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XLSX file - 30K, IC50 concentrations and CD22 expression levels for cell lines.

Antibody–drug conjugates (ADC), potent cytotoxic drugs linked to antibodies via chemical linkers, allow specific targeting of drugs to neoplastic cells. We have used this technology to develop the ADC DCDT2980S that targets CD22, an antigen with expression limited to B cells and the vast majority of non-Hodgkin lymphomas (NHL). DCDT2980S consists of a humanized anti-CD22 monoclonal IgG1 antibody with a potent microtubule-disrupting agent, monomethyl auristatin E (MMAE), linked to the reduced cysteines of the antibody via a protease cleavable linker, maleimidocaproyl-valine-citrulline-p-aminobenzoyloxycarbonyl (MC-vc-PAB). We describe the efficacy, safety, and pharmacokinetics of DCDT2980S in animal models to assess its potential as a therapeutic for the treatment of B-cell malignancies. We did not find a strong correlation between in vitro or in vivo efficacy and CD22 surface expression, nor a correlation of sensitivity to free drug and in vitro potency. We show that DCDT2980S was capable of inducing complete tumor regression in xenograft mouse models of NHL and can be more effective than rituximab plus combination chemotherapy at drug exposures that were well tolerated in cynomolgus monkeys. These results suggest that DCDT2980S has an efficacy, safety, and pharmacokinetics profile that support potential treatment of NHL. Mol Cancer Ther; 12(7); 1255–65. ©2013 AACR.

PDF file - 61K, Supplemental Figure 1. Human, cynomolgus monkey, and rat PBMCs were isolated from whole blood in accordance with BD Vacutainer CPT protocol. Mouse PBMCs were isolated from whole blood by ACK lysis buffer treatment to lyse red blood cells followed by centrifucation to recover PBMCs. Human antibodies were labeled in accordance with the protocol with Zenon Alexa Fluor 647 Human IgG Labeling Kit. Mean fluorescent intensity (MFI) was calculated from the CD20‑positive B cells (human and cynomolgus monkey), CD45RA‑positive B cells (rat), or CD45R‑positive B cells (mouse).

Supplementary Data from Antibodies to TWEAK Receptor Inhibit Human Tumor Growth through Dual Mechanisms

PDF file 155K, Principal component analysis (PCA) of the ten biomarkers provides a biomarker profile for each cell line

Purpose: Targeted therapeutics have significantly changed the outcome for patients diagnosed with cancer. Still, effective therapeutic intervention does not exist for many cancers and much remains to be done. The objective of this study was to identify novel genes that potentially regulate tumor growth, to target these gene products with monoclonal antibodies, and to examine the therapeutic potential of these antibodies.Experimental Design: Using cDNA microarray analysis, we identified genes overexpressed in several solid malignancies. We generated a mouse monoclonal antibody, 19.2.1, and its humanized counterpart, PDL192, to one such target, TweakR (TWEAK receptor, Fn14, TNFRSF12A, CD266), and characterized the antitumor activities in vitro and in mouse xenograft models.Results: Both 19.2.1 (mouse IgG2a) and PDL192 (human IgG1), like TWEAK, the natural ligand of TweakR, inhibited the growth of several TweakR-expressing cancer cell lines in anchorage-dependent and anchorage-independent assays in vitro. Both antibodies showed significant antitumor activity in multiple mouse xenograft models. PDL192 and 19.2.1 also induced antibody-dependent cellular cytotoxicity (ADCC) of cancer cell lines in vitro. A chimeric version of 19.2.1 containing the mouse IgG1 Fc region (19.2.1×G1) exhibited significantly less ADCC than 19.2.1. However, 19.2.1×G1 showed differential activity in vivo, with activity equivalent to 19.2.1 in one model, but significantly less efficacy than 19.2.1 in a second model. These results indicate that PDL192 and 19.2.1 mediate their antitumor effects by signaling through TweakR, resulting in reduced tumor cell proliferation, and by ADCC. Clin Cancer Res; 16(2); 497–508

PDF file 285K, Biomarker validation by Western blot

PDF file 252K, In vivo pharmacodynamic IHC-based biomarker dose-response quantifications

Figure S1. Characterization of SP44 specificity; Figure S2. Relationship of IHC intensity with FACS; Figure S3. Relationship of IHC intensity with mRNA; Figure S4. Representative IHC images; Figure S5 and S6. MET IHC H-scores; Figure S7. Relationship of IHC clinical score with MET copy number; Figure S8. Kaplan-Meier curves of OS according to MET copy number; Figure S9. Relationship of plasma HGF with MET Dx positivity.

PDF file 64K, Unsupervised clustering of the core biomarker modulation in cell lines, xenograft tumors, and in tumors from three patients in the 100mg cohort

PDF file 168K, Pearson and Spearman correlation with survival fraction for all cell lines together or individual cell lines

Purpose: Trastuzumab-emtansine (T-DM1) is an antibody–drug conjugate (ADC) comprising the cytotoxic agent DM1 conjugated to trastuzumab with a stable linker. Thrombocytopenia was the dose-limiting toxicity in the phase I study, and grade ≥3 thrombocytopenia occurred in up to 13% of patients receiving T-DM1 in phase III studies. We investigated the mechanism of T-DM1–induced thrombocytopenia.Experimental Design: The effect of T-DM1 on platelet function was measured by aggregometry, and by flow cytometry to detect the markers of activation. The effect of T-DM1 on differentiation and maturation of megakaryocytes (MK) from human hematopoietic stem cells was assessed by flow cytometry and microscopy. Binding, uptake, and catabolism of T-DM1 in MKs, were assessed by various techniques including fluorescence microscopy, scintigraphy to detect T-[H3]-DM1 and 125I-T-DM1, and mass spectrometry. The role of FcγRIIa was assessed using blocking antibodies and mutant constructs of trastuzumab that do not bind FcγR.Results: T-DM1 had no direct effect on platelet activation and aggregation, but it did markedly inhibit MK differentiation via a cytotoxic effect. Inhibition occurred with DM1-containing ADCs but not with trastuzumab demonstrating a role for DM1. MKs internalized these ADCs in a HER2-independent, FcγRIIa-dependent manner, resulting in intracellular release of DM1. Binding and internalization of T-DM1 diminished as MKs matured; however, prolonged exposure of mature MKs to T-DM1 resulted in a disrupted cytoskeletal structure.Conclusions: These data support the hypothesis that T-DM1–induced thrombocytopenia is mediated in large part by DM1-induced impairment of MK differentiation, with a less pronounced effect on mature MKs. Clin Cancer Res; 21(1); 123–33. ©2014 AACR.

XLS file 37K, RPPA quantification of laser captured microscopy needle biopsies in patients from the 100mg cohort

Purpose: The oncogenic PI3K/Akt/mTOR pathway is an attractive therapeutic target in cancer. However, it is unknown whether the pathway blockade required for tumor growth inhibition is clinically achievable. Therefore, we conducted pharmacodynamic studies with GDC-0068, an ATP competitive, selective Akt1/2/3 inhibitor, in preclinical models and in patients treated with this compound.Experimental Design: We used a reverse phase protein array (RPPA) platform to identify a biomarker set indicative of Akt inhibition in cell lines and human-tumor xenografts, and correlated the degree of pathway inhibition with antitumor activity. Akt pathway activity was measured using this biomarker set in pre- and post-dose tumor biopsies from patients treated with GDC-0068 in the dose escalation clinical trial.Results: The set of biomarkers of Akt inhibition is composed of 10 phosphoproteins, including Akt and PRAS40, and is modulated in a dose-dependent fashion, both in vitro and in vivo. In human-tumor xenografts, this dose dependency significantly correlated with tumor growth inhibition. Tumor biopsies from patients treated with GDC-0068 at clinically achievable doses attained a degree of biomarker inhibition that correlated with tumor growth inhibition in preclinical models. In these clinical samples, compensatory feedback activation of ERK and HER3 was observed, consistent with preclinical observations.Conclusion: This study identified a set of biomarkers of Akt inhibition that can be used in the clinical setting to assess target engagement. Here, it was used to show that robust Akt inhibition in tumors from patients treated with GDC-0068 is achievable, supporting the clinical development of this compound in defined patient populations. Clin Cancer Res; 19(24); 6976–86. ©2013 AACR.

Table S1. Overlap of biomarkers measured in OAM4558g; Table S2. Primer/probe information; Table S3. MET diagnostic scoring criteria; Table S4. MET IHC intratumoral heterogeneity; Table S5. Impact of KRAS/EGFR mutation on clinical outcome; Table S6. Biomarker status in EGFR-mutant patients; Table S7. Association of transcript expression with PFS in OAM4558g.

PDF file 161K, Tumor PIK3CA and PTEN status

XLS file 41K, RPPA biomarkers

XLS file 38K, Single-biomarker tumor growth inhibition projection

Purpose: In a recent phase II study of onartuzumab (MetMAb), patients whose non–small cell lung cancer (NSCLC) tissue scored as positive for MET protein by immunohistochemistry (IHC) experienced a significant benefit with onartuzumab plus erlotinib (O+E) versus erlotinib. We describe development and validation of a standardized MET IHC assay and, retrospectively, evaluate multiple biomarkers as predictors of patient benefit.Experimental Design: Biomarkers related to MET and/or EGF receptor (EGFR) signaling were measured by IHC, FISH, quantitative reverse transcription PCR, mutation detection techniques, and ELISA.Results: A positive correlation between IHC, Western blotting, and MET mRNA expression was observed in NSCLC cell lines/tissues. An IHC scoring system of MET expression taking proportional and intensity-based thresholds into consideration was applied in an analysis of the phase II study and resulted in the best differentiation of outcomes. Further analyses revealed a nonsignificant overall survival (OS) improvement with O+E in patients with high MET copy number (mean ≥5 copies/cell by FISH); however, benefit was maintained in “MET IHC-positive”/MET FISH-negative patients (HR, 0.37; P = 0.01). MET, EGFR, amphiregulin, epiregulin, or HGF mRNA expression did not predict a significant benefit with onartuzumab; a nonsignificant OS improvement was observed in patients with high tumor MET mRNA levels (HR, 0.59; P = 0.23). Patients with low baseline plasma hepatocyte growth factor (HGF) exhibited an HR for OS of 0.519 (P = 0.09) in favor of onartuzumab treatment.Conclusions: MET IHC remains the most robust predictor of OS and progression-free survival benefit from O+E relative to all examined exploratory markers. Clin Cancer Res; 20(17); 4488–98. ©2014 AACR.

Additional methodology describing cell lines and tissues, as well as detailed methodology for gene expression, flow cytometry, IHC and FISH studies.

Supplementary Methods, Figures S1-S7 Suppl. Fig. S1, Differentiation of hematopoietic stem cells (CD133+/CD34+) into immature megakarytocytes Suppl. Fig. S2, T-DM1 does not directly induce platelet aggregation in washed platelets Suppl. Fig. S3, At high concentrations, DM1 inhibits agonist-induced platelet aggregation in platelet-rich plasma Suppl. Fig. S4, DM1 conjugates alter the morphology of megakaryocytes Suppl. Fig. S5, Uptake of T-[3H]DM1 varies by differentiation stage Suppl. Fig. S6, HER2 is not expressed on megakaryocytes or platelets Suppl. Fig. S7, Prolonged exposure to T-DM1 results in disruption of cytoskeletal structure in maturing megakaryocytes

PDF file 117K, Supplementary Materials and Methods -Supplementary Figure Legends -Supplementary Table Legends

E-cadherin loss is frequently associated with ovarian cancer metastasis. Given that adhesion to the abdominal peritoneum is the first step in ovarian cancer dissemination, we reasoned that down-regulation of E-cadherin would affect expression of cell matrix adhesion receptors. We show here that inhibition of E-cadherin in ovarian cancer cells causes up-regulation of α5-integrin protein expression and transcription. When E-cadherin was blocked, RMUG-S ovarian cancer cells were able to attach and invade more efficiently. This greater efficiency could, in turn, be inhibited both in vitro and in vivo with an α5β1-integrin–blocking antibody. When E-cadherin is silenced, α5-integrin is up-regulated through activation of an epidermal growth factor receptor/FAK/Erk1–mitogen-activated protein kinase–dependent signaling pathway and not through the canonical E-cadherin/β-catenin signaling pathway. In SKOV-3ip1 ovarian cancer xenografts, which express high levels of α5-integrin, i.p. treatment with an α5β1-integrin antibody significantly reduced tumor burden, ascites, and number of metastasis and increased survival by an average of 12 days when compared with IgG treatment (P < 0.0005). α5-Integrin expression was detected by immunohistochemistry in 107 advanced stage ovarian cancers using a tissue microarray annotated with disease-specific patient follow-up. Ten of 107 tissues (9%) had α5-integrin overexpression, and 39% had some level of α5-integrin expression. The median survival for patients with high α5-integrin levels was 26 months versus 35 months for those with low integrin expression (P < 0.05). Taken together, we have identified α5-integrin up-regulation as a molecular mechanism by which E-cadherin loss promotes tumor progression, providing an explanation for how E-cadherin loss increases metastasis. Targeting this integrin could be a promising therapy for a subset of ovarian cancer patients. [Cancer Res 2008;68(7):2329–39]

Supplementary Figures 1-4 from Loss of E-Cadherin Promotes Ovarian Cancer Metastasis via α5-Integrin, which Is a Therapeutic Target

Utilising tissue whole exome sequencing (WES) and circulating tumor cell-free DNA (ctDNA), this Australasian Leukaemia & Lymphoma Group (ALLG) translational study sought to characterise primary and acquired molecular determinants of response and resistance of MZL to zanubrutinib for patients treated on the MAGNOLIA clinical trial. WES was performed on baseline tumor samples obtained from 18 patients. For seven patients, ctDNA was interrogated using a bespoke hybrid-capture next-generation sequencing (NGS) assay for 48 targeted genes. Somatic mutations were correlated with objective response data and survival analysis using Fisher's exact test and Kaplan-Meier (log-rank) method respectively. Baseline WES identified mutations in 33/48 (69%) prioritised genes. NFkB, NOTCH or BCR pathway genes were implicated in samples for 16/18 (89%) patients. KMT2D mutations (n=11) were most common followed by FAT1 (n=9), NOTCH1, NOTCH2, TNFAIP3 (n=5) and MYD88 (n=4). MYD88 or TNFAIP3 mutations correlated with improved PFS (not reached (NR) vs 11.1 months, p: 0.008, HR: 0.09, 95% CI: 0.01-0.52); KMT2D mutations trended to worse PFS (PFS: 13.40 months vs NR, p: 0.05, HR 6.5, 95%CI: 1.00-37.78). Acquired resistance mutations PLCG2 (R665W/R742P) and BTK (C481Y/C481F) were detected in two patients whose disease progressed. A BTK E41K non-catalytic activating mutation was identified prior to treatment in one zanubrutinib-refractory patient. MYD88, TNFAIP3 and KMT2D mutations correlate with PFS in patients with rrMZL treated with zanubrutinib. Detection of acquired BTK and PLCG2 mutations in ctDNA while on therapy is feasible and may herald clinical disease progression. This trial was registered at https://anzctr.org.au/ as ACTRN12619000024145.

T cells have a unique capability to eliminate cancer cells and fight malignancies. Cancer cells have adopted multiple immune evasion mechanisms aimed at inhibiting T cells. Dramatically improved patient outcomes have been achieved with therapies genetically reprogramming T cells, blocking T-cell inhibition by cancer cells, or transiently connecting T cells with cancer cells for redirected lysis. This last modality is based on antibody constructs that bind a surface antigen on cancer cells and an invariant component of the T-cell receptor. Although high response rates were observed with T-cell engagers specific for CD19, CD20, or BCMA in patients with hematologic cancers, the treatment of solid tumors has been less successful. Here, we developed and characterized a novel T-cell engager format, called TriTAC (for Trispecific T-cell Activating Construct). TriTACs are engineered with features to improve patient safety and solid tumor activity, including high stability, small size, flexible linkers, long serum half-life, and highly specific and potent redirected lysis. The present study establishes the structure/activity relationship of TriTACs and describes the development of HPN424, a PSMA- (FOLH1-) targeting TriTAC in clinical development for patients with metastatic castration-resistant prostate cancer.

537 Background: Tislelizumab, a humanized monoclonal antibody that targets programmed cell death protein 1 (PD-1), has shown promising activity in the treatment of advanced urothelial bladder cancer (UBC). Recent studies suggest that liver metastases (LM) are associated with reduced effectiveness of PD-1/PD-L1 therapies (Yu, et al. Nat Med. 2021;27[1]:152-164). We evaluated how LM correlate with survival outcomes and the tumor immune microenvironment in UBC patients treated with tislelizumab in the BGB-A317-204 trial (NCT04004221). Methods: Cox regression was used to evaluate the effect of LM on overall survival (OS). Other key baseline characteristics were further included as covariates in the model to investigate the adjusted effect of LM and the interactions of LM with them. Gene expression profiling and multiplex immunohistochemistry (mIHC) analysis were performed on baseline tumor samples. Gene expression differences between LM positive (LM+) and LM negative (LM–) patients were compared by Wilcoxon rank-sum test for continuous biomarkers, and Fisher’s exact test for categorical biomarkers. All P-values reported in this post-hoc exploratory analysis were descriptive, without multiplicity adjustment. A result of P

Patients with chronic lymphocytic leukemia or small lymphocytic lymphoma whose tumors carry deletion of chromosome 17p13.1 [del(17p)] have an unfavorable prognosis and respond poorly to standard chemoimmunotherapy. Zanubrutinib is a selective next-generation Bruton tyrosine kinase inhibitor. We evaluated the safety and efficacy of zanubrutinib 160 mg twice daily in treatment-naïve patients with del(17p) disease enrolled in a dedicated, nonrandomized cohort (Arm C) of the phase 3 SEQUOIA trial. A total of 109 patients (median age, 70 years; range, 42 – 86) with centrally confirmed del(17p) were enrolled and treated. After a median of 18.2 months (range, 5.0 – 26.3), seven patients had discontinued study treatment due to progressive disease, four due to an adverse event, and one due to withdrawal of consent. The overall response rate was 94.5% with 3.7% of patients achieving complete response with or without incomplete hematologic recovery. The estimated 18-month progression-free survival rate was 88.6% (95% CI, 79.0 – 94.0) and the estimated 18-month overall survival rate was 95.1% (95% CI, 88.4 – 98.0). Most common all-grade adverse events included contusion (20.2%), upper respiratory tract infection (19.3%), neutropenia/neutrophil count decreased (17.4%), and diarrhea (16.5%). Grade ≥ 3 adverse events were reported in 53 patients (48.6%), most commonly neutropenia (12.9%) and pneumonia (3.7%). An adverse event of atrial fibrillation was reported in three patients (2.8%). Zanubrutinib was active and well tolerated in this large, prospectively enrolled treatment cohort of previously untreated patients with del(17p) chronic lymphocytic leukemia/small lymphocytic lymphoma. This trial was registered at ClinicalTrials.gov as #NCT03336333.

Background: Zanubrutinib is a selective next-generation Bruton tyrosine kinase (BTK) inhibitor designed to have high specificity for BTK and minimize off-target effects (J Med Chem 2019;62:7923-40). Data from several phase 2 CLL trials assessing BCL-2 and BTK inhibitor combination treatment suggested that undetectable minimal residual disease (uMRD)-driven fixed-duration combination treatment was tolerable and enabled durable responses after treatment discontinuation (JAMA Oncol 2021;1649.; EHA 2021 S147). However, a limited number of patients with the high-risk feature, deletion of chromosome 17p13.1 [del(17p)], have been included in these studies. Preliminary data from Arm C of the SEQUOIA trial suggested that zanubrutinib monotherapy was active (18-mo progression-free survival: 90.6%) and well-tolerated in CLL/SLL patients with del(17p) (ASH 2020 1306). Here, we present early results for patients with TN del(17p) CLL/SLL receiving zanubrutinib + venetoclax in Arm D of the SEQUOIA trial (NCT03336333). Methods: SEQUOIA is an open-label, global, multicenter, phase 3 study that includes a nonrandomized cohort (Arm D) of patients with TN del(17p) CLL/SLL (Blood 2020;136 [supplement 1]:24-5). Patients in Arm D were treated with zanubrutinib (160 mg twice daily) for 3 mos followed by zanubrutinib (same dosing) + venetoclax (ramp-up cycle followed by 400 mg once daily) combination treatment for 12-24 cycles until progressive disease (PD), unacceptable toxicity, or achievement of uMRD at 7% aberrant nuclei present. Initial safety and tolerability of zanubrutinib + venetoclax was assessed, including the risk of tumor lysis syndrome (TLS) both at baseline and prior to initiation of venetoclax. Responses for CLL and SLL were investigator-assessed per modified iwCLL criteria (Blood 2008;111:5446-56; J Clin Oncol 2012;30:2820-2) and Lugano criteria (J Clin Oncol 2014;32:3059-68), respectively. Bone marrow exams to confirm a suspected complete response (CR) or CR with incomplete hematological recovery were required starting at the end of Cycle 9. Results: As of 1 JUN 2021 (data cutoff), 35 of approximately 80 planned patients with centrally confirmed del(17p) were enrolled. Median follow-up was 9.7 mos. In the safety analysis population (n=35), 94.3% had CLL and high-risk characteristics including Binet stage C (51.5%), bulky disease ≥5 cm (42.9%), unmutated immunoglobulin heavy chain variable locus (85.3%, n=34), median del(17p) frequency of 81.5%, and elevated β 2-microglobulin (71.4%). At data cutoff, 29 patients had started combination therapy and 27 patients completed ramp-up venetoclax dosing. Thirty-two patients remained on study treatment and 3 patients ended treatment due to withdrawal of consent, PD, or adverse event (AE of lung cancer), all n=1. The patient with lung cancer had lung nodules present at screening and died due to lung adenocarcinoma. AEs and serious AEs were reported in 29 patients (82.9%) and 4 patients (11.4%), respectively. AEs reported in ≥10% of patients included diarrhea (n=5), neutropenia (n=5), fatigue (n=4), nausea (n=4), and petechiae (n=4). Thirteen patients (37.1%) had grade ≥3 AEs; most frequently neutropenia (n=4) and diarrhea (n=2). One patient with ongoing grade 2 atrial fibrillation at baseline reported grade 3 atrial fibrillation on study. To date, no AEs of TLS have been reported. At baseline, the TLS risk categories were high, medium, and low in 12 (34.3%), 22 (62.9%), and 1 (2.9%) patients, compared with 0 (0%), 21 (67.7%), and 10 (32.3%) patients, respectively, prior to initiation of venetoclax. For the 31 patients who reached the initial efficacy assessment at 3 mos after starting zanubrutinib, the overall response rate was 96.8% (30/31); one patient reported PD after having an initial partial response while on combination therapy. Conclusion: Preliminary safety data with the 9.7-mo median follow-up suggest that zanubrutinib + venetoclax was generally well tolerated in this high-risk population, with no new safety signals identified and no TLS reported. Enrollment is ongoing; updated safety, efficacy, and biomarker data will be presented. Figure 1 Figure 1. Disclosures Tedeschi: AbbVie: Honoraria, Other: Advisory Board and Travel, Accommodations, Expenses, Speakers Bureau; Janssen: Honoraria, Other: Advisory Board and Travel, Accommodations, Expenses, Speakers Bureau; BeiGene: Honoraria, Other: Advisory Board, Speakers Bureau; AstraZeneca: Honoraria, Other: Advisory Board, Speakers Bureau. Ferrant: Janssen: Other: Travel, Accommodations, Expenses; AbbVie: Honoraria, Other: Travel, Accommodations, Expenses; AstraZeneca: Honoraria. Flinn: Calithera Biosciences: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Celgene: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Triphase Research & Development Corp.: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Agios: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Portola Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; ArQule: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Genentech: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Juno Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Kite, a Gilead Company: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Teva: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Incyte: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; BeiGene: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Forty Seven: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; AbbVie: Consultancy, Other: All Consultancy and Research Funding payments made to Sarah Cannon Research Institute, Research Funding; Janssen: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Yingli Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Loxo: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Great Point Partners: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Rhizen Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Pfizer: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Trillium Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Roche: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Verastem: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Takeda: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; TG Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Nurix Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Gilead Sciences: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Novartis: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Forma Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Seagen: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; IGM Biosciences: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; AstraZeneca: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Unum Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; MorphoSys: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Karyopharm Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Infinity Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Merck: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Constellation Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Curis: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Acerta Pharma: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Iksuda Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Century Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Hutchison MediPharma: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Vincerx Pharma: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Sarah Cannon Research Institute: Current Employment; Servier Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Yingli Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Seagen: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Servier Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Unum Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute, Research Funding; Johnson & Johnson: Current holder of individual stocks in a privately-held company; Seattle Genetics: Research Funding. Tam: Roche: Consultancy, Honoraria; Novartis: Honoraria; Pharmacyclics: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Loxo: Consultancy; AbbVie: Consultancy, Honoraria, Research Funding; BeiGene: Consultancy, Honoraria. Ghia: Acerta/AstraZeneca: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; ArQule/MSD: Consultancy, Honoraria; Celgene/Juno/BMS: Consultancy, Honoraria; BeiGene: Consultancy, Honoraria; Gilead: Consultancy, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria; Sunesis: Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding. Robak: Biogen, Abbvie, Octapharma, Janssen: Honoraria, Other: Advisory board; AstraZeneca, Abbvie, Janssen, Octapharma, Gilead,Oncopeptides AB, Pharmacyclics, Pfizer, GlaxoSmithKline, Biogen: Research Funding; Medical University of Lodz: Current Employment. Brown: MEI Pharma: Consultancy; Bristol-Myers Squib/Juno/Celegene: Consultancy; Pfizer: Consultancy; Abbvie: Consultancy; Sun: Research Funding; Gilead: Research Funding; Rigel: Consultancy; Catapult: Consultancy; Eli Lilly and Company: Consultancy; Genentech/Roche: Consultancy; Novartis: Consultancy; Invectys: Other: Data Safety Monitoring Committee Service; Beigene: Consultancy; Nextcea: Consultancy; Morphosys AG: Consultancy; TG Therapeutics: Research Funding; Acerta/Astra-Zeneca: Consultancy; Janssen: Consultancy; SecuraBio: Research Funding; Loxo/Lilly: Research Funding. Ramakrishnan: BeiGene: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months, Other: Travel, Accommodations, Expenses. Tian: AbbVie: Ended employment in the past 24 months; BeiGene: Current Employment. Kuwahara: BeiGene: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Paik: BeiGene USA, Inc.: Current Employment, Current equity holder in publicly-traded company. Cohen: BeiGene: Current Employment, Current equity holder in publicly-traded company, Other: Travel, Accommodations, Expenses. Huang: BeiGene: Current Employment, Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company, Divested equity in a private or publicly-traded company in the past 24 months, Other: Travel, Accommodations, Expenses; Protara Therapeutics: Current holder of individual stocks in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Hillmen: BeiGene: Honoraria; Janssen: Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; AbbVie: Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Pharmacyclics: Honoraria, Research Funding; Roche: Research Funding; Gilead: Research Funding; AstraZeneca: Honoraria; SOBI: Honoraria. OffLabel Disclosure: Zanubrutinib is an investigational agent and has not been approved for TN del(17p) CLL/SLL in the US

Background: Patients (pts) with CLL/SLL whose tumor exhibits the deletion of chromosome 17p13.1 [del(17p)] have an unfavorable prognosis and respond poorly to standard chemoimmunotherapy. Zanubrutinib (BGB-3111) is an investigational, next-generation Bruton tyrosine kinase (BTK) inhibitor. In the ASPEN study of pts with Waldenström macroglobulinemia, zanubrutinib was associated with important safety advantages compared to ibrutinib, especially regarding cardiovascular toxicity (Blood; in press). The initial results from Arm C of the SEQUOIA (BGB-3111-304) trial of zanubrutinib in a large cohort of TN CLL/SLL pts with del(17p) were recently presented with a median follow-up of 10 months (Blood 2019;134:851). Presented here is an updated analysis for safety and efficacy in this cohort. Methods : The SEQUOIA trial (NCT03336333) is an open-label, global, multicenter, phase 3 study that includes a nonrandomized cohort (Arm C) of TN pts with del(17p) CLL/SLL treated with zanubrutinib (160 mg twice daily). Adult pts with CLL/SLL who met International Workshop on CLL (iwCLL) criteria for treatment (Blood 2008;111:5446) were eligible if they were aged ≥65 y or unsuitable for treatment with fludarabine, cyclophosphamide, and rituximab. Use of long-term anticoagulation was permitted. Central verification of del(17p) by fluorescence in situ hybridization with a minimum of 7% aberrant nuclei present was required for entry into Arm C. Response was evaluated by investigator for CLL per modified iwCLL criteria (Blood 2008;112:5259; J Clin Oncol. 2012;30:2820) and for SLL per Lugano criteria (J Clin Oncol. 2014;32:3059). Results : As of 15 Apr 2020 (data cutoff), median follow-up was 18.2 mo (range, 5.0-26.3) for the 109 pts enrolled; 97 pts (89.0%) remained on treatment with zanubrutinib. The best overall response rate (ORR) was 94.5% (3.7% complete response [CR] or CR with incomplete bone marrow recovery, 87.2% partial response [PR], 3.7% PR with lymphocytosis, 4.6% stable disease, 0.9% progressive disease). Five pts (4.6%) met clinical CR criteria but did not undergo bone marrow biopsy. Median progression-free survival (PFS), duration of response (DoR), and overall survival (OS) were not reached. Estimated 18-mo PFS (Figure), 18-mo DoR, and 18-mo OS were 88.6% (95% CI, 79.0-94.0), 84.0% (95% CI, 67.5-92.6), and 95.1% (95% CI, 88.4-97.9), respectively. Investigator-reported transformation occurred in 5 pts (4.6%), of whom 4 had histologic confirmation. Median time to transformation was 13.6 mo (time to transformation for each pt: 3.9, 7.0, 13.6, 13.8, and 15.7 mo). In an exploratory analysis, 37.2% and 26.7% of pts with evaluable karyotypes had at least 3 or 5 distinct karyotypic abnormalities, respectively; no differences in ORR or PFS were observed between pts with or without complex karyotype. With extended follow-up, adverse events (AEs) reported in ≥10% of treated pts included contusion (20.2%), upper respiratory tract infection (19.3%), neutropenia/neutrophil count decreased (17.4%), diarrhea (16.5%), nausea (14.7%), constipation (13.8%), rash (13.8%), back pain (12.8%), cough (11.9%), arthralgia (11.0%), and fatigue (10.1%). Grade ≥3 AEs occurring in >2% of pts included neutropenia/neutrophil count decreased (12.9%) and pneumonia (3.7%). AEs of interest (pooled terms) included infections (64.2%), bleeding (47.7%; 5.5% grade ≥3 or serious), headache (8.3%), hypertension (8.3%), and myalgia (4.6%). Skin tumors were reported in 9.2%, and non-skin second malignancies were reported in 4.6% of pts. Three pts (2.8%) reported an AE of atrial fibrillation or flutter of which 2 events occurred in the setting of sepsis. Four pts (3.7%) discontinued zanubrutinib due to AEs (including pneumonia, sepsis secondary to Pseudomonas, melanoma, and acute kidney injury [in the context of disease progression]), of which 2 pts have died. Three additional pts died, 2 due to disease progression and 1 from sepsis after progression. No sudden or unknown deaths were reported. Conclusions : Extended follow-up of zanubrutinib monotherapy in TN CLL/SLL pts with del(17p) showed the durability of responses in this high-risk cohort, with an estimated 18-mo PFS of 88.6% and estimated 18-mo OS of 95.1%. Zanubrutinib was generally well tolerated, with low rates of discontinuation due to AEs. These data support the potential utility of zanubrutinib in the frontline management of pts with high-risk disease. Disclosures Brown: TG Therapeutics: Consultancy; Sunesis: Consultancy; MEI Pharma: Consultancy; Nextcea: Consultancy; Novartis: Consultancy; Octapharma: Consultancy; Pfizer: Consultancy; Rigel Pharmaceuticals: Consultancy; Verastem: Consultancy, Research Funding; Kite: Consultancy; Acerta: Consultancy; Genentech: Consultancy; Pharmacyclics: Consultancy; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other; Sun: Research Funding; Loxo: Consultancy, Research Funding; Dynamo Therapeutics: Consultancy; Catapult: Consultancy; BeiGene: Consultancy; Gilead: Consultancy, Research Funding; Invectys: Membership on an entity's Board of Directors or advisory committees, Other: DSMC; Eli Lilly and Company: Consultancy; Astra-Zeneca: Consultancy; Janssen: Honoraria; AbbVie: Consultancy; Juno/Celgene: Consultancy. Robak:Bristol Meyers Squibb: Research Funding; Sandoz: Consultancy, Honoraria; Pfizer: Research Funding; Momenta: Consultancy; UCB: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; Octapharma: Honoraria; BioGene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Roche: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Acerta: Research Funding; GSK: Research Funding; Medical University of Lodz: Current Employment; Morphosys: Research Funding; AbbVie: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Takeda: Consultancy; UTX-TGR: Research Funding; Pharmacyclics LLC, an AbbVie Company: Honoraria, Research Funding. Ghia:Novartis: Research Funding; ArQule: Consultancy, Honoraria; Acerta/AstraZeneca: Consultancy, Honoraria; BeiGene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Celgene/Juno: Consultancy, Honoraria; Lilly: Consultancy, Honoraria; MEI: Consultancy, Honoraria; Sunesis: Consultancy, Honoraria, Research Funding; Adaptive, Dynamo: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Gilead: Consultancy, Honoraria, Research Funding. Kahl:ADC Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Consultancy; Pharmacyclics LLC: Consultancy; Roche Laboratories Inc: Consultancy; Celgene Corporation: Consultancy; AbbVie: Consultancy; AstraZeneca Pharmaceuticals LP: Consultancy, Membership on an entity's Board of Directors or advisory committees; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Acerta: Consultancy, Research Funding. Walker:Alfred health: Current Employment; Peninsula Health: Current Employment; Roche: Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Janowski:Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy. Chan:Amgen: Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company); Janssen: Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding, Speakers Bureau; AbbVie: Membership on an entity's Board of Directors or advisory committees; Roche: Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company); Celgene: Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company). Shadman:AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sound Biologics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellectar: Consultancy, Membership on an entity's Board of Directors or advisory committees; Atara Biotherapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sunesis: Research Funding; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Meyers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees; Mustang Bio: Research Funding; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Acerta Pharma: Ended employment in the past 24 months; Gilead: Research Funding; MophoSys: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; TG therapeutics: Research Funding. Laurenti:Roche: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: 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. Opat:F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZenca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL Behring: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Epizyme: Research Funding. Ciepluch:Copernicus Wojewodzkie centrum Onkologii: Current Employment. Verner:Cilag Pty Ltd: Research Funding; Concord Repatriation General Hospital: Current Employment; Janssen: Research Funding. Šimkovič:University Hospital Hradec Kralove: Current Employment; Acerta Pharma: Consultancy; Gilead Sciences: Consultancy, Other: Travel, Accommodations, Expenses; Janssen-Cilag: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Speakers Bureau. Österborg:Sanofi: Consultancy; Kancera: Current equity holder in publicly-traded company, Research Funding; BeiGene: Research Funding; Karolinska Univeristy Hospital, Stockholm, Sweden: Current Employment. Trněný:Takeda: Consultancy, Honoraria, Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company); Amgen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); 1st Faculty of Medicine, Charles University, General Hospital in Prague: Current Employment; MorphoSys: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Bristol Meyers Squibb: Consultancy, Honoraria, Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company); Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Gilead Sciences: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Celgene: Consultancy. Tedeschi:BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen spa: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sunesis: Consultancy; Department of Hematology Niguarda Hospital Milano: Current Employment. Blombery:Invivoscribe: Honoraria; Janssen: Honoraria; Amgen: Consultancy; Novartis: Consultancy. Paik:BeiGene: Current Employment, Current equity holder in publicly-traded company. Yin:BeiGene: Current Employment, Current equity holder in publicly-traded company; Arcus Biosciences: Current equity holder in publicly-traded company; Cornell University: Patents & Royalties: A genetically modified mouse model, licensed to pharmaceutical companies. Feng:BeiGene: Current Employment, Current equity holder in publicly-traded company. Ramakrishnan:BeiGene: Current Employment, Current equity holder in publicly-traded company. Huang:BeiGene: Current Employment, Current equity holder in publicly-traded company, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Hillmen:F. Hoffmann-La Roche: Honoraria, Research Funding; Astra Zeneca: Honoraria; Gilead: Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding, Speakers Bureau; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding, Speakers Bureau; Pharmacyclics: Research Funding. Tam:BeiGene: Honoraria; AbbVie: Honoraria, Research Funding; Janssen: Honoraria, Research Funding. OffLabel Disclosure: Zanubrutinib has not been approved for TN CLL/SLL with del(17p) in the US

Pamiparib, an investigational, oral PARP 1/2 inhibitor, demonstrated preclinical brain penetration and synergistic cytotoxicity with TMZ. We report updated safety and antitumor data for pamiparib plus RT and/or TMZ in ND-GBM or R/R-GBM (SNO 2019, ACTR-39). This dose-escalation/expansion study includes three arms: A, pamiparib (2, 4, or 6 weeks) plus RT (6–7 weeks) in ND-GBM with unmethylated MGMT promoter (unmethylated-GBM); B, pamiparib (6 weeks) plus RT and increasing TMZ doses in Weeks 1 and 5 of RT in unmethylated ND-GBM; and C, pamiparib plus increasing TMZ doses in methylated/unmethylated R/R-GBM. Most patients in Arms A (expansion) and B received maintenance pamiparib plus TMZ after post-RT rest period at Arm C expansion. As of April 10, 2020, enrollment was complete (N=116; A, n=60; B, n=9; C, n=47). Median study follow-up was 11.3 mo (A/B) and 7.1 mo (C). Common grade ≥3 AEs were anemia (10%) in Arm A; decreased neutrophil and white blood cell count (each 22%) in B; anemia, fatigue, and decreased lymphocyte count (each 11%) in C. Brain edema (A) and pneumonia (C) (n=1 each) were fatal treatment-unrelated AEs. In ND-GBM, modified disease control rate (DCR following post-RT rest period) was 69.8% (95% CI, 55.7–81.7) overall, 68.8% (50.0–83.9) in A, and 80.0% (28.4–99.5) in B. Median duration of response was 5.1 mo (overall), 3.8 mo (A), and NE (B). In Arms A/B, median progression-free survival (PFS) and median overall survival (OS) were 4.4 mo and 12.7 mo, respectively; 12-mo OS rate, 54% (95% CI, 40–66). In R/R-GBM (Arm C), confirmed ORR was 9.1% (95% CI, 2.5–21.7); median PFS and OS were 1.9 mo and 7.3 mo, respectively; 6-mo PFS rate, 19% (95% CI, 9–32). These results showed a manageable safety profile for pamiparib +/- RT +/-TMZ; response and survival results support further evaluation of these combinations in GBM.

FcRH5 is a cell surface marker enriched on malignant plasma cells when compared to other hematologic malignancies and normal tissues. DFRF4539A is an anti-FcRH5 antibody-drug conjugated to monomethyl auristatin E (MMAE), a potent anti-mitotic agent. This phase I study assessed safety, tolerability, maximum tolerated dose (MTD), anti-tumor activity, and pharmacokinetics of DFRF4539A in patients with relapsed/refractory multiple myeloma. DFRF4539A was administered at 0.3–2.4 mg/kg every 3 weeks or 0.8–1.1 mg/kg weekly as a single-agent by intravenous infusion to 39 patients. Exposure of total antibody and antibody-conjugate-MMAE analytes was linear across the doses tested. There were 37 (95%) adverse events (AEs), 8 (21%) serious AEs, and 15 (39%) AEs ≥ grade 3. Anemia (n = 10, 26%) was the most common AE considered related to DFRF4539A. Two cases of grade 3 acute renal failure were attributed to DFRF4539A. There were no deaths; the MTD was not reached. DFRF4539A demonstrated limited activity in patients at the doses tested with 2 (5%) partial response, 1 (3%) minimal response, 18 (46%) stable disease, and 16 (41%) progressive disease. FcRH5 was confirmed to be expressed and occupied by antibody post-treatment and thus remains a valid myeloma target. Nevertheless, this MMAE-based antibody-drug-conjugate targeting FcRH5 was unsuccessful for myeloma.

Purpose: In a recent phase II study of onartuzumab (MetMAb), patients whose non–small cell lung cancer (NSCLC) tissue scored as positive for MET protein by immunohistochemistry (IHC) experienced a significant benefit with onartuzumab plus erlotinib (O+E) versus erlotinib. We describe development and validation of a standardized MET IHC assay and, retrospectively, evaluate multiple biomarkers as predictors of patient benefit. Experimental Design: Biomarkers related to MET and/or EGF receptor (EGFR) signaling were measured by IHC, FISH, quantitative reverse transcription PCR, mutation detection techniques, and ELISA. Results: A positive correlation between IHC, Western blotting, and MET mRNA expression was observed in NSCLC cell lines/tissues. An IHC scoring system of MET expression taking proportional and intensity-based thresholds into consideration was applied in an analysis of the phase II study and resulted in the best differentiation of outcomes. Further analyses revealed a nonsignificant overall survival (OS) improvement with O+E in patients with high MET copy number (mean ≥5 copies/cell by FISH); however, benefit was maintained in “MET IHC-positive”/MET FISH-negative patients (HR, 0.37; P = 0.01). MET, EGFR, amphiregulin, epiregulin, or HGF mRNA expression did not predict a significant benefit with onartuzumab; a nonsignificant OS improvement was observed in patients with high tumor MET mRNA levels (HR, 0.59; P = 0.23). Patients with low baseline plasma hepatocyte growth factor (HGF) exhibited an HR for OS of 0.519 (P = 0.09) in favor of onartuzumab treatment. Conclusions: MET IHC remains the most robust predictor of OS and progression-free survival benefit from O+E relative to all examined exploratory markers. Clin Cancer Res; 20(17); 4488–98. ©2014 AACR.

DNA damage caused by TMZ or RT sensitizes tumors to PARP inhibitors, especially in highly replicating tumors (eg, GBM). Pamiparib is a selective PARP1/2 inhibitor with potent PARP trapping that can cross the blood-brain barrier and has shown synergistic cytotoxicity with TMZ in nonclinical experiments. At 60mg BID, the human-equivalent dose-to-trough brain concentrations above the nonclinical efficacy threshold, pamiparib was generally well tolerated and showed antitumor activity in early clinical studies ({"type":"clinical-trial","attrs":{"text":"NCT02361723","term_id":"NCT02361723"}}NCT02361723; {"type":"clinical-trial","attrs":{"text":"NCT03333915","term_id":"NCT03333915"}}NCT03333915). This ongoing dose-escalation/expansion study ({"type":"clinical-trial","attrs":{"text":"NCT03150862","term_id":"NCT03150862"}}NCT03150862) will determine the safety/tolerability and antitumor effects of pamiparib (60mg BID)+RT and/or TMZ. The dose-escalation component consists of three arms. Arm A will establish tolerable duration of pamiparib (2, 4, 6 weeks)+RT in newly diagnosed GBM patients with unmethylated MGMT promoter (unmethyl-GBM). In Arm B, newly diagnosed patients with unmethyl-GBM will receive pamiparib+RT with increasing TMZ doses. Enrollment in Arm B will commence once RP2D for pamiparib+RT is established. In Arm C, patients with recurrent/refractory methylated- or unmethyl-GBM receive pamiparib with increasing TMZ doses. As of 28 March 2018, 15 patients were enrolled (A: 2-wk, n=3; 4-wk, n=6; C: TMZ [40mg], n=6). One DLT (grade 3 nausea) was reported in Arm C. Across arms, pamiparib-related AEs occurring in >3 patients were nausea (n=6) and fatigue (n=5). Two patients experienced three pamiparib-related AEs grade 3 (diarrhea [A: 4-wk, n=1]; fatigue and nausea [C: n=1]). All three resolved with concomitant medication and treatment interruption (A) or discontinuation (C). Of the seven patients with 1 tumor assessment, one (A: 4-wk) achieved an unconfirmed PR; four (A: 2-wk, n=2; 4-wk, n=2) had SD, and two (A: 2-wk, n=1; C: n=1) had PD. Preliminary data suggests pamiparib at 60mg BID is generally well tolerated by patients when administered 4 weeks concurrently with RT for newly diagnosed unmethyl-GBM and when combined with 40 mg TMZ for recurrent/refractory GBM.

E-cadherin loss is frequently associated with ovarian cancer metastasis. Given that adhesion to the abdominal peritoneum is the first step in ovarian cancer dissemination, we reasoned that down-regulation of E-cadherin would affect expression of cell matrix adhesion receptors. We show here that inhibition of E-cadherin in ovarian cancer cells causes up-regulation of α5-integrin protein expression and transcription. When E-cadherin was blocked, RMUG-S ovarian cancer cells were able to attach and invade more efficiently. This greater efficiency could, in turn, be inhibited both in vitro and in vivo with an α5β1-integrin–blocking antibody. When E-cadherin is silenced, α5-integrin is up-regulated through activation of an epidermal growth factor receptor/FAK/Erk1–mitogen-activated protein kinase–dependent signaling pathway and not through the canonical E-cadherin/β-catenin signaling pathway. In SKOV-3ip1 ovarian cancer xenografts, which express high levels of α5-integrin, i.p. treatment with an α5β1-integrin antibody significantly reduced tumor burden, ascites, and number of metastasis and increased survival by an average of 12 days when compared with IgG treatment (P < 0.0005). α5-Integrin expression was detected by immunohistochemistry in 107 advanced stage ovarian cancers using a tissue microarray annotated with disease-specific patient follow-up. Ten of 107 tissues (9%) had α5-integrin overexpression, and 39% had some level of α5-integrin expression. The median survival for patients with high α5-integrin levels was 26 months versus 35 months for those with low integrin expression (P < 0.05). Taken together, we have identified α5-integrin up-regulation as a molecular mechanism by which E-cadherin loss promotes tumor progression, providing an explanation for how E-cadherin loss increases metastasis. Targeting this integrin could be a promising therapy for a subset of ovarian cancer patients. [Cancer Res 2008;68(7):2329–39]

MNRP1685A is a human monoclonal antibody that blocks binding of vascular endothelial growth factor (VEGF), VEGF-B, and placental growth factor 2 to neuropilin-1 resulting in vessel immaturity and VEGF dependency. The safety of combining MNRP1685A with bevacizumab, with or without paclitaxel, was examined.Patients with advanced solid tumors received escalating doses of MNRP1685A (7.5, 15, 24, and 36 mg/kg) with bevacizumab 15 mg/kg every 3 weeks in Arm A (n = 14). Arm B (n = 10) dosing consisted of MNRP1685A (12 and 16 mg/kg) with bevacizumab 10 mg/kg (every 2 weeks) and paclitaxel 90 mg/m(2) (weekly, 3 of 4 weeks). Objectives were to determine safety, pharmacokinetics, pharmacodynamics, and the maximum tolerated dose of MNRP1685A.Infusion reactions (88 %) and transient thrombocytopenia (67 %) represent the most frequent study drug-related adverse events (AEs). Drug-related Grade 2 or 3 proteinuria occurred in 13 patients (54 %). Additional study drug-related AEs occurring in20 % of patients included neutropenia, alopecia, dysphonia, fatigue, and nausea. Neutropenia occurred only in Arm B. Grade ≥3 study drug-related AEs in ≥3 patients included neutropenia (Arm B), proteinuria, and thrombocytopenia. Two confirmed and three unconfirmed partial responses were observed.The safety profiles were consistent with the single-agent profiles of all study drugs. However, a higher than expected rate of clinically significant proteinuria was observed that does not support further testing of MNRP1685A in combination with bevacizumab.

The glycoprotein (GP) Ib-V-IX complex plays a critical role in initiating platelet adhesion to von Willebrand factor (vWF) at the site of vascular injury. The complex also forms a high-affinity binding site for thrombin. Using an intravital microscopy mouse model, it was previously established that vWF plays a critical role in mediating platelet adhesion and thrombus formation following mesenteric arteriolar injury induced by ferric chloride. Further characterization of this model showed that these thrombotic events were also thrombin dependent. Using this vWF- and thrombin-dependent model, this study shows that GP V gene deficiency significantly accelerates both platelet adhesion and thrombus formation in mice following arteriolar injury. The time required for vessel occlusion in GP V–deficient (GP V−/−) mice was significantly shorter than that in wild-type mice. Interestingly, large emboli were also produced in GP V−/− mice, but not in wild-type mice, causing frequent downstream occlusion. However, when the 2 genotypes were compared in the in vitro perfusion chamber where thrombin was inhibited by heparin, no significant differences were found in either initial single-platelet adhesion or thrombus volume. These results demonstrate that GP V−/− mice have accelerated thrombus growth in response to vascular injury and suggest that this is caused by enhanced thrombin-induced platelet activation rather than enhanced binding of GPIb-V-IX to vWF. Absence of GP V also compromises thrombus stability.

Glycoprotein (GP) V is a major substrate cleaved by the protease thrombin during thrombin-induced platelet activation. Previous analysis of platelets from GP V-null mice suggested a role for GP V as a negative modulator of platelet activation by thrombin. We now report the mechanism by which thrombin activates GP V −/− platelets. We show that proteolytically inactive forms of thrombin induce robust stimulatory responses in GP V null mouse platelets, via the platelet GP Ib–IX–V complex. Because proteolytically inactive thrombin can activate wild-type mouse and human platelets after treatment with thrombin to cleave GP V, this mechanism is involved in thrombin-induced platelet aggregation. Platelet activation through GP Ib–IX depends on ADP secretion, and specific inhibitors demonstrate that the recently cloned P2Y 12 ADP receptor (G i -coupled ADP receptor) is involved in this pathway, and that the P2Y 1 receptor (G q -coupled ADP receptor) may play a less significant role. Thrombosis was generated in GP V null mice only in response to catalytically inactive thrombin, whereas thrombosis occurred in both genotypes (wild type and GP V null) in response to active thrombin. These data support a thrombin receptor function for the platelet membrane GP Ib–IX–V complex, and describe a novel thrombin signaling mechanism involving an initiating proteolytic event followed by stimulation of the GP Ib–IX via thrombin acting as a ligand, resulting in platelet activation.

Platelets have a crucial role in the maintenance of normal haemostasis, and perturbations of this system can lead to pathological thrombus formation and vascular occlusion, resulting in stroke, myocardial infarction and unstable angina. ADP released from damaged vessels and red blood cells induces platelet aggregation through activation of the integrin GPIIb–IIIa and subsequent binding of fibrinogen. ADP is also secreted from platelets on activation, providing positive feedback that potentiates the actions of many platelet activators1. ADP mediates platelet aggregation through its action on two G-protein-coupled receptor subtypes2,3. The P2Y1 receptor couples to Gq and mobilizes intracellular calcium ions to mediate platelet shape change and aggregation4,5. The second ADP receptor required for aggregation (variously called P2YADP, P2YAC, P2Ycyc or P2TAC) is coupled to the inhibition of adenylyl cyclase through Gi. The molecular identity of the Gi-linked receptor is still elusive, even though it is the target of efficacious antithrombotic agents, such as ticlopidine and clopidogrel6,7,8 and AR-C66096 (ref. 9). Here we describe the cloning of this receptor, designated P2Y12, and provide evidence that a patient with a bleeding disorder10 has a defect in this gene. Cloning of the P2Y12 receptor should facilitate the development of better antiplatelet agents to treat cardiovascular diseases.

Proteinase-activated receptor-2 (PAR-2) is a member of a family of G-protein-coupled, seven-transmembrane domain receptors that are activated by proteolytic cleavage. The receptor is expressed in a number of different tissues and potential physiological activators identified thus far include trypsin and mast cell tryptase. Acrosin, a trypsin-like serine proteinase found in spermatozoa of all mammals, was found to cleave a model peptide fluorescent quenched substrate representing the cleavage site of PAR-2. This substrate was cleaved with kinetics similar to those of the known PAR-2 activators, trypsin and mast cell tryptase. Acrosin was also shown to induce significant intracellular calcium responses in Chinese hamster ovary cells stably expressing intact human PAR-2, most probably due to activation of the receptor. Immunohistochemical studies using PAR-2 specific antibodies indicated that the receptor is expressed by mouse oocytes, which suggests that acrosin may play additional role(s) in the fertilization process via the activation of PAR-2 on oocytes.

A role for glycoprotein (GP)V in platelet function has been proposed on the basis of observations that GP V is the major thrombin substrate on intact platelets cleaved during thrombin-induced platelet aggregation, and that GP V promotes GP Ib-IX surface expression in heterologous cells. We tested the hypotheses that GP V is involved in thrombin-induced platelet activation, in GP Ib-IX expression, and in other platelet responses by generating GP V null mice. Contrary to expectations, GP V −/− platelets were normal in size and expressed normal amounts of GP Ib-IX that was functional in von Willebrand factor binding, explaining why defects in GP V have not been observed in Bernard–Soulier syndrome, a bleeding disorder caused by a lack of functional GP Ib-IX-V. Moreover, in vitro analysis demonstrated that GP V −/− platelets were hyperresponsive to thrombin, resulting in increased fibrinogen binding and an increased aggregation response. Consistent with these findings, GP V −/− mice had a shorter bleeding time. These data support a role for GP V as a negative modulator of platelet activation. Furthermore, they suggest a new mechanism by which thrombin enhances platelet responsiveness independent of activation of the classical G-protein-coupled thrombin receptors.

IntroductionThe study of genetic bleeding disorders provided the first link between platelet functions and specific membrane glycoproteins. Two examples are well known and have been the subject of numerous reviews. First, Glanzmann’s thrombasthenia is a bleeding disorder caused by a defect of platelet aggregation in which the glycoprotein αIIbβ3 (GP IIb-IIIa) is either lacking or is expressed but is defective.1 We now know that αIIbβ3 exists on the surface of unstimulated platelets in an inactive form but, through a process known as “inside-out” signaling, responds to platelet stimulation to become a receptor for soluble fibrinogen and von Willebrand factor (vWF) to mediate platelet aggregation. αIIbβ3 is also known to bind immobilized fibrinogen and, through a process known as “outside-in” signaling, to induce platelet stimulation.2 A second example is Bernard-Soulier syndrome, a bleeding disorder caused by the failure of platelets to bind to subendothelial matrices due to the lack of or defective GP Ib-IX-V.3 It is now known that GP Ib-IX-V binds to vWF to mediate the adhesion of unstimulated platelets to injured blood vessel walls.4,5 GP Ib-IX-V interactions also induce platelet stimulation, a process mediated by signaling through GP Ib-IX-V.6 The mechanisms responsible for the binding of adhesive proteins to αIIbβ3 and GP Ib-IX-V are beginning to be understood and, as such, targets for therapeutic intervention have been identified. Three parenteral αIIbβ3 antagonists have demonstrated a therapeutic benefit in large-scale clinical trials of acute coronary syndromes, including unstable angina, non Q-wave myocardial infarction, and percutaneous intervention, and are now commercially available.7 Many orally available αIIbβ3 antagonists are presently in clinical trials. Although GP Ib antagonists have not been pursued as aggressively, animal studies have shown that they do have a proven antithrombotic benefit.8 Despite these advances in the understanding of glycoprotein ligand binding and development of therapeutic antagonists of adhesive protein receptors, the mechanisms responsible for transducing signals through these receptors have remained elusive.It is now established that signal transduction reactions through αIIbβ3 and GP Ib-IX-V are not only involved in platelet aggregation to cause vessel occlusions, but also that glycoprotein signaling affects thrombus growth and stability, as well as the biology and perhaps the pathology of the vessels in which aggregates occur. In one example, platelet-derived growth factor (PDGF), secreted in response to αIIbβ3 signaling from the α-granules of aggregated platelets, is a primary smooth muscle cell mitogen and is believed to be involved not only in the response to vascular injury but also in atherosclerotic lesion progression.9,10 In another example, CD 154 (previously termed CD40 ligand) redistributes from α-granule membranes to the surface of aggregated platelets in response to αIIbβ3 signaling.11 CD 154 is an important inflammatory mediator that induces the release of cytokines from endothelial and smooth muscle cells, initiates vascular inflammation, and participates in atherosclerotic lesion progression.12 A third example involves the assembly of prothrombinase and factor Xase on the surface of aggregated platelets, enabling platelet thrombi to be procoagulant and accounting for the apparent anticoagulant activity of αIIbβ3 antagonists.13,14 In addition, platelet aggregates also display fibrinogen and vWF bound to platelet membrane glycoproteins that function to recruit additional platelets and, therefore, enhance thrombus growth.15 More recent data also indicate that platelet aggregation induces de novo protein synthesis.16,17 These and other events are secondary to the initial adhesion and aggregation reactions of platelets and are consequences of signaling reactions induced by the adhesion and aggregation receptors. Thus, characterization of the membrane glycoprotein signal transduction pathways has become essential, not only to understand platelet function, but also to determine whether there are additional ways by which platelet-mediated pathologies can be regulated.Platelet membrane glycoprotein signaling reactions either do not occur in nucleated cells normally used for transfection studies or are insufficiently characterized. Accordingly, the use of genetics to study mechanisms of platelet adhesive protein receptor signaling has been limited. The advent of technologies that facilitate genetic manipulations in the mouse genome has produced new ways to define protein function and determine the structure-function relationships of individual proteins and is proving of value in unraveling signal transduction pathways in platelets. Although one should always be cautious in extrapolating data from mouse to human platelets (as demonstrated by the PAR receptors, see below), it is impressive that much of what has been learned about platelets appears to apply to both mouse and human. Indeed, this review summarizes the status of genetic manipulations of the mouse genome that have contributed to our understanding of platelet membrane adhesion receptor signaling in platelets.

Rat glioma C6 cells have been demonstrated to be a suitable model in the investigation of PAR-1-type thrombin receptors in brain. However, anti-PAR-1 antibodies, which should be very helpful tools in studying PAR-1 in rat cells, have not been available up until now. Therefore, we prepared a monoclonal anti-thrombin receptor antibody (Mab COR7-6H9) directed against the peptide sequence GRAVYLNKSRFPPMPPPPFISEDASG in the N-terminus below the thrombin cleavage site of the rat PAR-1-type thrombin receptor. Using this antibody, we demonstrated the presence of PAR-1 binding sites on the plasma membrane of rat glioma C6 cells both with confocal laser fluorescence and with scanning electron microscopy. In addition, Mab COR7-6H9 was shown to block PAR-1-mediated transmembranal signaling as demonstrated by measurement of free intracellular calcium and cyclic AMP. This novel anti-PAR-1 antibody is therefore likely to be a very helpful tool in studying PAR-1-type thrombin receptors in rat brain.

The biological effects of platelet-derived growth factor (PDGF) are mediated by alpha- and beta-PDGF receptors (PDGFR), which have an intracellular tyrosine kinase domain and an extracellular region comprising five immunoglobulin-like domains (D1-D5). Using deletion mutagenesis we mapped the PDGF binding site in each PDGFR to the D2-D3 region. In the case of alpha-PDGFR, 125I-PDGF AA and 125I-PDGF BB bound to the full-length extracellular domain, D1-D5, and D2-D3 with equal affinity (Kd = 0.21-0.42 nM). Identical results were obtained for 125I-PDGF BB binding to beta-PDGFR mutants D1-D5 and D2-D3, establishing that D1, D4, and D5 do not contribute to PDGF binding. Monoclonal antibodies (mAb) directed against individual PDGFR Ig-like domains were used to extend these observations. The anti-D1 mAb 1E10E2 and anti-D5 mAb 2D4G10 had no effect on alpha- or beta-PDGFR function, respectively. In contrast, mAb 2H7C5 and 2A1E2 directed against D2 of the alpha- and beta-receptor, respectively, blocked PDGF binding, receptor autophosphorylation and mitogenic signaling with IC50 values of 0.1-3.0 nM. An anti-D4 mAb 1C7D5 blocked beta-receptor autophosphorylation and signaling without inhibiting PDGF binding consistent with the observation that D4 is essential for PDGFR dimerization (Omura, T., Heldin, C.-H., and Ostman, A. (1997) J. Biol. Chem. 272, 12676-12682). mAbs identified here act as potent PDGFR antagonists that can be used as research tools and potentially as therapeutic agents for the treatment of diseases involving unwanted PDGFR signaling.

Purpose: The oncogenic PI3K/Akt/mTOR pathway is an attractive therapeutic target in cancer. However, it is unknown whether the pathway blockade required for tumor growth inhibition is clinically achievable. Therefore, we conducted pharmacodynamic studies with GDC-0068, an ATP competitive, selective Akt1/2/3 inhibitor, in preclinical models and in patients treated with this compound. Experimental Design: We used a reverse phase protein array (RPPA) platform to identify a biomarker set indicative of Akt inhibition in cell lines and human-tumor xenografts, and correlated the degree of pathway inhibition with antitumor activity. Akt pathway activity was measured using this biomarker set in pre- and post-dose tumor biopsies from patients treated with GDC-0068 in the dose escalation clinical trial. Results: The set of biomarkers of Akt inhibition is composed of 10 phosphoproteins, including Akt and PRAS40, and is modulated in a dose-dependent fashion, both in vitro and in vivo. In human-tumor xenografts, this dose dependency significantly correlated with tumor growth inhibition. Tumor biopsies from patients treated with GDC-0068 at clinically achievable doses attained a degree of biomarker inhibition that correlated with tumor growth inhibition in preclinical models. In these clinical samples, compensatory feedback activation of ERK and HER3 was observed, consistent with preclinical observations. Conclusion: This study identified a set of biomarkers of Akt inhibition that can be used in the clinical setting to assess target engagement. Here, it was used to show that robust Akt inhibition in tumors from patients treated with GDC-0068 is achievable, supporting the clinical development of this compound in defined patient populations. Clin Cancer Res; 19(24); 6976–86. ©2013 AACR.

Antibody–drug conjugates (ADC), potent cytotoxic drugs linked to antibodies via chemical linkers, allow specific targeting of drugs to neoplastic cells. We have used this technology to develop the ADC DCDT2980S that targets CD22, an antigen with expression limited to B cells and the vast majority of non-Hodgkin lymphomas (NHL). DCDT2980S consists of a humanized anti-CD22 monoclonal IgG1 antibody with a potent microtubule-disrupting agent, monomethyl auristatin E (MMAE), linked to the reduced cysteines of the antibody via a protease cleavable linker, maleimidocaproyl-valine-citrulline-p-aminobenzoyloxycarbonyl (MC-vc-PAB). We describe the efficacy, safety, and pharmacokinetics of DCDT2980S in animal models to assess its potential as a therapeutic for the treatment of B-cell malignancies. We did not find a strong correlation between in vitro or in vivo efficacy and CD22 surface expression, nor a correlation of sensitivity to free drug and in vitro potency. We show that DCDT2980S was capable of inducing complete tumor regression in xenograft mouse models of NHL and can be more effective than rituximab plus combination chemotherapy at drug exposures that were well tolerated in cynomolgus monkeys. These results suggest that DCDT2980S has an efficacy, safety, and pharmacokinetics profile that support potential treatment of NHL. Mol Cancer Ther; 12(7); 1255–65. ©2013 AACR.