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Background: Coronavirus disease 2019 (Covid-19) pneumonia is often associated with hyperinflammation. Safety and efficacy of the anti-interleukin-6 receptor antibody tocilizumab was evaluated in patients hospitalized with Covid-19 pneumonia. Methods: Nonventilated patients hospitalized with Covid-19 pneumonia were randomized (2:1) to tocilizumab (8 mg/kg intravenous) or placebo plus standard care. Sites enrolling high-risk and minority populations were emphasized. The primary endpoint was cumulative proportion of patients requiring mechanical ventilation or who had died by Day 28. Results: Of 389 randomized patients, 249 patients received tocilizumab and 128 received placebo in the modified intent-to-treat population (Hispanic/Latino, 56.0%; Black/African American, 14.9%; American Indian/Alaska Native, 12.7%; White, 12.7%; other/unknown, 3.7%). The cumulative proportion (95% confidence interval [CI]) of patients requiring mechanical ventilation or who had died by Day 28 was 12.0% (8.52% to 16.86%) and 19.3 % (13.34% to 27.36%) for the tocilizumab and placebo arms, respectively (log-rank P=0.0360; hazard ratio, 0.56 [95% CI, 0.33 to 0.97]). Median time to clinical failure up to Day 28 favored tocilizumab over placebo (hazard ratio 0.55 [95% CI, 0.33 to 0.93]). All-cause mortality by Day 28 was 10.4% with tocilizumab and 8.6% with placebo (weighted difference, 2.0% [95% CI, -5.2% to 7.8%). In the safety population, serious adverse events occurred in 15.2% of tocilizumab patients (38/250 patients) and 19.7% of placebo patients (25/127). Conclusions: This trial demonstrated the efficacy and safety of tocilizumab over placebo in reducing the likelihood of progression to requiring mechanical ventilation or death in nonventilated patients hospitalized with Covid-19 pneumonia.

Summary Patients with advanced solid malignancies were enrolled to an open-label, single-arm, dose-escalation study, in which CRLX101 was administered intravenously over 60 min among two dosing schedules, initially weekly at 6, 12, and 18 mg/m2 and later bi-weekly at 12, 15, and 18 mg/m2. The maximum tolerated dose (MTD) was determined at 15 mg/m2 bi-weekly, and an expansion phase 2a study was completed. Patient samples were obtained for pharmacokinetic (PK) and pharmacodynamic (PD) assessments. Response was evaluated per RECIST criteria v1.0 every 8 weeks. Sixty-two patients (31 male; median age 63 years, range 39-79) received treatment. Bi-weekly dosing was generally well tolerated with myelosuppression being the dose-limiting toxicity. Among all phase 1/2a patients receiving the MTD (n=44), most common grade 3/4 adverse events were neutropenia and fatigue. Evidence of systemic plasma exposure to both the polymer-conjugated and unconjugated CPT was observed in all treated patients. Mean elimination unconjugated CPT Tmax values ranged from 17.7 to 24.5 h, and maximum plasma concentrations and areas under the curve were generally proportional to dose for both polymer-conjugated and unconjugated CPT. Best overall response was stable disease in 28 patients (64 %) treated at the MTD and 16 (73 %) of a subset of NSCLC patients. Median progression-free survival (PFS) for patients treated at the MTD was 3.7 months and for the subset of NSCLC patients was 4.4 months. These combined phase 1/2a data demonstrate encouraging safety, pharmacokinetic, and efficacy results. Multinational phase 2 clinical development of CRLX101 across multiple tumor types is ongoing.

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IntroductionCombretastatin A4-phosphate, fosbretabulin tromethamine (CA4P) is a vascular disrupting agent that targets tumor vasculature. This study evaluated the safety of CA4P when combined with carboplatin, paclitaxel, and bevacizumab in chemotherapy-naïve subjects with advanced nonsquamous, non-small-cell lung cancer.MethodsAdult subjects with confirmed American Joint Committee on Cancer six stage IIIB/IV non-small-cell lung cancer and an Eastern Cooperative Oncology Group performance score of 0 or 1 were randomized to receive six cycles (treatment phase) of paclitaxel (200 mg/m2), carboplatin (area under the concentration versus time curve 6), and bevacizumab (15 mg/kg) on day 1 and repeated every 21 days, or this regimen plus CA4P (60 mg/m2) on days 7, 14, and 21 of each cycle. Subjects could then receive additional maintenance treatment (excluding carboplatin and paclitaxel) for up to 1 year.ResultsSixty-three subjects were randomized, 31 to control and 32 to CA4P, and 19 (61.3%) and 17 (53.1%), respectively, completed the treatment phase. Exposure to study treatment and dose modifications were comparable between the randomized groups. The overall incidence of treatment-emergent adverse events was similar between groups, with increased neutropenia, leukopenia, and hypertension in the CA4P group. Deaths, serious adverse events, and early discontinuations from treatment were comparable between the randomized treatment groups. The overall tumor response rate with CA4P was 50% versus 32% in controls. Overall and progression-free survival rates were comparable between the groups.ConclusionCA4P plus carboplatin, paclitaxel, and bevacizumab appears to be a tolerable regimen with an acceptable toxicity profile in subjects with advanced non-small-cell lung cancer.

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Introduction: Immunochemotherapy is standard of care treatment for previously untreated patients (pts) with advanced stage follicular lymphoma (FL). However, the majority of pts relapse, with around 20% relapsing within 2 years. Obinutuzumab (GA101; G) is a glycoengineered type II anti-CD20 monoclonal antibody (mAb) with increased antibody-dependent cell-mediated phagocytosis and cytotoxicity, and direct B-cell killing, compared with the type I mAb rituximab (R). The randomized Phase III GALLIUM study (NCT01332968) compared the efficacy and safety of G-chemotherapy (G-chemo) vs R-chemotherapy (R-chemo) in previously untreated pts with advanced stage FL. In the primary analysis (PA), a significant improvement in the primary study endpoint of investigator (INV)-assessed progression-free survival (PFS) was demonstrated with G-chemo relative to R-chemo after 34.5 months' median follow-up. Results for other time-to-event outcomes (including time-to-next treatment; TTNT) were supportive, and additional analyses demonstrated a higher rate of minimal residual disease, and a lower risk of disease progression within 24 months, in the G-chemo arm. Here we report the results from an updated analysis of time-to-event endpoints and safety in the GALLIUM study. Methods: In GALLIUM, enrolled pts were aged ≥18 years with previously untreated FL (grades 1-3a), Stage III/IV disease (or Stage II with bulky disease), and ECOG PS 0-2, and requiring treatment according to GELF criteria. Pts were randomized 1:1 to receive G 1000mg IV (days 1, 8 and 15 of cycle 1 and day 1 of subsequent cycles) or R 375mg/m2 IV (day 1 of each cycle) plus chemotherapy for 6 or 8 cycles, depending on the chemotherapy backbone (CHOP, CVP, or bendamustine). Chemotherapy backbone was a stratification factor and was chosen upfront by the participating centers. Pts with a complete or partial response at the end of induction received maintenance with the same antibody every 2 months for 2 years. The data cut-off for the current analysis was February 12, 2018. Results: In total, 1202 pts with FL were enrolled (G-chemo, n=601; R-chemo, n=601), with a median age of 59 years (46.8% male). After 57.3 months' median follow-up, a sustained and clinically meaningful improvement in INV-assessed PFS was observed with G-chemo relative to R-chemo (HR 0.73; 95% CI: 0.59, 0.90; p=0.0034; 4-year PFS rate: G-chemo, 78.1% [95% CI: 74.4%, 81.3%]; R-chemo, 67.2% [95% CI: 63.1%, 71.0%]; Figure 1A). Since the PA, 114 new PFS events (57 in G-chemo and 57 in R-chemo) had occurred. Overall survival (OS) data, which remain immature, were comparable across treatment arms (HR 0.88; 95% CI: 0.61, 1.27; p=0.49; 4-year OS rate: G-chemo, 92.6% [95% CI: 90.1%, 94.4%]; R-chemo, 90.3% [95% CI: 87.6%, 92.5%]; Figure 1B). A sustained benefit in favor of G-chemo was observed in TTNT (HR 0.70; 95% CI: 0.54, 0.90; p=0.0046; 4-year TTNT rate: G-chemo, 84.2% [95% CI: 80.9%, 86.9%]; R-chemo, 76.7% [95% CI: 73.1%, 80.0%]; Figure 1C). Since the PA, 29 and 36 additional pts in the G- and R-chemo arms, respectively, had received new anti-lymphoma treatment. At cut-off, 54 (9.1%) pts in the G-chemo arm and 61 (10.2%) in the R-chemo arm had died. Common causes were disease progression (G-chemo, n=21 [3.5%]; R-chemo, n=28 [4.7%]) and AEs (G-chemo, n=24 [4.0%]; R-chemo, n=24 [4.0%]). The most common fatal AEs were infections (9 vs 4 pts, respectively) and new malignancies (5 vs 6 pts, respectively). Incidences of AEs of any grade were comparable across the G-chemo (99.8%) and R-chemo (99.5%) arms, although grade 3-5 AEs (79.2% vs 71.2%) and serious AEs (48.7% vs 42.2%) were more common in the G-chemo arm. AEs led to discontinuation in 16.3% of G-chemo pts and 14.6% of R-chemo pts. As in the PA, the incidence of grade 3-5 infections (22.2% vs 18.6%), grade 3-5 neutropenia (and associated complications reported as AEs, 48.4% vs 41.4 %), and grade 3-5 second malignancies (6.9% vs 4.4%) was numerically higher in pts receiving G-chemo than R-chemo. Conclusions: In line with the PA, the results from this updated analysis of the GALLIUM study, with a median follow-up of almost 5 years, reinforce that G-chemo provides clinically meaningful improvements in outcomes relative to R-chemo in previously untreated FL pts. OS data remain immature, with additional follow-up needed to draw conclusions. Safety data are consistent with those reported in the PA. Figure 1. Figure 1. Disclosures Townsend: Gilead: Consultancy; Roche: Consultancy. Buske:Roche: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Bayer: Research Funding. Cartron:Roche: Consultancy, Honoraria; Sanofi: Honoraria; Gilead Sciences: Honoraria; Janssen: Honoraria; Celgene: Consultancy, Honoraria. Cunningham:Roche pharmaceuticals: Research Funding. Dyer:Roche: Honoraria, Research Funding. Gribben:Medical Research Council: Research Funding; Acerta Pharma: Honoraria, Research Funding; Roche: Honoraria; Novartis: Honoraria; Janssen: Honoraria, Research Funding; TG Therapeutics: Honoraria; Abbvie: Honoraria; Wellcome Trust: Research Funding; Unum: Equity Ownership; Pharmacyclics: Honoraria; NIH: Research Funding; Cancer Research UK: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Kite: Honoraria. Hess:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Other: travel expenses, Research Funding; CTI: Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Keller:BMS: Consultancy; Celgene: Research Funding; MSD: Consultancy; Takeda: Consultancy, Research Funding; Janssen-Cilag: Consultancy, Equity Ownership; Roche: Consultancy. Kneba:Roche: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Malladi:Roche: Membership on an entity's Board of Directors or advisory committees. Neidhart:Gilead: Consultancy; Roche: Consultancy, Other: Travel support and lecture fees. Rusconi:Celgene: Research Funding. Zhu:Beijing Cancer Hospital (Peking University Cancer Hospital): Employment. Catalani:Roche: Employment. Knapp:Roche: Employment. Zeuner:F. Hoffman-La Roche: Employment, Equity Ownership. Hiddemann:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; F. Hoffman-La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Consultancy, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Marcus:Roche: Consultancy, Other: Travel support and lecture fees ; Gilead: Consultancy; F. Hoffman-La Roche: Other: Travel support and lecture fees.

Introduction: Topoisomerase-1-inhibiting camptothecin (CPT) and derivatives such as irinotecan (CPT-11) and topotecan demonstrate clinical utility across multiple cancer types. Use of these agents remains limited by insufficient tumor exposure and high systemic toxicity. A novel cyclodextrin-containing polymer conjugate of CPT that self-assembles into nanoparticles, CRLX101 delivers sustained levels of active CPT into cancer cells while substantially reducing systemic exposure. In vitro and in vivo data suggest superior activity of CRLX101 in multiple tumor models. Efforts are made now to demonstrate the safety and efficacy of CRLX101 in human patients with advanced solid tumor malignancies. Experimental Procedures: CRLX101 was administered intravenously over 1 hour every other week (EOW) to patients (pts.) with advanced and multiply pre-treated solid tumor malignancies. In phase 1, 24 pts. received CRLX101 at 5 escalating dose levels. Following identification of a maximum tolerated dose (MTD), a 38 patient phase 2a MTD-expansion cohort was enrolled at 3 clinical sites. Summary of Data: As of a data cut-off of 6/1/11, 62 total pts. (31 F; 31 M) received CRLX101 at doses ranging from 6 mg/m2 to 18 mg/m2 of CPT equivalent per dose. In phase 1, 2 pts. (18 mg/m2) experienced dose limiting toxicity of CTCAE v3.0 grade (G)4 thrombocytopenia with one of these pts. additionally experiencing G4 neutropenia. An MTD/recommended phase 2 dose (RP2D) of CRLX101 was established at 15 mg/m2 EOW. Among 44 phase 1 or 2a pts. receiving the MTD/RP2D, most common grade 3/4 adverse events considered by investigators to be at least possibly related to study drug included neutropenia (9 events observed among 6 pts.) and lymphopenia (3 events observed among 2 pts.). Phase 2a pts. received CRLX101 for periods of time ranging from 1 day to approximately 13 months (mos.) with an average duration of 3.3 mos. Among 36 evaluable phase 2a pts. receiving the MTD, mean plasma Cmax and AUCall were 306 μg./L. and 27.1 mg./L.*hr. (polymer-unconjugated) and 8260 μg./L. and 300 mg./L.*hr. (polymer-conjugated), respectively. Mean urinary clearance of polymer-conjugated and free CPT over the 0–8 hr., 8–24 hr., and 24–48 hr. collection intervals post CRLX101 dosing were 0.0299, 0.0074, and 0.0062 L./hr. (polymer-conjugated) and 0.0888, 0.0898, and 0.1010 L./hr. (free CPT), respectively. Among all phase 2a pts., overall median progression-free survival (mPFS) was 3.7 mos., with mPFS of 4.4 mos. observed among 21 NSCLC pts. (4.8 mos. excluding 6/21 pts. with squamous cell histology). At time of data cut-off, 6 pts. (incl. 3 NSCLC pts.) remain on therapy. Notably, of the 21 NSCLC pts. in phase 2a (with an average of 3 prior regimens of chemotherapy), 66.7% (14/21) achieved stable disease (SD) ≥ 3 mos. and 14.3% (3/21) achieved SD ≥ 6 mos. Conclusions: CRLX101 appears to be extremely well tolerated with an MTD/RP2D of 15 mg/m2 EOW. Pharmacokinetics are linear and suggest prolonged duration of CPT tumor exposure. Similarly, extended periods of stable disease observed across multiple tumor types are encouraging and merit further investigation. Patients are currently being enrolled into a multinational randomized clinical trial in 2nd/3rd line NSCLC and additional studies in renal cell cancer, small-cell lung cancer, ovarian cancer, and gastric cancer are being developed. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A97.