ALBERT

Description: Background: The near ubiquity and persistence of CD20 expression in B-cell malignancies provides a strong rationale for novel CD20-directed therapies. MT-3724 is a novel engineered toxin body comprised of an anti-CD20 single chain variable fragment genetically fused to Shiga-like toxin A subunit, which forces internalization of CD20-bound MT-3724, irreversibly inactivating ribosomes and triggering apoptosis. As MT-3724 competes with rituximab (RTX) for the same CD20 binding domain, undetectable or low (〈 500 ng/mL) RTX levels (RTX-neg) allow potential response to MT-3724. We present final safety and efficacy results from dose escalation to maximum tolerated dose (MTD) in Non-Hodgkin Lymphoma (NHL) subjects (subj) and dose expansion in RTX-neg DLBCL subj. Methods: In Part 1, MT-3724 dose was escalated in 21 subj with B-cell NHL according to the 3+3 design based on ≤1 subj exhibiting DLT during Cycle 1 (28 days) in 6 sequential dose cohorts (5, 10, 20, 50, 75, and 100 μg/kg/dose IV over 2 hours 3 times per week for 2 of 4 consecutive weeks) for up to 5 cycles. In Part 2, the safety and efficacy of MT-3724 was further evaluated in 6 RTX-neg subj with DLBCL. Tumor response was assessed by the International Working Group Response Criteria for Clinical Trials (Cheson 2007). Results: Twenty-seven subj with NHL (DLBCL:16, composite DLBCL/Follicular Lymphoma (FL): 3, FL: 6, Mantle Cell Lymphoma: 2 were enrolled. Seventeen (63%) were female, mean age was 65 yrs (34-78). Performance status was ECOG 0: 44%, 1: 44%, 2: 11%; median follow-up was 50 (11-372) days; median cycles 2 (1-11). The most common AEs (%) of all grades were peripheral edema (63), fatigue (41), diarrhea (41), myalgia (41), muscle weakness (33), insomnia (30); 27 subj had AEs (%) with related causality, the most common were: peripheral edema (41), myalgia (33), fatigue (26). The most common related grade (G) ³3 AEs included neutropenia, myalgia, and infections (all 11%); There were 9 related SAEs among 6 subj. One subj died on study from disease progression. MT-3724 was not tolerated at 100 µg/kg/dose (DLTs: G3 pneumonia, G2 ileus). After 2 obese (BMI 〉35) subj treated at 75 µg/kg/dose in the expansion cohort had G2 capillary leak syndrome (CLS), the MTD was set at 50 µg/kg/dose with a 6000 mg/dose cap. Innate immune responses such as CLS or manifestations thereof (hypotension, hypoalbuminemia, peripheral edema) were noted with increasing frequency with higher doses of MT-3724. No cases of 〉G2 CLS have been observed. Of the 13 RTX-neg DLBCL subj, 5 (38%) responded across the range of 5 to 50 μg/kg/dose. All responses were partial responses (PRs) including 1 subj with composite DLBCL/FL post autologous stem cell transplantation (SCT) who had a complete metabolic response of a large mesenteric mass and proceeded to allogeneic SCT. Three subj had stable disease (SD) including two with 49% and 47% tumor reductions, one of whom had FL transformed from DLBCL post autologous SCT; another 5 had progressive disease. Given a limited prescribed period of treatment with MT-3724, duration of response cannot be calculated, however, generally the tumor burden in responders decreased with repeat treatment. Among the responders, mean age was 61 (50-76) yrs, and the median number of prior lines of NHL therapy received was 3 (1-8). Subj with detectable baseline RTX levels did not benefit from MT-3724. Of all 20 subj measured, 6 developed anti-drug antibodies (ADAs) during the first cycle of therapy; 5 developed ADAs at a later timepoint; 6 did not develop ADAs. ADAs were observed in all subj who showed a response, and in 4 of 5 subj with SD. Increasing MT-3724 dose was associated with a dose-dependent peripheral B-cell depletion, evidenced by decreasing CD19+ cells. Conclusions MT-3724 is the first CD20 targeted immunotoxin to enter clinical trials. Safety events were mostly mild-moderate, and DLTs were in line with the mechanism of action of MT-3724. A tolerable dose and schedule have been identified: 50 μg/kg/dose up to a maximum of 6000 μg/dose infused over 1 hour on days 1, 3, 5, 8, 10, and 12 of a 21-day cycle. A 38% objective response rate has been observed with monotherapy in a heavily pretreated, RTX-neg DLBCL population; of these subj, 5 were treated at 50 ug/kg (MTD) and 3 of whom responded. The development of ADAs did not preclude benefit of MT-3724. An ongoing phase 2 monotherapy study to confirm efficacy and safety in RTX-neg subj with DLBCL (NCT02361346) is open for recruitment. Disclosures Musteata: Institute of Oncology: Employment; Arensia EM: Other: Principal Investigator. Park:BMS: Consultancy, Research Funding; Rafael Pharma: Membership on an entity's Board of Directors or advisory committees; G1 Therapeutics: Consultancy; Teva: Consultancy, Research Funding; Gilead: Speakers Bureau; Seattle Genetics: Research Funding, Speakers Bureau. Burnett:Molecular Templates, Inc.: Employment. Dabovic:Molecular Templates, Inc.: Employment. Williams:Molecular Templates, Inc.: Employment. Higgins:Molecular Templates, Inc.: Employment, Equity Ownership. Persky:Sandoz: Consultancy; Morphosys: Other: Member, Independent Data Monitoring Committee; Debiopharm: Other: Member, Independent Data Monitoring Committee; Bayer: Consultancy.

Description: The light-wind, clear-sky, very stable boundary layer (vSBL) is characterized by large values of bulk Richardson number. The light winds produce weak shear, turbulence, and mixing, and resulting strong temperature gradients near the surface. Here five nights with weak-wind, very stable boundary layers during the Cooperative Atmosphere–Surface Exchange Study (CASES-99) are investigated. Although the winds were light and variable near the surface, Doppler lidar profiles of wind speed often indicated persistent profile shapes and magnitudes for periods of an hour or more, sometimes exhibiting jetlike maxima. The near-surface structure of the boundary layer (BL) on the five nights all showed characteristics typical of the vSBL. These characteristics included a shallow traditional BL only 10–30 m deep with weak intermittent turbulence within the strong surface-based radiation inversion. Above this shallow BL sat a layer of very weak turbulence and negligible turbulent mixing. The focus of this paper is on the effects of this quiescent layer just above the shallow BL, and the impacts of this quiescent layer on turbulent transport and numerical modeling. High-frequency time series of temperature T on a 60-m tower showed that 1) the amplitudes of the T fluctuations were dramatically suppressed at levels above 30 m in contrast to the relatively larger intermittent T fluctuations in the shallow BL below, and 2) the temperature at 40- to 60-m height was nearly constant for several hours, indicating that the very cold air near the surface was not being mixed upward to those levels. The presence of this quiescent layer indicates that the atmosphere above the shallow BL was isolated and detached both from the surface and from the shallow BL. Although some of the nights studied had modestly stronger winds and traveling disturbances (density currents, gravity waves, shear instabilities), these disturbances seemed to pass through the region without having much effect on either the SBL structure or on the atmosphere–surface decoupling. The decoupling suggests that under very stable conditions, the surface-layer lower boundary condition for numerical weather prediction models should act to decouple and isolate the surface from the atmosphere, for example, as a free-slip, thermally insulated layer. A multiday time series of ozone from an air quality campaign in Tennessee, which exhibited nocturnal behavior typical of polluted air, showed the disappearance of ozone on weak low-level jets (LLJ) nights. This behavior is consistent with the two-stratum structure of the vSBL, and with the nearly complete isolation of the surface and the shallow BL from the rest of the atmosphere above, in contrast to cases with stronger LLJs, where such coupling was stronger.