Assessment Of Antitumor Activity Research Articles

A First-in-Human Phase I Study of BXQ-350, a First-in-Class Sphingolipid Metabolism Regulator, in Patients with Advanced/Recurrent Solid Tumors or High-Grade Gliomas.

BXQ-350, a nanovesicle formulation of saposin C, is an allosteric sphingolipid metabolism regulator that increases proapoptotic ceramide and decreases oncogenic sphingosine-1-phosphate levels. We conducted a first-in-human phase I study of BXQ-350. Adults (≥18 years old) with advanced/recurrent, treatment-refractory solid tumors or high-grade gliomas received BXQ-350 intravenously in five dose cohorts (0.7-2.4 mg/kg) in a 3+3 dose escalation and expansion design. The primary endpoints during dose escalation were dose-limiting toxicities and maximum tolerated dose; the primary objective in expansion parts was assessment of antitumor activity (RECIST v1.1/Response Assessment in Neuro-Oncology criteria). Eighty-six patients were enrolled. Dose-limiting toxicities were not observed during dose escalation (n = 18), and a maximum tolerated dose was not identified. An additional 68 patients received the 2.4 mg/kg dose. Nine patients (10%) discontinued due to adverse events. The most common treatment-related adverse events were nausea (24%) and fatigue (23%). Eight patients had a progression-free survival of ≥6 months. Two of these achieved a partial response, and six had stable disease, among whom three had a reduction in ≥1 target lesion. Of those with progression-free survival of ≥6 months, seven remained on study for >12 months, five for >24 months, and after 7 years, two remained on study without disease progression. BXQ-350 was well-tolerated as monotherapy at doses up to 2.4 mg/kg. It provided some lasting clinical benefit in patients with recurrent solid malignancies across several tumor types, consistent with a decreased systemic sphingosine-1-phosphate/ceramide metabolic rheostat. BXQ-350 warrants further clinical investigation alone and combined with standard of care for advanced solid tumors.

Assessment of Patient-Derived Xenograft Growth and Antitumor Activity: The NCI PDXNet Consensus Recommendations.

Although patient-derived xenografts (PDX) are commonly used for preclinical modeling in cancer research, a standard approach to in vivo tumor growth analysis and assessment of antitumor activity is lacking, complicating the comparison of different studies and determination of whether a PDX experiment has produced evidence needed to consider a new therapy promising. We present consensus recommendations for assessment of PDX growth and antitumor activity, providing public access to a suite of tools for in vivo growth analyses. We expect that harmonizing PDX study design and analysis and assessing a suite of analytical tools will enhance information exchange and facilitate identification of promising novel therapies and biomarkers for guiding cancer therapy.

Preliminary data from a dose-escalation phase 1 study with HP518, an AR PROTAC degrader: Safety, tolerability, pharmacokinetics (PK), and first assessment of anti-tumor activity in patients (Pts) with metastatic castration-resistant prostate cancer (mCRPC).

124 Background: HP518 is an oral proteolysis targeting chimera (PROTAC) protein degrader that target androgen receptor (AR) mutations for the treatment of mCRPC. To evaluate the safety, PK, and anti-tumor activity of HP518, and select a recommended phase 2 dose (RP2D), we conducted a first-in-human, Phase 1, open-label, multicenter, non-randomized, dose escalation study in pts with mCRPC. We report results of the ongoing Phase 1 study at five Australian sites. Methods: Pts with mCRPC with disease progression on at least 1 novel hormonal agent (NHA) and ≤ 1 line of chemotherapy received HP518 QD orally in sequential cohorts (25, 50, 100, 200, and 300, 400, 500 mg per day, Bayesian N-CRM design). Primary objectives were to assess HP518 safety and select the RP2D. Secondary objectives included evaluating the PK of HP518, PSA50 response and radiographic progression per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 and Prostate Cancer Working Group 3 (PCWG3) criteria. Exploratory objectives were to evaluate AR expression in CTCs before and after 12 weeks of treatment and conduct genomic profiling using cfDNA. Results: As of 08Sep2023, a total of 22 pts were enrolled, with current one-daily dosing of 500 mg HP518. Overall, HP518 was well tolerated, with cumulative 10 SAE (1 related/9 unrelated). No DLT was observed. There were 13 Grade ≥3 treatment-emergent adverse events (TEAEs) in 6 pts treated up to 500 mg; no grade ≥4 TEAEs. The most common TEAE in all cohorts was grade 1 or 2 vomiting and nausea which were well managed with prophylactic anti-emetics. Preliminary PK results were obtained from 18 pts dosed with 25 mg to 500 mg per day. Following multiple oral doses of HP518, median peak plasma concentrations were observed at 3 -12 hours post-dose. Over the 5-fold dose range (100 to 500 mg), the increase in Cmax and AUC0-last was approximately dose proportional on day 1. Steady state was reached between day 56 and day 84. Among 16 pts who finished the DLT period, a PSA50 response was seen in 3 pts. 2 pts had confirmed partial responses per RECIST criteria, with 8 pts remaining on treatment. 2 pts received HP518 for ≥24 weeks including 1 pt with a durable PSA50 response for 52 weeks, who also showed PR. Notably, this patient harbored an F877L, E873_F879del AR ligand-binding domain (LBD) mutations. Conclusions: HP518, a novel AR PROTAC degrader, demonstrates in this Phase 1a dose-escalation study, an acceptable safety/tolerability profile and a signal of efficacy in an unselected mCRPC patient population. The presence of AR LBD mutations may predict benefit from HP518, and merits further investigation in pts with mCRPC. Clinical trial information: NCT05252364 .

Abstract 5557: PMC-309, a highly selective anti-VISTA antibody reverses immunosuppressive TME to immune-supportive TME

Abstract Purpose: We investigated the pharmacology of PMC-309 in ex vivo or in vivo characterization for the development of the preclinical study. Experimental procedures: Target selectivity: it was measured by SPR assay. Human VISTA expressing CHO k1 cells or CHO k1 mock cells were used in cell binding assay. Target cell analysis: human peripheral blood mononuclear cells (PBMC) containing lymphocyte and myeloid lineage cells were used for target cells analysis with flow cytometry. In vitro T cell activity: human PBMC was employed for the evaluation of T cell activity (IRB #1041107-201703-BR-002-02) and was stimulated with or w/o PMC-309 in the presence of anti-CD3/28 Antibody. In vivo study: MC38 bearing human VISTA knock-in (KI) mice were employed for the assessment of anti-tumor activity of PMC-309. The tumor infiltrated immune cells: Immune cells in the TME were evaluated by immunohistochemistry (IHC) or flow cytometry (FACS) analysis. Statistics: All data were presented as the mean ± SEM and analyzed using one-way ANOVA followed by Dunnett’s multiple comparison tests in Graph pad prism®. ***p<0.001, **p<0.01 and *p<0.05 compared to Control group. Summary of data: PMC-309 binding to VISTA expressing cells is highly selective and the selectivity is maintained even in the low pH conditions that mimic TME. PMC-309 enhances the secretion of IFN-gamma, TNF-alpha, and IL-2 in Mixed Lymphocyte Reaction (MLR) settings. In addition, PMC-309 promoted monocyte differentiation into M1 macrophage that stimulates proinflammatory cytokine secretion of T cells. For the in vivo study, PMC-309 was intravenously administrated in VISTA-KI mice. The tumor growth rate was suppressed in accompanied by a synergistic effect with an anti-PD1 antibody. The anti-tumor activity was associated with enhanced T cell activation, increased secretion of pro-inflammatory cytokines, and increased penetration of cytotoxic T cells, but lowing immune-suppressive MDSC cells into TME as demonstrated with IHC analysis. Conclusions: PMC-309 is a fully human anti-VISTA antibody that targets human VISTA specifically. PMC-309 enhanced both T cell activation and monocyte activation when monocytes were cultured with or without T cells by targeting VISTA. PMC-309 increased the number of T cell infiltration while a decrease of MDSCs in the TME. PMC-309 in combination with chemotherapy or other IO drugs could address highly medical unmet needs from patients with drug resistance to currently available IO treatment options. Citation Format: Cheon Ho Park, Sang Soon Byun, Jin Yong An, Hyerim Han, Weon Sup Lee. PMC-309, a highly selective anti-VISTA antibody reverses immunosuppressive TME to immune-supportive TME [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 5557.

Abstract P185: Preliminary antitumor activity of MCLA-158, an IgG1 bispecific antibody targeting EGFR and LGR5, in advanced head and neck squamous cell carcinoma

Abstract In the expansion part of an ongoing phase 1 study, MCLA-158 is being investigated at the recommended phase 2 dose (RP2D) in patients (pts) with advanced solid tumors, including head and neck squamous cell carcinoma (HNSCC). Epidermal growth factor receptor (EGFR) and WNT signaling are known oncogenic and mitogenic drivers in several cancers, including HNSCC. MCLA-158 is a human common light chain IgG1 bispecific antibody with enhanced antibody-dependent cellular cytotoxicity (ADCC) activity. It targets EGFR and the leucine-rich, repeat-containing, G-protein coupled receptor 5 (LGR5), a transmembrane receptor associated with tumor initiating cells, particularly cancer stem cells. Potent antitumor activity was seen with MCLA-158 in pt-derived HNSCC xenograft models. The RP2D of MCLA-158 was determined to be 1500 mg every 2 weeks (q2w), with 4-week cycles, during the dose escalation part of the study, based on safety, PK and receptor occupancy prediction. A maximum tolerated dose was not reached. The primary objective of the expansion part is to characterize the safety and tolerability of single-agent MCLA-158 and confirm the RP2D. Secondary objectives include assessment of antitumor activity (investigator-assessed overall response rate [ORR] per RECIST 1.1 and duration of response). Key eligibility criteria include prior exposure to standard therapy, ECOG performance status (PS) 0-1, measurable disease (RECIST 1.1), and availability of a baseline tumor biopsy. At the interim data cutoff date of 15 June 2021, 7 pts with advanced recurrent/metastatic HNSCC were enrolled and treated in the expansion phase. Median age was 63 years (range 50-74), ECOG PS 0/1: 2/5. Primary tumor locations were oropharynx (2 pts), hypopharynx (1 pts), larynx (3 pts), and unknown primary (1 pt). All pts had a histology of squamous cell carcinoma. Prior treatment included platinum-based chemotherapy in all pts, and anti-PD-1/PD-L1 in 6 pts. No pts received prior cetuximab. A median of 3 treatment cycles (range 1-8) were administered to the 7 pts, 4 of whom were continuing with therapy at the cutoff. Of the 5 pts who had a postbaseline assessment, 2 had confirmed partial responses (5+ and 8 cycles initiated), and 2 pts had stable disease (reduction in the sum of target lesions of 7% and 17%; 4+ and 5 cycles initiated, respectively). Scheduled first postbaseline tumor assessments for 2 pts occurred after the data cutoff date. Among 26 pts who were treated at the RP2D in the dose escalation and expansion cohorts, the most frequent adverse events regardless of causality (all grades/grade 3) were infusion-related reactions (73%/8%), rash (39%/0%), asthenia (35%/4%), decreased appetite (27%/4%), nausea (27%/4%), and acneiform dermatitis (23%/4%). There were no treatment-related grade 4 or 5 adverse events. In conclusion, MCLA-158 shows promising signs of antitumor activity in pretreated HNSCC, and a well-tolerated and favorable safety profile. Citation Format: Antoine Hollebecque, Irene Brana, Lara Iglesias, Caroline Even, Kato Shumei, Marc Díez García, Mateo Bover, Patricia Martin-Romano, Rocio Garcia-Carbonero, Guillen Argilés, Josep Tabernero, Rajan Khanna, Viktoriya Stalbovskaya, Jeroen Lammerts van Bueren, Kees Bol, Mohamed Bekradda, Andrew Joe, Ernesto Wasserman, Ezra E.W. Cohen. Preliminary antitumor activity of MCLA-158, an IgG1 bispecific antibody targeting EGFR and LGR5, in advanced head and neck squamous cell carcinoma [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P185.

First-in-human phase I study of the bifunctional EGFR/TGFβ fusion protein BCA101 in patients with EGFR-driven advanced solid cancers.

3074 Background: Therapeutic targeting of EGFR has demonstrated efficacy in common advanced malignancies such as colorectal cancer (CRC), squamous cell of the head and neck (SCCHN), and non-small cell lung cancer (NSCLC). TGFβ has pro-tumorigenic effects on migration, invasion and tumor-specific immunosuppression, which may enhance the oncogenic effects of activated EGFR. Inhibition of EGFR signaling can lead to TGFβ upregulation as a resistance mechanism. BCA101 is a bifunctional recombinant fusion protein consisting of a chimeric anti-EGFR antibody and an extracellular domain (ECD) of human TGFβRII which demonstrated anti-tumor activity in several preclinical models. Methods: Patients with EGFR-driven advanced solid cancers refractory to standard therapies received BCA101 at escalating doses from 64 mg to 1000 mg intravenously (IV) weekly across 6 dose levels using a 3+3 design to determine dose limiting toxicities (DLT, established within 21 days of initial dosing), maximum tolerated dose (MTD) and/or recommended dose (RD). Secondary endpoints include detailed pharmacokinetic (PK), pharmacodynamic (PD) studies in serial tumor and/or blood samples and assessment of anti-tumor activity. Results: As of 2/11/2021, 21 patients received single agent BCA101 at 64 (n = 3), 240 (n = 7), 500 (n = 2), 750 (n = 3), 800 (n = 3) or 1000 (n = 3) mg IV weekly, including patients with CRC (n = 6), SCCHN (n = 5) uveal melanoma (n = 2), ovarian cancer (n = 2), glioblastoma multiforme (n = 2), conjunctival melanoma, chordoma, pancreatic cancer and anal squamous cell carcinoma (all n = 1). These patients had 1-7 prior lines of antineoplastic therapy (median 4), including 3 patients with prior EGFR inhibitor exposure. Adverse events (AE) related to BCA101 observed in > 1 patient included grade (G) 1-2 rash (n = 9), G 1-2 lipase elevation (n = 2). G3 vitreous hemorrhage at the 240 mg dose level has been the only DLT. The MTD has not been reached and the RD will be based on safety, exposure and pending PD data. Saturation of the clearance was observed at doses above 500mg. Dose proportional increase in Cmax and AUC were observed with doses of 750-1000mg. Best RECISTv1.1 response was stable disease (SD) in 3/10 evaluable patients, with 1 patient on drug ≥4 months. Conclusions: BCA101 is well tolerated at biologically active doses. BCA101 is now being tested in combination with the PD-1 antibody pembrolizumab in patients with SCCHN and anal carcinoma. Clinical trial information: NCT04429542.

A Phase 1, Open-Label, Dose-Escalation Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of Multiple Intravenous Doses of IGN002 Administered Weekly to Subjects with Refractory Non-Hodgkin Lymphoma

Background:Non-Hodgkin lymphoma (NHL) is the most common, adult hematologic malignancy. Despite available treatment, relapse rates are high and novel therapies are warranted. IGN002 consists of an anti-CD20 monoclonal antibody (mAb) fused to interferon-alpha (IFNα) via a short peptide linker. The mAb portion of IGN002 is a chimeric IgG1 antibody with the same amino acid sequence as rituximab. The interferon amino acid sequence is human IFNα2b (hIFNα2b). In nonclinical pharmacology studies using CD20-positive human NHL cells, IGN002 demonstrates compelling anti-tumor effects. When compared to rituximab, IGN002 demonstrated enhanced complement-dependent cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC) effector functions against CD20-positive NHL cells. Moreover, compared to rituximab against normal human primary B-cells, IGN002 displayed higher maximal and more potent ADCC activity. Finally, in xenograft studies with immunodeficient mice using 3 different human NHL cell lines comparing IGN002 to rituximab, IGN002 demonstrated superior median and overall survival in all 3 NHL xenograft tumor lines. Study Design and Methods :This open-label, non-randomized, first-in-human, dose finding Phase 1 study comprises a Dose-Escalation Stage and an Expansion Stage (NCT02519270). In the Dose-Escalation Stage, ascending dose cohorts will be treated in 2 periods until the maximum tolerated dose (MTD) or recommended Phase 2 dose (RP2D) is identified. In Period 1, subjects will receive 2 doses of IGN002 administered weekly. Subjects with no anti-drug antibodies to IGN002 at Week 6 in Period 1 will proceed to Period 2 and receive up to 24 additional doses of IGN002 administered weekly in three 8-week cycles, with no treatment-free interval. In the Expansion Stage, subjects will receive up to 24 doses of IGN002 at the MTD or RP2D administered weekly in three 8-week cycles, with no treatment-free interval. Cohorts 1-5 at dose level 0.1, 0.3, 1, 3, and 10 ug/kg, respectively, have been completed without any dose limiting toxicity (DLT) and enrollment for Cohorts 6-8 is impending. Clinical Endpoints:The primary outcome measures are the evaluation of safety and tolerability of multiple doses of IGN002 administered weekly as an IV infusion to subjects with refractory NHL and the determination of MTD or RP2D of IGN002. The secondary outcome measures include characterizing the pharmacokinetic profile of ascending doses of IGN002, the incidence of anti-IGN002 antibody formation, and assessment of anti-tumor activity (e.g., response rate, duration) of IGN002 using the Lugano Classification criteria for NHL. Eligibility Criteria:This study is enrolling patients > 18 years with an ECOG <2 who have a documented history of immunohistochemistry-confirmed CD20-positive B-cell NHL, including diffuse large B-cell, mantle cell, marginal zone, lymphoplasmacytic, follicular, transformed follicular, or primary mediastinal B-cell lymphoma that is refractory to at least 1 documented regimen containing rituximab or a similar anti-CD20 therapy. Patients must also have measurable disease and adequate organ function. The exclusionary criteria encompass treatment with an approved or investigational chemotherapy or anti-CD20 drug within 28 days of Day 1, treatment with an approved or investigational biologic drug that does not target CD20 within 90 days of Day 1, or radiation therapy within 4 weeks of Day 1. Statistical Methods:The sample size was not predicated on formal statistical considerations. Descriptive statistics will be used to summarize continuous variables. Dichotomous endpoints will be summarized using frequencies, proportions, and exact binomial 95% CI. For subjects treated at the MTD or RP2D in Period 2 of the Dose-Escalation Stage and the Expansion Stage, time-to-event variables will be summarized using the Kaplan-Meier method. Target Accrual:In the Dose-Escalation Stage and Expansion Stage, approximately 9-18 (~3-6 subjects per cohort) and 14 subjects, respectively, will be accrued. Enrollment for Cohort 6 is expected to commence in September 2020. Disclosures Mataveli: Spectrum Pharmaceuticals:Current Employment, Current equity holder in publicly-traded company.

Phase I study of afatinib plus selumetinib in patients with KRAS mutation-positive colorectal, non-small cell lung and pancreatic cancer.

3613 Background: Mutations in the KRAS gene result in a constitutively activated RAS-RAF-MEK-ERK (MAPK) pathway. In KRAS mutant tumors, the anti-tumor activity of MEK inhibitors is limited due to intrinsic resistance caused by feedback activation of upstream epidermal growth factor receptors (HER). This upstream activation not only reactivates MAPK, but also the phosphoinositide 3-kinase (PI3K)-AKT pathway in preclinical research. Based on these data, a phase I clinical trial was initiated with the combination of the orally administered pan-HER inhibitor afatinib and the MEK inhibitor selumetinib in patients with KRAS mutant and PIK3CA wildtype colorectal cancer (CRC), non-small cell lung cancer (NSCLC), or pancreatic cancer to determine the recommended phase 2 regimen (RP2R). Methods: In this multicentre study, patients received escalating doses of afatinib and selumetinib according to a 3+3 design starting with 20 mg afatinib once daily (QD) continuously and 25 mg selumetinib twice daily (BID) in a 21 days on/7 days off schedule. Continuous and intermittent dosing were explored to assess optimal exposure and tolerability. The primary aim was determining the RP2R. Secondary objectives included assessment of anti-tumor activity and the analyses of pharmacokinetic and pharmacodynamic parameters for target inhibition. Clinicaltrials.gov identifier: NCT2450656. Results: In total, 26 mostly heavily pretreated patients with CRC (n=19), NSCLC (n=6) and pancreatic cancer (n=1) were enrolled among 5 dose-levels. Dose-limiting toxicities (DLTs) occurred in 6 patients and consisted of grade 3 diarrhea (n=3), decreased appetite (n=1), nausea/vomiting (n=1), dehydration (n=2) and mucositis (n=1). Clinical efficacy was limited with no responses according to RECIST v1.1 and stable disease for 221 days in a patient with NSCLC as best response. Conclusions: The RP2R was determined at 20 mg afatinib QD continuously and 25 mg selumetinib BID 21 days on/7 days off for continuous dosing. The 3 patients treated in the escalation cohort of the ongoing intermittent dose-level with 20 mg afatinib QD and 25 mg selumetinib BID 5 days on/2 days off, experienced no DLTs. Pending the latest safety results of the expansion cohort for this ongoing dose-level, the RP2R of intermittent dosing has not been established at the moment. Clinical trial information: NCT2450656 .

Abstract CT159: A phase 1 study of intraperitoneal MCY-M11 therapy for women with platinum resistant high grade serous adenocarcinoma of the ovary, primary peritoneum, or fallopian tube, or subjects with peritoneal mesothelioma with recurrence after prior chemotherapy

Abstract Background: Chimeric antigen receptor CAR T cell therapy for solid tumors has not yet achieved the success seen in hematologic malignancies. Many challenges remain, including the type of antigen being targeted, the risk for on-target off-tumor toxicity, a frequent high degree of immune tolerance within an immune suppressive environment, together with autologous product manufacturing hurdles, which hinder timely delivery of treatment to the patient. Also, most current CAR T therapies are viral based, limiting the ability to administer repeated, longer-term treatments. MaxCyte has developed its first CAR product, MCY-M11, applying the CARMA™ non-viral, mRNA-based platform for rapid (less than 1 day) manufacturing with efficient transfection of a human scFv targeting mesothelin, using fresh non-expanded peripheral blood mononuclear cells for autologous cell therapy. Mesothelin is an attractive and relevant therapeutic target because of its high differential expression in many solid tumors with only low levels of expression in mesothelial cells of mostly non-critical normal tissues. The transient expression of the CAR transgene may be important in limiting potential excessive or unwanted toxicity, while allowing for multiple therapeutic infusions needed to trigger a potent and more effective host immune response. In an in vivo murine model, MCY-M11 cells were shown to have the ability to traffic to and inhibit growth of mesothelin-expressing ovarian cancer and improve survival, both in a dose-dependent manner and with multicycle administration. The first in human phase 1 study of MCY-M11 in patients with advanced ovarian cancer and peritoneal mesothelioma (NCT03608618) is described here. Methods: A standard 3+3 design phase 1 study exploring 4 ascending cell dose levels, in patients with relapsed/refractory adenocarcinoma of the ovary, fallopian tube, primary peritoneum, or peritoneal mesothelioma. A minimum of 15 patients will be enrolled to receive one cycle of 3 weekly doses (D1, D8, D15) of MCY-M11 administered intraperitoneally. The primary objective is to characterize safety (Incidence and severity of adverse events assessed per NCI CTCAE v5.0), tolerability, and feasibility of infusion of MCY-M11. Secondary objectives include assessment of antitumor activity (RECIST, irRECIST, and serum biomarkers), and correlates of CAR performance and immune activation. The study is being conducted at two centers, and the first patient was dosed in October 2018. Recruitment in dose level 1 cohort continues. Citation Format: Armin Ghobadi, Premal Thaker, David Weng, Julie Vanas, Irene Ekwede, Mira Pavlova, Robert Keefe, Michael Kuo, Claudio Dansky Ullmann, Raffit Hassan, Christina Annunziata. A phase 1 study of intraperitoneal MCY-M11 therapy for women with platinum resistant high grade serous adenocarcinoma of the ovary, primary peritoneum, or fallopian tube, or subjects with peritoneal mesothelioma with recurrence after prior chemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT159.

Abstract OT2-07-06: Antibody-coupled T cell receptor (ACTR) engineered autologous T cells in combination with trastuzumab for the treatment of HER2-positive malignancies

Abstract Antibody-Coupled T cell Receptor (ACTR) is an autologous engineered T cell therapy developed to combine with tumor-targeting antibodies to exert potent anti-tumor immune responses and tumor cell killing. The ACTR construct is composed of the extracellular domain of CD16 fused to CD3ζ signaling and T cell co-stimulatory domains. ACTR-expressing T cells are universal in that they can be paired with a therapeutic antibody to target specific antigens on tumors. Unum has two ACTR constructs, ACTR087 and ACTR707, currently in clinical testing. ACTR087 and ACTR707 are being tested in combination with rituximab in subjects with CD20+ B cell lymphoma in two separate trials (NCT02776813 and NCT03189836, respectively). Preliminary data with ACTR087 + rituximab has demonstrated clinical proof-of-concept and a dose-response relationship in subjects with relapsed/refractory B cell lymphoma. ACTR087 is also being tested in combination with a novel BCMA-targeting antibody in subjects with multiple myeloma (NCT03266692). While T cell therapies, such as chimeric antigen receptor (CAR) T cells, have demonstrated clinical activity in hematological cancers, the therapeutic potential of this approach has yet to be established in solid tumors. Challenges associated with targeting solid tumors with CAR-T cells include tumor antigen heterogeneity and antigen expression on normal tissues. HER2 is a well-established therapeutic target that is over-expressed in a number of cancer indications. HER2 is also expressed at low levels on normal epithelial cells, creating a risk for on-target/off-tumor toxicities of HER2-targeted CAR-T cells. Here we present nonclinical studies demonstrating that ACTR T cells in combination with trastuzumab have antigen density-dependent activity on HER2-expressing tumor cell lines, while trastuzumab-based CAR-T cells do not. We observed that ACTR + trastuzumab had robust activity against HER2-amplified tumor cells and more modest activity against non-amplified tumor cells, whereas HER2-targeting CAR-T cells had comparable activity against HER2-amplified and non-amplified tumor cells. On normal human primary cells, ACTR + trastuzumab had minimal activity in comparison to HER2 CAR-T cells, suggesting that ACTR + trastuzumab may exhibit a superior clinical therapeutic index. Furthermore, the activity of ACTR T cells against HER2-amplified tumor cells was titratable with antibody concentration, allowing for control of ACTR activity by modulation of trastuzumab concentration. Together, these data demonstrate the specificity of the ACTR T cell therapeutic approach to target HER2-amplified tumors and support clinical testing in combination with trastuzumab. A phase 1, multicenter, single-arm, open-label dose escalation study, ATTCK-34-01, is proposed to evaluate ACTR T cells in combination with trastuzumab in subjects with advanced HER2-positive malignancies. The primary study objectives are to assess the safety and tolerability of the combination, and to define the recommended phase 2 dose combination for further study. Additional objectives include assessment of anti-tumor activity, ACTR T cell persistence and trastuzumab pharmacokinetics. Enrollment is expected to commence in early 2019. Citation Format: O'Callaghan KM, Shin J, Cheung AS, Cheema T, Judge C, Ranger A, Huet HA, Ettenberg SA, Sachs J, Vasconcelles M, Motz G. Antibody-coupled T cell receptor (ACTR) engineered autologous T cells in combination with trastuzumab for the treatment of HER2-positive malignancies [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT2-07-06.

Abstract CT046: A phase I basket study of the PI3K inhibitor taselisib (GDC-0032) in PIK3CA-mutated locally advanced or metastatic solid tumors

Abstract Background: PIK3CA, a gene that encodes the α-isoform of the catalytic subunit of Class I PI3K (PI3Kα), is frequently mutated or amplified in solid tumors. Taselisib is an oral, potent, selective inhibitor of Class I PI3Kα, γ, and δ isoforms with enhanced activity against PIK3CA-mutated cancer models. Preclinical and clinical data demonstrated that single-agent taselisib has activity in multiple PIK3CA-mutated tumor types. Methods: This open-label phase I study (Cohort X of PMT4979g; NCT01296555) enrolled patients (pts) with PIK3CA-mutated tumors who had progressed after, or failed to respond to, at least one prior treatment regimen and were not candidates for regimens known to provide clinical benefit. Pts received single-agent taselisib (4 or 6 mg tablet, daily). Eleven subcohorts comprised various solid tumor types: endometrial, bladder, head and neck squamous cell carcinoma (HNSCC), cervical, gastric/gastroesophageal junction, small cell lung, triple-negative breast, colorectal (excluding KRAS-mutated tumors), squamous (excluding histologies in the other subcohorts), ovarian, and pts with PIK3CA mutant tumors not otherwise specified (excluding breast, colorectal, and non-small-cell lung cancers). Tumor tissue (archival or fresh) was assessed centrally for PIK3CA mutation or amplification. The primary endpoint was tolerability and safety of taselisib. Other endpoints included assessment of antitumor activity per Response Evaluation Criteria In Solid Tumors (RECIST) v1.1. Results: At data cutoff (May 1, 2017), 146 pts have been enrolled. Overall, the most common adverse events (AEs; ≥30% of pts) were diarrhea (58.2%), nausea (39.0%), hyperglycemia (31.5%), and fatigue (30.8%). Ninety-four pts (64.4%) experienced ≥1 grade ≥3 AE and 53 pts (36.3%) had grade ≥3 AEs related to taselisib. Sixty-eight pts (46.6%) had serious AEs (SAEs) and the most common SAEs (>2 pts) related to taselisib treatment were colitis (5.5%), diarrhea (4.1%), and hyperglycemia (3.4%). Nine pts (6.2%) had grade 5 events; one AE with a fatal outcome (0.7%) was assessed by the investigator as related to taselisib (septic shock). AEs that led to dose reduction, interruption, or withdrawal were reported in 34 pts (23.3%), 59 pts (40.4%), and 14 pts (9.6%), respectively. Overall, confirmed response rates were 8.9% (n=13) and clinical benefit rates (confirmed response or without disease progression for ≥6 months) were 12.3% (n=18). Confirmed responses were observed in pts with endometrial cancer (2/10 [20.0%]), HNSCC (4/21 [19.0%]), and cervical cancer (2/19 [10.5%]), as well as other tumor types. Conclusions: Single-agent taselisib had an acceptable safety profile (with AEs that were generally reversible and manageable; no new safety signals were identified) and preliminary clinical activity in pts with PIK3CA-mutated locally advanced or metastatic solid tumors. Citation Format: Komal Jhaveri, Dejan Juric, Cristina Saura, Andrés Cervantes, Anton Melnyk, Manish R. Patel, Mafalda Oliveira, Valentina Gambardella, Vincent Ribrag, Cynthia X. Ma, Raid Aljumaily, Philippe L. Bedard, Jasgit C. Sachdev, John Bond, Surai Jones, Timothy R. Wilson, Michael C. Wei, José Baselga. A phase I basket study of the PI3K inhibitor taselisib (GDC-0032) in PIK3CA-mutated locally advanced or metastatic solid tumors [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 CT046.

Antitumor activity of ormustine against transplantable solid murine tumors. Part I

Background. Drugs of nitrosourea class are actively and successfully administered in oncology practice. However, at present, the search for new antitumor agents of this class is very urgent. Objective: to examine in vivo antitumor activity of ormustine, a new Russian drug from alkylnitrosourea class, against solid transplantable murine tumors: melanoma B16 and epidermoid Lewis lung carcinoma. Materials and methods. The assessment of antitumor activity of ormustine and a reference drug mustophoran (Les Labolatories Servier, France) was carried out in B6D2F1 mice. Ormustine was administered intravenously at a single dose of 50-135 mg/kg. Mustophoran was administered intravenously at a dose of 32 mg/kg twice (on days 2 and 9) and 3 times at a dose of 25 mg/kg (on days 2, 6 and 9). The follow-up period lasted till the death of animals. The antitumor effect of agents was assessed by the tumor growth inhibition and increase in life span of experimental mice compared to control animals. Results. It has been defined that the single intravenous dose of ormustine (125 mg/kg) is therapeutic for mice bearing melanoma B16 and epidermoid Lewis lung carcinoma. Conclusions. Ormustine possesses high antitumor effect against solid transplantable murine tumors. Ormustine is not inferior to mustophoran in the therapeutic effect against melanoma B16.

Functional Imaging and Assessment of Antitumor Activity in Systemic Therapy for Hepatocellular Carcinoma.

AbstractIncreasing use of novel systemic treatment options in the management of patients with advanced hepatocellular carcinoma (HCC) such as antiangiogenic and molecular-targeted therapies, poses unique challenges for effective treatment monitoring and efficacy assessment. The traditional morphological criteria such as response evaluation criteria in solid tumor (RECIST) rely on changes in tumor size to determine treatment efficacy. However, these criteria based on tumor morphology may not be suitable to monitor response to newer targeted therapies as early functional changes induced by these drugs precede changes in tumor size. Modifications of these morphological criteria that determine response based on tumor enhancement characteristics such as modified RECIST (mRECIST) will potentially allow improved determination of treatment response pending validation from prospective trials. Advanced functional imaging techniques such as perfusion imaging (computed tomography/magnetic resonance imaging [CT/MRI]), diffusion weighted MRI (DW-MRI) and positron emission tomography (PET/CT and PET/MRI) are being increasingly used as surrogate imaging biomarkers to provide superior assessment of changes in tumor physiology. Growing emphasis on precision oncological care tailored to specific tumor type and individual patients renders the use of these newer imaging modalities more pertinent and timely. In this review, the authors discuss the role of various imaging techniques and response assessment criteria in the evaluation of systemic therapy for advanced HCC with focus on functional imaging tools.

A phase 1, open-label, dose-escalation study of olaratumab as a single agent and in combination with doxorubicin, vincristine/irinotecan, or high-dose ifosfamide in pediatric patients with relapsed or refractory solid tumors.

TPS2599 Background: Olaratumab (LY3012207, IMC-3G3), a PDGFRα antagonist, is a targeted human IgG1 monoclonal antibody that specifically binds PDGFRα, blocking PDGF-AA, -BB, and -CC binding and receptor activation. Preclinical studies of olaratumab with or without chemotherapy have demonstrated antitumor activity in human sarcoma xenograft models. Positive survival outcomes were observed in adult patients with advanced soft tissue sarcoma when they were treated with olaratumab + doxorubicin vs doxorubicin alone in a randomized phase 2 trial. Methods: This multicenter clinical trial (NCT02677116) includes patients < 18 years of age with a diagnosis of relapsed or refractory solid tumors not amenable to curative treatment, for whom chemotherapy with doxorubicin, vincristine/irinotecan, or high-dose ifosfamide is deemed appropriate. The primary objective is to determine a recommended dose of olaratumab + ≥1 chemotherapy regimen(s) in pediatric patients based on any dose-limiting toxicity, and olaratumab serum exposure-matching between adult and pediatric patients. Secondary objectives include assessment of antitumor activity of each combination, immunogenicity, and pharmacokinetics. At least 12 pediatric patients will be treated with 1 cycle (21 days) of olaratumab monotherapy (dose level 1 [Part A] and dose level 2 [Part B]) on Days 1 and 8. If the patient does not experience a dose-limiting toxicity in the first cycle of monotherapy, the patient will then receive olaratumab plus either doxorubicin, vincristine/irinotecan, or high-dose ifosfamide per investigator discretion. Dose-limiting toxicity criteria will also be evaluated for the respective combinations in cycle 2. Treatment will continue until disease progression or other discontinuation criteria are met. Dose level 2 will be initiated after acceptable safety results from dose level 1 monotherapy (a minimum of 6 evaluable patients, and the pharmacokinetic profile). As of December 2016, enrollment is currently occurring in dose level 1. Clinical trial information: NCT02677116.

A phase I dose escalation (DE) and cohort expansion (CE) study of ERY974, an anti-glypican 3 (GPC3)/CD3 bispecific antibody, in patients with advanced solid tumors.

TPS3112 Background: Bispecific antibodies to facilitate T-cell directed cytotoxicity (TDCC) is a proven therapy strategy in cancer. ERY974 is a humanized IgG4 bispecific antibody designed to simultaneously bind to cytotoxic T-cell CD3 receptors and GPC3 (a glycoprotein expressed on cell surface of several tumors) to elicit T-cell activation and TDCC. The objectives of this multi-country, phase 1 study of ERY974 is to determine the maximum tolerated dose (MTD) and to perform a preliminary assessment of anti-tumor activity in patients with solid tumors expressing GPC3. Methods: ERY974 is dosed IV weekly. All patients receive premedication with dexamethasone (DEX) prior to 1st and 2nd ERY974 dose. DE uses an accelerated titration design (ATD), then a modified continual reassessment method (mCRM) described by one-parameter logistic model, to determine MTD, where DLT occurrence rate is 0.25. Combining ATD and mCRM is to permit rapid dose escalation whilst minimizing patient numbers exposed to sub-therapeutic doses, and to accurately determine MTD. Once grade 2 (G2) cytokine release syndrome (CRS) is observed, DEX is increased. If ≥G2 CRS is again observed, then at all subsequent doses the 1st dose of ERY974 is fixed at the last dose level when < G2 CRS was not seen, DE proceeds with the 2nd dose. ATD commences with n = 1, increasing to n = 3 once drug-related ≥G2 toxicity is seen. mCRM starts after 1st dose limiting toxicity (DLT), with the modifications of at least 3 patients required to dose escalate and up to 1.5x increment to minimize risk of toxicity. CE has 3 arms: GPC3+ gastric/gastroesophageal junction adenocarcinoma; GPC3+ squamous esophageal cancer; and other GPC3+ tumors. A 2-stage design is used to allow CE to stop early for futility. Subjects are adults with histologically confirmed, measurable malignant solid tumors and/or metastatic disease not amenable to standard therapy, and life expectancy ≥3 months. Patients with > 1cm or > 1 brain metastasis, current/previous interstitial lung disease, and acute/chronic infection are excluded. 3 cohorts have been completed without DLT. Cohort 4 began in January 2017. Clinical trial information: NCT02748837.

Antitumor activity of panRAF inhibition in BRAF V600E metastatic colorectal cancer.

616 Background: BRAF V600E mutations, present in <10% of patients with metastatic colorectal cancer (mCRC), are associated with low responses to chemotherapy and poor survival outcomes. Targeted therapies against BRAF and EGFR have shown promising clinical activity. The panRAF inhibitor (PRI) LSN3074753 inhibits dimerization of all RAF isoforms to impede downstream MEK activation, with no reflexive MAPK reactivation common with other BRAF inhibitors. Anti-tumor activity of PRI has not been compared to BRAF + EGFR inhibition in patient-derived xenograft (PDX) models of BRAF V600E mCRC. Methods: Two PDX models of BRAF V600E mCRC (B1003 and C0999) were generated. C0999 featured a concomitant KRAS G12D mutation following resistance to the BRAF V600E kinase inhibitor vemurafenib. Mice were treated daily with oral PRI or with the combination of vemurafenib + intraperitoneal cetuximab. Tumor volumes were measured twice weekly. B1003 and C0999 cell cultures were established to test the interaction between PRI and palbociclib or BYL319 (PI3K inhibitor). Results: PRI was tolerated at a dose of 60 mg/kg and demonstrated a reduced tumor volume in the B1003 model after 28 days when compared to untreated controls (P=.03). No difference in tumor volume was seen between PRI and vemurafenib + cetuximab (P=.08). Assessment of anti-tumor activity by PRI in the vemurafenib-resistant BRAF V600E/KRAS G12D C0999 model will be reported. Cell culture from both the B1003 and C0999 models demonstrated synergism for PRI with palbociclib (ED50 .41 and .62 for the 2 models, respectively) and with BYL319 (ED50 .48 and .86, respectively). Conclusions: panRAF inhibition demonstrates similar anti-tumor activity to BRAF + EGFR inhibition in PDX models of BRAF V600E and represents a promising treatment strategy for further combination studies targeting additional critical signaling pathways in mCRC.

Abstract CT027: A phase I, open-label study of GSK3174998 administered alone and in combination with pembrolizumab in patients (pts) with selected advanced solid tumors (ENGAGE-1)

Abstract Background: OX40 (CD134) belongs to the tumor necrosis factor receptor (TNFR) family, and transduces a costimulatory signal during T-cell activation. In the periphery, OX40 expression is limited to recently activated CD4+ and CD8+ cells. In tumors, infiltrating T lymphocytes are enriched for OX40, where it augments T-cell activation, proliferation and survival. OX40 is also expressed on tumor infiltrating regulatory T cells (Tregs). Intratumoral Treg depletion is critical for the in vivo antitumor activity of immune checkpoint antibodies. OX40 can also be found on natural killer (NK) cells, mediating antibody-dependent cellular cytotoxicity. Together, these mechanisms make stimulation of OX40 with agonistic agents an attractive target for a novel anti-cancer immunotherapy. GSK3174998 is a humanized IgG1 anti-OX40 agonistic monoclonal antibody identified through collaboration with MD Anderson Cancer Center and is currently in phase I development. Methods: The primary objective of this open-label non-randomized multicenter phase I study is to evaluate the safety of GSK3174998, as monotherapy in escalating doses every 3 weeks IV for up to 48 weeks (Part 1) or in combination with 200 mg pembrolizumab administered every 3 weeks IV for up to 2 years (Part 2). Secondary objectives include assessment of antitumor activity, pharmacokinetics, pharmacodynamics and immunogenicity. Adverse events will be monitored using NCI CTCAE v. 4.0. Radiographic imaging will be obtained every 12 weeks to assess clinical response defined by immune-related RECIST. Exploratory objectives include examination of changes in genomic DNA, RNA, protein, measures of immune function in tumor, and the association of these with antitumor activity. The study will enroll up to approximately 180 pts; eligible pts will have measurable disease with documentation of metastatic non-small cell lung cancer, squamous cell carcinoma of the head and neck, renal cell carcinoma, melanoma, bladder, soft tissue sarcoma, triple-negative breast cancer, and colorectal carcinoma displaying microsatellite instability that has progressed after standard therapy, or for which standard therapy is ineffective, intolerable, or inappropriate. A pre-treatment biopsy is requested of all pts. Matched pre-treatment and on-treatment biopsies will be performed in expansion cohorts to allow investigation of candidate biomarkers which may predict clinical response. As of Feb 1, 2016, monotherapy cohorts 1 and 2 have completed without DLT and enrollment to Cohort 3 is ongoing. This study (NCT02528357) is funded by GlaxoSmithKline. Citation Format: Jeffrey Infante, Christoph M. Ahlers, F Stephen Hodi, Sopie Postel-Vinay, Jan HM Schellens, John V. Heymach, Karen Autio, Mary Barnette, Herbert Struemper, Maura Watmuff, Elaine M. Paul, David R. Kaufman, Jeffrey S. Weber, Axel Hoos. A phase I, open-label study of GSK3174998 administered alone and in combination with pembrolizumab in patients (pts) with selected advanced solid tumors (ENGAGE-1). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT027.

Abstract 1816: Assessment of anti-tumor activity of the cathepsin L inhibitor, KGP94

Abstract Purpose: The cysteine cathepsin proteases are known to play an important role in tumor progression, invasion and angiogenesis. The present study evaluated the anti-tumor activity and pharmacokinetics of the small-molecule cathepsin L inhibitor KGP94. Materials and Methods: Male CDF1 or C3H/HeNHsd mice were inoculated on the right rear foot with a C3H mammary carcinoma or a SCCVII carcinoma, respectively. A solution of KGP94 was prepared each day by dissolving in a mixture of 10% Tween 80 and 90% HEPES-buffer. It was intraperitoneally injected at 0.01 ml/g mouse bodyweight. Various doses (1-20 mg/kg) were administered between 1-20 days, starting from the day of tumor inoculation. Anti-tumor activity was assessed by determining the tumor growth time, which was the time in days to reach a volume of 500 mm3 (TGT500). Pharmacokinetics of KGP94 were investigated by drawing blood samples before, and up to 24 hours after KGP94 injection. Results are listed as Mean (± Standard Error). One-way ANOVA comparison of group means was performed, and a P<0.05 was considered significant. Results: The TGT500 for control animals was 18.0 days (± 0.3) for the C3H mammary carcinoma and 13.6 days (± 0.7) for the SCCVII carcinoma. Treating tumors with KGP94 significantly increased the TGT500 for both tumor models to around 21 and 17 days respectively, when doses were at 10.0 mg/kg or higher. At a dose of 5.0 mg/kg the TGT500 of the C3H mammary carcinoma was significantly increased to 21.4 days (± 1.1), whereas the TGT500 of the SCCVII carcinoma was unchanged at 13.8 (± 0.2). At lower KGP94 doses neither tumor model showed significant growth delay. Additional experiments with the C3H mammary carcinoma model showed that treatment was most effective when started immediately after tumor inoculation, and that treatment for 5 days was just as effective as 20 days. Pharmacokinetic analysis of KGP94 levels in mouse plasma is ongoing. Conclusion: In the C3H mammary carcinoma KGP94 significantly delayed tumor growth, but the effect was primarily on the early phase following tumor cell inoculation. This suggests that KGP94 may have a more significant role in inhibiting the establishment of metastasis rather than influencing the growth of established tumors. Significant growth delay was also observed in the SCCVII tumor model. However, it occurred with higher doses of KGP94 compared to the C3H mammary carcinoma. The higher dose could be explained by the more aggressive nature of the SCCVII tumor model. Supported by The Danish Cancer Society, The Danish Council for Independent Research: Medical Sciences, and OXiGENE Inc. Citation Format: Thomas R. Wittenborn, Michael Stratford, Mary Lynn Trawick, Kevin G. Pinney, David J. Chaplin, Dietmar W. Siemann, Michael R. Horsman. Assessment of anti-tumor activity of the cathepsin L inhibitor, KGP94. [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 1816. doi:10.1158/1538-7445.AM2014-1816

Prognostic value of waterfall plots with the addition of nontarget lesion data.

11082 Background: In patients with solid tumors, the use of a waterfall plot displaying the best percentage change in sum of the longest diameters of target lesions per patient is a common way to depict anti-tumor activity for cytostatic agents (Booth 2008, Dhani 2009). This representation assumes that the best percentage change represents the maximum anti-tumor activity for each patient. Information about new lesions and/or changes in non-target lesions is not incorporated in the waterfall plot; yet these additional events were found to be significant prognostic factors for overall survival adjusting for change in the target lesions (Litiere 2012, Suzuki 2012). Methods: We analyzed two phase III lung cancer trials of 1st and 2nd line combination chemotherapy ± ASA404 (ATTRACT-1,n=1299, ATTRACT-2, n= 920). For patients whose best response in the target lesions was shrinkage, we calculated how often this best response was synchronously accompanied by non-target disease progression. Results: See Table. Conclusions: There can be substantial tumor shrinkage in target lesions synchronously with progressive disease outside the target lesions. Therefore, graphical displays of anti-tumor activity should consider incorporating new and non-target lesion information, as well as target lesion tumor burden. We propose an extended waterfall plot presenting a more complete assessment of anti-tumor activity by incorporating non-target lesion information. We illustrate its utility in an additional data set, the RECORD-1 phase III renal cell cancer trial. Clinical trial information: NCT00662597. [Table: see text]

MLN9708, a Novel, Investigational Proteasome Inhibitor, in Patients with Relapsed/Refractory Lymphoma: Results of a Phase 1 Dose-Escalation Study

Abstract 2672 Background:MLN9708 is an investigational, potent, reversible, and specific 20S proteasome inhibitor. It is immediately hydrolyzed in vivo to MLN2238, the biologically active dipeptidyl leucine boronic acid. In preclinical studies, MLN2238 showed faster proteasome dissociation and greater tissue penetration than bortezomib. In OCI-Ly10 and PHTX22L mouse models of lymphoma, prolonged tumor proteasome inhibition and enhanced antitumor activity was seen with MLN2238 compared with bortezomib. Both intravenous (IV) and oral formulations are in clinical development. Here we report data from the first phase 1 study of IV MLN9708 in patients with lymphoma (ClinicalTrials.gov: NCT00893464). Methods:The primary objectives were to determine the maximum tolerated dose (MTD) and safety of MLN9708. Other objectives included characterization of the pharmacokinetic (PK)/pharmacodynamic (PD) profile, and assessment of antitumor activity and tumor biomarkers. Adults with lymphoma who had failed at least 2 chemotherapeutic regimens received IV MLN9708 on days 1, 8, and 15 of 28-day cycles for up to 12 cycles or until disease progression or unacceptable toxicity occurred. Patients had ECOG PS 0–2, adequate renal, hepatic, and hematologic function, and no grade ≥2 peripheral neuropathy. One patient was enrolled at the starting dose of 0.125 mg/m2; dose doubling proceeded with 1 patient at each dose level up to 1.0 mg/m2. Dose escalation then proceeded in ≤40% increments via a standard 3+3 scheme based on DLT occurrence in cycle 1. The MTD was defined as the highest dose resulting in DLT during cycle 1 in 0/3 or 1/6 patients. Adverse events (AEs) were graded using NCI-CTCAE v3.0. Blood samples were collected at multiple time points after dosing on days 1 and 15 of cycle 1 for PK/PD analysis. PK and PD parameters were calculated using noncompartmental methods (WinNonlin v5.3). Archived tumor specimens were used for biomarker analysis. Response was assessed using International Working Group criteria for lymphoma. Results:At data cut-off (July 8, 2011), 17 patients had been enrolled and treated: 1 each at 0.125, 0.25, 0.5, and 1.0 mg/m2, 4 at 1.4 mg/m2, 7 at 1.76 mg/m2, and 2 at 2.34 mg/m2. The median age was 53 years (range 23–78). Histologies were follicular lymphoma (n=6), diffuse large B-cell lymphoma (n=3), Hodgkin lymphoma (n=3), T-cell lymphoma (n=3), and other (n=2). The median number of prior therapies was 5, including radiation and stem cell transplant in 29% of patients each; 47% had received ≥6. Patients received a median of 2 cycles (range 1–16); treatment is ongoing in 3 patients. Two DLTs were seen (1.76 mg/m2, grade 4 neutropenia; 2.34 mg/m2, grade 3 neutropenia delaying cycle 2 by >1 week); the MTD has not yet been reached. Drug-related AEs included fatigue (n=8), diarrhea (n=5), nausea (n=5) and vomiting, pyrexia, neutropenia, thrombocytopenia, and headache (n=4 each). Drug-related peripheral neuropathy was reported in 3 patients (one grade 1, two grade 2 in patients with peripheral neuropathy at baseline). Grade ≥3 drug-related AEs were seen in 8 patients, including neutropenia (n=4) and thrombocytopenia (n=3). Two patients treated at 1.4 mg/m2 had SAEs (grade 3 increased creatinine, grade 2 pyrexia). There were no on-study deaths. One patient treated at 2.34 mg/m2 discontinued due to drug-related grade 3 neutropenia. Three patients treated at 1.76 mg/m2 required dose reductions. Of 16 response-evaluable patients, 3 achieved partial response and continue to respond (2/6 with follicular lymphoma at 1.4 and 1.76 mg/m2, 1/3 with T-cell lymphoma at 2.34 mg/m2); duration of response is >9 months in a patient with follicular lymphoma. Stable disease, durable for up to 3.7 months, occurred in 4 patients. MLN2238 plasma concentration decreased by 90% within 4 hours post dose. After multiple dosing, the terminal half-life ranged from 4–8 days. Plasma exposure appeared to increase proportionally with increasing dose from 0.5–2.34 mg/m2. Whole blood 20S proteasome inhibition was immediate, and maximal inhibition correlated with maximum plasma concentration. Conclusions:These data suggest that once-weekly MLN9708 is generally well tolerated and has early signs of clinical activity in some patients with heavily treated lymphoma. Dose escalation continues to determine the MTD; a total of 16 patients will be evaluated at the MTD. Updated data and analyses of patient stratification biomarkers will be presented. Disclosures:Off Label Use: Use of investigational agent MLN9708 for the treatment of relapsed/refractory lymphoma. Rifkin:Amgen: Speakers Bureau; Celgene: Speakers Bureau; Millennium Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Onyx: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Hui:Millennium Pharmaceuticals, Inc.: Employment. Berg:Millennium Pharmaceuticals, Inc.: Employment. Gupta:Millennium Pharmaceuticals, Inc.: Employment. Xi:Millennium Pharmaceuticals, Inc.: Employment. Di Bacco:Millennium Pharmaceuticals, Inc.: Employment. Martin:Millennium Pharmaceuticals, Inc.: Research Funding, Speakers Bureau.