Combination Of Everolimus Research Articles

Risk of hyperglycemia attributable to everolimus in cancer patients: A meta-analysis

Everolimus has been used widely in cancer patients and is associated with the development of hyperglycemia. Due to confounding factors, its specific impact on hyperglycemia has not been well understood. We performed a meta-analysis of randomized controlled trials to determine the risk of hyperglycemia attributable to everolimus in cancer patients of varying tumor types.Material and methods: PubMed and American Society of Clinical Oncology conference abstracts up to June 2015 were systematically searched. Eligible studies included randomized controlled trials (RCTs) in which everolimus was compared to placebo in cancer patients with or without other agents. Heterogeneity tests were performed to examine between-study differences in hyperglycemia, and the incidence and relative risk of all- and high-grade hyperglycemia attributable to everolimus were determined using both random- or fixed-effects models.Results: A total of seven phase III and two phase II RCTs with various tumors, encompassing a total of 3879 cancer patients, were included in our analysis. Everolimus significantly increased the risk of all-grade (RR =2.60, 95% CI 2.03–3.31, p < 0.001) and high-grade (RR =3.0, 95% CI 1.72–5.23; p < 0.001) hyperglycemia. The incidences of all- and high-grade hyperglycemia attributable to everolimus were 6.8% (95% CI 3.4–13.2%) and 2.5% (95% CI 1.2–4.9%), respectively. The everolimus-specific risk of all-grade hyperglycemia varied significantly with tumor types (p < 0.001), with the highest incidence seen in renal cell carcinoma (RCC) (27.2%, 95% CI 22.2–32.8%) and the lowest in breast cancer (3.3%, 95% CI 1.3–8.2%). No significant variation was found between everolimus alone or everolimus in combination with other agents. Similar results were also found for the risk of high-grade hyperglycemia attributable to everolimus.Conclusion: The specific risk of hyperglycemia attributable to everolimus may vary significantly with tumor types. Close monitoring should be given to patients at high risk, such as RCC.

Evaluation of Treatment with a Combination of Everolimus and Low-Dose Cyclosporine A in De Novo Pediatric Kidney Transplantation Patients: A Systematic Review

Evaluation of Treatment with a Combination of Everolimus and Low-Dose Cyclosporine A in De Novo Pediatric Kidney Transplantation Patients: A Systematic Review

Birth defects in juvenile Wistar rats after exposure to immunosuppressive drugs during pregnancy.

Immunosuppressive drugs and their active metabolites can cross the placental barrier and enter fetal circulation. The adverse effects on the fetus include chromosomal aberrations, structural malformations, organ-specific toxicity and intrauterine growth retardation. The aim of our study was to investigate the impact of "safe" and "contraindicated" immunosuppressive drugs on birth defects in juvenile Wistar rats after exposure of pregnant female rats to these drugs. The study was conducted on 32 female Wistar rats, subjected to immunosuppressive regimens most commonly used in therapy of human kidney transplant recipients. The animals received drugs by oral gavage 2 weeks before pregnancy and during 3 weeks of pregnancy. Treatment with mycophenolate mofetil and everolimus turned out to be toxic. We have noticed a significantly reduced number of live births in all pregnant rats exposed to these drugs in combination with calcineurin inhibitors and prednisone. Malformations and histological changes of fetal organs were confirmed after mycophenolate mofetil exposure during pregnancy. Mycophenolate mofetil turned out to be more toxic when used with tacrolimus than with cyclosporin (delivery of live offspring was possible only in the latter group). Everolimus in combination with cyclosporin effectively suppressed the fetal maturation in utero, but did not contribute to the development of malformations.

Phase Ib Trial of mFOLFOX6 and Everolimus (NSC-733504) in Patients with Metastatic Gastroesophageal Adenocarcinoma

Objectives: Based upon preclinical data showing synergy with mTOR inhibition and platinum chemotherapy, this study explores the safety and tolerability of combining everolimus with mFOLFOX6 for patients with metastatic gastroesophageal adenocarcinoma. Methods: Eligible patients with metastatic gastroesophageal adenocarcinoma received standard-dose mFOLFOX6 chemotherapy in combination with escalating doses of everolimus. Results: Six patients were accrued to the first dose level of 2.5 mg everolimus daily with mFOLFOX6. Overall, the toxicity profile was manageable with expected grade 3 toxicities of mucositis and neutropenia. The dose-limiting toxicity (DLT) included a week delay in therapy greater than 7 days as a result of the first 2 courses of mFOLFOX6. Two patients experienced DLTs at the first dose level due to delays in their treatment caused by prolonged grade 2 neutropenia and fever with fatigue. They were allowed to continue with a dose reduction of their chemotherapy. The median overall survival and progression-free survival were 20.3 and 14.5 months, respectively. Conclusions: The combination of mFOLFOX6 and everolimus is an active regimen with 83% of the patients experiencing a partial response. p53 mutations were found in the 5 samples analyzed.

A phase II study of everolimus (RAD001), an mTOR inhibitor plus CHOP for newly diagnosed peripheral T-cell lymphomas

Everolimus, an oral mTOR inhibitor, has single-agent activity against relapsed lymphomas. Thus, we carried out a phase II study of everolimus in combination with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) as a first-line treatment for patients with peripheral T-cell lymphoma (PTCL) based on our phase I study results. Participants (n = 30) received CHOP with 5 mg everolimus per day from day 1 to 14 every 21 days for a total of six cycles. The primary end point was the overall response rate (ORR), which included complete response (CR) and partial response (PR) to this regimen. Immunohistochemistry was used to evaluate the expression of phosphatase and tensin homology (PTEN) and phosphorylated S6 kinase (pS6K) as a response. The objective response rate was 90% with CR (n = 17) and PR (n = 10). The CR rate was different among subtypes; angioimmunoblastic T-cell lymphoma (AITL, n = 3) had a CR whereas PTCL-not-otherwise specified and ALK-negative anaplastic large-cell lymphoma (ALCL) patients showed 63% (12/19) and 29% (2/7) of CR rate, respectively. This difference in CR rate among subtypes was associated with PTEN loss because PTEN loss was not seen in AITL but 33% of ALCL patients. The most common toxicity was hematological, with 80% of patients experiencing at least one event of grade 3/4 neutropenia, and 60% of patients had grade 3/4 thrombocytopenia. The everolimus plus CHOP was effective for PTCL patients, and its efficacy might be related with the preservation of PTEN.

Effectiveness of the Combination of Everolimus and Tacrolimus With High Dosage of Mizoribine for Living Donor–Related Kidney Transplantation

BackgroundEverolimus (EVR) has been used widely for the purpose of reducing the dosage of calcineurin inhibitor (CNI), leading to decreasing CNI nephrotoxicity. In Japan, high-dose mizoribine (MZR) (6 mg/kg/day) has been increasingly used because of incidences of virus infection and gastrointestinal disorder in kidney transplant recipients. However, the efficacy and safety of EVR and MZR combination therapy is still uncertain. MethodsA total of 29 living kidney transplant recipients from October 2012 to June 2014 were analyzed. Tacrolimus (TAC), MZR, basiliximab, and prednisolone were administered to all recipients. EVR was added to the regimen for 10 recipients from postoperative day 10 to 14; TAC trough levels were minimized simultaneously (EVR group). The remaining 19 recipients were defined as the control group. We evaluated the outcomes between the 2 groups. ResultsThe mean TAC trough level was 5.17 ng/mL at 1 month after transplantation in the EVR group, and 7.89 ng/mL in the control group (P = .007), respectively. The mean TAC trough level was 4.0 ng/mL at 18 months after transplantation in the EVR group, and 6.97 ng/mL in the control group (P = .003) respectively. There were no differences in the rate of acute rejection and serum creatinine level. There was no significant difference in the incidence of histological nephrotoxicity between the 2 groups in the 1-year biopsy results. ConclusionsWe succeeded in reducing TAC trough level immediately after transplantation by adding EVR. Our study results suggest that this combination therapy is effective for kidney transplantation recipients.

MTOR Inhibitors Suppress Homologous Recombination Repair and Synergize with PARP Inhibitors via Regulating SUV39H1 in BRCA-Proficient Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is a highly heterogeneous disease and has the worst outcome among all subtypes of breast cancers. Although PARP inhibitors represent a promising treatment in TNBC with BRCA1/BRCA2 mutations, there is great interest in identifying drug combinations that can extend the use of PARP inhibitors to a majority of TNBC patients with wild-type BRCA1/BRCA2 Here we explored whether mTOR inhibitors, through modulating homologous recombination (HR) repair, would provide therapeutic benefit in combination with PARP inhibitors in preclinical models of BRCA-proficient TNBC. We have studied the effects of mTOR inhibitors on HR repair following DNA double-strand breaks (DSB). We further demonstrated the in vitro and in vivo activities of combined treatment of mTOR inhibitors with PARP inhibitors in BRCA-proficient TNBC. Moreover, microarray analysis and rescue experiments were used to investigate the molecular mechanisms of action. We found that mTOR inhibitors significantly suppressed HR repair in two BRCA-proficient TNBC cell lines. mTOR inhibitors and PARP inhibitors in combination exhibited strong synergism against these TNBC cell lines. In TNBC xenografts, we observed enhanced efficacy of everolimus in combination with talazoparib (BMN673) compared with either drug alone. We further identified through microarray analysis and by rescue assays that mTOR inhibitors suppressed HR repair and synergized with PARP inhibitors through regulating the expression of SUV39H1 in BRCA-proficient TNBCs. Collectively, these findings strongly suggest that combining mTOR inhibitors and PARP inhibitors would be an effective therapeutic approach to treat BRCA-proficient TNBC patients.

Influence of everolimus on the pharmacokinetics of tacrolimus in Japanese renal transplant patients

To examine whether a trough concentration of everolimus in the therapeutic range of 3-5 ng/mL affects the pharmacokinetics of tacrolimus in renal transplant patients. A total of 52 Japanese renal transplant patients receiving tacrolimus were enrolled in this study. In 28 of them, everolimus was co-administered on day 14 after surgery. Changes in the dose-adjusted blood trough concentration of tacrolimus from day 14 to 28 after surgery were investigated. The dose-adjusted blood trough concentration of tacrolimus on day 28 was affected by CYP3A5*3/*3 and hemoglobin level (P < 0.001 and P = 0.007), but not by everolimus (P = 0.171). In addition, there was no change in the dose-adjusted blood trough concentration of tacrolimus in patients before or after everolimus coadministration (P = 0.165). On day 28, there was no correlation between the rate of change in the dose-adjusted blood trough concentration of tacrolimus and the blood trough concentration or area under the plasma concentration-time curve from 0 to 12 h for everolimus after initiation of combination therapy (r = 0.341, P = 0.076 and r = 0.234, P = 0.231). A pharmacokinetic interaction between tacrolimus and everolimus was not observed clinically in renal transplant patients. Safe and reliable immunosuppressive therapy in renal transplant patients might be achieved using a combination of tacrolimus and everolimus.

Abstract A48: Phase I study of Everolimus (mTOR inhibitor) in combination with Vandetanib (multikinase inhibitor of EGFR,VEGFR,RET) in children, adolescents, and young adults with advanced solid tumors

Abstract Background: Early phase clinical trials are often limited to adults, reducing the opportunity to explore safety and efficacy of new agents in children. Pre-clinical models have shown that combining an mTOR inhibitor (everolimus) with a multikinase VEGFR2 inhibitor (vandetanib) overcomes intrinsic and /or acquired resistance to either agent alone. Since this combination may have activity against pediatric cancer, pediatric patients were eligible for enrollment (NCT01582191). Methods: We designed a conventional 3+3 Phase I study to determine the safety, maximum tolerated dose (MTD), recommended Phase II dose (RP2D), and dose-limiting toxicities (DLTs) of this combination using oral vandetanib and oral everolimus in pediatric patients with advanced solid tumors. Younger patients were enrolled at the accruing dose level, with BSA-based dose adjustments for smaller children. Tumor responses were assessed using RECIST v1.1. Results: To date, 15 pediatric patients were enrolled between February 2013 and May 2015. The median age was 18 years (range 8-26 years) and 8 patients (53%) were male. The most common diagnosis was sarcoma (n=9; 5 soft tissue and 4 bone). Seven patients (47%) had 2 or more sites of metastases. One patient was treated at dose level 0 (vandetanib 100 mg daily + everolimus 2.5 mg daily), another at dose level 1 (vandetanib 200 mg daily + everolimus 2.5 mg daily), and 13 patients at dose level 4 (determined to be the MTD, vandetanib 300 mg daily + everolimus 10 mg daily). The most common adverse events observed in patients across different dose levels included G1 rash (n=4); G1 fatigue (n=2); G1-G2 hypertension (n=2); G1-G2 QTc prolongation (n=2); G1-G4 transaminitis (n=4); G1-G4 thrombocytopenia (n=3). Eight patients (53%) were taken off study due to disease progression and one patient (7%) due to drug toxicity. One patient with epithelioid sarcoma had a PR (74% tumor size reduction) and one patient with AKT1 p.E17K mutant pseudopapillary pancreatic tumor had a 15% reduction in tumor size. In addition, two patients with alveolar soft part sarcoma had stable disease with clinical benefit. Conclusions: The toxicities of the combination of everolimus with vandetanib seen in children are similar to those seen in adults. Evidence of response was noted in heavily pre-treated pediatric patients with refractory solid tumors. Including younger patients in institutional phase I trials provides a mechanism to study new combinations in children. Note: This abstract was not presented at the conference. Citation Format: Hatel Rana Moonat, Michael Roxas, Winston W. Huh, Cynthia E. Herzog, Sarina Piha-Paul, Najat C. Daw, Michael Rytting, Estella Mote, Erica N. Ward, Yazan Amin, Funda Meric-Bernstam, Cindy L. Schwartz, Vivek Subbiah. Phase I study of Everolimus (mTOR inhibitor) in combination with Vandetanib (multikinase inhibitor of EGFR,VEGFR,RET) in children, adolescents, and young adults with advanced solid tumors. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Pediatric Cancer Research: From Mechanisms and Models to Treatment and Survivorship; 2015 Nov 9-12; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(5 Suppl):Abstract nr A48.

Abstract P6-13-17: The combination of eribulin and everolimus results in enhanced suppression of tumors in mouse models of triple negative breast cancer

Abstract INTRODUCTION. Triple negative breast cancer (TNBC) is an aggressive form of breast cancer with poor overall and relapse free survival. TNBC does not have targeted or matched therapies. Patients have worse outcomes after chemotherapy than with other subtypes of breast cancer. TNBC accounts for 12-17% of all breast cancers, leaving an unmet need for targeted therapy. Efforts to profile these tumors have revealed several potential targets. The PI3K/AKT/mTOR pathway is a signal transduction pathway that links growth related hormone receptor interaction to downstream targets such as AKT and mammalian target of rapamycin (mTOR). This pathway targets affect cell proliferation, survival, and apoptosis. Patients with TNBC have high levels of AKT expression and activation of this pathway. Microtubule-targeting agents have been used in TNBC. Eribulin mesylate is a microtubule-targeting agent with benefits in treating taxane and anthracycline refractory breast cancer via a microtubule targeting anti-mitotic mechanism. It has been approved for the treatment of TNBC in heavily pretreated patients. Despite targeted therapy, breast cancer cells can grow resistant. Targeting multiple cancer growth pathways has been used in patients that progress on therapy or fail to respond. We hypothesized that targeting both mitotic blockade and PI3K/AKT/mTOR pathway may provide enhanced suppression of TNBC growth in both syngeneic and xenogeneic mouse models. MATERIALS AND METHODS. MDA-MB-468 is a human TNBC cell line. 4T1 is a highly metastatic mouse TNBC cell line derived from a spontaneously arising Balb/c mammary tumor. 4T1 and MDA-MB-468 tumor cells were injected into the mammary fat pad of female Balb/c and NOD/SCID/IL2Rgamma null (NSG) mice (with matrigel) respectively. After tumors were formed Balb/c mice were treated three times per week with vehicle, eribulin (0.75 mg/kg i.v.), RAD001 (5 mg/kg via oral gavage) or a combination of both. NSG mice were treated three times per week with vehicle, eribulin (0.5 mg/kg i.v.), RAD001 (5 mg/kg by oral gavage), or a combination of both. Tumor volumes and body weights were measured. Student t-test was used to compare the means of two groups and determine the p value (p&amp;lt;0.05 is significant). N=3-8 per group. Table I. 4T1 mouse breast cancer modelTreatmentTumor Volume (mm3)+/-SEMVehicle511.6+/-56.82Eribulin445.6+/-92.17Everolimus324.9+/-24.55Combination171.4+/-16.07 p valueCombination vs. Vehicle0.0001Combination vs. Eribulin0.01Combination vs. Everolimus0.001 Table II. MDA-MB-468 human breast cancer cells in immune deficient mice.TreatmentTumor Volume (mm3)+/-SEMVehicle966.8+/-69.2Eribulin67.81+/-11.79Everolimus830.6+/-156.3Combination31.37+/-3.37 p valueCombination vs. Eribulin0.041Combination vs. Everolimus0.0076 RESULTS. In the 4T1 syngeneic breast cancer mouse model, the combination of Eribulin and Everolimus resulted in marked suppression of tumor growth which was statistically significant versus vehicle treatment alone, or Eribulin or Everolimus alone (Table I). In the MDA-MB-468 model, the combination of Eribulin and Everolimus demonstrated marked suppression of tumor growth which was statistically significant compared to either agent alone (Table II). Citation Format: Marcinkowski E, Luu T, Yuan Y, Mortimer J, Leong L, Portnow J, Xing Q, Wen W, Yim J. The combination of eribulin and everolimus results in enhanced suppression of tumors in mouse models of triple negative breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P6-13-17.

Abstract P4-13-15: Dose intensity and efficacy of the combination of everolimus and exemestane (EVE/EXE) in a real world population of hormone receptor positive advanced breast cancer: A multicenter Italian experience

Abstract BACKGROUND: Everolimus, an mTOR inhibitor, in combination with exemestane is approved for hormone receptor (HR) positive advanced breast cancer (ABC), after failure of treatment with non-steroidal aromatase inhibitor (NSAI). We assessed the toxicity of the combination and the correlation between dose intensity and response to therapy, in a real world population of ABC from 11 Italian centers. Moreover, we evaluated OS of the whole population, RR and PFS according to line of treatment (from 1rd to 3th and from 4th on). METHODS: 154 pts were treated with combination of everolimus 10 mg and exemestane 25 mg daily from 05/2011 today. Median age was 62 (47-82). Median time to metastatic disease was 49 months (0-269). Median number of metastatic sites was 2 (55.2% of pts visceral versus 44.8% non visceral disease). N=117 (75.9%) pretreated with HT as adjuvant; N=126 pts (81.8%) treated with HT for advanced disease prior to EVE/EXE, with a median of one line (0-5). N=102 pts (66.2%) treated with chemotherapy for metastatic disease, with a median of one line (0-6) before everolimus treatment. RESULTS: Sixteen pts received EVE/EXE as 1st line (10.4%), 39 as 2nd (25.3%), 37 as 3rd (24%), 62 as 4th or more (40,3%). Response was evaluable in 127 out of 154 pts; CR/PR/SD respectively 5/27/56 pts. RR according to line (from 1st to 3rd vs ≥ 4th) was respectively 22.8% vs 26.4% (p=0,864). The median PFS for all population (150 pts) was 38 weeks (95% CI: 33-42). The PFS according to line (1st- 3rd vs ≥ 4th) was 38 wks in both subgroups, p=0.73. OS (126/154 pts) was 28 mths (95% CI: 31-38). The most frequent adverse events were collected in the table. Adverse eventsOverall %Grade 3-4 %Stomatitis55.810.4Hypercholesterolemia47.40.0Asthenia42.95.2Hyperglycemia36.45.8Hypertriglyceridemia29.20.6Anemia28.63.9Peripheral edema24.71.3Rash23.40.6Increased ALT/AST/GGT21.46.5Thrombocytopenia19.53.9Diarrhea18.81.9Weight loss18.21.3Dysgeusia17.50.6Pneumonitis15.61.9Cutaneous toxicity14.90.6Infection14.33.2Neutropenia11.71.9Nausea11.70.0Anorexia (without stomatitis)10.41.3Electrolyte alterations9.71.3Urea/creatinine increase6.51.3Vomiting6.50.0Uric acid increase4.50.0 Median duration of treatment with everolimus 10 mg and 5 mg was respectively 180 (9-854) and 129 days (3-738). Fifty-eight pts (37,6%) never stopped treatment with everolimus 10 mg; 16 pts (10,4%) definitively stopped everolimus for toxicity; 80 pts (52,0%) temporarily interrupted the treatment, resuming at dose level 10 mg (31 pts) or reducing at 5 mg (49 pts). Main reason for discontinuation/interruption was stomatitis G2-G3. RR and PFS evaluated according to dose intensity, 10 mg vs 5 mg, were respectively 25.9% vs 30% p=0.779, 38 wks (27-44) vs 40 wks (31-48) P=0.614 CONCLUSIONS: efficacy in terms of RR and PFS of the combination EVE/EXE is not related to dose intensity (10 mg vs 5 mg), the discontinuation of the treatment is high with the starting dose of 10 mg, the toxicity is consistent with previous phase II-III studies although we collected some different toxicities. Citation Format: Forcignanò R, Petrucelli L, Cazzaniga ME, Lupo LI, Chiuri VE, Cairo G, De Matteis E, Febbraro A, Giordano G, Campidoglio S, Fabi A, Giampaglia M, Bilancia D, La Verde N, Maiello E, Morritti M, Giotta F, Lorusso V, Scavelli C, Romito S, Cusmai A, Palmiotti G, Tornesello A, Ciccarese M. Dose intensity and efficacy of the combination of everolimus and exemestane (EVE/EXE) in a real world population of hormone receptor positive advanced breast cancer: A multicenter Italian experience. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-13-15.

Abstract OT1-03-08: DESIREE - A multicenter, randomized, double-blind, phase II study to evaluate the tolerability of an induction dose escalation of everolimus in patients with metastatic breast cancer

Abstract Background: The BOLERO-2 study demonstrated a relevant benefit for patients who received everolimus in addition to exemestane in patients who progressed during/after a non steroidal aromatase inhibitor (NSAI), which led to approval of everolimus in this indication. However, in routine use a high rate of intolerability due to side effects is reported. The most common side effect of everolimus is mucositis with a reported high rate of intolerability especially during the first 12 weeks of treatment. Mucositis is also considered to be the leading cause for treatment discontinuation not related to tumor progression. In the neoadjuvant GeparQuinto study, a dose-escalation schema was successfully used to improve tolerability of everolimus together with cytotoxic agents. Methods: DESIREE (NCT02387099) is a randomized, double-blind, phase II study of everolimus in addition to exemestane in patients who progressed during or after NSAI. Patients will be randomized in a 1:1 ratio to receive either everolimus 10 mg/day (week 1-3: 4x2.5 mg/day, blinded; week 4-24: 10mg/day, open according to label) or an escalating dose of everolimus as follows: week 1: 1x2.5 mg verum + 3x placebo/day; week 2: 2x2.5 mg verum + 2x placebo/day; week 3: 3x2.5 mg verum + 1x placebo/day; week 4-24: 10 mg/day (open according to label). The primary aim of the study is to evaluate the incidence of the first episode of mucositis grade 2-4 (WHO's oral toxicity scale) any time during a 12 week period after start of everolimus treatment. Secondary objectives are to compare the cumulative rate of mucositis grade 2-4 at 24 weeks after start of treatment, the cumulative rate of mucositis grade 1 and any grade at 12 and 24 weeks after start of treatment, the rate of patients on 10 mg daily at 12 weeks and 24 weeks after start of treatment, the clinical benefit rate after 24 weeks, safety, time to onset of grade ≥2 mucositis, the cumulative everolimus dose at 4 weeks, the relative dose intensity for everolimus, and quality of life using the FACT-B and the QSDQ questionnaire. Biomaterial (whole blood, serum, plasma and optional primary tumor/metastasis tissue) will be collected to evaluate potential biomarkers predicting safety and compliance. Overall, 156 evaluable patients (78 in each arm) are required to detect a clinically relevant difference of 20% in the mucositis rate between treatment arms using a continuity-corrected χ2-test on a significance two sided level alpha of 0.2 and a power of 90%. The rate was estimated to be 40% and 20% in the control arm and the treatment arm, respectively. Results: The study will be conducted in up to 60 German centers. Recruitment will start in June 2015. Enrollment is planned to be completed within 24 months. Conclusion: The combination of everolimus and exemestane has shown to improve the outcome of patients with metastatic breast cancer. In the DESIREE trial a dose-escalating schema will be employed to enhance patient compliance and tolerability necessary to achieve an adequate dose-intensity. Citation Format: Loibl S, Furlanetto J, Barinoff J, Bauerschlag D, Herr D, Lübbe K, Maass N, Müller V, Mundhenke C, Schmidt M, Schwedler K, Thill M, Gkantiragas I, Burchardi N, von Minckwitz G. DESIREE - A multicenter, randomized, double-blind, phase II study to evaluate the tolerability of an induction dose escalation of everolimus in patients with metastatic breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr OT1-03-08.

Abstract OT1-03-11: Phase III randomized, placebo-controlled clinical trial evaluating the use of adjuvant endocrine therapy +/- one year of everolimus in patients with high-risk, hormone receptor (HR) positive and HER2-negative breast cancer (BC): SWOG/NRG/Alliance S1207 (NCT01674140)

Abstract Background: Abnormalities of the PI3kinase/AKT/mTOR signaling network are common in BC. This pathway is associated with resistance to endocrine therapies among HR+ tumors. Everolimus, an mTOR-inhibitor, increases the biological activity of endocrine therapy. S1207 evaluates the role of everolimus in combination with endocrine therapy in the adjuvant setting. Methods: Specific aims/ design: Randomized phase III double-blinded, placebo-controlled trial. Primary objective is to assess whether the addition of everolimus to standard adjuvant endocrine therapy improves invasive disease-free survival (DFS) among patients with high risk, HR+ BC. Secondary objectives include overall survival, distant recurrence-free survival, safety, adherence and QoL. Patients are randomized to receive standard adjuvant endocrine therapy in combination with one year of everolimus (10 mg PO daily) or placebo. Submission of tissue specimens/blood samples is required for translational studies Eligibility criteria: Patients with histologically confirmed HER2-negative and HR+ invasive BC treated with surgery, adjuvant chemotherapy and radiation therapy (if indicated) are eligible if they have: node-negative disease and tumors &amp;gt;2cm and a recurrence score (RS) &amp;gt;25; 1-3 positive nodes and RS &amp;gt;25 or grade 3 in the absence of RS; &amp;gt;4 positive lymph nodes regardless of RS. Patients &amp;gt;1 positive lymph node after completing neoadjuvant chemotherapy are eligible. Statistics/Target accrual:Parallel randomization design with equal allocation to the two treatment groups, the study will randomize 3,500 patients. All analyses are intent-to-treat with the primary analysis conducted 3 years after the last patient is randomized. The study has 90% power (with 2-sided α=0.05) to detect an effective hazard ratio of 0.75 for everolimus versus placebo, corresponding to a gain in DFS of approximately 4.3% at 5 years. All patients will be followed for 10 years. Support: NIH/NCI NCTN Grants CA180888, 180819, 180868, 180821,180822 189867, and in part by Novartis Clinical trial information: NCT01674140. Citation Format: Chavez-MacGregor M, Barlow WE, Pusztai L, Goetz MP, Rastogi P, Ganz PA, Mamounas EP, Paik S, Bandos H, Gralow J, Lew DL, Hortobagyi GN. Phase III randomized, placebo-controlled clinical trial evaluating the use of adjuvant endocrine therapy +/- one year of everolimus in patients with high-risk, hormone receptor (HR) positive and HER2-negative breast cancer (BC): SWOG/NRG/Alliance S1207 (NCT01674140). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr OT1-03-11.

Abstract P3-05-05: Targeting tumor re-wiring by triple blockade of mTORC1, ERBB and ER signaling pathways in endocrine resistant breast cancer

Abstract AIM To target tumor re-wiring by combined mTORC1 inhibition plus hormonal treatment with or without co-blockade of ERBB signaling in endocrine resistant models of human breast cancer (BC). BACKGROUND Around 80% of BCs are estrogen receptor positive (ER+). Endocrine therapies target estrogenic stimulation of tumor growth but resistance remains problematic. Several strategies have shown that resistance often depends on the acquisition of enhanced cross-talk between ER and growth-factor pathways, allowing the disease to circumvent the need for steroid hormones. We have previously reported the antiproliferative effects of the combination of everolimus (RAD001-mTORC1 inhibitor) with endocrine therapy in resistance models, but potential routes of escape from treatment via ERBB2/3 signaling were observed. We hypothesised that combined targeting of three signaling pathways, namely ER, ERBB and mTORC1 may provide enhanced anti-tumor activity. METHODS ER+ BC cell lines (MCF7, SUM44 and HCC1428) adapted to long term estrogen-deprivation (LTED) which model relapse on an aromatase inhibitor, along with their wild-type (wt) cell lines were treated with neratinib, a pan-ERBB tyrosine kinase inhibitor, in combination with RAD001 ± estradiol (E2), tamoxifen or fulvestrant. End points included proliferation, cell signaling, cell cycle and effect on ER-mediated transactivation and recruitment by ChIP. RESULTS All cell lines showed a concentration-dependent decrease in proliferation in response to RAD001 (IC50 0.6-50nM in absence of E2 and 1-10nM in presence of E2). A wide range of IC50 values (300-1000nM) was observed with neratinib treatment in the presence of E2. However, in the absence of E2, wt cell lines showed IC50 values in excess of 1800nM with hormetic dose response curves, in which lower concentrations induced cell proliferation. In contrast, LTED IC50 values ranged between 400-900nM. Combination of either agent with endocrine therapy caused a concentration dependent decrease in proliferation in all wt cell lines and their LTED derivatives, but the maximum effect was observed when a triple combination of RAD001, neratinib and ER-blockade was used. Expression of pS6 was dramatically suppressed by RAD001 ± neratinib in all cell lines tested, whilst neratinib caused a cell line specific reduction in expression of ERBB family proteins. Upregulation of pAKT was observed in all cell lines following treatment with RAD001, indicating both inhibitors were effectively suppressing their respective targets. Combination of RAD001 with neratinib suppressed the upregulation of pAKT and significantly reduced cell cycle progression. In the absence of E2, RAD001 caused a reduction in ER-mediated transcription and decrease in recruitment of ER and the CREB-binding protein (CBP) to the TFF1 promoter. In contrast, neratinib induced a marked increase in ER-recruitment and concomitant rise in ER-mediated transactivation, which was reduced by the addition of RAD001. CONCLUSION Targeting tumor re-wiring by triple blockade of ERBB, ER and mTORC1 signaling pathways significantly reduces cell proliferation supporting the potential combination in patients who have relapsed on endocrine therapy and retain a functional ER. Citation Format: Nikitorowicz-Buniak J, Ribas R, Rani A, Pancholi S, Guest SK, Cutler Jr RE, Lalani A, Dowsett M, Johnston SR, Martin L-A. Targeting tumor re-wiring by triple blockade of mTORC1, ERBB and ER signaling pathways in endocrine resistant breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-05-05.

Abstract P4-13-12: Everolimus plus trastuzumab and vinorelbine for trastuzumab-resistant, taxane-pretreated, HER2+ advanced breast cancer: Overall survival results from BOLERO-3

Abstract Background PI3K/AKT/mTOR pathway activation due to PTEN loss may lead to trastuzumab (TRAS) resistance. mTOR inhibition has been shown to restore TRAS sensitivity in PTEN-deficient tumors. This provided the rationale for the BOLERO-3 trial which evaluated the combination of everolimus (EVE), an mTOR inhibitor, plus TRAS and a taxane in HER2+ advanced breast cancer (ABC). The addition of EVE to TRAS plus vinorelbine (VNB) led to a statistically significant prolongation of 1.2 months in median progression free survival (PFS) vs TRAS plus VNB in patients with TRAS-resistant and taxane-pretreated, HER2+ ABC (7.0 months vs 5.78 months; hazard ratio, 0.78; p=0.0067). The final overall survival (OS) analysis from this study is presented here. Materials and methods BOLERO-3 is a randomized, double-blind, placebo-controlled, phase 3 trial. Women with HER2+ ABC progressing on prior TRAS and taxane therapy were randomized (1:1) to receive either daily EVE (5 mg) or PBO plus weekly TRAS (2 mg/kg) and VNB (25 mg/m2), in 3-week cycles, stratified by previous lapatinib use. The primary endpoint was PFS by local investigator assessment. Overall survival was a key secondary endpoint. Results Overall, 569 patients were enrolled; 284 patients received EVE and 285 patients received PBO. As of April 1, 2015, after a median follow-up of 44.7 months, 388 deaths had occurred, 191 (67.3%) in the EVE arm and 197 (69.1%) in the PBO arm. The median OS in the EVE arm vs PBO arm was 23.5 months vs 24.1 months (HR = 0.96; 95% CI, 0.79-1.17; p = 0.3392). In the HR+ subgroup, the median OS with EVE was 23.5 months (vs 25.5 months with PBO; HR = 1.03; 95% CI, 0.79-1.35); in the HR subgroup, the median OS with EVE was 22.9 months (vs 23.1 months with PBO; HR = 0.86; 95% CI, 0.64-1.17). AEs leading to treatment discontinuation were reported in 81 (28.9%) vs 46 (16.3%) patients in the EVE vs PBO arms. Serious adverse events (SAEs) were reported in 122 (43.6%) vs 58 (20.6%) patients in the EVE vs PBO arms. Overall, 14 on-treatment deaths were observed, 7 (2.5%) in the EVE arm and 7 (2.5%) in the PBO arm; on-treatment deaths due to AEs were balanced between treatment arms (0.7% in each treatment arm). Types of post-progression therapies were balanced across both treatment arms. Conclusions In BOLERO-3, EVE showed a statistically significant prolongation of PFS. OS was similar in both treatment arms. The safety profile of EVE was comparable to that observed previously with EVE in breast cancer. (Funded by Novartis; BOLERO-3 ClinicalTrials.gov number, NCT01007942.) Citation Format: Isaacs C, O'Regan R, Xu B, Masuda N, Arena F, Yap Y-S, Papai Z, Lang I, Armstrong A, Lerzo G, White M, Shen K, Zhang Y, Jappe A, Pacaud LB, Taran T, Ozguroglu M. Everolimus plus trastuzumab and vinorelbine for trastuzumab-resistant, taxane-pretreated, HER2+ advanced breast cancer: Overall survival results from BOLERO-3. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-13-12.

Abstract OT3-01-12: Phase II trial of lapatinib and everolimus for HER2 positive metastatic breast cancer

Abstract Background: Although the treatment of HER2 positive metastatic breast cancer (MBC) has improved with anti-HER2 agents and chemotherapy, most patients will eventually develop resistance to these agents. Preclinical studies have shown that mTOR inhibition may reverse trastuzumab resistance. We hypothesize that combining mTOR inhibitor everolimus with lapatinib will be an effective strategy for patients who have progressed on prior anti-HER2 therapies. Trial Design: We are conducting an open-label phase II pilot study of the combination of everolimus and lapatinib for pts with HER-2 positive MBC. Eligible pts must have histologically documented locally advanced (inoperable) or metastatic HER-2 positive breast cancer that have progressed on at least one HER-2 based regimen in the metastatic or locally advanced setting. Pts with disease progression during or within 12 mos of the completion of adjuvant trastuzumab are eligible. Pts with untreated asymptomatic brain metastases are allowed. Pts with symptomatic brain metastases are allowed to enroll after they have completed radiation and are off steroids. Eligible pts are started on everolimus 5 mg PO daily and lapatinib 1250 mg PO daily without interruption. Among subjects progressing on lapatinib, lapatinib is continued and everolimus initiated. Pts will continue to receive treatment until there is evidence of progressive disease (PD), unacceptable toxicity, or withdrawal of consent. Pts will have radiological evaluation every 8 weeks with CT, bone scan, and MRI brain (for pts with known brain metastasis at baseline). Specific Aims: Primary objective is to assess the effectiveness of the combination of RAD-001 and lapatinib as measured by the six-month Overall Response Rate in women with MBC who have progressed on trastuzumab and/or lapatinib based therapies. Secondary objectives are six-month PFS, safety and tolerability of the combination, six-month objective CNS response rate, six-month clinical benefit rate of systemic disease, and six-month clinical benefit rate in CNS. Statistical methods: The response rate of lapatinib monotherapy in heavily pre-treated patients is estimated to be 7% (Blackwell 2009). For an expected ORR of 17%, a sample size of 45 subjects will provide 79% power to detect the difference at 0.10 Type I error rate according to 1-sided exact binomial test. Present accrual and target accrual: The trial has accrued 20 patients with a target accrual of 45 patients. Citation Format: Barr JA, Sharma P, Fabian CJ, Yeh H, Baccaray S, Springer M, Khan QJ. Phase II trial of lapatinib and everolimus for HER2 positive metastatic breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr OT3-01-12.

A Phase Ib Open-Label Study to Assess the Safety and Tolerability of Everolimus in Combination With Eribulin in Triple-Negative Breast Cancers

BackgroundThe VERITAS (A Phase 1B open-label study to assess the safety and tolerability of everolimus in combination with eribulin in triple-negative breast cancers) trial (EudraCT number: 2014-000135-17) is a phase Ib, open label, multicenter, dose-escalation, safety, pharmacokinetic, and pharmacodynamic study based on the combination of everolimus with eribulin in sequential cohorts of metastatic triple negative breast cancer (TNBC) patients. Patients and MethodsThe primary objective of the study is to identify the recommended dose of everolimus in combination with eribulin. Secondary endpoints include the assessment of pharmacokinetics and antitumor activity of the experimental treatment. The sample size is based on the Bayesisan approach with regards to the maximum tolerated dose (MTD) and maximum tolerated dose (MTD) observed. An average sample size of approximately 12 patients is deemed reasonable based on simulations. ConclusionThe VERITAS trial is expected to determine the recommended dose of everolimus in combination with eribulin in TBNC. This study may open the way for further analysis of this combination in phase II studies in this orphan disease of active drug combination such as the TNBC subset.

Occurrence and characterization of everolimus adverse events during first and subsequent cycles in the treatment of metastatic breast cancer.

Endocrine therapy remains the standard therapy for patients with metastatic hormone receptor (HR)-positive breast cancer. The novel combination of everolimus and exemestane has been shown to prolong progression-free survival but with increased adverse events compared to exemestane alone. In this study, we aimed to describe the frequency and timing of everolimus dose reductions and/or interruptions due to adverse events. This is a single-center retrospective case series including all patients who received everolimus in combination with exemestane from May 1, 2012, through July 31, 2013. The primary objective was to determine the incidence of first-cycle interruptions or dose reductions with everolimus. Forty-six patients were included in the analysis. First-cycle dose reductions or interruptions were observed in 21 (45.6%) patients. The most common adverse events leading to dose reduction or interruption was stomatitis (57.1%), fatigue (14.3%), and diarrhea (14.3%). The median time to dose reduction was 14days, and the median duration of the interruption was 14days. The median progression-free survival was 6.2months, and the median time to treatment failure was 4.4months. In this case series, almost half of the patients treated with everolimus and exemestane required a dose reduction or interruption of everolimus during the first cycle of treatment. This early onset of adverse events requires thorough patient education and close clinical monitoring during the first 28days of therapy.

Pharmacokinetics and Long-Term Safety and Tolerability of Everolimus in Renal Transplant Recipients Converted From Cyclosporine.

Conversion from cyclosporine (CsA) to everolimus (EVR) in kidney transplant recipients receiving mycophenolate sodium (MPS) and corticosteroids has been used to reduce CsA associated toxicities. Nevertheless, exposures produced by the initial EVR dose, the steady state pharmacokinetic and long-term safety and tolerability have not been explored in detail. Twenty-four stable kidney transplant recipients receiving CSA, MPS, and corticosteroids were converted from CSA to EVR. The initial EVR dose was 3 mg BID. Weekly monitoring of EVR blood concentrations was followed by a full 12 hour pharmacokinetic profile 28 days after conversion. Therapeutic drug monitoring, safety, and tolerability were analyzed during 5 years of follow-up. The study population was relatively young (mean of 42 years) with a predominance of males (62%) and White (67%) recipients of kidneys from living (54%) or deceased (46%) donors. Mean time of the conversion was 61 months after transplantation. In the first 7 patients, the initial EVR dose of 3 mg BID resulted in mean EVR trough blood concentration of 14.7 ± 3.7 ng/mL at day 7. The initial EVR dose was then reduced to 2 mg BID for the following 17 patients. Four weeks after conversion, mean EVR dose was 1.7 ± 0.5 mg BID (7 patients were receiving 1 mg BID and 17 were receiving 2 mg BID) resulting in mean EVR trough blood concentration of 4.0 ± 1.4 ng/mL. Whereas mean maximum concentration (13.4 ± 2.8 versus 22.9 ± 7.4 ng/mL, P = 0.003) and mean apparent clearance (232 ± 79 versus 366 ± 173 mL/min, P = 0.016) were higher, mean area under the curve (78.2 ± 22.1 versus 102.5 ± 38.5 ng.h/mL, P = 0.067) and mean C0 (3.7 ± 1.3 versus 4.1 ± 1.5 ng/mL, P = 0.852) were no different comparing patients receiving 1 mg and 2 mg EVR BID. Mean inter-subject variability of area under the curve, trough concentration, and maximum concentration was 38%, 36%, and 38%. EVR treatment was discontinued in 29% of patients due to proteinuria (N = 2), pneumonia (N = 2), dyslipidemia (N = 2), and anemia (N = 1) and MPS dose was reduced in 58% of patients. The initial 3 mg BID dose produced high EVR trough blood concentrations. The 2 mg BID dose appears to be the appropriate initial dose to provide therapeutic concentrations but still requires initial intensive therapeutic monitoring to achieve and maintain blood concentrations within the therapeutic target concentration. The combination of EVR and full dose MPS has limited long-term tolerability and safety.

Risk of hyperglycemia attributable to everolimus in renal cell and non–renal cell carcinoma patients: A meta-analysis.

515 Background: Everolimus has been used widely in cancer patients and is associated with the development of hyperglycemia. Due to confounding factors, everolimus’ specific impact on hyperglycemia has not been well understood. We performed a meta-analysis to determine the risk of hyperglycemia attributable to everolimus in cancer patients of varying tumor types. Methods: PubMed and ASCO conference abstracts up to June 2015 were systematically searched. Eligible studies included randomized controlled trials (RCTs) in which everolimus was compared to placebo in cancer patients with or without additional cancer therapies. Heterogeneity tests were performed to examine between-study differences in hyperglycemia. The incidence and relative risk of all-grade and high-grade hyperglycemia attributable to everolimus were determined using random- or fixed-effects models. Results: A total of 7 phase III and 2 phase II RCTs with various tumors were included in our analysis. Everolimus significantly increased the risk of all-grade (RR = 2.60, 95% CI: 2.03-3.31, P &lt; 0.001) and high-grade (RR = 3.00, 95% CI: 1.72-5.23; P &lt; 0.001) hyperglycemia. The incidences of all-grade and high-grade hyperglycemia attributable to everolimus were 6.8% (95% CI: 3.4-13.2%) and 2.5% (95%: 1.2-4.9%) respectively. The everolimus-specific risk of all-grade hyperglycemia varied significantly with tumor types (P &lt; 0.001), with the highest incidence seen in renal cell carcinoma (27.2%, 95% CI: 22.2-32.8%) and the lowest in breast cancer (3.3%, 95% CI: 1.3-8.2%). No significant variation was found between everolimus alone or everolimus in combination with other agents. Similar results were also found for the risk of high-grade hyperglycemia attributable to everolimus. Conclusions: The specific contribution of everolimus to both all-grade and high-grade hyperglycemia may be modified significantly by tumor types. Close monitoring should be given to patients with renal cell carcinoma.