Dataset Information

Phase I/II clinical trial of everolimus combined with gemcitabine/cisplatin for metastatic triple-negative breast cancer.

ABSTRACT: Background: The PI3K/AKT/mTOR pathway is an important oncogenic driver in triple-negative breast cancer (TNBC). This study investigated the clinical efficacy and safety of the combination of gemcitabine and cisplatin with everolimus (GPE) in patients with metastatic TNBC. Methods: In phase I, we assessed the maximum tolerated dose (MTD) of GPE in metastatic TNBC patients. Then, using a seamless design, we conducted a randomized phase II trial to compare GPE to GP in terms of progression-free survival (PFS) and toxicity. In addition, we investigated the mutational status of PIK3CA (E542K, E545K, H1047R) in tumor tissues (n=14) and cell-free DNA (cfDNA) from blood samples (n=23) using droplet digital PCR. Results: In phase I (n=9), we found that the MTD of GPE was gemcitabine 800 mg/m2 and cisplatin 30 mg/m2 on days 1 and 8 every 3 weeks along with everolimus 5 mg daily. Phase II was terminated early after 14 patients had been enrolled because of slow recruitment and concerns about efficacy. Results of the combined analysis of phases I and II showed the objective response rate (ORR) of GPE (n=16) was 31.3% and the median PFS was 5.5 months (95% CI, 3.5-7.5). Stomatitis and hematologic toxicities were observed most frequently in the GPE arm. PIK3CA mutations were identified in 8 (57.1%) tumor samples and 17 (73.9%) cfDNA samples; there was no significant association between PIK3CA mutation status and response to GPE treatment. Conclusions: Although the majority of patients with metastatic TNBC demonstrated PIK3CA mutations in cfDNA, the addition of everolimus to gemcitabine/cisplatin did not have a synergistic effect in these patients. Further studies are needed to determine the most effective way to target the PI3K/AKT/mTOR pathway in TNBC patients.

SUBMITTER: Park IH

PROVIDER: S-EPMC5907662 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Phase I/II clinical trial of everolimus combined with gemcitabine/cisplatin for metastatic triple-negative breast cancer.

Park In Hae IH Kong Sun-Young SY Kwon Youngmee Y Kim Min Kyeong MK Sim Sung Hoon SH Joo Jungnam J Lee Keun Seok KS

Journal of Cancer 20180308 7

<b>Background:</b> The PI3K/AKT/mTOR pathway is an important oncogenic driver in triple-negative breast cancer (TNBC). This study investigated the clinical efficacy and safety of the combination of gemcitabine and cisplatin with everolimus (GPE) in patients with metastatic TNBC. <b>Methods:</b> In phase I, we assessed the maximum tolerated dose (MTD) of GPE in metastatic TNBC patients. Then, using a seamless design, we conducted a randomized phase II trial to compare GPE to GP in terms of progre ...[more]

PMID: 29675095

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Project description:Our study aimed to compare the efficacy and safety of nab-paclitaxel plus cisplatin (AP) with nab-paclitaxel plus gemcitabine (AG) in patients with metastatic breast cancer (MBC). We collected data from two single-arm, phase II MBC studies. In NCT01149798, seventy-three MBC patients received 125 mg/m2 nab-paclitaxel on days 1, 8 and 15 followed by 75 mg/m2 cisplatin on day 1 of a 28-day cycle. In NCT01550848, eighty-four MBC patients received 125 mg/m2 nab-paclitaxel and 800 mg/m2 gemcitabine on days 1, 8, and 15 of a 28-day cycle. The endpoints were the overall response rate (ORR), progression-free survival (PFS), overall survival (OS) and safety profiles of these regimens. Among the 157 patients included, the ORR were 67.1% and 52.4% for the AP and AG arms, respectively (odds ratio [OR] = 0.246; hazard ratio [HR] = 1.485; 95% confidence interval [CI], 0.762-2.985). After median follow-up periods of 26.3 and 23.3 months in the AP and AG arms, the median PFS were 9.8 months (95%CI, 8.1-11.6) and 8.1 months (95%CI, 6.8-9.4), respectively, while the median OS were 26.9 months (95%CI, 22.4-31.4) and 25.5 months (95%CI, 19.3-31.4), respectively. Neither PFS nor OS adjusted for the number of metastases, occurrence of liver metastasis and chemotherapeutic lines differed significantly between the two arms (PFS:HR = 0.769; 95%CI, 0.541-1.092; p = 0.142; OS:HR = 0.686; 95%CI, 0.426-1.104; p = 0.120). However, PFS was significantly better with AP than with AG in metastatic triple-negative breast cancer (mTNBC) patients (HR = 0.308; 95%CI, 0.129-0.732; p = 0.008). Adverse events were more common with AP than with AG, except for edema and myalgia. Both regimens showed substantial efficacy and were tolerated well in MBC patients. mTNBC who received AP rather than AG showed longer PFS. However, adverse events were more common with AP. Thus, AP may be worth recommending to mTNBC, while AG may be a better alternative for MBC patients with other subtypes.

Project description:IntroductionRapamycin acts synergistically with platinum agents to induce apoptosis and inhibit proliferation in breast cancer cell lines. Combination of everolimus also known as RAD001 (oral mammalian target of rapamycin (mTOR) inhibitor) and carboplatin may have activity in metastatic triple-negative breast cancer (TNBC).MethodsThe primary objective of this study was to determine clinical benefit rate (CBR), that is (complete remission (CR) + partial remission (PR) + stable disease (SD) lasting ≥6 months) and the toxicity of everolimus/carboplatin in women with metastatic TNBC. Prior carboplatin was allowed. Treatment consisted of intravenous carboplatin area under the curve (AUC) 6 (later decreased to AUC 5 and subsequently to AUC 4) every 3 weeks with daily 5 mg everolimus.ResultsWe enrolled 25 patients in this study. Median age was 58 years. There were one CR, six PRs, seven SDs and eight PDs (progression of disease). CBR was 36% (95% confidence interval (CI) 21.1 to 57.4%). One SD was achieved in a patient progressing on single agent carboplatin. The median progression free survival (PFS) was 3 months (95% CI 1.6 to 4.6 months) and overall survival (OS) was 16.6 months (95% CI 7.3 months to not reached). There were seven patients (28%) with ≥ grade 3 thrombocytopenia; three (12%) with grade 3 neutropenia (no bleeding/febrile neutropenia) and one (4%) with grade 3 anemia. Greater hematological toxicity was seen in the first seven patients treated with carboplatin AUC5/6. After the amendment for starting dose of carboplatin to AUC 4, the regimen was well tolerated with only one out of 18 patients with grade 3 neutropenia and two patients with grade 3 thrombocytopenia. There was only one case of mucositis.ConclusionEverolimus-carboplatin was efficacious in metastatic TNBC. Dose limiting hematological toxicity was observed when AUC5/6 of carboplatin was combined with everolimus. However, carboplatin AUC 4 was well tolerated in combination with everolimus with continuing responses.Trial registrationsClinicalTrials.gov NCT01127763.

Project description:Apatinib is a tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor 2(VEGFR-2). This study was conducted to assess the efficacy and safety of apatinib in patients with non-triple-negative metastatic breast cancer who had received prior chemotherapy for their metastatic disease.This multicenter, open-label, single arm study enrolled patients with non-triple-negative breast cancer, pretreated with anthracycline, taxanes and capecitabine, and who failed in the metastatic setting at least 1 and at most 4 prior chemotherapy regimens and at least one endocrine drug for hormone receptor-positive patients as well as at least one anti-Her2 drug for Her2-positive patients. The primary end point of this study was progression free survival (PFS). Secondary end points included objective response rate (ORR), disease control rate (DCR), overall survival (OS), and toxicity. Apatinib was administered as 500 mg daily on days 1 through 28 of each 4-week cycle.38 patients were enrolled with a median age of 49 years (range, 35 to 62 years) and received apatinib for a median of 4 cycles (range from 0 to 10 cycles). 18 (47.4%) patients experienced dose reduction during treatment. The median relative dose intensity (relative to assigned dose for each cycle) was 82% (range, 45.0% to 100.0%). Median follow-up time was 10.1 months. Median PFS of all 38 patients was 4.0 months (95% confidence interval (CI), 2.8 m - 5.2 m). 36 patients were eligible for efficacy analysis. ORR was 16.7% (6/36). DCR was 66.7% (24/36). Median OS was 10.3 months (95% CI, 9.1 m - 11.6 m). The most common grade 3/4 treatment-related AEs were hypertension (20.5%), hand-foot syndrome (10.3%), and proteinuria (5.1%). Of three possibly drug-related SAEs recorded in the study, 2 (3.4%) deaths occurred within 28 days of last treatment and were both considered to be the result of disease progression. The other one was grade 2 diarrhea needing hospitalization.Apatinib exhibited objective efficacy in heavily pretreated, metastatic non-triple-negative breast cancer with manageable toxicity, and it might be better to be tested in breast cancer with high angiogenesis dependency.ClinicalTrials.gov: NCT01653561.

Project description:Currently, no targeted therapies are available for metastatic triplenegative breast cancer (mTNBC). We evaluated the safety, efficacy, and biomarkers of response to cabozantinib, a multikinase inhibitor, in patients with mTNBC. We conducted a single arm phase II and biomarker study that enrolled patients with measurable mTNBC. Patients received cabozantinib (60 mg daily) on a 3-week cycle and were restaged after 6 weeks and then every 9 weeks. The primary endpoint was objective response rate. Predefined secondary endpoints included progression-free survival (PFS), toxicity, and tissue and blood circulating cell and protein biomarkers. Of 35 patients who initiated protocol therapy, 3 (9% [95% confidence interval (CI): 2, 26]) achieved a partial response (PR). Nine patients achieved stable disease (SD) for at least 15 weeks, and thus the clinical benefit rate (PR+SD) was 34% [95% CI: 19, 52]. Median PFS was 2.0 months [95% CI: 1.3, 3.3]. The most common toxicities were fatigue, diarrhea, mucositis, and palmar-plantar erythrodysesthesia. There were no grade 4 toxicities, but 12 patients (34%) required dose reduction. Two patients had TNBCs with MET amplification. During cabozantinib therapy, there were significant and durable increases in plasma placental growth factor, vascular endothelial growth factor (VEGF), VEGF-D, stromal cell-derived factor 1a, and carbonic anhydrase IX, and circulating CD3 + cells and CD8 + T lymphocytes, and decreases in plasma soluble VEGF receptor 2 and CD14+ monocytes (all p < .05). Higher baseline concentrations of soluble MET (sMET) associated with longer PFS (p = .03). In conclusion, cabozantinib showed encouraging safety and efficacy signals but did not meet the primary endpoint in pretreated mTNBC. Exploratory analyses of circulating biomarkers showed that cabozantinib induces systemic changes consistent with activation of the immune system and antiangiogenic activity, and that sMET should be further evaluated a potential biomarker of response.Implications for practiceTriple-negative breast cancer (TNBC)-a disease with a dearth of effective therapies-often overexpress MET, which is associated with poor clinical outcomes. However, clinical studies of agents targeting MET and VEGF pathways-alone or in combination-have shown disappointing results. This study of cabozantinib (a dual VEGFR2/MET) in metastatic TNBC, while not meeting its prespecified endpoint, showed that treatment is associated with circulating biomarker changes, and is active in a subset of patients. Furthermore, this study demonstrates that cabozantinib therapy induces a systemic increase in cytotoxic lymphocyte populations and a decrease in immunosuppressive myeloid populations. This supports the testing of combinations of cabozantinib with immunotherapy in future studies in breast cancer patients.

Project description:BACKGROUND:Alteration of the PI3K/AKT/mTOR pathway is a common genomic abnormality detected in triple-negative breast cancer (TNBC). Everolimus acts synergistically with eribulin in TNBC cell lines and xenograft models. This phase I trial was designed to test the safety and tolerability of combining eribulin and everolimus in patients with metastatic TNBC. METHODS:The primary objective of this study was to evaluate the safety and toxicities of the combination. Patients with metastatic TNBC who had up to four lines of prior chemotherapies were enrolled. The combination of eribulin and everolimus was tested using three dosing levels: A1 (everolimus 5?mg daily; eribulin 1.4?mg/m2?days 1 and 8 every 3 weeks), A2 (everolimus 7.5?mg daily; eribulin 1.4?mg/m2, days 1 and 8 every 3 weeks), and B1 (everolimus 5?mg daily; eribulin 1.1?mg/m2?days 1 and 8 every 3 weeks). RESULTS:Twenty-seven patients with median age 55?years were enrolled. Among 8 evaluable patients who received dose level A1, 4 had dose-limiting toxicities (DLTs). Among 3 evaluable patients treated with dose level A2, 2 had DLTs. Among 12 evaluable patients who received dose level B1, 4 had DLTs. The DLTs were neutropenia, stomatitis, and hyperglycemia. Over the study period, 59% had a ??grade 3 toxicity, 44% had ??grade 3 hematologic toxicities, and 22% had grade 4 hematologic toxicities. The most common hematological toxicities were neutropenia, leukopenia, and lymphopenia. Thirty-three percent had grade 3 non-hematologic toxicities. The most common non-hematological toxicities were stomatitis, hyperglycemia, and fatigue. The median number of cycles completed was 4 (range 0-8). Among 25 eligible patients, 9 patients (36%) achieved the best response as partial response, 9 (36%) had stable disease, and 7 (28%) had progression. The median time to progression was 2.6?months (95% CI [2.1, 4.0]), and median overall survival (OS) was 8.3?months (95% CI [5.5, undefined]). CONCLUSION:Eribulin 1.1?mg/m2?days 1 and 8 every 3 weeks with everolimus 5?mg daily was defined as the highest dose with acceptable toxicity (RP2D). The combination is safe, and efficacy is modest. A post hoc analysis showed that participants that used dexamethasone mouthwash stayed on treatment for one additional cycle. TRIAL REGISTRATION:ClinicalTrials.gov, NCT02120469. Registered 18 April 2014.

Dataset Information

Phase I/II clinical trial of everolimus combined with gemcitabine/cisplatin for metastatic triple-negative breast cancer.

Publications

Phase I/II clinical trial of everolimus combined with gemcitabine/cisplatin for metastatic triple-negative breast cancer.

Similar Datasets

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