ALBERT

Description: Introduction: XmAb13676 is a humanized bispecific antibody that binds both CD20 and CD3 in order to recruit cytotoxic T cells to kill CD20 expressing malignant cells. Interim results of an ongoing first-in-human, dose-escalation study (XmAb13676-01; NCT02924402) in subjects with relapsed/refractory (R/R) non-Hodgkin's lymphoma (NHL) and chronic lymphocytic leukemia (CLL) are reported here. Methods: The study is a first-in-human, multi-center, open-label, phase 1, dose-escalation study in subjects with R/R NHL and R/R CLL with a standard 3 + 3 design. The primary objectives are to determine safety, tolerability, and the maximum tolerated dose (MTD) or recommended dose of XmAb13676. Secondary objectives include preliminary anti-tumor activity and PK/PD of XmAb13676. This study is designed in two parts: Part A, escalating dose cohorts that establish an initial priming dose as part of repeated weekly infusions at a fixed dose in a 28-day cycle; and Part B, with a dosing schedule consisting of a priming dose on C1D1 , established in Part A, followed by escalated dose(s) on subsequent weeks. Cytokine Release Syndrome (CRS) prophylaxis with dexamethasone was mandated prior to each administration of XmAb13676. Treatment was continued for 2 cycles or longer if there was evidence of therapeutic benefit. Results: At data cut-off, 44 subjects have been treated, 36 with NHL and 8 with CLL. NHL: Subjects with R/R NHL had a median age of 61.5 years (range 32-89), a median of 3.5 prior therapies (range 1-9) and had been diagnosed a median of 24.6 months (range 6.3-181.2) prior to treatment in the study. Treatment-emergent adverse events (TEAEs) related to treatment occurring in ˃ 3 subjects are shown in Table 1A. Nine treatment-related serious adverse events (SAE) occurred in 6 subjects. The most common treatment-related SAE was CRS, which occurred in 4 (11.1%) subjects with 1 of the events being Grade 4 and the other events being ≤ Grade 2. Treatment responses were assessed by the Lugano criteria or International Working Group criteria for Waldenström Macroglobulinemia (WM). There have been 7 objective responses: 2 complete responses (CR; DLBCL), 1 Very Good PR (VGPR; WM), and 4 partial responses (PR; 1FL, 3 DLBCL) at doses of 20-125 µg/kg. In the efficacy-evaluable population, at doses of 80-125 µg/kg, objective responses were observed in 6/18 patients. A priming dose of 45 µg/kg has been chosen for Part B. An MTD has not been reached and dose escalation is ongoing in Part B in NHL. CLL: Subjects with R/R CLL had a median age of 76 years (range 62-81), a median of 4.5 prior therapies (range 2-6) and had been diagnosed a median of 76.1 months (range 17.5-328.9) prior to treatment in the study. Treatment-related TEAEs occurring in ˃ 1 subject are shown in Table 1B. Three treatment-related serious adverse events (SAE) occurred in 2 subjects. The treatment related SAEs were CRS (Grade 3), hepatocellular injury (Grade 3), and jaundice cholestatic (Grade 2), each of which occurred in 1 (12.5%) subject. There has been 1 CR reported (Richter transformation) in 5 subjects at 20 µg/kg, the highest dose administered thus far. The treatment response was assessed by the Lugano criteria. An MTD has not been reached and dose escalation is ongoing in Part A in CLL. Conclusions: XmAb13676 demonstrated evidence of clinical activity in heavily pretreated subjects with R/R NHL and R/R CLL treated at doses between 20 and 125 µg/kg. CRS was generally manageable with premedication. The study is ongoing with further optimization of dose and schedule. Disclosures Patel: AstraZeneca: Consultancy, Research Funding, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Genentech: Consultancy, Speakers Bureau; Pharmacyclics/Janssen: Consultancy, Speakers Bureau; Sunesis: Consultancy. Chanan-Khan:AbbVie: Research Funding; Xencor: Research Funding; Pharmacyclics: Research Funding; Merck: Research Funding; Jansen: Research Funding; Mayo Clinic: Employment; Ascentage: Research Funding; Millennium: Research Funding. Salles:Novartis, Servier, AbbVie, Karyopharm, Kite, MorphoSys: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Epizyme: Consultancy, Honoraria; Roche, Janssen, Gilead, Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Autolus: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Other: Educational events; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; BMS: Honoraria. Cartron:Gilead: Honoraria; Jansen: Honoraria; Celgene: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Sanofi: Honoraria. Thomas:Celgene: Research Funding; Amgen: Research Funding; Xencor: Research Funding; BMS: Research Funding. Wierda:KITE pharma: Research Funding; Sunesis: Research Funding; Miragen: Research Funding; Gilead Sciences: Research Funding; Acerta Pharma Inc: Research Funding; GSK/Novartis: Research Funding; Cyclcel: Research Funding; Loxo Oncology Inc.: Research Funding; AbbVie: Research Funding; Genentech: Research Funding; Juno Therapeutics: Research Funding; Oncternal Therapeutics Inc.: Research Funding; Pharmacyclics LLC: Research Funding; Xencor: Research Funding; Janssen: Research Funding. Liebowitz:Xencor: Employment, Equity Ownership. Pagel:AstraZeneca: Consultancy; Gilead Sciences: Consultancy; Pharmacyclics: Consultancy. Ribrag:MSD: Membership on an entity's Board of Directors or advisory committees; Roche: Other: Travel, accommodations, and expenses ; Nanostring: Membership on an entity's Board of Directors or advisory committees; Epizyme: Consultancy, Research Funding; Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Infinity: Membership on an entity's Board of Directors or advisory committees; AZ: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, and expenses ; Incyte: Membership on an entity's Board of Directors or advisory committees; ArgenX: Research Funding. Saville:Xencor: Employment, Equity Ownership. Johnson:Xencor: Employment, Equity Ownership. Ly:Xencor: Employment, Equity Ownership. Phillips:Pharmacyclics: Consultancy, Research Funding; Bayer: Consultancy; Abbvie: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy; Seattle Genetics: Consultancy; Gilead: Consultancy; Incyte: Membership on an entity's Board of Directors or advisory committees.

Description: Background: EZH2 is the methyltransferase component of the polycomb repressive complex 2 (PRC2) that represses transcription of target genes via trimethylation of histone H3 at lysine 27 (H3K27me3), resulting in proliferative and migratory activity. EZH2 deregulation (via mutation or overexpression) in many cancers is associated with a more aggressive cancer phenotype and poor prognosis. GSK2816126, a highly selective and potent inhibitor of both wild type (wt) and mutant (mut) EZH2, decreases H3K27 tri-methylation, releases transcriptional repression of PRC2 target genes and induces anti-proliferative activity in several EZH2 wt/mut cancer cell lines. Methods: Part I of this 2-part study is a combined accelerated plus classic 3+3 with adaptive Bayesian design dose escalation of GSK2816126 in pts (≥18 years) with relapsed/refractory DLBCL, tFL, other NHL, MM and solid tumors. Primary objectives are to determine safety, tolerability and the recommended expansion dose. Secondary objectives include pharmacokinetic (PK) and pharmacodynamic (PD) analysis and preliminary evaluation of activity. Patients received two intravenous (IV) doses weekly for 3 weeks with one week off (3W-on/1W-off) in a 28 day cycle. Dose limiting toxicity (DLT) observation period for dose escalation was first 28 days. Results: As of 13 June 2016 data cut, a total of 30 pts have been treated with 50mg (n=2), 100mg (n=1), 200mg (n=1), 400mg (n=1), 800mg (n=3), 1200mg (n=4), 1800mg (n=10), 2400mg (n=5) and 3000mg (n=3) of GSK2816126 given IV twice weekly (3W-on/1W-off). Tumor types included 10 DLBCL, 2 tFL, 2 other NHL (FL and MZL) and 16 solid tumors. Preliminary results demonstrate GSK2816126 is well tolerated with no DLTs observed. Dose expansion is ongoing at 3000 mg IV (3W-on/1W-off). The most common drug-related adverse events (AEs) reported at 〉20% incidence were fatigue (53%), nausea (30%), anemia (20%) and vomiting (20%). PK was linear from 50mg to 3000mg given twice weekly, with moderate to high inter-subject variability and no accumulation. At 3000mg, Cmax was 22 ±34.1 ng/mL; t ½ 33.3 ±11.5 hour; AUC (0-∞) 109.8 ±53.5 ng*h/mL. Of 22 evaluable pts, 1 durable confirmed partial response (PR) was observed in an advanced GCB+ DLBCL patient (1800mg GSK2816126). 7 patients had stable disease, including an advanced FL patient with 45% tumor regression and a cholangiocarcinoma patient lasting 〉6 cycles. Conclusion: GSK2816126 is well tolerated with evidence of antitumor activity. Expansion of 3000 mg IV (3W-on/1W-off) is ongoing to confirm safety and efficacy. Part 2 of the study will enroll pts with EZH2 wt/mut GCB+ DLBCL and tFL, relapsed/refractory myeloma and solid tumors including castration-resistant and small cell prostate cancers. This study was funded by GSK. Disclosures Winter: Medivation: Other: Provision of investigational agent for clinical trial; GSK: Research Funding; Seattle Genetics: Research Funding; Pharmacyclics: Research Funding. Ribrag:Gilead, Infifnity, Pharmamarr, BMS, Esai, Incyte, Nanostring: Membership on an entity's Board of Directors or advisory committees; ArgenX: Research Funding. Michot:Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Horner:GlaxoSmithKline: Employment. Carver:GSK: Employment. Pene Dumetrescu:GSK: Employment. He:GSK: Employment. McCabe:GSK: Employment. Creasy:GlaxoSmithKline: Employment. Dhar:GlaxoSmithKline: Employment. Carpenter:GSK: Employment. Johnson:Celldex Therapeutics: Research Funding.

Description: Background: Patients with classical Hodgkin lymphoma (cHL) who progress after brentuximab vedotin (BV) have a poor prognosis. cHL frequently harbors genetic alterations at the 9p24.1 locus, resulting in the overexpression of the PD-L1 and PD-L2 immune checkpoint ligands. Pembrolizumab is a humanized monoclonal antibody that blocks the interaction between the PD-1 receptor and PD-L1/PD-L2, and can restore antitumor immune activity in several different tumors. Based on its likely genetically driven dependence on PD-1, cHL was included as an independent expansion cohort in the KEYNOTE-013 study (NCT01953692), a multicenter, multicohort phase 1b trial of pembrolizumab in patients with hematologic malignancies. Updated results from this cohort, including long-term efficacy, are presented. Methods: Key eligibility criteria for the cHL cohort of KEYNOTE-013 included relapse after or ineligibility for autologous stem cell transplantation (ASCT), and relapse after or refractory to BV treatment. Pembrolizumab was administered intravenously at a dose of 10 mg/kg every 2 weeks for up to 2 years or until confirmed progression or unacceptable toxicity. Response was assessed at week 12 and every 8 weeks thereafter according to the International Harmonization Project 2007 criteria. The primary end points were safety and complete remission (CR) rate (CRR); secondary end points included overall response rate (ORR) and duration of response (DOR). Patients who achieved a CR could opt to stop treatment after 24 weeks provided that they received at least 2 doses after CR. This report includes CRR, ORR, and DOR by blinded independent central review (BICR). Results: At the time of data cutoff on June 3, 2016, 31 patients were enrolled, and all were evaluable for analysis. Median follow-up duration was 24.9 months (range, 7.0-29.7 months). The median number of prior lines of therapy was 5 (range, 2-15), 74% of patients had failed prior ASCT, and by design 100% had failed prior BV. Per investigator review, ORR was 65%, and CRR was 19%. Per BICR, ORR was 58% (18/31), with 6 patients (19%) achieving CR and 12 (39%) partial remission; 7 patients (23%) had stable disease as their best response. Median DOR was not reached, with a range of 0.0+ to 21.4+ months (95% CI, 3.7 months to not reached) (Figure). An analysis with hierarchical mutually exclusive categories of refractory disease (RD; defined as no response to ≥1 prior line of therapy) or relapse after ≥3 prior lines of therapy (Re ≥3) was conducted. Per BICR, the ORR was 56% in RD (n = 27 patients) and 75% in Re ≥3 (n = 4). As of the data cutoff date, 3 patients (10%) remained on treatment, 5 (16%) completed 2 years of treatment, and 23 (74%) discontinued treatment: 3 (10%) for toxicity, 14 (45%) for progressive disease, 3 (10%) per physician decision (all ultimately underwent allogeneic SCT), 1 in CR (underwent allogeneic SCT), 1 for clinical progression, and 1 who withdrew consent. Per BICR, median progression-free survival (PFS) was 11.4 months; 6-month and 12-month PFS rates were 66% and 48%, respectively. Median overall survival (OS) was not reached; 6-month and 12-month OS rates were 100% and 87%, respectively. Conclusions: With nearly 2.5 years of median follow-up, the present results demonstrate that a subset of heavily pretreated patients who failed BV therapy can achieve a long-term response with single-agent pembrolizumab, without consolidative therapy. PD-1 blockade may offer a new treatment paradigm for patients with relapsed/refractory cHL, supporting the hypothesis that this tumor has a genetic dependence on the PD-1 pathway. Figure Figure. Disclosures Armand: BMS: Consultancy, Research Funding; Sequenta: Research Funding; Roche: Research Funding; Infinity: Consultancy; Merck & Co., Inc.: Consultancy, Research Funding; Sigma Tau: Research Funding; Tensha: Research Funding; Otsuka: Research Funding. Shipp:Cell Signaling: Honoraria; Bayer: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Merck, Gilead, Takeda: Other: Scientific Advisory Board. Ribrag:Incyte: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Nanostring: Membership on an entity's Board of Directors or advisory committees; ArgenX: Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees; Infinity: Membership on an entity's Board of Directors or advisory committees; Pharmamar: Membership on an entity's Board of Directors or advisory committees; Esai: Membership on an entity's Board of Directors or advisory committees. Michot:Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Zinzani:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; TG Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Infinity: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Sandoz: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees. Kuruvilla:Gilead: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Amgen: Honoraria; Celgene: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Merck: Honoraria; Roche Canada: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria; Lundbeck: Honoraria. Zhu:Merck: Employment. Ricart:Merck & Co.: Employment; Pfizer: Equity Ownership. Balakumaran:Merck & Co.: Employment, Other: stock, stock options. Moskowitz:Pharmacyclics: Research Funding; Merck: Consultancy, Research Funding; Genentech: Consultancy; Seattle Genetics: Consultancy, Research Funding; Celgene: Consultancy.

Description: Hepatitis C virus (HCV) infection is a well-established risk factor for the development of B cell non-Hodgkin lymphoma (B-NHL). Two main pathways have been proposed to explain the role of the virus in lymphomagenesis: 1) transformation of B cells either directly by oncogenic viral proteins, or by a hit-and-run mechanism inducing a mutator phenotype, and 2) chronic antigenic stimulation through the B cell receptor (BcR) in conjunction to the binding of the viral E2 protein to its receptor CD81. There are however conflicting data regarding whether the BcR of the lymphomatous cells are capable of directly recognizing viral proteins or, rather, they possess a rheumatoid factor (RF) activity, binding instead polyclonal immunoglobulin (IG) within immune complexes trapping the virus. To further elucidate the role of antigenic stimulation in the natural history of HCV-associated B-NHL, we analyzed the IG gene repertoire of both heavy and light chains expressed by neoplastic cells in 41 cases of HCV-associated NHL, including: 29 marginal zone lymphoma (MZL); 7 diffuse large B-cell lymphoma (DLBCL) of which 3 originated from transformed MZL ; and 5 other low-grade B-cell NHL. Tumor cells were obtained from blood in 39 cases, bone marrow and a lymph node biopsy in 1 case each. Forty-three productive IGHV-IGHD-IGHJ gene rearrangements were obtained, which displayed a clear biased gene composition as 3 IGHV genes contributed to almost half of the repertoire: IGHV1-69 (11/43, 25,6%), IGHV3-7 (5/43, 11.6%), IGHV3-21 (4/43, 9.3%). This was also true for both IGHD genes (IGHD3-22: 12/43, 27.9%), and IGHJ genes (IGHJ4: 17/43, 39.5%; IGHJ3: 17/43, 25.6%). All but 3 sequences carried somatic hypermutations (SHM) in their IGHV genes with a median identity to the germline of 97.6% (range 86.5-100%). Thirty-eight productive IG light chain rearrangement sequences were obtained from 36 cases, of which 30 (78.9%) were IGK. Similarly, they exhibited strong gene usage bias with an over-representation of IGKV3-20 (9/30, 30%), as well as IGKJ1 (11/30, 33.3%) and IGKJ2 (6/30, 20%). IG light chain sequences were found to harbor similar SHM load with a 97% median identity to germline (range 91-100%). As previously described, we observed preferential pairing of heavy and light chain genes, with 6 of the 9 IGHV1-69 cases (with available light chain sequence data) being associated with IGKV3-20. Using established criteria, we found 5 cases (11.6%) carrying stereotyped BcR i.e. IGHV-IGHD-IGHJ gene rearrangements with quasi-identical amino-acid (AA) sequences, including the highly variable complementary determining region 3 (CDR3). Three cases concerned IGHV3-7/IGHD3-22/IGHJ3 rearrangements with an 18 AA-long CDR3, and 2 concerned IGHV1-69/IGHD3-22/IGHJ4 rearrangements with a 13 AA-long CDR3. Identity within the CDR3 extended to AA encoded by randomly inserted N-region nucleotides. We failed to establish correlations between histological categories and IG repertoire, probably due to the uneven distribution of lymphoma subtypes within our cohort. In contrast, most if not all sequences with biased IG gene usage, including the 5 stereotyped BcR ones, were found amongst the 28/41 cases (68.3%) with mixed cryoglobulinemia type II and/or positive for RF (MC/RF+). These two categories of patients differed also regarding the SHM load of their IGHV genes since MC/RF+ cases were signlificantly less mutated than MC/RF- cases (median identity to germline: 97.9% vs 95.9%, p= 0.048). We then searched for similar sequences in public databases and collaborative studies. Stereotyped BcR sequences similar to those of our cases were detected in HCV-associated lymphoma, but also in other HCV-negative B-cell maligancies e.g. MALT lymphoma (some associated with RF) and chronic lymphocytic leukemia, non malignant B cells with RF activity, and non malignant marginal zone splenic B cells. Sequence similarity extended to some shared AA replacements, e.g. identical AA introduced by HSM at the same positions. In conclusion we confirm the highly biased IG repertoire of HCV-associated lymphoma. However this feature seems to be linked essentially to the presence of a MC and/or RF. As quasi-identical sequences are found in HCV-negative malignant and normal B cells, our data support the hypothesis that HCV-associated lymphomatous cells originate from precursors endowed with auto-immune properties rather than B cells expressing an anti-virus BcR. Disclosures Stamatopoulos: Gilead Sciences: Research Funding; Janssen Pharmaceuticals: Research Funding.

Description: Background: Whole-genome sequencing has identified a 4-6% incidence of BRAF mutations in multiple myeloma (MM). We undertook a histology-independent, "basket" study of VEM in BRAF V600m-positive cancers (NCT01524978). Six disease cohorts were prespecified; remaining tumors were classified in a 7th "all-comers" cohort. Here we present preliminary efficacy and safety data for the MM cohort. Methods: A multicenter, Simon, 2-stage adaptive design in patients with relapsed refractory BRAF V600m-positive MM who were receiving VEM (960 mg bid) until disease progression (PD) or unacceptable toxicity was used. Primary end point is investigator-assessed response rate (RR) at week 8 by International Myeloma Working Group criteria. Secondary objectives include overall RR, clinical benefit rate, duration of response, progression-free survival, overall survival, and safety. Stage 1 was complete after the 7th patient received a minimum of 8 weeks of treatment, died, or withdrew early from the study. Results: Eight patients had been enrolled in the MM cohort at the time of the data cutoff (December 3, 2014). Data are presented on patients in stage 1. Twelve patients were screened, of which 4 patients did not meet eligibility criteria. Of the 8 patients enrolled in the study, 6 were men and 2 were women, with a median age of 64 years (range, 55-68). High-risk features were seen in 3 patients by cytogenetics and fluorescence in situ hybridization (FISH). Prior treatment included immunomodulators (IMiDs) in 100% of patients, proteasome inhibitors in 75%, and chemotherapy (melphalan, bendamustine, cytoxan, doxorubicin, etoposide, and cisplatin) in 87.5%. Patients had received between 2 and 7 lines of treatment before enrolling in the BASKET trial, and 5 were refractory to IMiDs or proteasome inhibitors, or both. Median duration of treatment was 3.3 months (range, 1-5) at the time of data cutoff; 3 patients continue to be treated and 5 patients discontinued study drug. Response data were available for 7 patients at the end of 2 cycles. One patient achieved partial response (PR); 4 patients had stable disease; 1 patient had progressive disease; and 1 patient response was reported as not evaluable (objective response rate [ORR] week 8, 14%; 95% confidence interval [CI], 0.4-57.9). Of the patients enrolled, 71% (95% CI, 29.0-96.3) had clinical benefit with single-agent VEM. Responses occurred beyond 2 cycles: 1 patient went on to achieve very good PR (after cutoff date, January 2015). Three patients experienced disease progression between study days 57 and 85, and 1 of these patients died as a result of progressive disease. Single-agent VEM was well tolerated, with a safety profile similar to that observed in melanoma patients. Seven patients (88%) had at least 1 adverse event (AE) of grade 3 or 4, and 3 patients (38%) had at least 1 serious AE, including sepsis and lower respiratory tract infection, that was attributable to the underlying disease. Toxicity was manageable, and 1 patient discontinued treatment because of lower respiratory tract infection and skin lesions. Dose modification was necessary in 5 of 8 patients because of toxicity. Conclusions: This is the first mutation-specific clinical trial in MM. VEM has promising activity in patients with BRAF V600m-positive MM despite these patients being heavily pretreated. Because obvious clinical benefit for patients has been observed, the decision to recruit additional patients was made, and recruitment is ongoing. Updated efficacy results from all patients currently participating in the study will be presented. Disclosures Raje: Amgen: Consultancy; Celgene: Consultancy; Astra Zeneca: Research Funding; Eli Lilly: Research Funding; BMS: Consultancy; Roche: Consultancy; Takeda: Consultancy; Onyx: Consultancy. Off Label Use: Vemurafenib is a potent inhibitor of BRAF mutated at codon 600 (BRAFV600). Here we explored the efficacy of vemurafenib in multiple myeloma patients with BRAFV600 mutations.. Chau:Roche: Research Funding. Hyman:Chugai Pharma: Consultancy; Biotherapeutics: Consultancy; Atara: Consultancy, Honoraria. Ribrag:Gilead: Membership on an entity's Board of Directors or advisory committees; Esai: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmamar: Honoraria, Membership on an entity's Board of Directors or advisory committees. Blay:roche: Research Funding. Tabernero:Taiho: Consultancy; Millennium: Consultancy; Merck: Consultancy; Amgen: Consultancy; Imclone: Consultancy; Chugai: Consultancy; Merck Serono: Consultancy; Boehringer Ingelheim: Consultancy; Eli Lilly: Consultancy; Celgene: Consultancy; Sanofi: Consultancy; Roche: Consultancy; Novartis: Consultancy; Symphgen: Consultancy. Wolf:Roche: Consultancy, Equity Ownership, Honoraria, Research Funding. Sirzen:F. Hoffmann-La Roche: Employment, Equity Ownership. Faris:Merrimack Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Roche: Research Funding; N-of-One-Therapeutics: Consultancy. Kaiser:Bristol-Myers Squibb: Consultancy; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Honoraria; Chugai: Consultancy. Veronese:F. Hoffmann-La Roche: Employment. Makrutzki:F. Hoffmann-La Roche: Employment. Lasserre:F. Hoffmann-La Roche: Employment, Other: Unspecified, Patents & Royalties. Puzanov:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Baselga:Roche: Consultancy.

Description: Introduction: The PD-1 pathway provides an important mechanism of immune evasion and an actionable therapeutic target for many tumors. Classical Hodgkin lymphoma (cHL) frequently contains genetic amplification at the 9p24.1 locus, resulting in the overexpression of the PD-1 ligands PD-L1 and PD-L2 on the tumor cell surface. cHL may therefore have a unique sensitivity to PD-1 blockade. Pembrolizumab is a humanized monoclonal antibody that blocks the interaction of PD-1 with its ligands and can restore antitumor immune activity in several solid tumors. Based on its possible genetically driven dependence on PD-1, cHL was included as an independent expansion cohort in the KEYNOTE-013 study (NCT01953692), a phase 1b multicenter multicohort trial of pembrolizumab in patients with hematologic malignancies. Updated results of the cHL cohort are presented. Methods: This cohort enrolled patients with relapsed or refractory cHL. Patients had to have relapsed after, be ineligible for, or refused autologous stem cell transplantation (ASCT). In addition, patients were required to have relapsed after or be refractory to brentuximab vedotin (BV) treatment. Pembrolizumab was administered intravenously at a dose of 10 mg/kg every 2 weeks for up to 2 years or until confirmed progression or unacceptable toxicity. Response was assessed by computed tomography and positron emission tomography scans after 12 weeks of treatment and every 8 weeks thereafter, using International Harmonization Project 2007 criteria. The primary objectives were safety and complete remission (CR) rate; secondary objectives were progression-free survival, overall survival, overall response rate (ORR), duration of response (DOR), and biomarker assessments. Biomarkers included PD-L1/PD-L2 expression in formalin-fixed, paraffin-embedded tissue; flow cytometry evaluating absolute and relative numbers of circulating NK cells and T-cell subsets (naive and memory T cells, activated T cells, and regulatory T cells); and gene expression using the NanoString platform. Results: At the time of data cutoff on May 26, 2015, 31 patients were evaluable for analysis. Median (range) age was 32 (20-67) years. 68% of patients had received ≥4 prior lines of therapy, 71% had failed prior ASCT, and by design 100% had failed prior BV. The most common treatment-related AEs were hypothyroidism (16%), diarrhea (13%), nausea (13%), and pneumonitis (10%). Five patients had grade 3 related AEs; no grade 4 AEs or treatment-related deaths occurred. ORR among the 31 patients was 65% (90% CI, 48-79). Five patients (16%) achieved CR, 15 (48%) partial remission, and 7 (23%) stable disease as their best response. With a median follow-up of 9.7 (1.3-17.5) months, the median DOR had not been reached (0+ to 13.4+ months). As of the data cutoff, 14 patients (45%) remained on treatment; 2 (6%) patients discontinued for toxicity, 12 (39%) for progression, and 3 (10%) for other reasons. Of the 20 responses, 14 are ongoing. Eleven patients had evaluable pretreatment tumor tissue (archival or obtained for study). Among them, 10 (91%) were PD-L1+ by immunohistochemistry (IHC). Among 6 available tumor samples obtained at week 13, 4 (57%) were PD-L1+. Additionally, 10/10 patients assessed for PD-L2 expression by IHC showed high levels of PD-L2 staining. Based on flow cytometry analyses, a significant increase was observed at the 13-week time point in the absolute number of circulating total lymphocytes, T cells (CD4 and CD8 subsets), as well as NK cells. NanoString RNA profiling of pre- and posttreatment blood samples showed that several prespecified gene expression signatures were significantly upregulated with treatment, including the 10-gene IFN-γ-induced signature, the 18-gene expanded immune signature, and the 13-gene TCR signature. Conclusion: PD-1 blockade with pembrolizumab was associated with a favorable safety profile and a high response rate in a very heavily pretreated cohort of patients with cHL. Responses appear durable with ongoing follow-up. Biomarker analyses confirm the frequent presence of PD-L1 and PD-L2 in tumors and further suggest that pembrolizumab results in an expansion of circulating T- and NK-cell populations, as well as in activation of IFN-γ and other pathways involved in regulation and differentiation of immune cells. Those biomarkers may be tested in larger ongoing studies for their relationship with treatment outcomes. Disclosures Armand: Merck: Consultancy, Research Funding; Sequenta, Inc.: Research Funding; Infinity: Consultancy, Research Funding; BMS: Research Funding. Off Label Use: The PD-1 pathway is an important mechanism of immune evasion for many tumors. Pembrolizumab is a humanized monoclonal antibody that blocks the interaction of PD-1 with its ligands PD-L1 and PD-L2 on the tumor cell surface and, based upon pembrolizumab's antitumor immune activity in several solid tumors, it may be an effective option for treating hematological malignancies.. Shipp:Bayer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy; Sanofi: Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees. Ribrag:Gilead: Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmamar: Honoraria, Membership on an entity's Board of Directors or advisory committees. Zinzani:Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; J&J: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Snyder:Merck: Employment, Equity Ownership. Ricart:Merck: Employment; Pfizer Inc.: Equity Ownership. Balakumaran:Merck: Employment, Equity Ownership; Amgen: Equity Ownership. Moskowitz:Seattle Genetics: Honoraria, Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Description: Introduction:Low-dose radiation therapy (LD-RT) is a therapeutic option in indolent non Hodgkin B-cell lymphomas (iNHL), usually in the palliative setting. If most iNHL are highly sensitive to radiation therapy, with good local control obtained with a dose of 4 Gy in 2 fractions, little is known about the efficacy and outcome of repetitive courses of LD-RT. We report here the results of a study cohort of repetitive LD-RT in iNHL. Methods : We retrospectively reviewed the records of all iNHL patients treated by two or more courses of LD-RT at Gustave Roussy, between January 1990 and December 2015. Patients received LD-RT as palliative treatment for low-bulky disease, patient's comfort or painful adenopathy. Clinical data, histological types, outcome and treatment lines were collected. Overall survival was the time between lymphoma diagnosis and death from any cause. Last LD-RT follow-up period was the time between the last LD-RT session and latest news. Results: Thirty-five pts were analyzed. Among them, 24 pts (69%) had Follicular Lymphoma (FL), 6 pts (17%) Marginal Zone Lymphoma (MZL), 3 pts (9%) had B-cell primitive Cutaneous Lymphoma Follicular Type (CL-FL) and 2 pts (6%) Nodular Lymphocyte Predominant Hodgkin Lymphoma (NLPHL). At lymphoma diagnosis, median age was 57 years [range 20-80]. Ann Arbor stage was I-II in 18 pts (51%), and III-IV in 17 pts (49%). Patients received a median of 4 therapeutics lines (range 2-11), and 2 LD-RT courses (range 2-6). Median overall survival was 146 months [29-298 months]. Four patients had died: 2 of disease progression and 2 others from concomitant illness (1 cardiac disease and 1 hepatocellular carcinoma). No patient had experienced transformation to diffuse large B cell lymphoma after RT-LD treatments. In the vast majority of cases (31/35; 89%), the LD-RT were successively performed to lymphoma relapse outside irradiation fields. Exclusive repetitive courses of LD-RT without chemotherapy were received by 8/35 (23%) of patients; while 24/35 (69%) patients received repetitive LD-RT alternately with immunotherapies or chemotherapies; and 3/35 (9%) others repetitive LD-RT alternately with standard dose RT. After the second course of LD-RT, 12/35 (34%) patients were managed in watch and wait approach, 6/35 (17%) received another LD-RT and 17/35 (49%) patients had experienced a progressive disease and were treated with immunotherapy or chemotherapy or standard dose radiotherapy. The LD-RT was the last treatment modality in 18/35 (51%) patients with histological types distributed in FL (n=10), MZL (n=5) and CT-FL (n=3). With a median last LD-RT follow up of 32 months [7-177 months], 23/35 (66%) patients remained in complete remission, 9/35 patients (26%) had experienced progressive disease and 3/35 (9%) patients had obtained stable disease. Conclusion: As palliative treatment modality, the repetitive low dose radiation therapy 4 Gy in two fractions could provide alternative option treatment in iNHL. This study support further investigations of this simple, well tolerated and not costly therapy in iNHL, especially in the context of new immunotherapeutic agent's area. Disclosures Michot: Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Ribrag:ArgenX: Research Funding; Esai: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Infinity: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Pharmamar: Membership on an entity's Board of Directors or advisory committees; NanoString: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees.

Description: Background: CC-122, a pleiotropic pathway modifier, modulates the cullin 4 ring E3 ligase complex, which results in recruitment and degradation of Aiolos and Ikaros. This substrate degradation results in cell autonomous anti-lymphoma and immunomodulatory effects on T- and NK-cell function (Gandhi, ASH 2012). The anti-CD20 monoclonal antibody, obinutuzumab, improves direct cell killing and antibody-dependent cell-mediated cytotoxicity (ADCC) activity compared to rituximab (Mössner, 2010; Niederfellner, 2011). The combination of obinutuzumab with CC-122 revealed synergistic effects in follicular lymphoma (FL) and additive effects in diffuse large B-cell lymphoma (DLBCL) in in vivo models when compared to either as single agents (Hsiling Chiu, ASH 2015). CC-122 monotherapy has shown encouraging activity against DLBCL and FL in a Phase I clinical trial (Rasco, ASH 2013). Obinutuzumab has demonstrated efficacy in patients with relapsed/refractory indolent non-Hodgkin lymphoma (iNHL) (Salles, 2013) and DLBCL (Morschhauser, 2013) and has been approved by the FDA and the European Medicinal Agency for patients with previously treated FL. The current study was designed to evaluate the safety and efficacy of escalating doses of CC-122 in combination with obinutuzumab in patients with relapsed/refractory DLBCL and iNHL (NCT02417285). Methods: Subjects with relapsed/refractory DLBCL and iNHL (FL and marginal zone lymphoma [MZL]) were enrolled in this phase 1b study of CC-122 given orally on 5 out of 7 days per week (5/7 days) for 28 day cycles. Subjects were enrolled in cohorts of escalating dose levels of CC-122 (1.0 mg [n=4], 2.0 mg [n = 4], 3.0 mg [n = 7], 4.0 mg [n = 6]), with a fixed dose of obinutuzumab. Obinutuzumab is administered as an intravenous (IV) infusion at a dose of 1000 mg on Days 2, 8, and 15 of Cycle 1 and on Day 1 of Cycles 2 through 8. The initial 4 dose levels evaluated active ingredient in capsule (AIC) CC-122 formulation. In Cohort 5 (3.0 mg, [n = 5]), subjects received CC-122 formulated capsules. Prophylaxis with granulocyte-colony stimulating factor (G-CSF) was not allowed during Cycle 1. As the study is ongoing, the CC-122 dose will be escalated until the maximum tolerated dose (MTD) is established on the CC-122 formulated capsule, using a modified 3+3 design. Subjects are evaluated for efficacy every 2 cycles(c) through c6 then every 3 cycles through c12, then every 6 cycles. Results: As of 1 June 2016, 26 subjects with relapsed/refractory DLBCL or iNHL were enrolled; all were evaluable for safety. The median age was 60 years and 84.6% were male. Thirteen subjects had DLBCL (50%), 13 (50%) had iNHL (12 FL [46.2%], 1 had MZL [3.8%]). All subjects were ECOG 0-1. One subject experienced a dose-limiting toxicity (DLT) of Grade 4 neutropenia (Cohort 3) and no dose was considered a non-tolerated dose (NTD). The most common (≥ 10%) study drug-related treatment emergent adverse events (TEAEs) were neutropenia (50%), thrombocytopenia (30.8%), diarrhea, chills, and increased ALT (11.5% each). Seventeen subjects (65.4%) experienced at least one NCI CTCAE grade 3-4 TEAE related to study treatment (most common [≥ 10%] were neutropenia [42.3%], thrombocytopenia [15.4%], and increased ALT [11.5%]). Seven subjects experienced at least one serious AE suspected to be related to study treatment by the investigator (infusion related reaction [3 subjects], febrile neutropenia, neutropenia, thrombocytopenia, and pneumonia, [1 subject each]). The overall response rate (ORR) for the 26 subjects enrolled, as of the efficacy cut off of 7 July 2016, was 53.8% (14/26); 8 of 12 (66.7%) FL, 5/13 (38.5%) DLBCL, and 1/1 MZL. Responses are ongoing in 12 of 14 of these subjects. ORR in the pooled higher dose cohorts of CC-122 (eg, a dose of 3 mg or higher, cohorts 3, 4, and 5) was 66.7% (12 of 18 subjects). Conclusion: The combination of CC-122 and obinutuzumab was well-tolerated in subjects with relapsed-refractory DLBCL and iNHL. AEs observed were consistent with the toxicity profile of CC-122 or obinutuzumab. Response rates observed were promising in this heavily pretreated population. Response rate appears higher in patients with FL however this warrants further investigation in a larger population. An NTD has not been reached and the MTD has not yet been established. Disclosures Michot: Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Vitolo:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria; Gilead: Honoraria; Takeda: Honoraria. Zinzani:Karyopharm: Membership on an entity's Board of Directors or advisory committees; Sandoz: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Infinity: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees; TG Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kersten:Celgene: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding. Chiappella:Teva: Speakers Bureau; Janssen-Cilag: Speakers Bureau; Amgen: Speakers Bureau; Pfizer: Speakers Bureau; Roche: Speakers Bureau; Celgene: Speakers Bureau. Sarmiento:Celgene CITRE: Employment, Equity Ownership. Zuraek:Celgene Corporation: Employment, Equity Ownership. Pourdehnad:Celgene Corporation: Employment, Equity Ownership. Hege:Celgene Corporation: Employment, Equity Ownership. Nikolova:Celgene International: Employment, Equity Ownership. Ribrag:BMS: Membership on an entity's Board of Directors or advisory committees; ArgenX: Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees; Infinity: Membership on an entity's Board of Directors or advisory committees; Esai: Membership on an entity's Board of Directors or advisory committees; Pharmamar: Membership on an entity's Board of Directors or advisory committees; NanoString: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees.

Description: Introduction: The BEAM (carmustine (BCNU), etoposide, aracytin and melphalan) standard conditioning regimen in autologous stem-cell transplantation is widely used since 1990 in patients with relapsed/refractory non Hodgkin's lymphoma (NHL) and Hodgkin's lymphoma (HL) who remain sensitive to salvage therapy. Recently, a phase Ib-II feasibility study using bendamustine rather than BCNU in the same indication was reported, but was not really compared to BEAM concerning safety. We report herein a safety analysis of Bendamustine-EAM (BeEAM) with a control BEAM counterpart paired cohort (2/1). Methods: We performed a case control retrospective study of patients with NHL and HL who underwent high-dose chemotherapy (HDC) with BeEAM regimen between January 2015 and December 2015. We matched each BeEAM patient with two patients having the same age, sex and number of treatment lines who underwent BEAM and ASCT between January 2008 and December 2014. No patient presented significant comorbidity. The BEAM regimen consisted in BCNU on day -6 (300mg/m2) cytarabine daily from day -6 to day -3 (200mg/m2 every 12 hours), etoposide daily from day -6 to day -3 (100mg/m2 every 12 hours) and melphalan on day -2 (140mg/m2). A similar scheme was adopted in BeEAM arm with bendamustine on day -6 and -5 (100mg/m2/d) replacing BCNU. Autologous stem cells were reinfused on day 0. Unfractionated heparin was used with Bendamustine to prevent veno-occlusive disease. Pegfilgrastim 6mg was injected subcutaneously on day 4. Febrile neutropenia was treated according to ESMO guidelines. Results: One hundred and two patients (68 BEAM and 34 BeEAM) were analyzed. Median age was 48 years in both arms. 61.8% of patients were male and 38.2% female. A median number of 4.4 x106 CD34 were reinfused in the two groups. The median time to neutrophils recovery (〉 0.5 x109) was similar between the two arms (9.06 vs 8.86 days, p=0.3). Grade 3 or greater diarrhea according to Commun Terminology Criteria for Adverse Events (CTCAE v4.03) classification was significantly more frequent in BeEAM patients (44 vs 13.2%, p=0.001). Median time to hospital discharge was significantly longer in BeEAM group (23 vs 20.8 days, p=0.0047). The median loss of weight during hospitalization was significantly greater in BeEAM patients (3.3 vs 1.9 kg, p=0.014). The median number of days with fever 〉38°C and with intravenous antibiotics was significantly higher in BeEAM group (6.06 vs 3.38, p