Combination chemotherapy with temsirolimus and trabectedin for recurrent clear cell carcinoma of the ovary: A phase II single arm clinical trial.

Takano, Masashi; Kouta, Hiroko; Ikeda, Yuji; Sasaki, Naoki; Kudoh, Kazuya; Ikeda, Sayaka; Kita, Toru; Kikuchi, Ryoko; Gotō, Tomoko; Furuya, Kenichi; Kikuchi, Yoshihiro

doi:10.1200/jco.2014.32.15_suppl.5517

Cited by 6 publications

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“…Three other phase I studies of rapalogs in combination with chemotherapy (temsirolimus plus carboplatin/paclitaxel [30] , ridaforolimus plus carboplatin and paclitaxel [31] , and everolimus plus weekly paclitaxel [32] ) also included a small number of patients with advanced OC, and the responses were described (3 of 6 patients with OC had a PR to temsirolimus plus carboplatin and paclitaxel). Another phase II trial evaluating the efficacy of temsirolimus and trabectedin in patients with recurrent clear cell carcinoma was performed, with no treatment discontinuations due to unmanageable adverse events [33] . Among the 17 patients enrolled, the objective response rate (ORR) was 18%, including 1 patient with complete response (CR) and 5 (29%) with SD beyond 3 months, resulting in a clinical benefit rate (CBR; CR + PR + SD > 3 months) of 47% [33] .…”

Section: Targeting the Pi3k/akt/mtor Pathway With Mtor Inhibitorsmentioning

confidence: 99%

“…Another phase II trial evaluating the efficacy of temsirolimus and trabectedin in patients with recurrent clear cell carcinoma was performed, with no treatment discontinuations due to unmanageable adverse events [33] . Among the 17 patients enrolled, the objective response rate (ORR) was 18%, including 1 patient with complete response (CR) and 5 (29%) with SD beyond 3 months, resulting in a clinical benefit rate (CBR; CR + PR + SD > 3 months) of 47% [33] . However, given the small number and the use of different chemotherapeutics in the combination studies, it is difficult to draw conclusions regarding the true added value of an mTOR inhibitor.…”

Section: Targeting the Pi3k/akt/mtor Pathway With Mtor Inhibitorsmentioning

confidence: 99%

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The PI3K/Akt/mTOR pathway in ovarian cancer: therapeutic opportunities and challenges

2015

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The phosphatidylinositol 3 kinase (PI3K) pathway is frequently altered in cancer, including ovarian cancer (OC). Unfortunately, despite a sound biological rationale and encouraging activity in preclinical models, trials of first-generation inhibitors of mammalian target of rapamycin (mTOR) in OC have demonstrated negative results. The lack of patient selection as well as resistance to selective mTOR complex-1 (mTORC1) inhibitors could explain the disappointing results thus far. Nonetheless, a number of novel agents are being investigated, including dual mTORC1/mTORC2, Akt, and PI3K inhibitors. Although it is likely that inhibition of the PI3K/Akt/mTOR pathway may have little effect in unselected OC patients, certain histological types, such as clear cell or endometrioid OC with frequent phosphatidylinositol-4,5-biphosphate 3-kinase, catalytic subunit alpha (PIK3CA) and/or phosphatase and tensin homolog (PTEN) alterations, may be particularly suited to this approach. Given the complexity and redundancy of the PI3K signaling network, PI3K pathway inhibition may be most useful in combination with either chemotherapy or other targeted therapies, such as MEK inhibitors, anti-angiogenic therapy, and hormonal therapy, in appropriately selected OC patients. Here, we discuss the relevance of the PI3K pathway in OC and provide an up-to-date review of clinical trials of novel PI3K inhibitors alone or in combination with cytotoxics and novel therapies in OC. In addition, the challenges of drug resistance and predictive biomarkers are addressed.

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Section: Targeting the Pi3k/akt/mtor Pathway With Mtor Inhibitorsmentioning

confidence: 99%

Section: Targeting the Pi3k/akt/mtor Pathway With Mtor Inhibitorsmentioning

confidence: 99%

The PI3K/Akt/mTOR pathway in ovarian cancer: therapeutic opportunities and challenges

2015

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“…As a standard tool to assess treatment efficacy in oncology clinical trials, Response Evaluation Criteria for Solid Tumors (RECIST) has helped advance cancer treatment, such as chemotherapy [1][2][3][4], targeted therapy [5][6][7][8][9][10], immunotherapy [11][12][13][14][15][16][17], or combinations of these [14,15,[18][19][20][21][22]. In parallel, recent studies have discovered several unique tumor response subgroups outside of RECIST response classification, such as mixed response [23][24][25][26], oligometastasis [27][28][29][30], and pseudo-progression [31][32][33].…”

Section: Rationale For Incorporation Of Lesion Heterogeneity To Evaluate Treatment Responses In Oncology Clinical Trialsmentioning

confidence: 99%

Utilization of target lesion heterogeneity for treatment efficacy assessment in late stage lung cancer

et al. 2021

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Rationale Recent studies have discovered several unique tumor response subgroups outside of response classification by Response Evaluation Criteria for Solid Tumors (RECIST), such as mixed response and oligometastasis. These subtypes have a distinctive property, lesion heterogeneity defined as diversity of tumor growth profiles in RECIST target lesions. Furthermore, many cancer clinical trials have been activated to evaluate various treatment options for heterogeneity-related subgroups (e.g., 29 trials so far listed in clinicaltrials.gov for cancer patients with oligometastasis). Some of the trials have shown survival benefit by tailored treatment strategies. This evidence presents the unmet need to incorporate lesion heterogeneity to improve RECIST response classification. Method An approach for Lesion Heterogeneity Classification (LeHeC) was developed using a contemporary statistical approach to assess target lesion variation, characterize patient treatment response, and translate informative evidence to improving treatment strategy. A mixed effect linear model was used to determine lesion heterogeneity. Further analysis was conducted to classify various types of lesion variation and incorporate with RECIST to enhance response classification. A study cohort of 110 target lesions from 36 lung cancer patients was used for evaluation. Results Due to small sample size issue, the result was exploratory in nature. By analyzing RECIST target lesion data, the LeHeC approach detected a high prevalence (n = 21; 58%) of lesion heterogeneity. Subgroup classification revealed several informative distinct subsets in a descending order of lesion heterogeneity: mix of progression and regression (n = 7), mix of progression and stability (n = 9), mix of regression and stability (n = 5), and non-heterogeneity (n = 15). Evaluation for association of lesion heterogeneity and RECIST best response classification showed lesion heterogeneity commonly occurred in each response group (stable disease: 16/27; 59%; partial response: 3/5; 60%; progression disease: 2/4; 50%). Survival analysis showed a differential trend of overall survival between heterogeneity and non-heterogeneity in RECIST response groups. Conclusion This is the first study to evaluate lesion heterogeneity, an underappreciated metric, for RECIST application in oncology clinical trials. Results indicated lesion heterogeneity is not an uncommon event. The LeHeC approach could enhance RECIST response classification by utilizing granular lesion level discovery of heterogeneity.

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“…The PI3K/AKT/mTOR is a key mediator of oncogenic signalling, which may be overactive due to PTEN loss. The PI3K pathway is a complex signalling network that coordinates signals from other membrane receptors such as MET [35].…”

Section: Recurrent Clear Cell Ovarian Carcinomamentioning

confidence: 99%

A Succinct Molecular Profile of High-Grade Ovarian Cancer

Malik¹,

Idris²

2023

Recent Advances, New Perspectives and Applications in the Treatment of Ovarian Cancer

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Several studies have been carried out to determine the complexity of ovarian cancer as a disease with multiple distinct types that presents with symptoms similar to those in other gynaecological, gastrointestinal and genitourinary diseases. The malignant variants of common epithelial and germ cell tumours constitute the bulk of ovarian tumours and are classified histologically based on the presumed tissue of origin. Molecular diagnosis is now aiding in the early detection and treatment of ovarian cancer even before metastasis sets in. Thus studying the molecular profiles of each type is key to understanding the origin and pathogenesis as well as genetic aberrations and mutations involved in the development of the disease. Ovarian cancers originate either from the ovary or fallopian tube and are found majorly to harbour mutations in PTEN, KRAS, BRAF, BRCA1, BRCA2 and TP53, with TP53 mutations being the most frequent. Genetic testing for ovarian cancers involves testing for the aforementioned genes, and in the nearest future, an advanced method that would detect these genes in blood and uterine lavage is expected. There is an urgent need for further studies on the detailed mechanisms underlying the roles of mutant TP53 in ovarian cancer development and its potential role in therapeutic interventions.

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Combination chemotherapy with temsirolimus and trabectedin for recurrent clear cell carcinoma of the ovary: A phase II single arm clinical trial.

Cited by 6 publications

References 0 publications

The PI3K/Akt/mTOR pathway in ovarian cancer: therapeutic opportunities and challenges

The PI3K/Akt/mTOR pathway in ovarian cancer: therapeutic opportunities and challenges

Utilization of target lesion heterogeneity for treatment efficacy assessment in late stage lung cancer

A Succinct Molecular Profile of High-Grade Ovarian Cancer

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