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.

Carcinogenicity study of CKD-501, a novel dual peroxisome proliferator-activated receptors α and γ agonist, following oral administration to Sprague Dawley rats for 94-101 weeks.

CKD-501 is a peroxisome proliferator-activated receptor (PPAR) agonist. The current study was conducted in Sprague Dawley (SD) rats for 94-101 weeks to investigate the carcinogenic potential of CKD-501. 60 males received 0, 0.03, 0.12, or 1.0mg/kg/day, which was changed after 66 weeks to 0.24 mg/kg/day due to increased mortality, while 60 females received 0, 0.03, 0.06, or 0.12 mg/kg/day throughout the study period. After switching the dosage, no significant changes in the survival rates were observed. Non-neoplastic lesions such as bladder transitional cell hyperplasia and a diminished corpus luteum were observed in females administered 0.12 mg/kg/day and the right chamber dilation and left ventricular hypertrophy were increased dose dependently in both males and females. Non-neoplastic lesions such as bone marrow hypoplasia and fat cell proliferation and neoplastic lesions such as lipomas and liposarcomas observed in males and/or females were considered expected pharmacological effects for this compound. Compared to rosiglitazone, CKD-501 had a 4.4-fold higher margin of safety for tumor induction and did not cause bladder carcinoma as was observed with pioglitazone.

Histopathology of hemangiosarcomas in mice and hamsters and liposarcomas/fibrosarcomas in rats associated with PPAR agonists.

Peroxisome proliferator-activated receptors (PPAR) are involved in the pathogenesis of insulin resistance, diabetes, and related complications. Consequently, the identification of PPAR subtypes and the potential for their activation provides promising therapeutic targets for the management of type 2 diabetes mellitus. Available data from rodent carcinogenicity studies, however, demonstrate that PPAR agonists can be tumorigenic in one or more species of rodents at multiple sites. In 2005, the Health and Environmental Sciences Institute (HESI) PPAR Agonist Project Committee was established by a group of pharmaceutical companies to advance research on and to understand the modes of action and human relevance of this emerging rodent tumor data for PPAR agonists. Since the most commonly observed tumor types reported in rodents are hemangiosarcomas, fibrosarcomas and liposarcomas, the PPAR Agonist Project Committee approved a Pathology Working Group (PWG) to develop consensus of morphologic criteria for tumor diagnoses and consistency of diagnoses across multiple studies for hemangiosarcomas in mice and hamsters and liposarcomas/fibrosarcomas in rats. Therefore, the focus of the PWG review was to establish consistent tumor diagnostic criteria, to assess evidence of potentially preneoplastic changes and to identify distinguishing morphologic differences which may exist between spontaneous changes present in control animals with similar changes from treated animals. Specific diagnostic criteria and nomenclature are recommended for the classification of proliferative vascular lesions which may be present in mice or hamsters and for proliferative mesenchymal changes in rats in studies that are conducted with PPAR agonists.

A case representing coexistence of acute myeloblastic leukemia and dedifferentiated liposarcoma: the possible role of chemotherapy in triggering dedifferentiation.

Acute myelogenous leukemia (AML) is a hematological disorder that is characterized by an abnormal proliferation of immature myeloid cells. Dedifferentiated and well-differentiated liposarcomas are the two pathological subtypes of liposarcoma, based on the WHO classification. Transition from well-differentiated to dedifferentiated liposarcoma is a well-recognized phenomenon. Well-differentiated tumors are known to have low malignancy grade. However, when dedifferentiation occurs, the tumor acquires the aggressive features of a fully malignant lesion. This process largely is believed to progress in a time-dependant manner; however, time is not the only factor of importance. The potential roles of other factors in this transition are still unclear. To date, the coexistence of AML and liposarcoma has not been reported in the literature. In this paper, we report on a case of coexistence of AML and liposarcoma, and on the unusual behavior of a well-differentiated tumor after dedifferentiation occurs.

Pleomorphic liposarcoma of the uterus: case report and literature review.

A 62-year-old woman with a history of breast carcinoma being treated with tamoxifen presented with a rapidly enlarging pelvic mass. Imaging studies suggested a uterine leiomyoma with possible sarcomatous transformation. Laparotomy revealed a 15-cm, oval, well-circumscribed mass emanating from the posterior cervix and left uterosacral ligament. The tumor had a variegated fleshy, tan, myxoid, and necrotic sectioned surface. Microscopic examination revealed a variety of patterns and cell types characteristic of liposarcoma that included myxoid/round cell, storiform/pleomorphic, epithelioid, and spindle cell areas. Lipogenic areas exhibited a "crow's feet" vasculature and characteristic lipoblasts. The tumor cells were highly pleomorphic with numerous mitotic figures, some of them atypical. The tumor cells were immunoreactive for vimentin, estrogen receptors, and S-100. The tumor recurred 9 months postoperatively. Although a variety of uterine tumors have been associated with tamoxifen treatment, this appears to be the first example of tamoxifen-associated uterine liposarcoma.

An evaluation of reports of dioxin exposure and soft tissue sarcoma pathology among chemical workers in the United States.

A review of employment records and tissue specimens of seven workers, reported previously as having occupational dioxin exposure and soft tissue sarcomas, confirms that four workers had employment of 2 to 19 years in the production of 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) or trichlorophenol, products contaminated with 2,3,7,8-tetrachlorodibenzodioxin, the most toxic dioxin isomer. Of these individuals, two have confirmed soft tissue sarcomas. In addition three individuals who worked for companies which made 2,4,5-T also have confirmed soft tissue sarcomas. Their employment records do not show specific assignment to 2,4,5-T or trichlorophenol departments; however, one individual worked for 10 d in the production of pentachlorophenol, which is contaminated with different isomers of dioxin. Methodological problems are discussed which must be addressed in the epidemiologic evaluation of the outcome of soft tissue sarcoma.

Responses of tumors induced in inbred guinea pig strain JY=1 and strain Hartley/F to BCG.

A transplantable fibrosarcoma induced in inbred JY-1 guinea pig strain by 3-methylcholanthrene (MCA) and designated J4, an allotransplantable subline of J4 (JH4) which was obtained by the transplantation of J4 into the inbred Hartley/F guinea pig strain and maintained by passages in this strain, and a syngeneic liposarcoma H10 induced in a Hartley/F guinea pig by MCA were tested for their immunotherapeutic response with BCG. The growth of J4 and H10 tumors was suppressed in most of the animals when tumor cells were mixed with BCG before being injected sc into BCG-immune or BCG-nonimmune recipients. The growth of the JH4 tumor was suppressed at the sites of injection with a mixture of tumor cells and BCG in BCG-immune recipients but not in nonimmune animals. All guinea pigs surviving the injection of a tumor cell-BCG mixture resisted a second tumor cell challenge. When subcutaneous sarcomas grew to about 8-15 mm in diameter, BCG was injected into the tumors. The growth of JH4 tumor was not influenced by the injection in either BCG-immune or BCG-nonimmune animals, while the regression of the established J4 transplants was produced in 2 of 3 nonimmune recipients. The growth of the H10 tumor was not inhibited with an intratumor injection into nonimmune guinea pigs, while the H10 tumor regressed in BCG-immune animals for 4-5 weeks after intratumor injection and thereafter grew progressively. Skin reactions in animals that received repeated intradermal injections of the tumor cells and BCG were tested with 10(6) viable tumor cells as eliciting antigens. Typical delayed-type hypersensitivity reactions that were specific to the homologous antigens were observed. The possible reasons for the different responses to BCG among the guinea pig tumors, including line-10 hepatocarcinoma in strain-2 guinea pigs, were discussed.

Transplantable sarcomas induced by 3-methylcholanthrene in inbred guinea pigs of JY-1 and Hartley/F strains.

Inbred strains of guinea pigs, JY-1 and Hartley/F, established in this Institute, were injected subcutaneously with 3-methylcholanthrene. During 1972 to 1974, 15 solid tumors (7 fibrosarcomas, 6 liposarcomas, and 2 atheroma-like tumors) have been induced in 12 animals out of 30 employed. Among the 15 tumors, 1 fibrosarcoma induced in JY-1 and 2 liposarcomas and 1 fibrosarcoma induced in Hartley/F were transplantable and established as the syngeneic lines named J4, H10, H12, and H9A, respectively. In addition, a transplant of J4 into the Hartley/F strain animal was established as an allogeneic subline and named JH4. Pathological and biological characteristics of these tumors are described and differences between these tumors and line 10 hepatoma, established by Rapp et al. in strain-2 guinea pig, are discussed.

The induction of tumours in the guinea-pig with methylcholanthrene and diethylnitrosamine and their propagation in vivo and in vitro.

Tumour induction with diethylnitrosamine (DEN) and methylcholanthrene (MCA) has been studied in 3 strains of guinea-pig. A DEN concentration of 80 µg/ml drinking water daily proved too toxic but reasonable survival was obtained with 20 µg/ml 3 times per week in Hartley guinea-pigs and a local inbred strain. Heston Strain 13 guinea-pigs were particularly susceptible to the toxic effects of the diethylnitrosamine. In all3strains, 100% of the animals which survived the early toxic effects subsequently developed hepatomata, the mean time being 15 months. Methylcholanthrene was less toxic but more erratic as a carcinogen, the incidence of tumours in Hartley guinea-pigs varying from 18 to 100% in different experiments, the mean time of tumour development being 10 months.Three transplantable hepatomata and 3 transplantable sarcomata have been developed. The hepatomata are all predominantly hepatocellular carcinomata and the sarcomata comprise two liposarcomata and a fibrosarcoma. Successful shortterm primary cultures of hepatomata, sarcomata and of normal liver tissues have been accomplished. Established cell lines in tissue culture have been developed from one cholangiocarcinoma from an outbred guinea-pig and one transplanted hepatocellular carcinoma from an inbred guinea-pig.