Penella J. Woll

Guidelines for time-to-event endpoint definitions in sarcomas and gastro-intestinal stromal tumors (GIST) trials. Results of the DATECAN initiative (Definition for the Assessment of Time-to-event Endpoints in CANcer trials)

BACKGROUNDnThe use of potential surrogate end points for overall survival, such as disease-free survival (DFS) or time-to-treatment failure (TTF) is increasingly common in randomized controlled trials (RCTs) in cancer. However, the definition of time-to-event (TTE) end points is rarely precise and lacks uniformity across trials. End point definition can impact trial results by affecting estimation of treatment effect and statistical power. The DATECAN initiative (Definition for the Assessment of Time-to-event End points in CANcer trials) aims to provide recommendations for definitions of TTE end points. We report guidelines for RCT in sarcomas and gastrointestinal stromal tumors (GIST).nnnMETHODSnWe first carried out a literature review to identify TTE end points (primary or secondary) reported in publications of RCT. An international multidisciplinary panel of experts proposed recommendations for the definitions of these end points. Recommendations were developed through a validated consensus method formalizing the degree of agreement among experts.nnnRESULTSnRecommended guidelines for the definition of TTE end points commonly used in RCT for sarcomas and GIST are provided for adjuvant and metastatic settings, including DFS, TTF, time to progression and others.nnnCONCLUSIONnUse of standardized definitions should facilitate comparison of trials results, and improve the quality of trial design and reporting. These guidelines could be of particular interest to research scientists involved in the design, conduct, reporting or assessment of RCT such as investigators, statisticians, reviewers, editors or regulatory authorities.

Angiogenic growth factor expression in benign and malignant vascular tumours.

Angiosarcomas are rare malignant vascular tumours. Angiosarcoma expression of vascular endothelial growth factor (VEGF) has previously been reported, but angiosarcoma expression of other angiogenic growth factors has not been systematically studied. Non-VEGF angiogenic growth factors are a potential mechanism of resistance to VEGF-targeted therapy, but they also represent potential therapeutic targets. Immunohistochemistry analysis evaluated the expression of 13 angiogenic growth factors and receptors in 27 separate benign and malignant archived human vascular tumour samples. The expression of 55 angiogenesis-related proteins was subsequently profiled in five fresh human angiosarcoma tumour samples using antibody arrays. Angiosarcomas expressed a variety of angiogenic growth factors. Significantly higher levels of Notch1 were detected compared with benign haemangiomas (p=0.033), but lower levels of basic fibroblast growth factor (bFGF) compared to benign haemangiomas (p=0.07) and inflammatory vascular lesions (p=0.009). Vascular tumour expression of FGF receptor (FGFR)-1 correlated with angiopoietin (Ang)-2, Tie2, hepatocyte growth factor (HGF) and Notch1 expression (p=0.001, p=0.001, p<0.001 and p<0.001 respectively). Notch1 also correlated with Tie2 expression (p=0.004). In conclusion, angiosarcomas express multiple angiogenic growth factors. Treatments could be targeted at individual angiogenic growth factors. However, our findings provide a rationale for combination therapy, or for treatments that target common downstream signalling intermediaries, such as Akt, mTOR or ERK.

Phase II Study of Liposomal Muramyl Tripeptide Phosphatidylethanolamine (MTP/PE) in Advanced Soft Tissue Sarcomas of the Adult. An EORTC Soft Tissue and Bone Sarcoma Group Study

The EORTC Soft Tissue and Bone Sarcoma Group conducted a phase II study with intravenous muramyl tripeptide phosphatidylethanolamine (MTP/PE) at a dose of 4 mg once weekly in 20 patients with metastatic soft tissue sarcomas. Responses were not seen in 19 evaluable patients. Toxicity consisted mainly of a mild flu-like syndrome after 62% of drug administrations. It is concluded that MTP/PE at this dose and schedule has no activity in metastatic soft tissue sarcoma.

Bone-targeted agents in the treatment of lung cancer

Over a third of patients with lung cancer will develop bone metastases during the course of their disease, resulting in symptoms of pain and immobility, and skeletal-related events (SREs) such as fracture, hypercalcaemia, surgery or radiotherapy to bones, and malignant spinal cord compression. These reduce quality of life and increase mortality. Preclinical research has identified the interactions between tumour cells and bone that are key to tumour cell survival and associated osteolysis. These data have led to the development of drugs to prevent osteoclast-mediated bone breakdown, such as zoledronic acid and denosumab, which are now licensed for use in patients with bone metastases from solid tumours. Both zoledronic acid and denosumab reduce the risk of SREs and increase time to first SRE, with minimal side effects. In addition, denosumab improved survival in patients with lung cancer compared with zoledronic acid. Ongoing trials are testing whether these drugs can prevent the development of bone metastases from lung cancer. New bone-targeted agents showing promise in breast and prostate cancer include radium-223, cabozantinib and Src inhibitors. These agents require further evaluation in patients with lung cancer.

Abstract B237: Clinical experience of IMGN901 (BB‐10901, huN901‐DM1) in patients with Merkel cell carcinoma (MCC)

Background: MCC is a neuroendocrine cancer of the skin that predominantly occurs in older individuals of northern European ancestry. While localized disease can often be treated with surgery and radiation therapy, there is a need for effective, well‐tolerated chemotherapeutic options for patients with progressive or metastatic disease. Among patients with metastatic MCC, overall 5‐year survival rate is 11% and median survival is in the range of 7 to 9 months. To date, no chemotherapeutic agent has been able to demonstrate a significant improvement in survival. Toxicity also is a major concern with these older patients. IMGN901 is a novel CD56‐targeting anticancer agent. CD56 is expressed on virtually all MCC tumors. IMGN901 consists of a potent maytansinoid cytotoxic agent, DM1, attached to a CD56‐binding monoclonal antibody, huN901, using an engineered linker. Once bound to CD56, IMGN901 is internalized into the cancer cell and the DM1 is released to kill the cell via inhibition of the polymerization of tubulin. Objective: Study 002 is an ongoing phase I trial established to determine the maximum tolerated dose (MTD), pharmacokinetics (PK) and activity of IMGN901 in patients with CD56‐expressing solid tumors, including patients with MCC. Methods: IMGN901 is administered intravenously as monotherapy daily for 3 consecutive days every 3 weeks. Results: Six patients with MCC have been enrolled in Study 002 in addition to patients with other types of CD56+ solid tumors. Clinical benefit has been observed in 3 of these 6 patients including one complete response (CR), one partial response (PR) and one stable disease (SD). The patient who experienced a CR has remained disease free for more than 4 years. The patient who experienced a PR received 1 cycle of IMGN901 treatment, but had a serious adverse event and declined further treatment. This patient had sustained clinical benefit for more than 5 months, including additional tumor shrinkage. The patient who experienced SD entered Study 002 with bone metastases and had received 3 prior therapies. This patient had SD lasting approximately 3 months. Overall, a clinical benefit rate (CR+PR+SD) of 50% has been observed. The 6 MCC patients received IMGN901 at doses ranging from 36 to 75 mg/m2/day. The MTD of IMGN901 has not been defined in Study 002 and a dose level of 94 mg/m2/day will be evaluated next. Earlier this year, we reported pooled data from two studies in CD56+ solid tumors summarizing the encouraging experience with IMGN901 for the treatment of small‐cell lung cancer (SCLC). SCLC and MCC have shared morphologic characteristics and a common clinical course. Conclusion: There are encouraging findings to date with IMGN901 for the treatment of MCC. The findings are supportive of the initial findings with the compound for the treatment of SCLC and vice versa. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B237.

Phase II Study of Nimustine in Metastatic Soft Tissue Sarcoma

The EORTC Soft Tissue and Bone Sarcoma Group has conducted a phase II trial in 33 eligible patients with metastatic soft tissue sarcoma with nimustine 100 mg/m2 every 6 weeks. In 31 evaluable patients there were 3 (10%) partial responses lasting 4.5, 6 and 7.5 months, and 5 cases of stable disease. 12 patients had progressive disease and 11 patients early progressive disease. Toxicity consisted mainly of leukopenia and thrombocytopenia and nausea and vomiting. It is concluded that nimustine has only minor activity in soft tissue sarcoma.

Anti-angiogenic therapies for the treatment of angiosarcoma: a clinical update

SummaryAngiosarcomas are rare aggressive endothelial tumours, and are associated with axa0poor prognosis. Due to their vascular nature, there is great interest in their response to anti-angiogenic agents. Axa0number of small prospective studies have reported angiosarcoma response to vascular-targeted agents, including agents that target vascular endothelial growth factor. To date, the response to these agents has been disappointing, and similar to the response observed in other soft tissue sarcoma subtypes. This short review will summarise the recent data in this field.

Eribulin in soft-tissue sarcoma

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