.0 mg. 50 pts were enrolled at this dose in phase 2. At data cut-off (July 1, 2013), the median follow-up was 6.9 months and median number of cycles received was 8 (range 1–26); 73% had received ≥8 cycles and 9% had received ≥16 cycles. At data cut-off, 22% of pts had discontinued to undergo ASCT (median CD34+ stem cell yield 14.9 x 106/kg [range 7–52 x 106]), a further 14%, 5%, and 19% had discontinued due to AEs, progressive disease, and other reasons, respectively, and the other 41% remained on treatment. In 58 response-evaluable pts, ≥PR rate to date was 93%, including 67% ≥VGPR (24% CR, including 14% sCR). 54% of pts had 100% decreases in M-protein or serum free light chain from baseline. Analysis of minimal residual disease is ongoing; data will be presented. Depth of response increased over the course of treatment; median time to first response (≥PR) was 0.69 mos and to best response to date was 2.07 mos. Median DOR to date was 5.9+ mos, ranging up to 18+ mos. Most common AEs were rash (61%; pooled high-level terms), fatigue, peripheral edema (each 50%), diarrhea (41%), and neuropathy peripheral (36%). Drug-related (to any drug in the regimen) grade 3 AEs were seen in 56% of pts, including rash (16%), hyperglycemia (8%), pneumonia (6%), and PN (5%; high-level term). No drug-related grade 4 AEs were seen; 58% of pts required dose reductions of at least one drug due to AEs including rash (16%), anxiety (11%), and PN (8%). AEs resulting in discontinuation were seen in 11%, with the majority reported as not related to therapy. There was 1 on-study death due to cardio-respiratory arrest, likely a pulmonary embolism, considered by the investigator to be unrelated to MLN9708 or dex, but probably len. Based on phase 1 preliminary PK data, MLN2238 was absorbed quickly with a Tmaxof 0.5–4 hours. Terminal half-life was 2–8 days. PK data were similar to single-agent twice-weekly dosing studies, suggesting no MLN2238 PK interaction with len or dex. Conclusions These data suggest that twice-weekly oral MLN9708 plus len-dex is feasible and active in pts with newly diagnosed MM. However, rates of rash, PN, and dose reductions appear higher than in the parallel study using weekly MLN9708, with similar response rates and better convenience, supporting use of weekly dosing in ongoing phase 3 trials. Disclosures: Richardson: Millennium: The Takeda Oncology Company: Membership on an entity’s Board of Directors or advisory committees; Celgene: Membership on an entity’s Board of Directors or advisory committees; Johnson & Johnson: Membership on an entity’s Board of Directors or advisory committees. Off Label Use: Investigational agent MLN9708 in combination with lenalidomide and dexamethasone for the first-line treatment of patients with multiple myeloma. Hofmeister:Celgene: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau. Rosenbaum:Janssen: Membership on an entity’s Board of Directors or advisory committees; Celgene: Speakers Bureau. Vesole:Millennium: The Takeda Oncology Company: Speakers Bureau; Celgene: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Onyx Pharmaceuticals: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau. Liedtke:Celgene: Research Funding; Millennium: The Takeda Oncology Company: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Chari:Celgene: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Millennium: The Takeda Oncology Company: Membership on an entity’s Board of Directors or advisory committees; Onyx Pharmaceuticals: Membership on an entity’s Board of Directors or advisory committees. Lebovic:Celgene: Membership on an entity’s Board of Directors or advisory committees; Onyx: Membership on an entity’s Board of Directors or advisory committees. Berg:Millennium: The Takeda Oncology Company: Employment. Liao:Millennium: The Takeda Oncology Company: Employment. Gupta:Millennium: The Takeda Oncology Company: Employment. Di Bacco:Millennium: The Takeda Oncology Company: Employment. Estevam:Millennium: The Takeda Oncology Company: Employment. Hui:Millennium: The Takeda Oncology Company: Employment. Baz:Celgene: Research Funding; Millennium: The Takeda Oncology Company: Research Funding; Bristol-Myers Squibb: Research Funding; Novartis: Research Funding; Sanofi: Research Funding; Karyopharm: Research Funding.

Description: Abstract 4562 Analysis of Risk Factors and Outcome for Extramedullary Relapses post Allogeneic Stem Cell Transplantation for Myeloma Relapse after both autologous and allogeneic hematopietic stem cell transplant (HSCT) is common in multiple myeloma (MM). Unusual sites of relapse have been reported after allogeneic HSCT in the form of isolated extramedullary (EM) lesion or light chain escape. It is hypothesized that these EM relapses are due to changes in the marrow microenvironment or selection of resistant subclones from therapy with novel agents and or allogeneic stem cell transplantation. Several case reports have shown that EM relapse is associated with dismal prognosis compared to medullary or bone marrow (BM) relapse. To study the relapse patterns and outcome, we performed a retrospective analysis of 56 pts who underwent tandem autologous-nonmyeloablative allogeneic HSCT (auto-allo) or reduced intensity conditioning (RIC) allogeneic transplant. Between January, 2000 to March 2008, 38 pts received planned auto-allo HSCT using melphalan (200 mg/m2) prior to auto-HSCT and TBI (200 cGy) prior to allo-HSCT and 18 pts received RIC allo-HSCT following fludarabine (125mg/m2) and melphalan 140mg/m2. Donors included 52 HLA matched siblings and 4 matched unrelated donors.Table 1.Patients characteristicsParametersPts without relapse (n)BM relapse (n)EM relapse (n)P-valueTotal number of patients33167.Age at transplant (median, yr.)50.85154.10.84Interval between diagnosis-transplant (median, mo.)11.79.414.60.12B2-micr (median)2.06 (1.18-10)1.67 (1.28-2.15)2.08 (0.79- 9.05)0.15Median f/u for alive pts (yr.)6.88.79.6.Type of transplant....Auto- allo graft70% (23)69 % (11)57 % (4)0.84RIC30% (10)31% (5)43% (3)Response before allograft....CR/PR64% (21)56% (9)71% (5)0.79MR/SD/RE/refractory36% (12)44% (7)29% (2)Stage III disease at the time of transplant78% (25)81% (13)100% (7)0.94Ch 13 del at dx18% (6)12% (2)29% (2)0.69Novel agent prior to transplant45% (15)38% (6)57% (4)0.74 RESULTS After a median follow up of 7.8 years; there were 16 BM and 7 EM relapses. There was no correlation between either relapse or the pattern of relapse (BM and EM) and development of acute and chronic graft vs. chronic disease (GVHD). The risk ratio for BM relapse in 5 year is 0.27 for patients with chronic GVHD (cGVHD) and 0.15 for patients without cGVHD (P=0.69). The risk ratio for EM relapse in 5 year is 0.12 for patients with cGVHD and 0.25 for patients without cGVHD (P=0.10) (Figure 1). Overall survival (OS) and progression-free survival (PFS) for the whole group (N=56) is shown in figure 1. Four year OS was 43% in EM group and 88% in BM group (P=0.005) (Figure 3). There were no significant differences between age, B2 microglobulin, numbers of treatment before HSCT, use of novel agents before HSCT, cytogenetics, stage, transplant regimen and development of GVHD and pattern of relapse (BM vs. EM). In conclusion our data suggest that EM relapse can occur post allogeneic HSCT and is associated with shorter overall survival. The development of GVHD does not prevent against EM relapse. Disclosures: No relevant conflicts of interest to declare.

Description: Background: MM patients with enhanced immune responses following AHSCT are known to have better long-term disease control. While it has been shown that early responses are mediated by NK cells and alternate inhibitory/stimulatory pathways, including costimulatory molecules, the characterization of these costimulatory molecule profiles in MM patients post AHSCT is not well established. To address this issue, we conducted a pilot study designed to characterize NK cells and function after AHSCT in MM patients through the expression of a cytolytic receptor (CD16), an antibody-dependent cell mediated cytotoxic (ADCC) receptor, and through NK cells functional status based on interferon gamma (IFN-γ) expression as well as the expression of stimulatory (4-1BB) and inhibitory (PD-1 and CTLA-4) molecules. The aims are to characterize the inhibitory and activating costimulatory pathways involved in immune reconstitution after autologous transplantation and to describe changes in the immune signature profile post transplant in response to maintenance therapy and disease status. Methods: A prospective consecutive case-series of 37 MM patients who underwent AHSCT, median age 59.6 years (36-71.4), were enrolled. Peripheral blood samples were collected pre-AHSCT and again on days 14, 30, 60, 90, 180 and 360 post-AHSCT. IMWG criteria were used for response assessment. NK cells and NK costimulatory molecules were evaluated by flowcytometry using two, six color panels of antibodies. Kruskal-Wallis (KW) test using Graphpad Software was used to plot data/assess differences. The specific time trend for each molecule was modeled using a repeated measures model with unstructured covariance using SAS v9.3. Models were evaluated graphically by taking a scatter plot of data for each molecule and then fit using categorical time, d60-90 response and their interaction as covariates. Since NK expression values were positively skewed, the log-transformed expression + 0.1 (to account for 0) were used as model outcomes. Model outcomes were assessed as absolute number of NK/uL, percent of NK cells, and MFI (mean fluorescence intensity) of NK cell receptor expression. Statistical significance was set at α=0.05 for all analyses. Results: Table Disease Status d60-90 d180* d360* PR or worse (≤ PR) 18 14 17 Very Good Partial Response or better (≥VGPR) 19 22 19 * One patient - in evaluable The patients were grouped into ≤ PR (PR + SD+PD: n=18) and ≥VGPR (VGPR +CR: n=19) based on their d60-90 disease status. · Median percent NK cell was highest (20% of total lymphocytes) at d14 (KW p=0.0001) but returned at d60 to baseline value (11.6% of total lymphocytes). · The median percent of NK cells post-AHSCT was significantly higher in ≥VGPR group than the ≤ PR group at D 90, 180 and 360 (p= 0.01,

Description: 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.

Description: Introduction: B-cell maturation antigen (BCMA) is expressed on malignant plasma cells and is an attractive therapeutic target for multiple myeloma. BCMA CAR T-cells, antibody drug conjugates and bispecific T-cell engagers have demonstrated substantial preclinical and clinical activity to date. JCARH125 is a BCMA-targeting CAR T product containing a lentiviral CAR construct with a fully human scFv, optimized spacer, 4-1BB co-stimulatory and CD3z activation domains. The construct has shown minimal tonic signaling and lack of inhibition by soluble BCMA. JCARH125 is generated using a manufacturing process developed to optimize various aspects, including increased consistency of cell health, in the drug product. Methods: EVOLVE (NCT03430011) is a multi-center, phase 1/2 trial of JCARH125 in patients with relapsed and/or refractory multiple myeloma, who have received 3 or more prior regimens, which must include autologous stem cell transplant, a proteasome inhibitor, immunomodulatory drug and an anti-CD38 monoclonal antibody, unless not a candidate (i.e. contraindicated) to receive one or more of the above treatments. Lymphodepleting chemotherapy (LDC) consisting of 3 days of fludarabine (30 mg/m2) and cyclophosphamide (300 mg/m2) is given 2 to 7 days prior to JCARH125 infusion. A single dose of JCARH125 is given on day 1. Dose escalation is determined using the modified toxicity probability interval 2 (mTPI-2). A minimum of 3 patients are evaluated at each dose level (DL). The first 2 DLs evaluated were 50 and 150x 106 CAR+ T cells. Additional DLs are planned, followed by an expansion at the recommended phase 2 dose (RP2D). The primary objectives of the phase 1 portion are safety and identifying a RP2D. Results: At the time of the July 12, 2018 data analysis, 19 patients have been enrolled (i.e. apheresed) and 13 patients dosed with JCARH125. Only one patient was unable to receive JCARH125, due to sepsis after LDC, leading to death before JCARH125 administration. Eight patients were evaluable for safety (≥ 1 mo follow-up). (n = 5 DL1; n = 3 DL2). Three patients (all from DL1) were evaluable for confirmed response (≥ 2 mo follow-up) per International Myeloma Working Group (IMWG) criteria. Data reported here are from these initial 8 patients. Median follow-up is 5 weeks (range 4 - 13 weeks). Median age is 53 years (range 36 - 66) with a median time from diagnosis of 4 years (range 2 - 12). Patients had received a median of 10 prior regimens (range 4 - 15). Of these 8 patients, 4 (50%) were refractory (no response or progression within 60 days of last therapy) to bortezomib, carfilzomib, lenalidomide, pomalidomide and an anti-CD38 monoclonal antibody. Seven of 8 (88%) had prior autologous stem cell transplant and 4 of 8 (50%) have IMWG high risk cytogenetics. As of the data cut, no DLTs have been observed at the first 2 DLs. Cytokine release syndrome (CRS), all grade 1 or 2, was observed in 6 of 8 (75%) patients. Median onset of CRS was 9 days (range 4 - 10) with a median duration of 4.5 days (range 2 - 19 days). None of the patients with grade 2 CRS required vasopressor support and only 1 patient received tocilizumab. No patients had grade ≥ 3 CRS. Three of 8 (38%) patients experienced neurologic adverse events (AE). Two patients had grade 1 events, and 1 had a grade 3 event (lethargy), which resolved within 24 hours after receiving steroids. Onset of neurologic AEs was 9,11 and 12 days with a duration of 2, 3 and 1 days respectively. Notably, the patient who experienced grade 3 neurotoxicity (NT), developed secondary plasma cell leukemia (PCL) just prior to receiving LDC. All 8 patients have evidence of objective response (≥ MR), including the patient with secondary PCL. 3 patients, all treated at DL1 (50 x 106 CAR+ T-cells), have confirmed responses (1 PR, 2 sCR) with the remainder unconfirmed (1 CR, 2 VGPR, 1 PR, 1 MR). As of the data cut, no patients have progressed. Additional clinical and translational data on at least 30 patients and additional follow up of at least 4 months will be available at time of presentation. Conclusion: At initial lower dose levels, JCARH125 showed an acceptable safety profile with no DLTs reported thus far. Incidence of grade ≥ 3 NT was low and no grade ≥ 3 CRS has occurred with clear clinical activity. Although durability of response and response rate in a greater number of patients remain to be determined, early experience with JCARH125 support a favorable risk-benefit profile and rapid clinical development. Disclosures Mailankody: Takeda: Research Funding; Janssen: Research Funding; Physician Education Resource: Honoraria; Juno: Research Funding. Bensinger:celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; amgen: Speakers Bureau; Takeda: Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Devries:Junot Therapeutics: Employment. Piasecki:Juno Therapeutics: Employment, Equity Ownership; Cascadian Therapeutics: Patents & Royalties; Amgen: Patents & Royalties. Ziyad:Juno Therapeutics: Employment, Equity Ownership. Blake:Celgene: Employment, Equity Ownership. Byon:Juno Therapeutics: Employment, Equity Ownership. Jakubowiak:Janssen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Adaptive Biotechnologies: Consultancy, Honoraria; SkylineDx: Consultancy, Honoraria.

Description: Introduction: Despite significant progress in the treatment of multiple myeloma (MM), the disease remains incurable and typically follows a pattern of multiple responses and relapses. In the relapsed/refractory MM setting (RRMM), outcomes for patients may be particularly discouraging. New treatments that are safe and effective are therefore of urgent need for this population. Since its FDA approval in 1998 for the treatment of rheumatoid arthritis, leflunomide has been used in over 300,000 patients worldwide. Leflunomide is hepatically cleared and has a favorable toxicity profile even when given over long periods. Its primary mechanism of action is inhibition of pyrimidine synthesis by targeting dihydroorotate dehydrogenase, thus achieving anti-proliferative effects on B and T lymphocytes. The anti-neoplastic potential of this agent has been studied in a number of pre-clinical tumor models. Leflunomide's immunoregulatory action may be related to functional inhibition of CD4+ effector T cells, including Th17 cells as well as dysregulation of T regulatory cells (Tregs). We found that leflunomide-treated C57BL/KaLwRij mice engrafted with 5TGM1 cells had more robust expansion of CD8+ cytotoxic T cells and subsequent decrease of CD4+ Tregs compared to untreated mice. We have also noted that leflunomide impairs growth of MM cells at least partly through inhibition of PIM kinases and c-Myc signaling. We present here final results from a phase 1 study of leflunomide in patients with RRMM. Methods: This single center, single agent, phase 1 dose-escalation trial was designed to determine the maximum tolerated dose of leflunomide in patients with RRMM. The trial implemented a modified rolling six phase 1 dose escalation design. The primary objectives were as follows: 1) to determine the maximum tolerated dose and recommended phase 2 dose of leflunomide; 2) to assess the safety and tolerably of leflunomide at each dose level by evaluation of toxicities. Leflunomide was administered at a loading dose of 100 mg daily for the first three days, then daily in 28-day cycles. The starting dose of daily leflunomide was 20 mg daily, with dose escalation in increments of 20 mg/day, up to 60 mg/day. Dose de-escalation in decrements of 10mg/day was planned. Results: A total of 12 patients have been enrolled starting in December 2015 and treated. The median age is 68 (range 48 - 85), and the median number of prior therapies is 5 (range: 3 - 14). Nine patients had prior autologous stem cell transplant. Double refractory (lenalidomide/bortezomib) disease was noted in 9 patients. High-risk cytogenetics were observed in 5 patients including 2 patients with del17p. All 12 subjects were evaluable for toxicity. One subject was not evaluable for response because of non-compliance. Of the eleven patients evaluable for response, the median number of cycles was 3 (range 1- 15). The median follow up was 177 days (range: 42 - 602). Three patients were treated on DL 1 (20 mg) and three on DL3 (40 mg) without incidence of DLT. At DL5 (60 mg), one patient had a DLT with grade III elevation of alanine aminotransferase; an additional three patients were enrolled at this dose level without further DLTs. One out of 12 subjects remains on treatment, 8 patients were removed from study due to disease progression, two due to adverse events (bacteremia at 60 mg, possibly related to study drug and angioedema at 40 mg, not related to study drug) and one from noncompliance. The most common toxicities were hematologic. There were 4 patients with grade 1 or 2 neutropenia on the 20 and 40 mg dose levels and 1 patient with grade 4 lymphopenia on the 40 mg dose. Except for the DLT, all non-hematologic toxicities were ≤ grade 2. Response: Although not all patients were treated at the 60 mg dose, a clinical benefit rate of 90% has been seen, with 9/10 achieving stable disease (SD). The median duration of SD among 9 patients thus far is 56 days (range: 27-401). In the five evaluable patients with high risk cytogenetics, four of them achieved a clinical benefit. Two subjects had SD lasting nearly one year or longer. In this small cohort, no association between dose and benefit was observed. Conclusion: Leflunomide is a safe and well-tolerated oral option for patients with RRMM, with a clinical benefit from single agent dosing. On the basis of our preclinical work showing synergistic inhibition of MM using leflunomide, pomalidomide, and dexamethasone, we plan clinical testing of this drug combination. Disclosures Rosenzweig: Celgene: Speakers Bureau. Krishnan:Janssen: Consultancy, Speakers Bureau; Sutro: Speakers Bureau; Onyx: Speakers Bureau; Takeda: Speakers Bureau; Celgene: Consultancy, Equity Ownership, Speakers Bureau. Forman:Mustang Therapeutics: Other: Licensing Agreement, Patents & Royalties, Research Funding.

Description: Background ARRY-520 is a novel KSP inhibitor with encouraging activity in patients (pts) with RRMM. In preclinical models, the activity of ARRY-520 is synergistic with BTZ, providing a rationale to combine these drugs in the clinic. Methods ARRAY-520-111 is a Phase 1 study to identify the maximum tolerated dose of ARRY-520, BTZ and dex. Eligible pts have RRMM with ≥ 2 prior lines of therapy, including a proteasome inhibitor (PI) and an immunomodulatory agent. ARRY-520 is administered intravenously (IV) on Days 1, 2, 15 and 16 (Schedule 1) or on Days 1 and 15 (Schedule 2); BTZ is administered IV or subcutaneously (SC) on Days 1, 8 and 15; and 40 mg oral dex, if applicable, is taken on Days 1, 8 and 15 in a 28-day cycle. Results A total of 41 pts have been treated to date at various dose levels of ARRY-520 and BTZ. Patients had a median of 5 prior regimens (range 2-10). All pts received a prior PI, 39 pts received prior BTZ, and 25 pts received at least 2 prior PI- including regimens (range 1-6). In Schedule 1, the initial dose level of ARRY-520 (1.0 mg/m2/day) with BTZ (1.3 mg/m2/day) and dex was not tolerated, with dose-limiting toxicities (DLT) in 2/3 pts (pneumonia and pseudomonal sepsis). After a protocol amendment, dose escalation resumed at reduced doses of ARRY-520 (0.5 mg/m2/day) and BTZ (1.0 mg/m2/day) without dex. The addition of prophylactic filgrastim (G-CSF) enabled escalation to full dose ARRY-520 and BTZ (1.5 and 1.3 mg/m2/day, respectively). Only 1 DLT of pneumonia was observed during the further dose escalation, at 1.0 mg/m2/day ARRY-520 and 1.0 mg/m2/day BTZ. Dex has been added to the combination at 1.25 mg/m2/day ARRY-520 and 1.3 mg/m2/day BTZ and this dose level has been well tolerated. Enrollment is ongoing in the final planned dose level. In Schedule 2, the initial dose level of ARRY-520 (2.25 mg/m2/day) with BTZ (1.3 mg/m2/day) and dex was well tolerated and enrollment is ongoing at 3.0 mg/m2/day ARRY-520 and 1.3 mg/m2/day BTZ + dex, the maximum planned dose of both drugs. The most commonly reported adverse events (AEs) (in ≥ 15% of pts) include anemia, diarrhea, pyrexia, upper respiratory tract infection, thrombocytopenia, cough, neutropenia, constipation, headache, fatigue, hyperuricemia, nausea, vomiting, and dizziness. All Grade 3 – 4 non-hematologic AEs have an incidence of 〈 10%. Based on the laboratory data, Grade 4 neutropenia was observed in 15% of patients, Grade 4 thrombocytopenia was observed in 10%. Apart from the one pt described above with the DLT of pseudomonal sepsis, no other febrile neutropenic events were reported. Neuropathy (Grade 2) was observed in 1 pt. Monopolar spindles have been observed in a post-dose biopsy for a pt treated at 1.0 mg/m2/day ARRY-520 + 1.3 mg/m2/day BTZ, indicating that pharmacodynamic activity of ARRY-520 is maintained in the presence of full dose BTZ. Preliminary signs of efficacy have been observed in this ongoing dose-escalation study. To date, among the subset of 13 evaluable pts who received doses at ≥ 1.25 mg/m2/day ARRY-520 + 1.3 mg/m2/day BTZ, 4 (31%) partial responses (PR) and 1 minimal response (MR) have been observed. By contrast, in the 27 patients receiving lower doses of ARRY-520 and BTZ, only 1 MR has been reported. An additional 29 pts experienced stable disease (SD) on ARRY-520 + weekly BTZ without the use of steroids (dex), including 17 pts with disease refractory to BTZ. Conclusions ARRY-520 + BTZ with prophylactic G-CSF appears well tolerated with manageable non-hematologic AEs in this heavily pretreated pt population and has demonstrated preliminary evidence of activity, including PRs and SD in pts with disease refractory to BTZ. These data support further exploration of this novel KSP inhibitor in combination with BTZ in expansion cohorts. The authors would like to acknowledge the dedicated research staff and physicians at the participating centers of the Multiple Myeloma Research Consortium for their contribution to this study. Disclosures: Chari: Onyx Pharmaceuticals: Membership on an entity’s Board of Directors or advisory committees; Millenium Pharmaceuticals: Membership on an entity’s Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity’s Board of Directors or advisory committees. Off Label Use: ARRY-520 is an investigational drug being combined with bortezomib in multiple myeloma. Zonder:Celgene Corporation: Consultancy; Onyx: Consultancy; Skyline Diagnostics: Consultancy. Jakubowiak:Millenuim: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Janssen Cilag: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Bristol Myers Squibb: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Onyx: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau. Hilder:Array BioPharma: Employment. Ptaszynski:Array BioPharma: Employment. Rush:Array BioPharma: Employment. Kaufman:Millenium: Consultancy; Merck: Research Funding; Novartis: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Onyx: Consultancy; Janssen: Consultancy.

Description: 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

Description: Multiple myeloma (MM) is an incurable malignancy of plasma cells even with great advances in treatment. Chimeric Antigen Receptor (CAR) directed T cell therapy, which can specifically recognize tumor associated antigens and kill tumor cells in an MHC independent manner, is a promising approach for hematological malignancy. There are several candidate antigens for CAR T cell targeting of multiple myeloma, including BCMA and CS1. Our goal is to develop novel CARs for the treatment of MM and explore the potential benefits of combinatorial therapy of CAR T cells and immunomodulatory drugs (IMiDs) such as lenalidomide. In the present study, we redirected central memory T cells to express second-generation CARs specific for either CS1 or BCMA that incorporate CD28 signaling moieties. Central memory T cells were activated by CD3/CD28 bead stimulation, transduced with lentivirus encoding the CAR construct, and expanded ex vivo. The engineered and expanded CS1 and BCMA CAR T cells exhibited similar phenotypes and comparable in vitro effector function. However, once adoptively transferred into MM tumor-bearing NOD/Scid IL2RγCnull (NSG) mice by intravenous injection of 1x10^6 CAR T cells, CS1 CAR T cells exhibited superior antitumor activity over BCMA CART cells and significantly prolonged mouse survival (P