Tocilizumab in Patients Hospitalized with Covid-19 Pneumonia.

BACKGROUND: Coronavirus disease 2019 (Covid-19) pneumonia is often associated with hyperinflammation. Despite the disproportionate incidence of Covid-19 among underserved and racial and ethnic minority populations, the safety and efficacy of the anti-interleukin-6 receptor antibody tocilizumab in patients from these populations who are hospitalized with Covid-19 pneumonia are unclear. METHODS: We randomly assigned (in a 2:1 ratio) patients hospitalized with Covid-19 pneumonia who were not receiving mechanical ventilation to receive standard care plus one or two doses of either tocilizumab (8 mg per kilogram of body weight intravenously) or placebo. Site selection was focused on the inclusion of sites enrolling high-risk and minority populations. The primary outcome was mechanical ventilation or death by day 28. RESULTS: A total of 389 patients underwent randomization, and the modified intention-to-treat population included 249 patients in the tocilizumab group and 128 patients in the placebo group; 56.0% were Hispanic or Latino, 14.9% were Black, 12.7% were American Indian or Alaska Native, 12.7% were non-Hispanic White, and 3.7% were of other or unknown race or ethnic group. The cumulative percentage of patients who had received mechanical ventilation or who had died by day 28 was 12.0% (95% confidence interval [CI], 8.5 to 16.9) in the tocilizumab group and 19.3% (95% CI, 13.3 to 27.4) in the placebo group (hazard ratio for mechanical ventilation or death, 0.56; 95% CI, 0.33 to 0.97; P = 0.04 by the log-rank test). Clinical failure as assessed in a time-to-event analysis favored tocilizumab over placebo (hazard ratio, 0.55; 95% CI, 0.33 to 0.93). Death from any cause by day 28 occurred in 10.4% of the patients in the tocilizumab group and 8.6% of those in the placebo group (weighted difference, 2.0 percentage points; 95% CI, -5.2 to 7.8). In the safety population, serious adverse events occurred in 38 of 250 patients (15.2%) in the tocilizumab group and 25 of 127 patients (19.7%) in the placebo group. CONCLUSIONS: In hospitalized patients with Covid-19 pneumonia who were not receiving mechanical ventilation, tocilizumab reduced the likelihood of progression to the composite outcome of mechanical ventilation or death, but it did not improve survival. No new safety signals were identified. (Funded by Genentech; EMPACTA ClinicalTrials.gov number, NCT04372186.).

A randomized Phase II trial of the tumor vascular disrupting agent CA4P (fosbretabulin tromethamine) with carboplatin, paclitaxel, and bevacizumab in advanced nonsquamous non-small-cell lung cancer.

INTRODUCTION: Combretastatin 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. METHODS: Adult 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. RESULTS: Sixty-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. CONCLUSION: CA4P 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.

First-in-human phase 1/2a trial of CRLX101, a cyclodextrin-containing polymer-camptothecin nanopharmaceutical in patients with advanced solid tumor malignancies.

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/m(2) and later bi-weekly at 12, 15, and 18 mg/m(2). The maximum tolerated dose (MTD) was determined at 15 mg/m(2) 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.

Prolonged survival after splenectomy in Wiskott-Aldrich syndrome: a case report.

Wiskott-Aldrich syndrome is a rare X-linked immunodeficiency disorder that is characterized by a variable clinical phenotype. Matched donor bone marrow transplantation is currently the only curative therapeutic option. We present the case of a 24-year-old male who was diagnosed at the age of seven with Wiskott-Aldrich syndrome. He did not respond to intravenous gammaglobulin and he experienced recurrent pulmonary infections despite prophylactic antibiotics. The patient had no matched donor. At the age of nine, he was submitted to splenectomy and his platelet count was normalized. Fifteen years later, the patient remains asymptomatic with a normal platelet count. He is still receiving prophylactic antibiotics and no bleeding episodes or septic complications have been reported. This case demonstrates that splenectomy can represent a safe therapeutic option in selected WAS patients, provided that there is a tight follow-up program, patient education and adherence to guidelines regarding post-splenectomy prophylaxis.

Effect of docetaxel chemotherapy on the activity of a gonadotropin releasing hormone vaccine in patients with advanced prostate cancer.

BACKGROUND: Gonadotropin releasing hormone (GnRH)-DT vaccine elicits antibody that may inhibit prostate cancers indirectly by blocking GnRH induced gonadotropin release, and consequent androgen synthesis, and directly by immune effector and antiproliferative mechanisms. A pilot study was performed to determine how to best combine GnRH-DT vaccine with potentially immunosuppressive chemotherapy. METHODS: Patients with metastatic, hormone-refractory prostate cancer were randomized into either a concurrent cohort, in which they received docetaxel on day 1 of weeks 1, 4, 7, and 10 and GnRH-DT vaccine on day 2 of weeks 1, 3, and 7 or a sequential cohort, in which they received GnRH-DT vaccine on weeks 1, 3, and 7 before beginning docetaxel on week 10. GnRH-DT vaccine was administered intramuscularly. Docetaxel was infused intravenously after pre-medication with high-dose dexamethasone, and infusions repeated every 3 weeks in the absence of toxicity or progressive cancer. RESULTS: GnRH-DT vaccine and docetaxel were well tolerated without evidence of significant local or systemic toxicities. Anti-GnRH antibody was elicited in six of six treated concurrently and five of six treated sequentially. The kinetics of antibody induction and the titers of antibody achieved in both treatment cohorts were similar. Anti-GnRH antibody persisted for up to 28 weeks in a patient maintained on docetaxel. CONCLUSION: The administration of docetaxel with high-dose dexamethasone does not inhibit the ability of patients with advanced prostate cancer to be immunized with GnRH-DT vaccine.

Immunization of colorectal cancer patients with recombinant baculovirus-derived KSA (Ep-CAM) formulated with monophosphoryl lipid A in liposomal emulsion, with and without granulocyte-macrophage colony-stimulating factor.

KSA (Ep-CAM) is highly expressed by colorectal cancers. The safety and immunologic effects of a vaccine consisting of recombinant baculovirus-derived KSA formulated with monophosphoryl lipid A (MPL) in liposomes and emulsified in mineral oil were evaluated, with and without co-administration of granulocyte-macrophage colony-stimulating factor (GM-CSF). Eleven patients with metastatic colorectal cancer received three subcutaneous (s.c.) injections of the vaccine at 4-week intervals. Six patients were randomized to also receive human recombinant GM-CSF (rGM-CSF) by subcutaneous injection daily for 4 days with each vaccination. Immunizations with and without rGM-CSF were well tolerated. Seven of the 11 patients developed significant KSA-specific cellular immune responses as assessed by lymphoproliferation and interferon-gamma (IFN-gamma) ELISPOT assays. All nine tested patients developed positive delayed type hypersensitivity reactions. Eight of the 11 patients developed KSA-specific antibody responses. The highest levels of cellular immune responses were observed in patients who received GM-CSF. Immunization with baculovirus-derived KSA formulated with monophosphoryl lipid A in liposomal emulsion is safe and can elicit KSA-specific immune responses. Co-administration of GM-CSF with this formulation is an effective method of generating KSA-specific T-helper (Th) 1-associated cellular immune responses.