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PURPOSE To evaluate the safety, pharmacokinetics, and pharmacodynamics of Hu5F9-G4 (5F9), a humanized IgG4 antibody that targets CD47 to enable phagocytosis. PATIENTS AND METHODS Adult patients with solid tumors were treated in four cohorts: part A, to determine a priming dose; part B, to determine a weekly maintenance dose; part C, to study a loading dose in week 2; and a tumor biopsy cohort. RESULTS Sixty-two patients were treated: 11 in part A, 14 in B, 22 in C, and 15 in the biopsy cohort. Part A used doses that ranged from 0.1 to 3 mg/kg. On the basis of tolerability and receptor occupancy studies that showed 100% CD47 saturation on RBCs, 1 mg/kg was selected as the priming dose. In subsequent groups, patients were treated with maintenance doses that ranged from 3 to 45 mg/kg, and most toxicities were mild to moderate. These included transient anemia (57% of patients), hemagglutination on peripheral blood smear (36%), fatigue (64%), headaches (50%), fever (45%), chills (45%), hyperbilirubinemia (34%), lymphopenia (34%), infusion-related reactions (34%), and arthralgias (18%). No maximum tolerated dose was reached with maintenance doses up to 45 mg/kg. At doses of 10 mg/kg or more, the CD47 antigen sink was saturated by 5F9, and a 5F9 half-life of approximately 13 days was observed. Strong antibody staining of tumor tissue was observed in a patient at 30 mg/kg. Two patients with ovarian/fallopian tube cancers had partial remissions for 5.2 and 9.2 months. CONCLUSION 5F9 is well tolerated using a priming dose at 1 mg/kg on day 1 followed by maintenance doses of up to 45 mg/kg weekly.

Estrogens occurring naturally in the body are metabolized to catecholestrogens (2- and 4-hydroxyestradiol) by the cytochrome P450 enzymes. 2-Hydroxy catecholestrogens are further metabolized by catechol-O-methyltransferase to 2-methoxyestradiol, which is known to be protective against tumor formation. 2-Methoxyestradiol exhibits potent apoptotic activity against rapidly growing tumor cells. It also possesses antiangiogenic activity through a direct apoptotic effect on endothelial cells. Other molecular mechanisms, including microtubule stabilization by inhibition of the colchicine-binding site, have been reported. The exact mechanism of action of 2-methoxyestradiol is still unclear, but it has been shown to be effective in preventing tumor growth in a variety of cell lines. 2-Methoxyestradiol also possesses cardioprotective activity by inhibiting vascular smooth muscle cell growth in arteries. It has a lower binding affinity for estrogen receptor alpha compared with that of estradiol, and its affinity for estrogen receptor beta is even lower than that of estrogen receptor alpha, thus it has minimal estrogenic activity. 2-Methoxyestradiol is distinct because of its inability to engage estrogen receptors as an agonist, and its unique antiproliferative and apoptotic activities are mediated independently of estrogen receptors alpha and beta. A phase I clinical trial of 2-methoxyestradiol 200, 400, 600, 800, and 1,000 mg/day in 15 patients with breast cancer showed significant reduction in bone pain and analgesic intake in some patients, with no significant adverse effects. Another phase I study of 2-methoxyestradiol 200-1,000 mg/day in combination with docetaxel 35 mg/m2/week for 4-6 weeks performed in 15 patients with advanced refractory metastatic breast cancer showed no serious drug-related adverse effects. A phase II randomized, double-blind trial of 2-methoxyestradiol 400 and 1,200 mg/day in 33 patients with hormone-refractory prostate cancer showed that it was well tolerated and showed prostate specific antigen stabilizations and declines. We have started a phase I clinical trial to explore dosages greater than 1,000 mg/day.

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ANG1005, a novel taxane derivative, consists of 3 paclitaxel molecules covalently linked to Angiopep-2, designed to cross the blood-brain and bloodcerebrospinal barriers and to penetrate malignant cells via LRP1 transport system. Preclinical and clinical evidence of efficacy with ANG1005 has been previously shown. EXPERIMENTAL DESIGN A multi-center, open-label phase 2 study in adult patients with measurable recurrent brain metastases from breast cancer (BCBM), with or without leptomeningeal carcinomatosis (LC) was conducted (n=72 BCBM; n=28 LC subset). ANG1005 was administered intravenously (IV) at 600 mg/m 2 q3w. Tumor assessment was based on CNS RECIST 1.1 for intracranial, and RECIST 1.1 for extracranial response. The primary endpoint was determination of intracranial objective response rate (iORR). RESULTS Median age was 47.5 years. Safety profile was similar to that of paclitaxel with myelosuppression as the predominating toxicity. Average number of prior CNS directed therapies was 2.8 and 94% of the patients had prior taxane treatment. Patient benefit (stable disease or better) was seen in 77% (intracranial) and 86% (extracranial) of the evaluable patients, with iORR of 15% (investigator) or 8% (independent radiology review). In the LC subset, 79% of the patients had intracranial disease control and estimated median overall survival of 8.0 months (95% CI 5.4-9.4). CONCLUSION Even though the study pre-set rule for iORR per IRF was not met in this heavily pretreated population, a notable CNS and systemic treatment effect was seen in Research.

This is one of the first clinical trials to evaluate the strategy of combining a putative antiangiogenic agent with a cytotoxic agent in patients with primary brain tumors. Our data demonstrate that thalidomide in combination with BCNU is well tolerated and has antitumor activity in patients with recurrent high-grade gliomas. Although the combination seems to be more active than either agent alone, such conclusions await confirmatory trials.

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Background: VATS is currently the most popular form of access for lung cancer resection in the UK. However, there is limited comparative information from high quality randomised controlled trials and no information on early oncologic outcomes for quality assurance for a minimal access approach. VIOLET is the largest randomised trial conducted to date to compare clinical efficacy, safety and oncologic outcomes of VATS versus open surgery for lung cancer. Method: VIOLET is a parallel group randomised trial conducted across 9 UK thoracic surgery centres. Participants with known or suspected primary lung cancer were randomised in a 1:1 ratio to VATS (one to four ports) or open lobectomy. Randomisation was stratified by surgeon. Patients within clinical stage cT1-3, N0-1 and M0 using TNM 8 with disease suitable for VATS or open surgery were eligible to join the trial. We report on early outcomes in the period from randomisation to hospital discharge after surgery. Result: From Jul 2015 to Feb 2019, 2,109 patients were screened to randomise 503 participants to VATS (n¼247) or open (n¼256) lobectomy. The mean age (SD) was 69 (8.8) years and 249 (49.5%) were male. Baseline clinical T category was cT1 333 (67.3%), cT2 125 (25.2%), cT3 37 (7.5%) with cN0 466 (94%) and cN1 30 (6%). Lobectomy was undertaken in 221 (89.5%) patients randomised to VATS and 232 (90.6%) patients randomised to open surgery. The in-hospital mortality rate was 1.4% (7/502) and the conversion rate from VATS to open was 5.7% (14/246) with the main reasons listed as pleural adhesions (n¼4) and bleeding (n¼4). There were no differences in R0 resection; which was 98.8% ( 218/223) in the VATS group and 97.4% (228/234) in the open group; P¼0.839 or in nodal upstaging from cN0/1 to pN2 disease which was observed in 6.2% (15/244) of the VATS group and 4.8% (12/252) of the open group; P¼0.503. The median (visual analogue) pain score was 4 (interquartile range, IQR 2 to 5) in both groups on day one with 3 (1 to 5) in the VATS group and 4 (2 to 5) in the open group on day two. A significant reduction of overall in-hospital complications was observed in patients receiving VATS at 32.8% (81/247) compared to open 44.3% (113/255) surgery; P¼0.008 without any difference in serious adverse events between the two groups, which was 8.1% (20/247) for VATS and 7.8% (20/255) for open surgery; P¼0.897. Patients randomised to VATS had a shorter median (IQR) length of stay of 4 (3 to 7) versus 5 (3 to 8) days compared to patients randomised to open surgery, P¼0.008. Conclusion:In early stage lung cancer, VATS lobectomy is associated with significantly lower in-hospital complications and shorter length of stay compared to open lobectomy. This was achieved without any compromise to early oncologic outcomes (pathologic complete resection and upstaging of mediastinal lymph nodes) nor any difference in serious adverse events in the early post-operative period.