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Introduction We previously examined how expanding access to chimeric antigen receptor (CAR) T cell therapy administration sites impacted patient travel distances and time. In the current study, we estimated travel-related economic burden associated with site-of-care options among patients with relapsed/refractory diffuse large B cell lymphoma. Methods We used geographic information system methods to quantify travel-related economic burden across three site-of-care scenarios: academic hospitals; academic and community multispecialty hospitals; and academic and community multispecialty hospitals plus nonacademic specialty oncology network centers. Socioeconomic status, administration sites, and county of residence were derived from the US Census Bureau and publicly available sources. Travel costs were based on governmental guidelines, US census wage data, and Bureau of Transportation Statistics. Travel distance and time to the nearest CAR T cell therapy administration sites were estimated from previous research. Results Total national estimated costs associated with traveling for CAR T cell therapy were $21.1 million if CAR T cell therapy was offered exclusively in academic hospitals, and $14.7 million if expanded to include community hospitals plus nonacademic specialty oncology network centers, representing a $6.5-million reduction associated with expanding access to eligible patients. The largest cost-saving component was lodging/meals. Regional and demographic cost differences were statistically significant between academic hospitals and nonacademic hospitals/specialty oncology centers. In all scenarios, patients living below the federal poverty level (FPL) had higher weighted mean total costs versus patients living above the FPL. White and Native American patients were estimated to have the highest weighted mean total costs across race/ethnicity groups. For all subgroups, costs were reduced by expanding access beyond academic hospitals. Conclusion CAR T cell therapy is currently restricted to academic hospitals; total travel costs could be substantially decreased if access is expanded to nonacademic hospitals and specialty oncology centers. Patients in rural areas and those living below the FPL are particularly disadvantaged by restricted access. Supplementary Information The online version contains supplementary material available at 10.1007/s12325-021-01839-y.

Chimeric antigen receptor (CAR) T-cell therapy has been shown to produce profound results in the treatment of certain hematologic malignancies, however treatment of solid tumors with CAR T cells has not been as successful. Studies have suggested that T-cell exhaustion plays a role in limiting the ability of CAR T cells to eradicate solid tumors. Additionally, stem-like qualities of T cells have been associated with better outcomes in patients treated with cellular therapies, including CAR T cells. Therefore, maintaining stem-like qualities and overcoming T-cell exhaustion may be key to improving clinical efficacy of CAR T cells in patients with solid tumors. ROR1 is a cell surface antigen expressed in several solid tumor types and chronic lymphocytic leukemia (CLL). ROR1 expression has been reported in 57% of triple-negative breast cancer (TNBC), as well as 42% of adenocarcinoma and 12% of squamous cell carcinoma subtypes of non-small cell lung cancer (NSCLC). These expression data of ROR1 in TNBC and NSCLC provide support for anti-ROR1 agents as a therapeutic strategy for these cancers. LYL797 is a novel, ROR1-targeted chimeric antigen receptor (CAR) T-cell product that incorporates genetic and epigenetic reprogramming technologies, Gen-R and Epi-R, to overcome barriers of CAR T-cell therapies in solid tumors. The ROR1-specific CAR contains a single-chain variable fragment (scFv) derived from an R12 rabbit monoclonal antibody that recognizes and binds with high specificity to human ROR1. Gen-R is ex vivo genetic reprogramming technology that engineers CAR T cells to overexpress c-Jun. Dysregulation of activator protein 1 (AP-1) has been implicated in CAR T-cell exhaustion, and studies have demonstrated that overexpression of c-Jun renders CAR T cells less susceptible to exhaustion, enhancing both anti-tumor efficacy and persistence in preclinical models of hematologic and solid tumors. Epi-R is a proprietary optimized manufacturing process that results in maintenance of stem-like phenotype and function of T-cell products. In preclinical studies LYL797 cells reprogrammed with Gen-R and Epi-R led to improved functional activity in the presence of ROR1+ tumor cells compared to conventional ROR1 CAR T cells. Additional studies are underway to determine the mechanisms by which antitumor activity of LYL797 in ROR1-positive solid tumor xenograft models is enhanced. LYL797 is anticipated to enter into Phase 1 clinical trials for TNBC and NSCLC in 2022. Citation Format: Spencer Park, Courtney Simianer, Sydney Spadinger, Xiao Wang, Purnima Sundar, Shobha Potluri, Rachel Lynn, Bijan Boldajipour, Grace Wang, Neeraj Sharma, Hajime Hiraragi, Veena Krishnamoorthy, Suman Kumar Vodnala, E-Ching Ong, Chang-Chih Wu, Martin Wohlfahrt, Byoung Ryu, Lisa Song, Brian D. Weitzner, Howell Moffett, Marc Lajoie, Scott Boyken, Tamer Shabaneh, Shivani Srivastava, Tina Albertson, Blythe Sather. LYL797, a ROR1 CAR T-cell therapy with genetic and epigenetic reprogramming for solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2754.

Summary Background Lisocabtagene maraleucel (liso-cel) is an autologous, CD19-directed, chimeric antigen receptor (CAR) T-cell product. We aimed to assess the activity and safety of liso-cel in patients with relapsed or refractory large B-cell lymphomas. Methods We did a seamless design study at 14 cancer centres in the USA. We enrolled adult patients (aged ≥18 years) with relapsed or refractory large B-cell lymphomas. Eligible histological subgroups included diffuse large B-cell lymphoma, high-grade B-cell lymphoma with rearrangements of MYC and either BCL2, BCL6, or both (double-hit or triple-hit lymphoma), diffuse large B-cell lymphoma transformed from any indolent lymphoma, primary mediastinal B-cell lymphoma, and follicular lymphoma grade 3B. Patients were assigned to one of three target dose levels of liso-cel as they were sequentially tested in the trial (50 × 106 CAR+ T cells [one or two doses], 100 × 106 CAR+ T cells, and 150 × 106 CAR+ T cells), which were administered as a sequential infusion of two components (CD8+ and CD4+ CAR+ T cells) at equal target doses. Primary endpoints were adverse events, dose-limiting toxicities, and the objective response rate (assessed per Lugano criteria); endpoints were assessed by an independent review committee in the efficacy-evaluable set (comprising all patients who had confirmed PET-positive disease and received at least one dose of liso-cel). This trial is registered with ClinicalTrials.gov, NCT02631044. Findings Between Jan 11, 2016, and July 5, 2019, 344 patients underwent leukapheresis for manufacture of CAR+ T cells (liso-cel), of whom 269 patients received at least one dose of liso-cel. Patients had received a median of three (range 1–8) previous lines of systemic treatment, with 260 (97%) patients having had at least two lines. 112 (42%) patients were aged 65 years or older, 181 (67%) had chemotherapy-refractory disease, and seven (3%) had secondary CNS involvement. Median follow-up for overall survival for all 344 patients who had leukapheresis was 18·8 months (95% CI 15·0–19·3). Overall safety and activity of liso-cel did not differ by dose level. The recommended target dose was 100 × 106 CAR+ T cells (50 × 106 CD8+ and 50 × 106 CD4+ CAR+ T cells). Of 256 patients included in the efficacy-evaluable set, an objective response was achieved by 186 (73%, 95% CI 66·8–78·0) patients and a complete response by 136 (53%, 46·8–59·4). The most common grade 3 or worse adverse events were neutropenia in 161 (60%) patients, anaemia in 101 (37%), and thrombocytopenia in 72 (27%). Cytokine release syndrome and neurological events occurred in 113 (42%) and 80 (30%) patients, respectively; grade 3 or worse cytokine release syndrome and neurological events occurred in six (2%) and 27 (10%) patients, respectively. Nine (6%) patients had a dose-limiting toxicity, including one patient who died from diffuse alveolar damage following a dose of 50 × 106 CAR+ T cells. Interpretation Use of liso-cel resulted in a high objective response rate, with a low incidence of grade 3 or worse cytokine release syndrome and neurological events in patients with relapsed or refractory large B-cell lymphomas, including those with diverse histological subtypes and high-risk features. Liso-cel is under further evaluation at first relapse in large B-cell lymphomas and as a treatment for other relapsed or refractory B-cell malignancies. Funding Juno Therapeutics, a Bristol-Myers Squibb Company.

e20046 Background: Clinical studies of liso-cel show low incidences of severe CRS and NEs. Pts with high tumor burden and inflammation are at higher risk of CRS and NEs (Borrega, Hemasphere 2019). Here, we characterize the presenting symptoms, timing, and management of CRS and NEs in pts with R/R LBCL treated with liso-cel in TRANSCEND NHL 001 (NCT02631044). A deeper understanding of CRS/NEs after liso-cel treatment may help clinicians identify and manage these toxicities. Methods: Pts with R/R LBCL and ≥2 lines of therapy received liso-cel after lymphodepletion (LD) with fludarabine and cyclophosphamide. Bridging therapy was allowed for pts with PET-positive disease before LD (Abramson, ASH 2019 #241). Investigators were educated on prospectively identifying liso-cel–related NEs and CRS, which were collected and graded per NCI CTCAE v4.03 (NEs) or 2014 Lee criteria (CRS). Timing and severity of individual CRS/NE symptoms and interventions were also collected. Results: The analysis included 269 pts (median age, 63 y): 38% had sum of perpendicular diameters ≥50 cm2 or lactate dehydrogenase ≥500 U/L, and 59% received bridging therapy. CRS and NEs had delayed onset (median, 5 and 9 d, respectively) and a low incidence of grade (Gr) ≥3 events (CRS 2%; NE 10%). CRS occurred before NEs in most pts and was Gr 1/2 at onset in all but 2 pts (Table). The most common CRS symptoms were pyrexia (40%), hypotension (20%), and tachycardia (18%). Overall, 20% of pts received tocilizumab and/or corticosteroids for CRS (10% tocilizumab only; 2% corticosteroids only; 8% both); 3% received vasopressors. The most common NE symptoms were confusional state (11%), tremor (9%), and aphasia (8%); most were low grade. A total of 17% of pts received tocilizumab and/or corticosteroids for NEs (13% corticosteroids only; < 1% tocilizumab only; 3% both); < 1% received vasopressors. Overall, 4% of pts were admitted to the ICU for CRS and/or NEs. Additional analyses on timing of intervention and type/severity of initial symptoms will be presented. Conclusions: In pts with high-risk, aggressive R/R LBCL, liso-cel treatment was associated with a low incidence of severe CRS/NEs, late onset of mostly low-grade events at presentation, and low use of tocilizumab/corticosteroids. Clinical trial information: NCT02631044 . [Table: see text]

CD19, a member of the immunoglobulin superfamily, is a B-cell specific marker that is found on B cells as early as the pro-B cell stage. CD19 is maintained upon malignant transformation and is expressed in the majority of patients with B-lineage acute lymphocytic leukemia (ALL) and non-Hodgkin lymphoma (NHL). SGN CD19A is a novel antibody-drug conjugate (ADC) composed of a humanized anti-CD19 monoclonal antibody conjugated to the microtubule-disrupting agent monomethyl auristatin F (MMAF) via a maleimidocaproyl (mc) linker. Upon binding to CD19, SGN-CD19A internalizes and releases cys-mcMMAF, which binds to tubulin and induces G2/M arrest and apoptosis in the targeted cells. In mice bearing B-lineage ALL and lymphoma xenografts, SGN-CD19A induced dose-dependent tumor growth delay and extended survival. Two first-in-human, phase 1, dose-escalation studies are ongoing to investigate the safety, tolerability, pharmacokinetics (PK), and antitumor activity of SGN CD19A; one trial in adult and pediatric patients with relapsed or refractory (R/R) B cell ALL or highly aggressive B-cell lymphoma (CT.gov NCT01786096) and the second trial in adult patients with R/R B-cell NHL (CT.gov NCT01786135). Both trials employ a modified continual reassessment method (CRM) to estimate the dose-toxicity relationship and to estimate the maximum tolerated dose. Exploratory analyses include correlation of target (CD19) expression, target saturation, and apoptotic cellular markers with clinical response and clearance of leukemic blasts; dose and PK of SGN-CD19A will also be correlated with target saturation and intracellular levels of cys-mcMMAF. Early PK analyses indicate that plasma SGN-CD19A ADC generally increases with higher doses. Rapid clearance of ADC was observed at low doses in patients with leukemia, suggesting target-mediated drug disposition. Dose escalation of SGN-CD19A is ongoing in both clinical trials. In preliminary safety analyses, SGN-CD19A was generally tolerable at doses examined to date. Encouraging antitumor activity has been observed, with multiple patients achieving complete remissions in both trials. Citation Format: Tina M. Albertson, Lali Sandalic, Baiteng Zhao, Ana Kostic, Che-Leung Law. SGN-CD19A: A novel Anti-CD19 antibody drug conjugate. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr DDT01-04. doi:10.1158/1538-7445.AM2014-DDT01-04

Background Lisocabtagene maraleucel (liso-cel) is an investigational, CD19-directed, genetically modified, autologous cellular immunotherapy administered as a defined composition of CD8+ and CD4+ components to deliver target doses of viable chimeric antigen receptor (CAR) T cells from both components. The CAR comprises a CD19-specific scFv and 4-1BB-CD3ζ endodomain. Liso-cel is being developed for the treatment of multiple B cell malignancies, including relapsed/refractory large B cell non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). The liso-cel manufacturing process design includes controls that enable robustness across heterogeneous patient populations and disease indications, minimizing between-lot variability. This is highlighted by consistency in process duration, reduction of terminally differentiated T cells present in the T cell starting material, and consistency in T cell purity across B cell NHL and CLL/SLL indications. Methods The liso-cel manufacturing process involves selection of CD8+ and CD4+ T cells from leukapheresis, followed by independent CD8+ and CD4+ activation, transduction, expansion, formulation, and cryopreservation. Liso-cel was manufactured in support of the TRANSCEND NHL 001 (NCT02631044) and TRANSCEND CLL 004 (NCT03331198) clinical trials. Phenotypic analysis of T cell and B cell composition from leukapheresis, T cell starting material, and CAR T cell product was performed by flow cytometry. Molecular characterization of T cell receptor (TCR) clonality was estimated from the T cell starting material and CAR T cell product through transcriptional profiling. Results Liso-cel manufacturing process optimizations have been implemented in advance of commercialization. These optimizations have significantly improved process duration consistency (Figure 1; F test P=4.1×10−36). Both phenotypic and molecular TCR clonality analyses demonstrated a significant reduction in terminally differentiated CD8+ T cells across the manufacturing process. Frequencies of CD45RA+ CCR7− populations were measured by flow cytometry in CD8+ T cell starting material (median=35.1%) and CAR T cell product (median=11.7%; Wilcoxon rank sum P=3.1×10−25). Characterization of TCR clonality showed a significant decrease in clonality in the CAR T cell product compared with T cell starting material (Wilcoxon rank sum P=5.6×10−6), suggesting selective expansion of clonally diverse, less differentiated T cell populations. These findings are supported by the predominant memory T cell composition observed in liso-cel. Manufacturing process robustness enabled by in-process T cell selection is further demonstrated by the capability to produce highly pure T cell products across heterogeneous patient populations and different disease indications. T cell and B cell composition were characterized in the leukapheresis, selected T cell material, and CAR T cell product, demonstrating consistent clearance of non-T cells, including CD19+ B cells in both B- cell NHL and CLL/SLL patient cohorts. Although the CD19+ B cell composition is significantly higher in leukapheresis from patients with CLL/SLL (median=10.0% of leukocytes) compared with B cell NHL patients (median=0.0% of leukocytes, Wilcoxon rank sum P=1.6×10−9), CAR T cell products manufactured from both CLL/SLL and B cell NHL patient populations consistently demonstrated clearance of non-T cells, including CD19+ cells, to below levels of quantitation. Conclusion Despite variation between B cell NHL and CLL/SLL patient leukapheresis, T cell enrichment before activation and transduction enables consistent downstream process performance and T cell purity, and a substantially reduced risk of transducing residual tumor cells. In addition, the reduction of terminally differentiated effector T cells and capacity to retain T cell diversity further improved consistency in product quality. Taken together, process modifications have enabled consistent manufacturing duration and quality of liso-cel product, which support operational efficiency and scalability for commercial production. Disclosures Teoh: Juno Therapeutics, a Celgene Company: Employment, Equity Ownership. Johnstone:Juno Therapeutics, a Celgene Company: Employment, Patents & Royalties: Author on a number of patent applications and invention disclosures relating to cell therapy and immunosequencing. Christin:Juno Therapeutics, a Celgene Company: Employment, Equity Ownership. Yost:Juno Therapeutics, a Celgene Company: Employment, Equity Ownership. Haig:Juno Therapeutics, a Celgene Company: Employment, Equity Ownership. Mallaney:Juno Therapeutics, a Celgene Company: Employment. Radhakrishnan:Juno Therapeutics, a Celgene Company: Employment, Equity Ownership. Gillenwater:Juno Therapeutics, a Celgene Company: Employment, Equity Ownership. Albertson:Juno Therapeutics, a Celgene Company: Employment, Equity Ownership. Guptill:Juno Therapeutics, a Celgene Company: Employment. Brown:Juno Therapeutics, a Celgene Company: Employment. Ramsborg:Juno Therapeutics, a Celgene Company: Employment, Equity Ownership, Patents & Royalties: Numerous patents. Hause:Juno Therapeutics, a Celgene Company: Employment, Equity Ownership. Larson:Juno Therapeutics, a Celgene Company: Employment, Equity Ownership.

Background : CAR T cell therapies have demonstrated high response rates in patients (pts) with R/R B cell NHL. Liso-cel is an investigational anti-CD19, defined composition, 4-1BB CAR T cell product administered at target doses of CD4+ and CD8+ CAR T cells. The seamless phase 1 TRANSCEND NHL 001 study evaluated liso-cel in pts with R/R large B cell NHL (NCT02631044). We present data with long-term follow-up from pts treated in the DLBCL cohort. Methods: Pts aged ≥18 yrs in the DLBCL cohort had R/R DLBCL not otherwise specified (NOS; including transformed from any indolent lymphoma), high-grade B cell lymphoma (HGBCL) with MYC and BCL2 and/or BCL6 rearrangements, primary mediastinal B cell lymphoma (PMBCL), or follicular lymphoma grade 3B (FL3B). Pts had R/R disease after ≥2 lines of therapy and ECOG PS 0‒2. Pts with grade 3/4 cytopenias, mild-moderate organ dysfunction, and secondary CNS lymphoma were eligible. Bridging therapy was allowed, but pts had to have PET-positive disease before lymphodepletion (LD) with fludarabine and cyclophosphamide. Liso-cel was administered at 1 of 3 target dose levels (DLs) of 50×106 (DL1), 100×106 (DL2), or150×106 (DL3) viable CAR+ T cells in the dose-finding cohorts. All dose levels were expanded, and DL2 was chosen as the target DL for dose confirmation. Primary endpoints were treatment-emergent adverse events (TEAEs) and overall response rate (ORR). Secondary endpoints included CR rate, DOR, PFS, PFS ratio, and OS. TEAEs, including investigator-identified neurological events (NE) related to liso-cel, were graded using CTCAE criteria; CRS was graded per the Lee criteria (2014). ORR was assessed by independent review using the Lugano criteria. Data from all liso-cel-treated pts in the DLBCL cohort were analyzed across DLs. Results: A total of 342 pts were leukapheresed; 268 pts received liso-cel (DL1, n=51; DL2, n=176; DL3, n=41). Twenty-four pts received nonconforming product; product could not be manufactured for 2 pts. Pts did not receive liso-cel primarily due to death (n=33). In the optimized manufacturing process, median time from leukapheresis to liso-cel availability was 24 days. Median age was 63 (range, 18‒86) yrs, including older subpopulations (≥65 yrs, 41%; ≥75 yrs, 10%); 65% of pts were male. At screening, 58% had ECOG PS 1. Pts were heavily pretreated and had aggressive disease: 26% had ≥4 prior lines of systemic therapy (median of 3; range, 1‒8); 34% underwent prior auto-HSCT and 3% prior allo-HSCT; 67% were chemorefractory; and 44% had never achieved CR. 59% required bridging therapy. 22% had LDH ≥500 U/L and 28% had SPD ≥50 cm2 before LD. Outcomes were similar between DLs; therefore, data were pooled. Twenty-five pts were treated in the outpatient setting. Safety analysis showed 79% of pts had grade ≥3 TEAEs, primarily cytopenias (neutropenia, 60%; anemia, 37%; thrombocytopenia, 27%). CRS or NE occurred in 47% of pts. Any grade CRS occurred in 42% of pts at a median onset of 5 days; only 2% had grade ≥3 CRS. NEs occurred in 30% of pts (grade ≥3, 10%) at a median onset of 9 days (Table). 19% of pts received tocilizumab and 21% received corticosteroids for CRS and/or NEs. Four grade 5 TEAEs related to liso-cel and LD occurred (diffuse alveolar damage, pulmonary hemorrhage, multiple organ dysfunction syndrome, cardiomyopathy). Prolonged grade ≥3 cytopenia (based on laboratory assessment at Day 29) was reported in 37% of pts. Safety was similar between age groups, histologies, and pts with organ dysfunction. The study met all primary and secondary efficacy endpoints. Among pts evaluable for efficacy (n=255), ORR was 73% (95% CI, 67‒78); the CR rate was 53% (95% CI, 47‒59). Responses were similar across all pt subgroups (Table). Median DOR was 13.3 mo (95% CI, 8.2‒not reached [NR]) with 10.8 mo of median follow-up; median DOR for pts in CR was NR (13.3‒NR). Median PFS was 6.8 mo (95% CI, 3.3‒11.8). Median OS was 19.9 mo (95% CI, 10.9‒NR). Overall, PFS after liso-cel infusion was substantially longer than PFS from the immediate prior therapy. Conclusions: Liso-cel demonstrated durable clinical activity with a favorable safety profile in this large study of CAR T cell therapy in R/R large B cell NHL. Low incidence and late onset of CRS and NE allowed for outpatient administration. Clinically meaningful efficacy was observed across histologic subgroups and those with poor prognosis, including pts who were refractory, elderly, comorbid, and/or had high tumor burden. Disclosures Abramson: AbbVie Inc, Amgen Inc, Bayer HealthCare Pharmaceuticals, Celgene Corporation, EMD Serono Inc, Genentech, Gilead Sciences Inc, Janssen Biotech Inc, Juno Therapeutics, a Celgene Company, Karyopharm Therapeutics, Kite Pharma Inc, Merck, Novartis, Seattle Gen: Consultancy. Palomba:Kite Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Merck & Co Inc.: Consultancy; MSK (IP for Juno and Seres): Patents & Royalties; Noble Insights: Consultancy; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Seres Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; STRAXIMM: Membership on an entity's Board of Directors or advisory committees; Evelo: Equity Ownership; Hemedicus: Speakers Bureau. Gordon:Gilead: Other: Advisory Board; Bayer: Other: Advisory Board; Juno/Celgene: Other: Advisory Board, Research Funding; Zylem LLC: Other: co-founder; research in nanoparticles in cancer. Lunning:Spectrum: Consultancy; Seattle Genetics: Consultancy; Portola: Consultancy; OncLive: Consultancy; Novartis: Consultancy; Kite: Consultancy; Gilead Sciences, Inc.: Consultancy; DAVA: Consultancy; Bayer: Consultancy; AbbVie: Consultancy; TG Therapeutics: Consultancy, Research Funding; MiRagen: Research Funding; Juno Therapeutics: Consultancy, Research Funding; Janssen Scientific Affairs, LLC: Consultancy, Research Funding; Curis: Research Funding; VANIUM: Consultancy; Verastem: Consultancy. Wang:Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pharmacyclics: Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding, Speakers Bureau; MoreHealth: Consultancy, Equity Ownership; Acerta Pharma: Consultancy, Research Funding; Kite Pharma: Consultancy, Research Funding; Guidepoint Global: Consultancy; BioInvent: Consultancy, Research Funding; VelosBio: Research Funding; Loxo Oncology: Research Funding; Celgene: Honoraria, Research Funding; Juno Therapeutics: Research Funding; Aviara: Research Funding; Dava Oncology: Honoraria. Arnason:Celgene/Juno: Consultancy; Regeneron Pharmaceuticals, Inc.: Consultancy. Mehta:Pharmacyclics: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Spectrum: Consultancy, Speakers Bureau; Imbrium therapeutics: Consultancy; Roche-Genentech: Research Funding; Incyte: Research Funding; Kite/Gilead: Research Funding, Speakers Bureau; Takeda: Research Funding; Rhizen: Research Funding; ADC therapeutics: Research Funding; Forty Seven Inc: Research Funding; Juno/Celgene: Research Funding; Affimed: Research Funding; Seattle Genetics: Research Funding, Speakers Bureau; Astex: Research Funding; TG Therapeutics: Research Funding; miRagen: Research Funding; Kyowa-Kirin: Consultancy, Speakers Bureau; Astra-Zeneca: Speakers Bureau; Sanofi: Consultancy. Maloney:Celgene,Kite Pharma: Honoraria, Research Funding; Juno Therapeutics: Honoraria, Patents & Royalties: patients pending , Research Funding; BioLine RX, Gilead,Genentech,Novartis: Honoraria; A2 Biotherapeutics: Honoraria, Other: Stock options . Andreadis:Juno: Research Funding; Pharmacyclics: Research Funding; Genentech: Consultancy, Employment; Kite: Consultancy; Gilead: Consultancy; Jazz Pharmaceuticals: Consultancy; Roche: Equity Ownership; Novartis: Research Funding; Celgene: Research Funding; Merck: Research Funding. Sehgal:Merck: Research Funding; Juno/Celgene: Research Funding; Kite/Gilead: Research Funding. Ghosh:AstraZeneca: Honoraria, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Speakers Bureau; Gilead: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding, Speakers Bureau; SGN: Consultancy, Honoraria, Research Funding, Speakers Bureau; TG Therapeutics: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Research Funding; Genentech: Research Funding; Forty Seven Inc: Research Funding. Albertson:Juno Therapeutics, a Celgene Company: Employment, Equity Ownership. Garcia:Celgene: Employment, Equity Ownership. Kostic:Juno Therapeutics, a Celgene Company: Employment. Li:Juno Therapeutics, a Celgene Company: Employment. Kim:Juno Therapeutics, a Celgene Company: Employment. Siddiqi:TG Therapeutics: Research Funding; Kite, A Gilead Company: Research Funding; Seattle Genetics: Speakers Bureau; Janssen: Speakers Bureau; AstraZeneca: Consultancy, Research Funding, Speakers Bureau; PCYC: Consultancy, Research Funding, Speakers Bureau; Juno Therapeutics: Consultancy, Other: travel support, Research Funding; Celgene: Research Funding; BeiGene: Research Funding.

In this case, a woman with refractory diffuse large-B-cell lymphoma had a CNS recurrence that responded completely to anti-CD19 CAR T-cell therapy. After biopsy of a subsequent skin recurrence, the lesions cleared in association with an expansion of the CAR T cells in the blood.

JCAR017 is a CD19-directed 41BB chimeric antigen receptor (CAR) T cell product administered in a defined composition at a precise dose of CD8 and CD4 CAR T cells. JCAR017 manufacturing employs process controls that enable precise independent control of the infused dose of CD8 and CD4 cells. Preliminary safety data from JCAR017 administered in relapsed/refractory B cell non-Hodgkin lymphoma (NHL) demonstrated lower rates of cytokine release syndrome (CRS) and neurotoxicity (NT) compared to those reported for other CD19-directed CAR T cell therapies with heterogeneity in total infused dose and CD8 and CD4 composition. Multiple patient factors and blood biomarkers have been identified that correlate with JCAR017 CAR T cell in vivo expansion, antitumor activity, and toxicity (Heipel M et al. and Siddiqi T et al. ASH 2017). However, little is known regarding the contribution of CAR T cell product differentiation state to pharmacokinetics (PK), clinical outcome, or toxicity. Product characterization is executed on JCAR017 to define the CAR T cell memory phenotype composition and antigen-specific function. Product attributes were assessed for relationships with clinical response, safety, and PK through univariate, multivariate, and machine learning-based analyses. JCAR017 memory T cell composition demonstrated strong relationships with cytokine production profile observed following in vitro CD19 stimulation of the CAR T cell drug product. Specifically, products with elevated frequencies of CCR7+ central memory T cells exhibited increased production of IL-2 (Spearman ρ=0.55, P Citation Format: Ryan P. Larson, Rachel Lower, Todd DeVries, Yue Jiang, Ronald J. Hause, Rich Getto, Brian Christin, Nathan K. Yee, Michael A. Bowen, Clinton Weber, Daniel Li, Tina Albertson, Claire Sutherland, Christopher G. Ramsborg. Defined cell composition and precise control over JCAR017 dose enables identification of relationships between chimeric antigen receptor T cell product attributes, pharmacokinetics, and clinical endpoints in NHL [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 960.

7505Background: Lisocabtagene maraleucel (liso-cel; JCAR017) is a CD19-directed 4-1BB CAR T cell product administered in defined composition at a precise dose of CD8 and CD4 CAR T cells. A multicen...

120 Background: JCAR017 is a defined composition, CD19-directed 4-1BB CAR T cell product administered at a precise dose of CD8 and CD4 CAR T cells in a seamless design Phase 1 pivotal trial of relapsed/refractory (R/R) B-cell NHL (TRANSCEND NHL 001; NCT02631044). Methods: Patients (pts) with R/R DLBCL NOS, PMBCL, FL grade 3B, or MCL and adequate organ function are eligible. The FULL dataset includes all pts in the DLBCL cohort (i.e. excludes MCL). The CORE dataset includes pts meeting inclusion for a planned pivotal DLBCL cohort (DLBCL NOS [ de novo or transformed from follicular lymphoma], ECOG 0-1, no prior allo-SCT). Results: As of July 7, 2017, 69 pts were treated in the DLBCL cohort and evaluable for safety. In the FULL dataset, 21 pts (30%) had cytokine release syndrome (CRS), with 1 serious CRS event (1%; Gr 4). Neurotoxicity (NT) at any grade developed in 14 (20%), including 10 (14%) with Gr 3-4 events. There were no Gr 5 CRS or NT events. Median time to onset of first CRS and NT was 5 days and 10 days, respectively, 13 (19%) received anti-cytokine therapy and only one required vasopressor support. In the CORE dataset (n = 49), similar rates of CRS and NT were shown. The majority of pts, 64% (44/69), had no CRS or NT, and median onset of CRS and NT were 5 and 11 days, respectively, suggesting outpatient delivery of JCAR017 may be feasible. In the DLBCL cohort, 68 pts were evaluable for efficacy; best overall response, 3-month, and 6-month response rates in the FULL dataset were 75% (51/68), 49% (27/55), and 40% (14/35), respectively; and, in the CORE dataset, were 84% (41/49), 65% (26/40), and 57% (13/23). The best overall, 3-month, and 6-month CR rates were 61% (30/49), 53% (21/40), and 52% (12/23), respectively, in the CORE dataset. Among 16 double/triple hit pts, best ORR was 81%, and 3-month CR rate was 60%. A trend toward improved response rate at 3 months was observed in pts treated at DL2 compared to DL1. Conclusions: At the symposium, we will report updated efficacy and the preliminary safety profile for JCAR017, which supports potential outpatient administration in R/R Aggressive B-NHL patients. Clinical trial information: NCT02631044.

We present a Phase I dose escalation trial design based on a modified continual reassessment method that allows for sharing of information between populations. We describe our approach in the context of a trial for patients with acute lymphoblastic leukemia (ALL) that is currently being conducted. The ALL trial enrolls both adult and pediatric patient populations. Dose escalation and the determination of the maximum tolerated dose (MTD) are performed separately for each population, but to increase efficiency, information about the dose–toxicity curve is shared. Dose escalation rules allow pediatric patients to skip dose levels provided safety has been shown in adults and the dose level is estimated to be safe for pediatric patients. Trial objectives are to efficiently determine the MTD for each population and to minimize the number of pediatric patients required for dose escalation.

7513 Background: JCAR017 is a second-generation, CD19-directed, 4-1BB CAR T cell product comprising CD8 and CD4 CAR T cells in a 1:1 ratio. A multicenter phase 1 trial of JCAR017 in R/R B-cell NHL (NCT02631044) is underway. Methods: Patients with R/R DLBCL, PMBCL, FL grade 3B, or MCL and adequate organ function are eligible. There was no minimum ALC requirement for apheresis; no test expansion was required. Treatment includes lymphodepletion with fludarabine and cyclophosphamide, followed by JCAR017. Multiple dose levels (DLs)/administration schedules of JCAR017 are being evaluated. Study objectives include safety, PK, and antitumor response. Results: As of November 23, 2016, 28 patients have been treated and are evaluable for safety and efficacy. Nineteen were male, 9 female; 25 DLBCL, 2 MCL, and 1 FL grade 3B. Median age was 63 years (range 37-79), median number of prior therapies was 4 (range 1-8), 23 (82%) were refractory to their last chemotherapy, and 16 (57%) had prior transplant. No severe cytokine release syndrome (sCRS) was observed; 10 patients had grade 1-2 CRS (1 received tocilizumab). Five patients developed neurotoxicity, including 4 grade 3-4; all events resolved in the 4 patients who had adequate follow up. Median onset of CRS and neurotoxicity were 5 and 11 days, respectively. Four deaths after disease progression occurred, none related to JCAR017. In 20 patients treated at DL1 (5×107 cells), the RR was 80% with 60% achieving CR. One patient with secondary CNS involvement achieved CR without neurotoxicity. JCAR017 was detected at 3 and 6 months in responding patients, including some who relapsed; higher mean peak levels were detected in patients with durable response at 3 months. Data on patients treated at DL2 (1×108 cells), alternative dose schedules, tumor biopsy, and additional biomarkers will be presented. Conclusions: Treatment with JCAR017 results in high CR rate in patients with heavily pretreated R/R DLBCL. Relapses can occur despite persistence of JCAR017, suggesting tumor immune evasion mechanisms may contribute to relapse. Observed toxicities are manageable and occurred at rates lower than those reported for other CD19-directed CAR T cell products. Clinical trial information: NCT02631044.

Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA SGN-CD19A is an antibody drug conjugate (ADC) that recognizes CD19, a B-cell specific marker expressed in B-cell malignancies including non-Hodgkin lymphoma (NHL). SGN-CD19A is currently in a phase I clinical trial for adult patients with relapsed refractory B-cell NHL (CT.gov [NCT01786135][1]) in which it has shown evidence of single-agent activity (1). This ADC binds CD19, internalizes, and releases cys-mcMMAF, which ultimately induces apoptosis in targeted cells (2). Lymphoma tumor xenografts treated with SGN-CD19A show growth delay in a dose dependent manner. Here we show that SGN-CD19A in combination with standard of care [rituximab/ifosfamide/carboplatin/etoposide (R-ICE), rituximab/cyclophosphamide/doxorubicin/vincristine/prednisone (R-CHOP), or components] exceeds the activity of SGN-CD19A alone and results in impressive anti-tumor activity in multiple xenograft models. It was notable that in some xenograft models, SGN-CD19A + R-CHOP or SGN-CD19A + R-ICE yielded activity that was similar to SGN-CD19A plus rituximab alone. This strong interaction between rituximab and SGN-CD19A was modeled in vitro. SGN-CD19A synergized with rituximab, in the absence of cross-linking, to cause decreased cell viability in NHL cell lines. These data suggest that cell autonomous signaling contributes to the unique interaction between rituximab and SGN-CD19A. Our in vivo and in vitro data support R-CHOP, R-ICE, or rituximab as viable combination therapies for NHL patients with SGN-CD19A. 1) Uma Borate et al. A first-in-human phase 1 study of the antibody-drug conjugate SGN-CD19A in relapsed or refractory B-lineage acute leukemia and highly aggressive lymphoma. Blood 2013 122:1437 2) Che-Leung Law et al. Preclinical characterization of an auristatin-based anti-CD19 drug conjugate, SGN-19A. Abstract number 625. In: Proceedings of the 102th Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Citation Format: Heather A. Van Epps, Kerry Klussman, Martha Anderson, Weiping Zeng, Devra Olson, Maureen Ryan, Tina Albertson, Che-Leung Law. Preclinical results of SGN-CD19A in combination with R-ICE or R-CHOP in non-Hodgkin lymphoma models. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2541. doi:10.1158/1538-7445.AM2015-2541 [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01786135&atom=%2Fcanres%2F75%2F15_Supplement%2F2541.atom

Background CD19, a B cell-specific marker, is expressed in the majority of patients with B-lineage leukemia and non-Hodgkin lymphoma. SGN-CD19A is a novel antibody-drug conjugate (ADC) composed of a humanized anti-CD19 monoclonal antibody conjugated to the microtubule-disrupting agent monomethyl auristatin F (MMAF) via a maleimidocaproyl linker. Methods This first-in-human, phase 1, open-label, dose-escalation study is investigating the safety, tolerability, pharmacokinetics, and antitumor activity of SGN-CD19A in adult and pediatric patients with relapsed or refractory B-cell leukemia or highly aggressive lymphoma (NCT 01786096). Eligible patients must have B-cell acute lymphoblastic leukemia (B-ALL) or lymphoma (B-LBL), Burkitt leukemia or lymphoma, and be relapsed or refractory to at least 1 prior systemic regimen. A modified continual reassessment method is used for dose allocation and maximum tolerated dose (MTD) estimation for both pediatric and adult patients. The study is evaluating 2 schedules of IV SGN-CD19A administration: weekly (Days 1 and 8 of 21-day cycles; 0.3-4.5 mg/kg) or every 3weeks (q3week; 0.5-6 mg/kg). Results To date, 49 patients with relapsed or refractory leukemia (n=40) or lymphoma (n=9) have been treated. Median age of adult (n=38) and pediatric patients (n=11) was 37 and 11 years (range, 18-74 and 1-16), respectively. Patients received a median of 2 prior therapies (range 1-9); 14 patients (29%) previously received an allogeneic stem cell transplant. On the weekly schedule, 39 patients (28 adult, 11 pediatric) have been treated, and the median number of cycles is 2.5 (adults; range, 1-12) or 1 (pediatric; range, 1-4). On the q3week schedule, 10 adult patients have been treated, and the median number of cycles is 2.5 (range, 1-4) to date. Six patients remain on study treatment (3 on each schedule), and enrollment is ongoing. The toxicity profiles were similar across both dosing schedules (0.3-2.3 mg/kg weekly and 4-5 mg/kg q3week) and across adult and pediatric patients. The most frequently reported drug-related AEs included pyrexia, nausea, chills, vomiting, blurred vision, and dry eye. Frequent infusion-related reactions were observed early in the study, and recommendation for premedication was instituted. Ocular events were also observed and treated with ophthalmic steroids; steroid eye drop prophylaxis was instituted with each dose. Corneal findings consistent with superficial microcystic keratopathy were observed in 13 adult patients (34%) and in 1 pediatric patient (9%). Grade 3/4 corneal AEs have been observed in 4 adult patients; the majority of these events have resolved or improved to Grade 1 or 2. Steroid eye drop prophylaxis has reduced the incidence of Grade 3/4 events at this interim analysis. Three DLTs were observed: acidosis in a pediatric patient at 1 mg/kg weekly, cytokine release syndrome in an adult patient at 2 mg/kg weekly, and asymptomatic Grade 4 AST elevation in an adult patient at 5 mg/kg q3week. MTD has not yet been determined. SGN-CD19A ADC pharmacokinetic profiles indicate target-mediated drug disposition in patients with leukemia. Plasma ADC exposures generally increased with doses and were lower than those in patients with lymphoma. To date, no objective responses were observed in 9 efficacy-evaluable pediatric patients or in 3 adult patients with Burkitt lymphoma/leukemia. However, in efficacy-evaluable adult patients with B-ALL/B-LBL, objective responses were observed in 6 of 25 patients treated on the weekly schedule (3 CR, 2 CRp, 1 PR), and in 4 of 8 patients treated on the q3week schedule (2 CR, 2 CRp). Of 8 B-ALL patients with CR/CRp, 6 were MRD negative. Conclusions MTDs have not yet been identified, and dose escalation continues on weekly and q3week schedules. SGN-CD19A has been generally well tolerated. At this interim analysis, objective responses were observed in 30% (10 of 33) of heavily pretreated adult B-ALL/B-LBL patients dosed weekly or q3week. Evidence of activity in relapsed/refractory patients and lack of overlapping toxicities suggest opportunities for combination with conventional anti-leukemic therapies in lymphoblastic malignancies. Disclosures Fathi: Ariad: Consultancy; Exelixis: Research Funding; Takeda pharmaceuticals International Co.: Research Funding; Seattle Genetics, Inc.: Consultancy, Research Funding. Off Label Use: SGN-CD19A is an investigational agent being studied in patients with B-cell malignancies. SGN-CD19A is not approved for use. . Chen:Seattle Genetics, Inc.: Consultancy, Research Funding, Speakers Bureau, Travel expenses Other. Trippett:OSI Pharmaceuticals: Research Funding; Seattle Genetics, Inc.: Research Funding. O'Brien:Seattle Genetics, Inc.: Research Funding. DeAngelo:Seattle Genetics, Inc.: Research Funding. Shah:Pharmacyclics: Consultancy; SWOG: Consultancy; Celgene: Consultancy, Speakers Bureau; NCCN: Consultancy; Seattle Genetics, Inc.: Research Funding; Janssen: Consultancy. Cooper:Seattle Genetics, Inc.: Research Funding. Foran:Seattle Genetics, Inc.: Research Funding. Hale:Seattle Genetics, Inc.: Research Funding. Pressey:Seattle Genetics, Inc.: Research Funding. Silverman:Seattle Genetics, Inc.: Research Funding. Tibes:Seattle Genetics, Inc.: Research Funding. Kim:Bayer: Consultancy; Eli Lily: Consultancy; Seattle Genetics, Inc.: Consultancy, Research Funding. Albertson:Seattle Genetics, Inc.: Employment, Equity Ownership. Sandalic:Seattle Genetics, Inc.: Employment, Equity Ownership. Zhao:Seattle Genetics, Inc.: Employment, Equity Ownership. Borate:Genoptix: Consultancy; Seattle Genetics, Inc.: Research Funding.

Introduction: Positron emission tomography (PET) imaging is a non-invasive tool to quantitatively describe the drug distribution in vivo. To answer the question whether radiolabeled antibody-drug conjugates (ADCs) can be utilized as PET imaging probes, and to explore PET imaging sensitivity for detecting antigen expression, we conducted preclinical microPET/CT imaging studies with radiolabeled SGN-35 in SCID mice bearing tumors with varying levels of CD30 expression. Methods: SGN-35 was either directly labeled with 124Iodine or conjugated with the chelator desferrioxamine (DFO) and subsequently labeled with 89Zirconium. Karpas 299, TF1-α, and Daudi were selected as the representative high (CD30high), low (CD30low) and negative (CD30neg) CD30 expressing tumor cell lines, respectively. Expression of CD30 and receptor copy number on each cell line was confirmed by quantitative FACS assay. One mouse from each CD30 expression group was administered a single IV bolus dose of either 124I-SGN-35 (0.5 mg/kg) or 89Zr-Df-SGN-35 (1 mg/kg), and serially imaged 0 - 2 hours (dynamic scan), and at 4, 24, 48, 72, 96 and 144 hours (10 min static scans). An additional 3 mice with CD30high and CD30low tumors, and 2 mice with CD30neg tumors, were dosed and imaged at 72, 96 and 144 hours (10 min static scans). Blood samples (10 μL) were taken from mice at 0, 4, 24, 48, 72, 96 hours and by cardiac puncture at 144 hours for pharmacokinetic (PK) analysis. Additional mice (n=4 per group) were sacrificed at 72 and 144 hours to determine tissue biodistribution via gamma counting. Results: The elimination of 124I-SGN-35 and 89Zr-Df-SGN-35 followed 2-compartment PK, and the calculated elimination T1/2 was 3.6-3.9 days. In mice bearing CD30high tumors with ∼291,000 CD30 copies per cell, the tumor:blood ratio of 124I-radioactivity after a dose of 124I-SGN-35 fell from 1.24 after 72 hours to 0.78 after 144 hours, whereas after a dose of 89Zr-Df-SGN-35, mean tumor:blood ratio of 89Zr-radioactivity increased from 7.38 at 72 hours to 15.05 (157.5 %ID/g) at 144 hours. The 124I-radioactivity and 89Zr-radioactivity tumor:blood ratio in the CD30neg tumors was 0.2 and 0.5 after 144 hours, respectively. The tumor:blood ratio of 89Zr-radioactivity continued to increase from 0.57 after 72 hours to 0.90 (13.4 %ID/g) at 144 hours after a dose of 89Zr-Df-SGN-35 in TF1-α (CD30low) tumor bearing mice. Conclusions: These results indicate that 89Zr-Df-SGN-35 retains the specific anti-CD30 immune-reactivity and PK of the parent SGN-35 molecule. 89Zr labeling generated superior imaging results compared with 124I labeling. With respect to specificity, a favorable tumor:blood ratio was observed in the CD30high tumor bearing mice in contrast to the lack of accumulation of 89Zr-radioactivity in the CD30 negative tumors. The accumulation of 89Zr-radioactivity in CD30low TF1-α tumors suggests that 89Zr-Df-SGN-35 is a very sensitive CD30 targeted PET/CT imaging agent. Citation Format: Aaron Moss, Jean Gudas, Tina Albertson, Nancy Whiting, Che-Leung Law. Preclinical microPET/CT imaging of 89Zr-Df-SGN-35 in mice bearing xenografted CD30 expressing and non-expressing tumors. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 104. doi:10.1158/1538-7445.AM2014-104

8505 Background: CD19, a member of the immunoglobulin superfamily, is expressed in most patients with B-cell NHL. SGN-CD19A is a novel antibody-drug conjugate composed of a humanized anti-CD19 mono...

Background. CD19 is a member of the immunoglobulin superfamily that regulates B-lineage cell development and differentiation. It is not known to be expressed by any cell outside of the B-lineage and expression is maintained upon malignant transformation. Due to its restricted normal tissue expression profile, CD19 is an attractive target for antibody-based therapeutics for the treatment of B-lineage malignancies. SGN-CD19A is a novel antibody-drug conjugate composed of a humanized anti-CD19 monoclonal antibody conjugated to the microtubule-disrupting agent monomethyl auristatin F (MMAF) via a maleimidocaproyl (mc) linker. Upon binding to CD19, SGN-CD19A internalizes and releases cys-mcMMAF, which binds to tubulin and induces G2/M arrest and apoptosis in the targeted cells. We describe two first-in-human, dose-escalation studies of SGN-CD19A. Methods. The objectives of both studies include evaluation of safety, tolerability, the pharmacokinetic (PK) profile, and antitumor activity of SGN-CD19A in patients with relapsed or refractory B-lineage malignancies. SGN19A-001 will evaluate a weekly (days 1 and 8 of 21-day cycles) and an every 3 week (q3wk) IV dosing schedule in adult and pediatric patient populations with B-lineage acute lymphoblastic leukemia and aggressive lymphoma. SGN19A-002 will enroll adult patients with B-lineage non-Hodgkin lymphoma and will test a q3wk IV dosing schedule. Both trials will employ a modified continual reassessment method (CRM) to estimate the dose-toxicity relationship, estimate the maximum tolerated dose (MTD), and allocate patients to dose levels. Each trial has an additional dose-finding expansion phase that can be initiated to further evaluate multiple doses and schedules to help identify a recommended phase 2 dose based on a utility score that weighs both toxicity and efficacy in different patient populations. The CRM algorithm estimates the efficacy and toxicity of each patient population and disease subgroup by borrowing information across groups (age and disease). Exploratory analyses will include correlation of target (CD19) expression, target saturation, and apoptotic cellular markers with clinical response and clearance of leukemic blasts; dose and PK of SGN-CD19A will also be correlated with target saturation and intracellular levels of cys-mcMMAF. These studies are scheduled to be initiated by late 2012. Expected Results. The CRM design will allow the MTDs to be identified with high probability. As designed, we expect 10 pediatric and/or 20 adult patients to be treated at or around the estimated MTDs during dose escalation. During the dose-finding expansion portions, refined estimates of the MTDs and estimates of antitumor activity at multiple dose levels will provide rationale for the best dosing regimen for future phase 2 trials. Citation Format: Tina M. Albertson, Lali Sandalic, Che-Leung Law, Kristine Broglio, Scott Berry. Phase 1, open-label, dose-escalation studies of SGN-CD19A in patients with relapsed or refractory B-lineage acute leukemia and non-Hodgkin lymphoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2412. doi:10.1158/1538-7445.AM2013-2412

3069 Background: CD30 is commonly expressed in Hodgkin lymphoma (HL), anaplastic large cell lymphoma (ALCL), and testicular embryonal carcinoma. Expression of CD30 in other solid tumors and non-lymphomatous malignancies has been reported but not investigated systematically. CD30 is the target of brentuximab vedotin (Adcetris), an antibody drug conjugate (ADC) that is approved for the treatment of patients with relapsed HL and systemic ALCL after failure of other therapies. A study was initiated to determine the incidence of CD30 expression in non-lymphomatous malignancies and to identify patients who may be candidates for treatment with brentuximab vedotin. Methods: Patients with non-lymphomatous malignancies were eligible for screening if they were relapsed or refractory to previous therapy or had no effective treatment options available. Archived tissue from solid tumors was tested for CD30 expression by immunohistochemistry (IHC); fresh bone marrow or blood samples from multiple myeloma or leukemia patients were tested by flow cytometry. Patients were considered CD30 positive and eligible for a companion treatment protocol with brentuximab vedotin if ≥10% of malignant cells stained positive by IHC or ≥20% by flow cytometry. Results: At this interim analysis, a total of 875 patients have been tested for CD30 expression: 95% had solid tumors, 3% had leukemia, and 2% had multiple myeloma. Twenty-two patients (2.5%) were CD30 positive, including 7 of 94 patients with ovarian cancer (7%), 5 of 20 with melanoma (25%), 2 of 5 with mesothelioma (40%), 1 of 4 with skin squamous cell carcinoma (25%), 2 of 41 with triple negative breast cancer (5%), 1 of 37 with pancreatic cancer (3%), 1 of 26 with small cell lung cancer (4%), and 1 of 3 with anal cancer (33%), and thyroid carcinoma (33%). One patient was identified with CD30-positive mast cell leukemia. In positive patients, the percent of CD30-positive malignant cells varied between 10 and 80%. Conclusions: CD30 expression was observed in multiple types of non-lymphomatous malignancies, thereby identifying additional populations who may be candidates for treatment with a CD30-targeted ADC, such as brentuximab vedotin. A companion clinical trial with brentuximab vedotin is currently ongoing.