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Phase II study of the PI3K inhibitor BKM120 in patients with advanced or recurrent endometrial carcinoma: a stratified type I-type II study from the GINECO group.

ABSTRACT: Backround:Patients with metastatic endometrial carcinoma have a poor prognosis and PIK3CA mutations and amplifications are common in these cancers. This study evaluated the efficacy and safety of the pure PI3K inhibitor BKM120 in advanced or recurrent endometrial carcinoma.This phase II, multicentre, single-arm, double strata (histological low grade (LG) or high grade (HG)) open-label study enrolled patients with histologically confirmed advanced or recurrent endometrial carcinoma who had received not more than one prior chemotherapy regimen. Patients received initially BKM120 100?mg tablets once daily. Primary end points were proportion of patients free of progression at 2 months (HG strata) or at 3 months (LG strata), objective response rate (ORR), and safety.A total of 40 patients were enrolled, of whom 16 patients had received BKM120 at 100?mg. Because of high toxicities (cutaneous rash (54%), depressive events (47%), and anxiety (40%), the IDMC has proposed to stop recruitment at 100?mg and to continue the clinical trial with a lower dose of 60?mg per day. In addition, 24 patients (median age 67 years old) were newly enrolled (14 in the LG strata and 10 in the HG strata). Rate of nonprogression at 2 months in the HG strata was 70% and at 3 months was 60% in the LG strata. Median progression-free survival (PFS) for all patients is 4.5 months (CI 95% 2.8-6.1), and the median PFS for LG strata is 8.3 months compared with 3.8 months for the HG strata. No response was reported. At 60?mg per day, the most commonly reported treatment-related adverse events (AEs) were hyperglycaemia (58%), cognitive (31%), digestive (28%), hepatic liver functions (26%), and rash (23%). The most commonly reported treatment-related grade ?3 AEs were HTA (17%), hyperglycaemia (17%), and increased alanine aminotransferase (24%). Five patients (21%) stopped BKM120 for toxicity.The BKM120 was associated with an unfavourable safety profile and minimal antitumour activity in monotherapy in advanced or recurrent endometrial carcinoma. The clinical trial was stopped before end of recruitment for toxicity.

SUBMITTER: Heudel PE

PROVIDER: S-EPMC5294485 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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Phase II study of the PI3K inhibitor BKM120 in patients with advanced or recurrent endometrial carcinoma: a stratified type I-type II study from the GINECO group.

Heudel P-E PE Fabbro M M Roemer-Becuwe C C Kaminsky M C MC Arnaud A A Joly F F Roche-Forestier S S Meunier J J Foa C C You B B Priou F F Tazi Y Y Floquet A A Selle F F Berton-Rigaud D D Lesoin A A Kalbacher E E Lortholary A A Favier L L Treilleux I I Ray-Coquard I I

British journal of cancer 20170110 3

Backround:Patients with metastatic endometrial carcinoma have a poor prognosis and PIK3CA mutations and amplifications are common in these cancers. This study evaluated the efficacy and safety of the pure PI3K inhibitor BKM120 in advanced or recurrent endometrial carcinoma.<h4>Methods</h4>This phase II, multicentre, single-arm, double strata (histological low grade (LG) or high grade (HG)) open-label study enrolled patients with histologically confirmed advanced or recurrent endometrial carcinom ...[more]

PMID: 28072765

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Project description:BACKGROUND:Endometrial cancer is a cancer of the lining of the womb and worldwide is the seventh most common cancer in women. Treatment with hormones is thought to be beneficial in patients with endometrial cancer. OBJECTIVES:To assess the indications, effectiveness and safety of hormone therapy for advanced or recurrent epithelial endometrial cancer. SEARCH STRATEGY:We searched the Cochrane Gynaecological Cancer Group Trials Register, MEDLINE, EMBASE up to May 2009 and and CENTRAL (Issue 2, 2009). We also searched registers of clinical trials, abstracts of scientific meetings, reference lists of included studies, and contacted experts in the field. SELECTION CRITERIA:Randomised controlled trials (RCTs) that studied hormonal therapy in adult women diagnosed with advanced or recurrent endometrial cancer. DATA COLLECTION AND ANALYSIS:Two review authors independently abstracted data and assessed risk of bias. Comparisons were restricted to single-trial analyses so we did not synthesise data in meta-analyses. MAIN RESULTS:We found six trials (542 participants) that met our inclusion criteria. These trials assessed the effectiveness of hormonal therapy in women with advanced or recurrent endometrial cancer as a single agent, as part of combination therapy and as low versus high dose. All comparisons were restricted to single-trial analyses, where we found no evidence that hormonal therapy as a single agent or as a combination treatment prolonged overall or five-year disease-free survival of women with advanced or recurrent endometrial cancer. However, low-dose hormonal therapy may have had a benefit in terms of overall and progression-free survival (PFS) compared to high-dose hormonal therapy (HR 1.31, 95% CI 1.04 to 1.66 and HR 1.35, 95% CI 1.07 to 1.71 for overall and PFS, respectively). AUTHORS' CONCLUSIONS:We found insufficient evidence that hormonal treatment in any form, dose or as part of combination therapy improves the survival of patients with advanced or recurrent endometrial cancer. However, a large number of patients would be needed to demonstrate an effect on survival and none of the included RCTs had a sufficient number of patients to demonstrate a significant difference. In the absence of a proven survival advantage and the heterogeneity of patient populations, the decision to use any type of hormonal therapy should be individualised and with the intent to palliate the disease. It is debatable whether outcomes such as quality of life, treatment response or palliative measures such as relieving symptoms should take preference over overall and PFS as the major objectives of future trials.

Project description:BackgroundAlthough endometrial adenocarcinoma is a common gynaecological cancer, a comparatively small proportion of patients present with, or develop, recurrent or advanced disease. However, for those women whose disease does progress or recur the prognosis is poor and the best treatment is yet to be identified. Co-morbidity, including obesity and cardiac disease, and concerns over toxicity have prevented more extensive studies of cytotoxic chemotherapy, although there are a number of active agents.ObjectivesTo assess any benefits or adverse effects of cytotoxic chemotherapy in women with advanced, recurrent or metastatic endometrial adenocarcinoma.Search methodsSystematic searches of MEDLINE, EMBASE, CENTRAL and the Cochrane Gynaecological Cancer specialist trials register were conducted to identify all eligible randomised controlled trials (RCTs).Databases were searched from 1966 to January 2012. Literature searches were supplemented with searches of relevant trials registers and conference proceedings.Selection criteriaRCTs comparing chemotherapy versus another intervention (including different chemotherapy) in advanced disease were considered. Trials of adjuvant treatment or for sarcomatous tumours were excluded.Data collection and analysisData were extracted from the papers by review authors and authors of included studies contacted for further information.Main resultsFourteen eligible trials, which recruited patients between 1974 and 2005, were identified, eight of which compared 'more' with 'less' chemotherapy. Results from these eight trials, including 1519 patients, showed that treatment consisting of 'more' chemotherapy was associated with longer overall survival (OS) (hazard ratio (HR) 0.86; 95% confidence intervals (CI) 0.77 to 0.96; P = 0.005) and with longer progression-free survival (PFS) (n = 1526; HR 0.82; 95% CI 0.74 to 0.90; P < 0.0001). However, serious acute toxicities were more common in women randomised to the more-intense chemotherapy regimens.There was no evidence to suggest that any particular doublet chemotherapy was better (or worse) than any other, or that any single-agent chemotherapy was better (or worse) than another; however, data for these two comparisons were limited. There were no comparative trials of chemotherapy with endocrine therapy or best supportive care alone.Authors' conclusionsThis review suggests that more-intense chemotherapy regimens may improve both OS and PFS for women with advanced or recurrent endometrial cancer. However, owing to inconsistencies between cytotoxic drug combinations that have been assessed in randomised trials to date, the optimum regimen has still to be defined. Future trials should aim to include measures of quality of life (QoL) and symptom control in addition to survival and progression outcomes.

Dataset Information

Phase II study of the PI3K inhibitor BKM120 in patients with advanced or recurrent endometrial carcinoma: a stratified type I-type II study from the GINECO group.

Publications

Phase II study of the PI3K inhibitor BKM120 in patients with advanced or recurrent endometrial carcinoma: a stratified type I-type II study from the GINECO group.

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