The MDM2-p53 Antagonist Brigimadlin (BI 907828) in Patients with Advanced or Metastatic Solid Tumors: Results of a Phase Ia, First-in-Human, Dose-Escalation Study.

Brigimadlin (BI 907828) is an oral MDM2-p53 antagonist that has shown encouraging antitumor activity in vivo. We present phase Ia results from an open-label, first-in-human, phase Ia/Ib study investigating brigimadlin in patients with advanced solid tumors (NCT03449381). Fifty-four patients received escalating doses of brigimadlin on day 1 of 21-day cycles (D1q3w) or days 1 and 8 of 28-day cycles (D1D8q4w). Based on dose-limiting toxicities during cycle 1, the maximum tolerated dose was selected as 60 mg for D1q3w and 45 mg for D1D8q4w. The most common treatment-related adverse events (TRAE) were nausea (74.1%) and vomiting (51.9%); the most common grade ≥3 TRAEs were thrombocytopenia (25.9%) and neutropenia (24.1%). As evidence of target engagement, time- and dose-dependent increases in growth differentiation factor 15 levels were seen. Preliminary efficacy was encouraging (11.1% overall response and 74.1% disease control rates), particularly in patients with well-differentiated or dedifferentiated liposarcoma (100% and 75% disease control rates, respectively). SIGNIFICANCE: We report phase Ia data indicating that the oral MDM2-p53 antagonist brigimadlin has a manageable safety profile and shows encouraging signs of efficacy in patients with solid tumors, particularly those with MDM2-amplified advanced/metastatic well-differentiated or dedifferentiated liposarcoma. Further clinical investigation of brigimadlin is ongoing. See related commentary by Italiano, p. 1765. This article is highlighted in the In This Issue feature, p. 1749.

Brightline-1: phase II/III trial of the MDM2-p53 antagonist BI 907828 versus doxorubicin in patients with advanced DDLPS.

Dedifferentiated liposarcoma (DDLPS) is a rare, aggressive liposarcoma associated with poor prognosis. First-line treatment for advanced/metastatic DDLPS is systemic chemotherapy, but efficacy is poor and toxicities substantial. Most DDLPS tumors have amplification of the MDM2 gene, which encodes a negative regulator of the p53 suppressor protein. BI 907828 is a highly potent, oral MDM2-p53 antagonist that inhibits the interaction between p53 and MDM2, thereby restoring p53 activity. BI 907828 has shown promising activity in preclinical studies and in a phase Ia/Ib study in patients with solid tumors, particularly those with DDLPS. This manuscript describes the rationale and design of an ongoing multicenter, randomized, phase II/III trial (Brightline-1; NCT05218499) evaluating BI 907828 versus doxorubicin as first-line treatment for advanced DDLPS.

Dedifferentiated liposarcoma (DDLPS) is a rare, fast-growing cancer that begins in fat cells. Patients with DDLPS that cannot be removed surgically or has spread to other areas of the body are usually treated with chemotherapy at first, but this typically stops working only 2­4 months after the start of treatment and has a lot of side effects. The drug BI 907828 works differently to chemotherapy by specifically targeting a gene called MDM2. This gene is abnormally increased in most DDLPS tumors and causes cancer by shutting down one of the pathways that the body uses to kill cancerous cells. BI 907828 restores this pathway, leading to the targeted destruction of tumor cells. Results from initial studies show that BI 907828 is able to slow the growth of DDLPS, and is now being investigated further, in a study called Brightline-1. Brightline-1, which is currently underway, is comparing BI 907828 with the chemotherapy drug doxorubicin for the initial treatment of DDLPS that is inoperable or has spread to other areas of the body. Clinical Trial Registration: NCT05218499 (ClinicalTrials.gov).

The Expression of Anti-Müllerian Hormone Type II Receptor (AMHRII) in Non-Gynecological Solid Tumors Offers Potential for Broad Therapeutic Intervention in Cancer.

The anti-Müllerian hormone (AMH) belongs to the TGF-ß family and plays a key role during fetal sexual development. Various reports have described the expression of AMH type II receptor (AMHRII) in human gynecological cancers including ovarian tumors. According to qRT-PCR results confirmed by specific In-Situ Hybridization (ISH) experiments, AMHRII mRNA is expressed in an extremely restricted number of normal tissues. By performing ISH on tissue microarray of solid tumor samples AMHRII mRNA was unexpectedly detected in several non-gynecological primary cancers including lung, breast, head and neck, and colorectal cancers. AMHRII protein expression, evaluated by immunohistochemistry (IHC) was detected in approximately 70% of epithelial ovarian cancers. Using the same IHC protocol on more than 900 frozen samples covering 18 different cancer types we detected AMHRII expression in more than 50% of hepato-carcinomas, colorectal, lung, and renal cancer samples. AMHRII expression was not observed in neuroendocrine lung tumor samples nor in non-Hodgkin lymphoma samples. Complementary analyses by immunofluorescence and flow cytometry confirmed the detection of AMHRII on a panel of ovarian and colorectal cancers displaying comparable expression levels with mean values of 39,000 and 50,000 AMHRII receptors per cell, respectively. Overall, our results suggest that this embryonic receptor could be a suitable target for treating AMHRII-expressing tumors with an anti-AMHRII selective agent such as murlentamab, also named 3C23K or GM102. This potential therapeutic intervention was confirmed in vivo by showing antitumor activity of murlentamab against AMHRII-expressing colorectal cancer and hepatocarcinoma Patient-Derived tumor Xenografts (PDX) models.

Cell substrates for the production of viral vaccines.

Vaccines have been used for centuries to protect people and animals against infectious diseases. For vaccine production, it has become evident that cell culture technology can be considered as a key milestone and has been the result of decades of progress. The development and implementation of cell substrates have permitted massive and safe production of viral vaccines. The demand in new vaccines against emerging viral diseases, the increasing vaccine production volumes, and the stringent safety rules for manufacturing have made cell substrates mandatory viral vaccine producer factories. In this review, we focus on cell substrates for the production of vaccines against human viral diseases. Depending on the nature of the vaccine, choice of the cell substrate is critical. Each manufacturer intending to develop a new vaccine candidate should assess several cell substrates during the early development phase in order to select the most convenient for the application. First, as vaccine safety is quite naturally a central concern of Regulatory Agencies, the cell substrate has to answer the regulatory rules stringency. In addition, the cell substrate has to be competitive in terms of viral-specific production yields and manufacturing costs. No cell substrate, even the so-called "designer" cell lines, is able to fulfil all the requested criteria for all viral vaccines. Therefore, the availability of a variety of cell substrates for vaccine production is essential because it improves the chance to successfully respond to the current and future needs of vaccines linked to new emerging or re-emerging infectious diseases (e.g. pandemic flu, Ebola, and Chikungunya outbreaks).

[Uterine fibromyomas: fertility after myomectomy. About 41 cases]. / Fibromes utérins: fertilité après myomectomie. A propos de 41 cas.

Fibromyomas are among the most frequent pathologies of women in their reproductive years; that's why clinicians studied their impact on fertility especially when no other cause is found. In this retrospective study of 41 infertile patients between January 1996 and December 1999, the authors tried to define the assess of myomectomy in these cases and the relevant factors that influence the post-operative results in terms of fertility. 24 patients were operated by laparotomy, 7 by laparoscopy and 10 by hysteroscopy. Once surgery was performed, 19 women conceived (46.34%) with delays ranging between 3 and 36 months (mean delay: 15.5 months). An age of less than 40, a sterility of less than 5 years duration and the absence of associated factors seems to enhance the chances of these patients to conceive after mytomectomy. No significant difference was noted in terms of subsequent fertility between the group of primary infertility and that of secondary sterility; neither concerning the myomas' number, size or place. Pregnancy rates after surgery were equivalent whether the myomectomy was performed by laparotomy or laparoscopy. It is, then, reasonable to propose to infertile patients with uterine myomas, a conservative surgery especially if they are young and if their sterility is unexplained for less than five years.

[Management of severe thrombopenia in pregnancies and labor. Report of 14 cases and review of the literature]. / La prise en charge des thrombopénies sévères au cours de la grossesse et de l'accouchement. A propos de 14 cas et une revue de la littérature.

Thrombocytopenia occured in 14 of 5557 pregnant women (0.25%) in our hospital over 4-year interval. The patients with thrombocytopenia could be devided into two groups: healthy women: 2 patients (14.28%). hypertensive patients and patients with immune thrombocytopenia: 12 patients (85.72%). Cesarian section rate for delivery was 35.7%. Six foetal loss were observed. Foetal morbidity is represented by prematurity and low weight at delivery (3 cases) and in one case cerebral bleeding was observed.