A Phase I Trial of CT900, a Novel α-Folate Receptor-Mediated Thymidylate Synthase Inhibitor, in Patients with Solid Tumors with Expansion Cohorts in Patients with High-Grade Serous Ovarian Cancer.

PURPOSE: CT900 is a novel small molecule thymidylate synthase inhibitor that binds to α-folate receptor (α-FR) and thus is selectively taken up by α-FR-overexpressing tumors. PATIENTS AND METHODS: A 3+3 dose escalation design was used. During dose escalation, CT900 doses of 1-6 mg/m2 weekly and 2-12 mg/m2 every 2 weeks (q2Wk) intravenously were evaluated. Patients with high-grade serous ovarian cancer were enrolled in the expansion cohorts. RESULTS: 109 patients were enrolled: 42 patients in the dose escalation and 67 patients in the expansion cohorts. At the dose/schedule of 12 mg/m2/q2Wk (with and without dexamethasone, n = 40), the most common treatment-related adverse events were fatigue, nausea, diarrhea, cough, anemia, and pneumonitis, which were predominantly grade 1 and grade 2. Levels of CT900 more than 600 nmol/L needed for growth inhibition in preclinical models were achieved for >65 hours at a dose of 12 mg/m2. In the expansion cohorts, the overall response rate (ORR), was 14/64 (21.9%). Thirty-eight response-evaluable patients in the expansion cohorts receiving 12 mg/m2/q2Wk had tumor evaluable for quantification of α-FR. Patients with high or medium expression had an objective response rate of 9/25 (36%) compared with 1/13 (7.7%) in patients with negative/very low or low expression of α-FR. CONCLUSIONS: The dose of 12 mg/m2/q2Wk was declared the recommended phase II dose/schedule. At this dose/schedule, CT900 exhibited an acceptable side effect profile with clinical benefit in patients with high/medium α-FR expression and warrants further investigation.

Phase 1, dose-escalation study of guadecitabine (SGI-110) in combination with pembrolizumab in patients with solid tumors.

BACKGROUND: Data suggest that immunomodulation induced by DNA hypomethylating agents can sensitize tumors to immune checkpoint inhibitors. We conducted a phase 1 dose-escalation trial (NCT02998567) of guadecitabine and pembrolizumab in patients with advanced solid tumors. We hypothesized that guadecitabine will overcome pembrolizumab resistance. METHODS: Patients received guadecitabine (45 mg/m2 or 30 mg/m2, administered subcutaneously on days 1-4), with pembrolizumab (200 mg administered intravenously starting from cycle 2 onwards) every 3 weeks. Primary endpoints were safety, tolerability and maximum tolerated dose; secondary and exploratory endpoints included objective response rate (ORR), changes in methylome, transcriptome, immune contextures in pre-treatment and on-treatment tumor biopsies. RESULTS: Between January 2017 and January 2020, 34 patients were enrolled. The recommended phase II dose was guadecitabine 30 mg/m2, days 1-4, and pembrolizumab 200 mg on day 1 every 3 weeks. Two dose-limiting toxicities (neutropenia, febrile neutropenia) were reported at guadecitabine 45 mg/m2 with none reported at guadecitabine 30 mg/m2. The most common treatment-related adverse events (TRAEs) were neutropenia (58.8%), fatigue (17.6%), febrile neutropenia (11.8%) and nausea (11.8%). Common, grade 3+ TRAEs were neutropaenia (38.2%) and febrile neutropaenia (11.8%). There were no treatment-related deaths. Overall, 30 patients were evaluable for antitumor activity; ORR was 7% with 37% achieving disease control (progression-free survival) for ≥24 weeks. Of 12 evaluable patients with non-small cell lung cancer, 10 had been previously treated with immune checkpoint inhibitors with 5 (42%) having disease control ≥24 weeks (clinical benefit). Reduction in LINE-1 DNA methylation following treatment in blood (peripheral blood mononuclear cells) and tissue samples was demonstrated and methylation at transcriptional start site and 5' untranslated region gene regions showed enriched negative correlation with gene expression. Increases in intra-tumoural effector T-cells were seen in some responding patients. Patients having clinical benefit had high baseline inflammatory signature on RNAseq analyses. CONCLUSIONS: Guadecitabine in combination with pembrolizumab is tolerable with biological and anticancer activity. Reversal of previous resistance to immune checkpoint inhibitors is demonstrated.

UK practice regarding reversal of vasectomy 2001-2010: relevance to best contemporary patient management.

UNLABELLED: Study Type - Practice trends (survey) Level of Evidence 2c What's known on the subject? and What does the study add? Approximately 6% of men who have had a vasectomy subsequently decide to have it reversed. For such men there are various options available, including vasal reconstruction, surgical sperm retrieval with assisted reproductive techniques, use of donated sperm or adoption. The decision-making process with regard to the most appropriate management is challenging and the urologist requires both an intimate knowledge of the advantages and disadvantages of each of the available options and the opportunity to counsel a couple appropriately. The study confirms that patient management after previous vasectomy is a complex process, demanding detailed knowledge about the availability and outcomes of alternatives to vasectomy reversal. It recommends that couples should not be seen by urologists with diverse interests but by those with appropriate knowledge of all of the factors influencing outcome and the available management options and their costs. Urologists should also have appropriate facilities to offer intra-operative demonstration of and, potentially, storage of sperm. OBJECTIVES: To review the management of men presenting for reversal of vasectomy amongst consultant members of the British Association of Urological Surgeons (BAUS) between 2001 and 2010. • To make recommendations for contemporary practice. SUBJECTS AND METHODS: Three consecutive questionnaire-based surveys were undertaken by BAUS consultant members in 2001, 2005 and 2010. • Standard questionnaires were sent on each occasion asking urologists about their counselling of couples regarding options in achieving a conception, expectation of outcome from reconstructive surgery and the techniques of vaso-vasostomy used. • In 2005 additional information was obtained about the availability of fertility treatments and sub-specialization of the urologist and in 2010 about the eligibility criteria for in-vitro fertilization (IVF) treatment and synchronous sperm retrieval. RESULTS: Overall there was a 47% response rate with >80% of respondents still performing vaso-vasostomy. • More than 75% of respondents were doing <15 procedures a year and <50% of respondents counselled couples about other management options. • Only 41% gave their personalized outcomes from vaso-vasostomy, whilst >80% were using some form of magnification intra-operatively. • Members of the BAUS section of andrology were more likely to discuss options for becoming a parent and criteria for IVF treatment, to present their individualized outcomes from vaso-vasotomy and to carry out >15 procedures a year than urologists with no andrological affiliation. CONCLUSIONS: • Patient management after previous vasectomy is a complex process necessitating detailed knowledge concerning the availability and outcomes of alternatives to vaso-vasostomy. • Couples should not be seen by urologists with diverse interests but by those with appropriate knowledge of all of the factors influencing outcome. • Vaso-vasostomy should no longer be seen as a procedure within the remit of any adequately trained urologist but as one option to be considered by a sub-specialist with access to appropriate micro-surgical training and assisted reproductive technologies.