Oral Everolimus Research Articles

Effective use of everolimus as salvage chemotherapy for ovarian clear cell carcinoma: a case report

A case study using mammalian target of rapamycin complex 1 in recurrent ovarian clear cell carcinoma (CCC) was recently conducted. We report our experience with a patient suffering from recurrent ovarian CCC who achieved long-term disease control with everolimus administration. The patient was a 53-year-old woman who was diagnosed with recurrent ovarian CCC with dissemination throughout the abdominal cavity. Previously, she had received three chemotherapy regimens, but the disease was progressive and she showed no response to treatment. Therefore, oral everolimus administration (everolimus 10 mg/day on days 1–28, a 28-day period comprised one cycle) was started. She was administered six cycles. The antitumor response was stable disease, and grade 3 anemia was observed. Chemotherapy was then switched to gemcitabine/docetaxel therapy. In the middle of the second cycle, a rapid increase in ascitic fluid and CA125 elevation were observed. Thereafter, the patient received best supportive care and died of the disease. Everolimus may inhibit malignant progression of ovarian CCC.

A Case Report on the Effect of Everolimus in Renal Angiomyolipoma Associated With Tuberous Sclerosis Complex

Tuberous Sclerosis (TS) is a well known disorder which manifests with benign tumors in various organ systems, including angiomyolipomas (AML) of the kidneys. The mTOR inhibitors have emerged as a potential systemic treatment strategy to halt the growth of renal angiomyolipomas and to prevent life threatening complications such as bleeding. This report shows that everolimus treatment may have an impact on size and density of renal AML lesions which may lead to prevention or delay the development of renal cell carcinoma as well as prevent bleeding from the renal AML lesions. A 20-year-old Hispanic female and a 24-year-old Asian female both with sporadic TS were administered daily oral everolimus therapy. Both showed stability in their renal AML lesions and notable improvement of their extra-renal TS manifestations. Treatment with daily everolimus may lead to reduction in size and/or decreases in density or renal AML lesions. This may have an impact on the risk of developing renal cell carcinoma as well as preventing bleeding from renal AML lesions. J Med Cases. 2014;5(3):129-136 doi: http://dx.doi.org/10.14740/jmc1665w

Abstract OT2-6-14: Phase 2, single arm study of a steroid-based mouthwash to prevent stomatitis in women with hormone receptor–positive advanced breast cancer treated with everolimus plus exemestane

Abstract BACKGROUND: Stomatitis, the inflammation of mucous membranes lining the mouth and throat, is a frequent adverse event that is associated with the oral mTOR inhibitor everolimus and can significantly impact treatment adherence. Specific strategies to prevent and/or lessen the severity of everolimus-associated stomatitis are not well documented. Steroid mouthwashes and steroid gels or pastes used to treat recurrent aphthous stomatitis may be effective for stomatitis associated with everolimus. This phase 2, single-arm study will evaluate a steroid-based therapeutic intervention to prevent stomatitis (Grade ≥2) in breast cancer patients taking everolimus + exemestane. METHODS: Eligible participants will be patients with HR-positive, HER2-negative advanced breast cancer with no evidence of oral stomatitis or other oral pathology who have been prescribed everolimus + exemestane but have not yet started treatment. A baseline oral assessment will be conducted, and patients will be provided instructions on how to self-monitor for stomatitis, along with instructions to contact the study site at the first sign of oral pain or changes to the oral mucosa. All patients will be instructed to perform routine good oral care. Eligible patients will receive a steroid-based mouthwash (alcohol-free 0.5mg/5ml dexamethasone solution) prophylactically. Patients will be instructed to perform the mouthwash regimen four times per day and swish the mouthwash in mouth for a minimum of 120 seconds before spitting it out. Patients will be instructed to abstain from eating or drinking for at least an hour after taking the mouthwash. Mouthwash regimen will begin on the first day of everolimus after administration of the dose and patients will continue the regimen for the first 4 months of everolimus therapy. Primary endpoint is the incidence of stomatitis (Grade ≥2) at 2 months defined as meeting at least one of the following criteria: ≤50 on Normalcy of Diet Scale to assess oral intake and a rating of 7 on two consecutive days or a rating of 8, 9 or 10 on any one day using Visual Analog Scale to assess oral pain. Evidence of stomatitis must be confirmed by investigator on physical exam and/or phone call assessment. Secondary endpoints include average number of times per day the mouthwash regimen was performed and time to resolution of stomatitis (Grade ≥2) that occurs during the trial. Assuming a 13% absolute reduction in the rate of grade ≥ stomatitis from the historical control rate of 33% and one sided Type 1 error = 0.05 and power = 80%,73 evaluable patients will be needed. To account for 25% of the total patient population being non-evaluable, 97 patients will be enrolled for this study. Supported by funding from Novartis Pharmaceuticals Corporation. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT2-6-14.

Abstract PD1-5: Targeting PI3K overcomes in vivo resistance to everolimus in estrogen receptor (ER+) breast cancer

Abstract Background: The selective mTORC1 inhibitor everolimus (RAD001/Affinitor®) has recently been approved, in combination with exemestane, for treatment of advanced hormone receptor positive breast cancer after demonstrating significantly improved progression free survival for patients having progressed on a previous non-steroidal aromatase inhibitor. However, despite these improved outcomes many tumors go on to develop resistance to everolimus. Alterations in PI3K/AKT signaling, either through activating mutations in PIK3CA or loss of PTEN, have been shown to influence responses to everolimus treatment in vitro (Weigelt et al., 2011). In this study we used cell line xenograft models of everolimus resistance to assess the potential of a pan-PI3K inhibitor (BKM120) or a p110a-specific inhibitor (BYL719) to reverse resistance either as single agents or in combination with anti-ER therapy (Fulvestrant). Materials and Methods: Everolimus resistant xenografts were developed from three originally everolimus sensitive ER+ cell lines carrying distinct genetic alterations that confer aberrant PI3K/AKT signaling; ZR75-1 (PTEN null), MCF7 (PIK3CA mutant) and KPL1 (wild-type). Mice were treated by daily oral everolimus (10 mg/kg) until tumors began to progress on treatment (∼ 35 days of daily treatment). Mice that developed everolimus resistant tumors were randomized into six treatment groups (n = 6) as follows: continued on everolimus (10 mg/kg), fulvestrant (5 mg/wk), BKM120 (35 mg/kg), BYL719 (50 mg/kg), fulvestrant + BKM120 or BYL719. Results: All three cell line xenografts were initially responsive to everolimus. ZR75-1 xenografts were allowed to progress on everolimus until they reached a mean tumor volume greater than that on day zero, at which point mice were randomized into treatment groups. Tumor selected to continue on everolimus gained a mean tumor volume of 550 mm3 over the six-week duration of study, demonstrating resistance to everolimus. These tumors showed a partial response to Fulvestrant (28% TGI), BYL719 alone (40% TGI) and BYL719 combined with fulvestrant (61% TGI). In contrast, over 100% tumor growth inhibition (tumor regression) was observed with both single agent BKM120 or BKM120 plus fulvestrant. This is consistent with our in vitro findings that PTEN null tumor cells might be less sensitive to inhibition by BYL719 yet sensitive to BKM120. Data from the ongoing PIK3CA mutant and wild-type KPL1 models will inform whether these molecular subtypes of ER+ breast cancer are more sensitive to the pan-PI3K inhibitor or the p110α-specific inhibitor. Comprehensive pharmacodynamic analyses of these tumor tissues may identify the additional molecular determinants responsible for resistance to everolimus and help guide the design of future clinical studies. Discussion: These pre-clinical data indicate that targeting PI3K either alone or in combination with fulvestrant overcomes resistance to everolimus in ER+ breast cancer. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr PD1-5.

A Phase I/II Study Of Hyper-CVAD Plus Everolimus In Patients With Relapsed/Refractory Acute Lymphoblastic Leukemia

IntroductionThe outcomes of patients (pts) with relapsed/refractory acute lymphoblastic leukemia (ALL) remain poor. Dysregulation of the PI3K/AKT/mTOR signal transduction pathway is central to leukemic cell growth and survival. Everolimus is an orally active inhibitor of mTOR approved for the treatment of pts with several tumor types. AimThe purpose of this phase I/II study was to establish the safety and efficacy of everolimus in combination with hyper-CVAD (cyclophosphamide, vincristine, doxorubicin, dexamethasone) in pts with relapsed/refractory ALL and lymphoblastic lymphoma (LL). MethodsPts ≥ 10 years of age with relapsed/refractory ALL or LL, ECOG performance status 2 2 and adequate organ function were eligible. Pts were treated with oral everolimus at 5 or 10 mg (phase 1 dosing) continuously concurrently with 8 cycles of the standard hyper-CVAD regimen, starting day 0 of course 1. Everolimus 5 mg daily was established as maximum tolerated dose (MTD) after 2 cycles. Comprehensive proteomic profiling of 10 proteins along with their phosphorylated forms was performed using reverse-phase protein arrays (RPPA). Total RNA was isolated from patient samples using TRIzol reagent and gene expression analysed using a HumanHT-12 v4 gene expression chip from Illumina (N = 5). Pharmacokinetic (PK) studies were performed on day 0 and day 15 of course 1 (N = 8). BackgroundTwenty pts were enrolled between April 2010 and June 2013, with accrual ongoing. Clinical characteristics included 9 pts in first salvage, 2 in second salvage and 9 beyond second salvage (Table 1). Median (Med) number of cycles given was 2 (1-5). Med follow-up was 19 months (1-35). Seven of 20 pts responded for an overall response rate of 35% with complete remission (CR) in 6 pts (30%), CR with incomplete count recovery (CRi) in 1 (5%), and partial remission (PR) in 2 (10%). Six of 9 pts (66%) in first salvage achieved CR, and one of 2 pts in second salvage achieved CRi. Four pts proceeded to stem cell transplant in CR. Med event-free survival (EFS) and med overall survival (OS) were 6 and 7 months, respectively, for pts in 1st salvage, and 2 and 4 months, respectively for pts in second salvage and beyond (P=0.01 and P=0.002). The 1-year OS is 47% for 1st salvage pts and 9% for pts in second salvage and beyond. Grade 3 mucositis was dose-limiting toxicity. Other grade 3/4 toxicities including infections, transaminitis, diarrhea, headache, and increased bilirubin occurred in 18 (90%), 6 (30%), 2 (10%), 2 (10%), and 2 (10%) pts. Among the 10 pts profiled by RPPA, inhibition of mTOR signaling (p-pS6K) was observed in 7/10 (70%). Everolimus significantly inhibited phosphorylation of S6K on both, pS235-S236 and pS240-S244 sites (P=0.007 and P=0.01, respectively). Inhibition of pS6 was observed at both 5 mg and 10 mg doses. No statistically significant difference in phosphorylation of 4EBP1, AKT or other proteins was noted. Gene set enrichment analysis performed in paired PB samples from 5 pts showed enrichment of the ABC transporter gene set in pts who failed to respond. Analysis of PB samples 24 hrs post everolimus exposure was associated with reduction of the signature for miR-21, miR-30 and miR-507 gene sets, irrespective of a biological response to mTOR inhibition as assessed by S6K phosphorylation. PK analysis showed that area under the curve (AUC) for everolimus was dose-dependent with higher AUC at 10 mg versus 5 mg. Those achieving CR had significantly higher AUC and lower clearance at steady state compared to pts with PR/no response (Fig. 1, P=0.025), but it was not associated with toxicity.Table 1Pt characteristics (N = 20)CharacteristicN (%) / [range]Med age, years24 [11-64]Male13(65%)Med prior chemotherapies2 [1-7]Prior radiotherapy3(15%)Prior stem cell transplant4(20%)ECOG PS0-117(85%)DiagnosisB-ALL12(60%)T-ALL8(40%)Med WBC X 1095.7 [0.3-100.7]Med hemoglobin g/dL9.6 [6.9-12.7]Med platelets x 10957 [5-240]Med bone marrow blasts %67 [0-98]Med peripheral blood blasts %19.5 [0-100]CNS involvement at enrollment3 (15%)CytogeneticsDiploid5(25%)Hyperdiploid4(20%)Miscellaneous4(20%)Insufficient7(35%) [Display omitted] ConclusionThe combination ofhyper-CVAD plus everolimus was well tolerated, and findings indicate that further testing of mTOR inhibitors with standard chemotherapy in the frontline therapy of ALL and LL is warranted. Disclosures:Kantarjian:Sanofi-Aventis: Research Funding. Ravandi:Sunesis: Consultancy, Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Teva: Consultancy, Honoraria; Pfizer: Honoraria; Merck: Research Funding; Bayer/Onyx: Consultancy, Honoraria; EMD Serono: Research Funding; Medimmune: Research Funding; Amgen: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria.

Prospective, Multicenter Study Of The Mtor Inhibitor Everolimus (RAD001) As Primary Therapy In Waldenstrom's Macroglobulinemia

IntroductionEverolimus (RAD001) is an inhibitor of MTORC1 and exhibits activity in WM patients with relapsed/refractory disease (JCO 2010; 28:1408-14). We therefore initiated this multicenter, prospective study to delineate the efficacy and tolerability of Everolimus as primary therapy in WM. Patients and MethodsPatients with symptomatic WM, with adequate organ function, who were not previously treated, and who did not have symptomatic hyperviscosity were eligible. Intended therapy consisted of 10 mg of oral Everolimus daily, with sequential dose de-escalation to 7.5 mg daily, 5 mg daily, and 5 mg every other day permitted for toxicity. Patients were treated until progression or unacceptable toxicity. Patients were encouraged to use an oral dexamethasone solution to swish and spit up to 4 times daily for prevention of oral ulcerations. Study participants were assessed monthly for the first three months, and thereafter every 3 months which included a physical examination, complete blood counts, chemistries, and serum IgM monitoring. Bone marrow (BM) biopsies and aspirations were performed at baseline, at months 6 and 12, and as required for response assessment. Patients who received at least one cycle of therapy were evaluable for response. Results33 patients were enrolled on this prospective, multicenter study and are evaluable for response. Median baseline characteristics for all patients: Age 62 (range 41-80 years); Hematocrit 31.3% (range 24.5-44.2%); Hemoglobin 10.8 (range 7.8-15.7 g/dL); serum IgM 4,440 (range 959-10,256 mg/dL), with 23 (69.7%) patients demonstrating an IgM level ≥3,000 mg/dL; serum M-protein 2.60 g/dL (range 0.31-5.31 g/dL), B2M 3 mg/L (1.6-6.7 mg/L). The median baseline BM disease burden was 70% (range 7.5-95%), and 21 patients (63.6%) demonstrated adenopathy or splenomegaly by CT scans at baseline. At best response, median serum IgM levels declined from 4,440 to 1,360 (p<0.0001), and serum M-protein decreased from 2.60 to 0.93 g/dL (p<0.0001). The median time to best serum IgM response was 6 months (range 6-36 months). Median hematocrit and hemoglobin levels increased from 31.3% to 34.5% (p=0.0112) and 10.8 to 11.8 g/dL (p= 0.009), respectively. Twenty-two patients were evaluable for response by both BM biopsy and IgM level determination at 6 months, at which time BM disease burden remained unchanged with a median of 65% involvement (range 10-95%; p=0.3595). The best overall response rate utilizing consensus criteria was 72.2% (2 Very Good Partial Responses, 18 Partial Responses, 4 Minor Responses, and 9 Stable Disease), and the major response rate (PR or better) was 60.6%. However, discordance between serum IgM levels upon which consensus criteria for response are based, and BM disease response were common and complicated response assessment. At 6 month assessments, 10 of 22 (45.5%) patients for whom both serum IgM and BM assessments were performed, discordance between serum IgM and BM disease involvement were observed. Among these patients, 2 had no change, and 8 had increased bone marrow disease involvement despite decreases in serum IgM levels. Grade ≥2 hematologic and non-hematologic toxicities possibly, probably or definitively associated with Everolimus included anemia (n=13, 39.4%), thrombocytopenia (n=4, 12%), neutropenia (n=6, 18.2%), hyperglycemia (n=3, 9.1%), oral ulcerations (n=9, 27.3%), pneumonitis (n=5, 15%), fatigue (n=5, 15.2%), rash (n=9, 27.3%), cellulitis (n=2, 6%), nausea (n=1, 3%), and diarrhea (n=1, 3%). With a median follow-up of 9 months (range 1-45 months), 6 patients remain on study. Reasons for study discontinuation included non-response or disease progression (n=17), unacceptable toxicity (n=6, including 5 for pneumonitis and 1 for neutropenia), noncompliance (n=2), and loss of follow-up (n=2). ConclusionsEverolimus is active in the primary therapy of WM, with rapid reductions observed in serum IgM levels in most patients. Serum IgM discordance to underlying BM disease burden is common, and serial BM assessments are important for response monitoring in WM patients receiving Everolimus.) [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Phase 1 and pharmacodynamic trial of everolimus in combination with cetuximab in patients with advanced cancer

Preclinical and clinical studies suggest mTOR (mammalian target of rapamycin) inhibitors may have metabolic and antiangiogenic effects, and synergize with epidermal growth factor pathway inhibitors. Therefore, a phase 1/pharmacodynamic trial of everolimus with cetuximab was performed. A total of 29 patients were randomized to a run-in of oral everolimus (30, 50, or 70 mg) or cetuximab (400 mg/m(2) loading, 250 mg/m(2) maintenance) weekly, followed by the combination in this dose-escalation study. Primary endpoints were phase 2 dose and toxicity characterization. [(18)F]Fluorodeoxyglucose positron emission tomography (FDG-PET) was performed as a pharmacodynamic marker of mTOR inhibition, and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was performed as an indicator of tumor perfusion changes, at 3 time points. Everolimus and cetuximab were tolerable at full doses, with an expected toxicity profile. Dose-limiting toxicities in the everolimus 70 mg group included grade 3 skin toxicity in 2 patients, and mucositis in 1 patient. Of 16 patients evaluable for response, 5 had stable disease lasting 4 to 19 months. Mean change in maximum standardized uptake value (SUV(max)) for those treated initially with everolimus was -24% (2% to -54%), and with cetuximab was -5% (-23 to 36%). The K(trans) measured by DCE-MRI did not decrease, regardless of run-in drug. Everolimus and cetuximab can be safely administered at standard doses, and are associated with prolonged disease control. The recommended phase 2 dose of oral weekly everolimus is 70 mg in combination with standard cetuximab. Imaging studies reveal that metabolic inhibition by everolimus alone and in combination with cetuximab predominates over changes in tumor perfusion in this patient population.

Everolimus in Erdheim–Chester disease

AbstractA 43-year-old man presented with bony pains, repeated pathological fractures with overlying skin ulcerations, and forearm and chest wall swellings. Investigations led to the diagnosis of Erdheim–Chester disease. Treatment with low-dose prednisolone, oral everolimus, and zoledronic acid was started, with a marked improvement in his condition.

ASCO 2013 Report: Genitourinary Cancer

At this year's annual meeting of the American Society of Clinical Oncology (ASCO 2013), held May 31 through June 5 in Chicago, specialists discussed the latest findings in cancer research. The editors of Journal Watch Oncology and Hematology were in attendance to report highlights of the conference. Here, Dr, Robert Dreicer reviews new treatments for genitourinary cancers. Sequential Sunitinib and Everolimus for Metastatic Renal Cancer Sequential therapy for patients with good- or intermediate-risk metastatic renal cancer involves the use of a vascular endothelial growth factor receptor (VEGFR)–targeted tyrosine kinase inhibitor (TKI) followed by a mammalian target of rapamycin (mTOR) inhibitor, typically the oral agent everolimus. To test whether this is the most effective sequence in which to administer these agents, Motzer and colleagues conducted a manufacturer-sponsored, phase II, randomized trial [Abstract 4504] comparing the standard dose and schedule of the TKI sunitinib followed at time of progression by the mTOR inhibitor everolimus (10 mg/day) versus the reverse order of everolimus followed by sunitinib. The study involved 471 treatment-naive patients with good- or intermediate-risk metastatic …

RTOG 0913: A Phase 1 Study of Daily Everolimus (RAD001) in Combination With Radiation Therapy and Temozolomide in Patients With Newly Diagnosed Glioblastoma

To determine the safety of the mammalian target of rapamycin inhibitor everolimus (RAD001) administered daily with concurrent radiation and temozolomide in newly diagnosed glioblastoma patients. Everolimus was administered daily with concurrent radiation (60 Gy in 30 fractions) and temozolomide (75 mg/m(2) per day). Everolimus was escalated from 2.5 mg/d (dose level 1) to 5 mg/d (dose level 2) to 10 mg/d (dose level 3). Adjuvant temozolomide was delivered at 150 to 200 mg/m(2) on days 1 to 5, every 28 days, for up to 12 cycles, with concurrent everolimus at the previously established daily dose of 10 mg/d. Dose escalation continued if a dose level produced dose-limiting toxicities (DLTs) in fewer than 3 of the first 6 evaluable patients. Between October 28, 2010, and July 2, 2012, the Radiation Therapy Oncology Group 0913 protocol initially registered a total of 35 patients, with 25 patients successfully meeting enrollment criteria receiving the drug and evaluable for toxicity. Everolimus was successfully escalated to the predetermined maximum tolerated dose of 10 mg/d. Two of the first 6 eligible patients had a DLT at each dose level. DLTs included gait disturbance, febrile neutropenia, rash, fatigue, thrombocytopenia, hypoxia, ear pain, headache, and mucositis. Other common toxicities were grade 1 or 2 hypercholesterolemia and hypertriglyceridemia. At the time of analysis, there was 1 death reported, which was attributed to tumor progression. Daily oral everolimus (10 mg) combined with both concurrent radiation and temozolomide followed by adjuvant temozolomide is well tolerated, with an acceptable toxicity profile. A randomized phase 2 clinical trial with mandatory correlative biomarker analysis is currently under way, designed to both determine the efficacy of this regimen and identify molecular determinants of response.

Phase II trial of intravenous carboplatin (C), oral everolimus (E), and prednisone (P) in docetaxel-pretreated (DP) metastatic castrate-resistant prostate cancer (mCRPC): A Prostate Cancer Clinical Trials Consortium study.

5041 Background: A phase II clinical trial was conducted of the combination of C and E due to the synergy noted. Methods: The primary endpoint was time to progression (TTP). Intravenous C at a target AUC of 5 on day 1, and oral E 5mg once daily and P 5mg twice daily were administered in 21 day cycles. PSA was assessed every 21 days and radiologic response was assessed every 3 cycles. Secondary endpoints included overall survival (OS), the correlation of TTP with phosphorylated (p) mTOR, pAKT, p70S6, and circulating tumor cells (CTC). A 1-stage study design assumed: a reference median TTP = 1.5 months; 1-sided alpha = 0.15; and power = 0.90, requiring 26 patients (pts). Results: 26 pts enrolled; median age 69 years (range 54-86) ;8 African American and 18 Caucasians. Median pretherapy PSA was 190 ng/ml (range 13 - 2174). 18 pts (69%) each had bone pain and Gleason score &gt; 8. 125 cycles have been administered; median 3 cycles (range 1 - 16). Predominant grade 3 or 4 toxicities were thrombocytopenia in 8 pts, pulmonary embolism in 2 and neutropenia in 3. No treatment related deaths occurred. 4 (15%) had a &gt; 30% PSA decline and 1 had a &gt;90% PSA decline. 8/19 pts had stable disease but no objective responses in MD. The median TTP and OS were 2.5 months (90% CI: 1.8 - 4.3), and 12.5 months (90% CI: 6.7 - 16.1), respectively. Median area under curves were 5.9 (range, 4.3 – 11.0) and 4.5 (range, 4.1 – 7.1) mg/mL*min with C given alone and in combination with E, respectively. E did not influence pharmacokinetics of C. Median baseline CTC (n=18) was 30 (range 0-2372). 5/18 pts had favorable CTC (CTC&lt;5/7.5 mL) pretherapy. Patients with TTP &gt;18 weeks had reduction in post-therapy CTC with a median decrease of 63% (range 11%-100%). Lack of IHC staining for pAKT was noted in 2/2 pts on therapy for &gt; 30 weeks vs increased expression was noted in 8/8 pts on therapy for &lt; 9 weeks. Testing for TSC1 mutation is planned and will be reported. Conclusions: The combination was tolerable but revealed modest clinical efficacy. Biomarker evaluations such as pAKT may help identify a subset likely to benefit from mTOR inhibitor strategy in mCRPC. Clinical trial information: NCT01051570.

Oral everolimus inhibits intimal proliferation in injured carotid artery in rats

Background Everolimus, a derivative of sirolimus, is a potent immunosuppressant that has important anti-proliferative properties. In the present study, we demonstrated the inhibiting neointimal hyperplasia in injured carotid arteries in rats by using two different doses of everolimus administrated via the oral route for a long time. Methods A rat model of carotid artery injury was established by balloon inflation. Eighty rats were randomly divided into the sham-operated group (n=20), injury group (n=20), low dosage of everolimus group (n=20), and high dosage of everolimus group (n=20). The low dose of everolimus (1.5 mg/kg) was given one day before injuring the carotid artery by balloon, followed by 0.75 mg/kg per day for 28 days via intragastric gavage. High dose everolimus (2.5 mg/kg) was given one day before injuring the carotid artery by balloon, followed by 1 mg/kg per day for 28 days. Expression of eukaryotic translation initiation factor 4E (eIF-4E) and phosphorylation of ribosomal protein S6 kinase 1 (P70S6K) were determined by reverse transcription-polymerase chain reaction and Western blotting analysis. Results In the injured carotid artery, neointimal hyperplasia was normally observed four weeks after injury. Everolimus inhibited neointimal hyperplasia after balloon injury in a dose dependent manner. At the same time, the study demonstrated that everolimus reduced the expression of P-P70S6K, eIF-4E, transforming growth factor (TGF)-β1 and of proliferating cell nuclear antigen (PCNA). Conclusions Everolimus significantly inhibited neointimal hyperplasia of the injured carotid artery. The effect depended on dosage and was associated with the reduction of phosphorylation of P70S6K and the eIF-4E expression level.

RTOG 0913: A phase I study of daily everolimus (RAD001) in combination with radiation therapy and temozolomide in patients with newly diagnosed glioblastoma.

2047 Background: To determine the safety of the mTOR inhibitor everolimus (RAD001) administered daily with concurrent radiation and temozolomide in newly diagnosed glioblastoma patients. Methods: Everolimus was administered daily with concurrent radiation (60 Gy in 30 fractions) and temozolomide (TMZ) (75 mg/m2/day). Everolimus was escalated from 2.5 (Dose Level 1), to 5 (Dose Level 2), to 10 mg/day (Dose Level 3). Maintenance TMZ was delivered at 150-200 mg/m2 on days 1 to 5 every 28 days for up to 12 cycles with concurrent everolimus at the previously established daily dose of 10 mg/day. Dose escalation continued if a dose level produced DLTs in ≤ 2 of the first 6 evaluable patients. Results: Between October 28, 2010 and July 2, 2012, the Radiation Therapy Oncology Group (RTOG) 0913 protocol initially registered a total of 35 patients, with 25 patients successfully meeting enrollment criteria, receiving drug and evaluable for toxicity. Everolimus was successfully escalated to the predetermined MTD of 10 mg/day. Two of the first 6 eligible patients experienced a DLT at each dose level. DLTs included: gait disturbance, febrile neutropenia, rash, fatigue, thrombocytopenia, hypoxia, ear pain, headache, and mucositis. Other common toxicities were Grade 1/2 hypercholesterolemia and hypertriglyceridemia. At the time of analysis, there was one death reported, which was attributed to tumor progression. Conclusions: Daily oral everolimus (10 mg) combined with both concurrent radiation therapy and TMZ followed by maintenance TMZ, is well tolerated, with an acceptable toxicity profile. A phase II randomized clinical trial with mandatory correlative biomarker analysis is currently underway, designed to both determine the efficacy of this regimen and identify molecular determinants of response. Supported by RTOG U10 CA21661 and CCOP U10 CA37422 grants from NCI and Novartis. Clinical trial information: NCT01062399.

Phase I study of everolimus and mitomycin C for patients with metastatic esophagogastric adenocarcinoma

This study aimed at determining the recommended dose of the mammalian target of rapamycin inhibitor everolimus in combination with mitomycin C (MMC) in patients with previously treated metastatic esophagogastric cancer. In this phase I trial, patients received escalated doses of oral everolimus (5, 7.5, and 10 mg/day) in combination with intravenous MMC 5 mg/m2 every 3 weeks. Endpoints were the dose-limiting toxicity (DLT), safety, and response rates. Tumor tissues were tested for HER2-status and mutations in the PTEN, PIK3CA, AKT1, CTNNB1, and E-cadherin type 1 genes. Sixteen patients (12 male, four female) with gastric/gastroesophageal junction cancer were included. All patients were previously treated with a platinum-based chemotherapy. Treatment cohorts were: 5 mg/day, three patients; 7.5 mg/day, three patients; and 10 mg/day, 10 patients. No DLTs occurred during dose escalation. Most frequent grade 3 toxicities were leukopenia (18.8%) and neutropenia (18.8%). All other grade 3 toxicities were below 10%. No grade 4 toxicities occurred. Three (18.8%) patients experienced partial responses and four patients had stable disease (SD). Antitumor activity according to Response Evaluation Criteria In Solid Tumors (RECIST)-criteria was highest in the 10 mg/day cohort. No associations between HER2-status or detected mutations and response were observed. The recommended dose of everolimus combined with MMC is 10 mg/day. Encouraging signs of antitumor activity were seen (http://www.ClinicalTrials.gov; Clinical trial registration number: NCT01042782).

Multicenter Phase II Study of Tivozanib (AV-951) and Everolimus (RAD001) for Patients With Refractory, Metastatic Colorectal Cancer

Treatments that target the vascular endothelial growth factor (VEGF) pathway have efficacy in colorectal cancer. We evaluated tolerability and efficacy of tivozanib (an oral VEGF receptor-1, -2, -3 inhibitor) plus everolimus (an oral mammalian target of rapamycin inhibitor). The phase Ib study followed a 3 + 3 dose-escalation design with three dose levels. The primary objective in the follow-on phase II study was improvement in 2-month progression-free survival (PFS) from 30% (historical benchmark) to 50% in patients with refractory, metastatic colorectal cancer. Dose-limiting toxicities in the phase Ib study were grade 3 fatigue and dehydration. Oral tivozanib (1 mg daily for 3 of 4 weeks) and oral everolimus (10 mg daily continuously) were advanced to a 40-patient phase II study. The most common grade 3-4 adverse events were thrombocytopenia and hypophosphatemia. The 2-month PFS rate was 50%, with 20 of 40 patients having stable disease (SD). Seven (18%) patients were treated for ≥6 months. Median PFS and overall survival (OS) times were 3.0 months (95% confidence interval [CI]: 1.9-3.6 months) and 5.6 months (95% CI: 4.4-10.6 months), respectively. Patients who developed grade 1+ hypertension had increased SD rates (65.2% vs. 29.4%) and longer OS times (10.6 vs. 3.7 months). The oral combination of tivozanib and everolimus was well tolerated, with stable disease achieved in 50% of patients with refractory, metastatic colorectal cancer.

The Selective JAK1/3 Inhibitor R507 Prevents Acute Rejection and Chronic Obliteration of Transplanted Rat Tracheas

Purpose Despite advances in the field of immunosuppression, obliterative airway disease remains an unsolved problem after clinical lung transplantation and the incidence of chronic renal failure remains high. The efficacy of the highly selective JAK1/3 inhibitor R507 on preclinical airway transplantation was investigated. Methods and Materials Orthotopic Lew-BN trachea transplantations were performed. Treatment groups received oral R507 (60mg/kg BID) or everolimus (4mg/kg QD). Mechanistic studies were performed in vitro using full-thickness human airway epithelium and R507-enriched medium. Results On postoperative day 6, mononuclear CD3 and CD68 graft infiltration were significantly reduced in both treatment groups compared to the control group, but significantly more potently with R507. IFN-γ Elispot frequencies were significantly lower with R507 and everolimus treatment. At 60 days, airway obliteration was significantly reduced from 32±5% in the control group to 24±6% (p=0.004) and 14±5% (p Conclusions R507 is a potent lymphocyte-targeting immunosuppressant without kidney and airway toxicity. It effectively prevents acute graft rejection as well as the development of obliterative airway disease. We believe it will be a valuable drug for lung transplantation.

Everolimus in Combination with Exemestane: A Review of its Use in the Treatment of Patients with Postmenopausal Hormone Receptor-Positive, HER2-Negative Advanced Breast Cancer

Oral everolimus (Afinitor(®)) in combination with exemestane is indicated for the treatment of hormone receptor-positive, human epidermal growth factor receptor (HER) 2-negative advanced breast cancer in postmenopausal women after failure of treatment with letrozole or anastrozole (in the USA) or after recurrence of progression following a nonsteroidal aromatase inhibitor (AI) in women without symptomatic visceral disease (in the EU). Everolimus, a selective inhibitor of mammalian target of rapamycin (mTOR), inhibits the downstream signalling events of the mTOR pathway. This review summarizes the pharmacology of everolimus and reviews its efficacy and tolerability when administered in combination with exemestane in postmenopausal women with oestrogen receptor-positive, HER2-negative advanced breast cancer refractory to nonsteroidal AIs. In the well-designed BOLERO-2 study, the addition of everolimus to exemestane was shown to significantly prolong progression-free survival in this patient population. However, treatment-emergent adverse events and treatment discontinuations occurred more frequently with combination therapy than with exemestane alone, suggesting a need for careful benefit/risk assessment prior to initiating therapy. Mature survival data from this study are awaited and additional studies would help to further demonstrate the benefit of combination therapy. Nevertheless, current evidence suggests that everolimus plus exemestane combination therapy may be a useful treatment option in patients with postmenopausal hormone receptor-positive, HER2-negative, advanced breast cancer refractory to nonsteroidal AIs.

Health‐related quality of life of patients with advanced breast cancer treated with everolimus plus exemestane versus placebo plus exemestane in the phase 3, randomized, controlled, BOLERO‐2 trial

The randomized, controlled BOLERO-2 (Breast Cancer Trials of Oral Everolimus) trial demonstrated significantly improved progression-free survival with the use of everolimus plus exemestane (EVE + EXE) versus placebo plus exemestane (PBO + EXE) in patients with advanced breast cancer who developed disease progression after treatment with nonsteroidal aromatase inhibitors. This analysis investigated the treatment effects on health-related quality of life (HRQOL). Using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) questionnaire, HRQOL was assessed at baseline and every 6 weeks thereafter until disease progression and/or treatment discontinuation. The 30 items in 15 subscales of the QLQ-C30 include global health status wherein higher scores (range, 0-100) indicate better HRQOL. This analysis included a protocol-specified time to definitive deterioration (TDD) analysis at a 5% decrease in HRQOL versus baseline, with no subsequent increase above this threshold. The authors report additional sensitivity analyses using 10-point minimal important difference decreases in the global health status score versus baseline. Treatment arms were compared using the stratified log-rank test and Cox proportional hazards model adjusted for trial stratum (visceral metastases, previous hormone sensitivity), age, sex, race, baseline global health status score and Eastern Cooperative Oncology Group performance status, prognostic risk factors, and treatment history. Baseline global health status scores were found to be similar between treatment groups (64.7 vs 65.3). The median TDD in HRQOL was 8.3 months with EVE + EXE versus 5.8 months with PBO + EXE (hazard ratio, 0.74; P = .0084). At the 10-point minimal important difference, the median TDD with EVE + EXE was 11.7 months versus 8.4 months with PBO + EXE (hazard ratio, 0.80; P = .1017). In patients with advanced breast cancer who develop disease progression after treatment with nonsteroidal aromatase inhibitors, EVE + EXE was associated with a longer TDD in global HRQOL versus PBO + EXE.

Effects of Hepatic Impairment on the Pharmacokinetics of Everolimus: A Single-Dose, Open-Label, Parallel-Group Study

BackgroundAlthough the pharmacokinetics of everolimus, an oral mammalian target of rapamycin inhibitor, have been characterized in patients with moderate hepatic impairment, they have not been assessed in those with mild or severe hepatic impairment. ObjectiveThe goal of this study was to assess the pharmacokinetics and safety of everolimus in healthy volunteers with normal hepatic function and patients with mild (Child-Pugh class A), moderate (Child-Pugh class B), and severe (Child-Pugh class C) hepatic impairment in otherwise good health to inform dosing in the clinical setting. MethodsA multicenter, open-label, Phase I study in which all enrollees received a single, 10-mg, oral everolimus dose was conducted. Blood samples for pharmacokinetic assessment were collected at predetermined time points up to 168 hours postdosing. Safety was also assessed. Proposed dose recommendations based on Child-Pugh status at baseline and day 8 were calculated based on AUC0–∞ geometric mean ratios and their associated 90% CIs. Post hoc analysis of the relationship between pharmacokinetic parameters and markers of hepatic function was also performed to identify thresholds for dose adjustment. ResultsThirteen subjects with normal hepatic function and 7 patients with mild, 8 patients with moderate, and 6 patients with severe hepatic impairment were enrolled. Compared with normal subjects, everolimus AUC0–∞ for patients with mild, moderate, and severe hepatic impairment increased by 1.60-, 3.26-, and 3.64-fold, respectively. Based on Child-Pugh classification at day 8, the everolimus doses required to adjust the exposure of patients with mild, moderate, and severe hepatic impairment to that of normal subjects were 6.25, 3.07, and 2.75 mg, respectively. Thresholds for 2-fold everolimus dose reduction were 15.0 μmol/L for bilirubin, 43.1 g/L for albumin, and 1.1 for the international normalized ratio; using these thresholds could lead to underdosing or overdosing in some patients. Most adverse events were of grade 1 severity, ≤1 day in duration, and not everolimus related. ConclusionsEverolimus exposure after a single 10-mg dose was influenced by the degree of hepatic impairment. Child-Pugh classification was found to be the most conservative means of guiding dose adjustment in patients with hepatic impairment. Based on these data, as well as previously reported data for patients with moderate hepatic impairment, everolimus once-daily dosing should be 7.5 mg and 5 mg in patients with mild and moderate impairment, respectively. Everolimus is not recommended in patients with severe hepatic impairment unless benefits outweigh risks; in that case, 2.5 mg once daily should not be exceeded. ClinicalTrials.gov identifier: NCT00968591.

Phase II trial of combination therapy with intravenous carboplatin (C) and oral everolimus (EVE) and prednisone (P) in docetaxel-pretreated (DP) metastatic castrate-resistant prostate cancer (mCRPC): A Prostate Cancer Clinical Trial Consortium study.

156 Background: Platinum based therapies have demonstrated efficacy in DP mCRPC. EVE demonstrated preclinical efficacy in chemotherapy resistant prostate cancer models. Clinical synergy was noted between C and EVE, hence a phase II trial of the combination was conducted. Methods: Primary endpoint was time to progression (TTP). Progression was defined per RECIST criteria for measurable disease (MD), or skeletal event, or &gt; 2 new areas of bone metastases. DP mCRPC patients with adequate renal and liver function, and performance status of 0 or 1 were eligible. Intravenous C at target AUC of 5 on day 1, and oral EVE 5mg once daily and P 5mg twice daily were administered in 21 day cycles. PSA was assessed every 21 days and radiologic response was assessed every 3 cycles. Secondary endpoints included overall survival (OS), correlation of TTP and PSA response, with markers such as phopho mTOR, pAKT, p70S6 and circulating tumor cells (CTC). Results: 26 patients (pts) enrolled, including 8 African Americans, and accrual is complete. Median age was 69 years (range 54-86). Median pretherapy PSA was 190 ng/ml (range 13 - 2174). 18 pts (69%) had bone pain. Gleason score was &gt; 8 in 18 pts. 19 pts had measurable disease of which 15 had MD progression, 18 had bone scan progression, and 2 had PSA-only progression. 124 cycles have been administered; median 3 cycles (range 1 - 16). The predominant grade 3 or 4 toxicities were thrombocytopenia in 8 pts, pulmonary embolism in 2 and neutropenia in 3. No treatment related deaths occurred. Of 26 pts who are response evaluable, 4 (15%) had a &gt; 30% PSA decline and 1 had a &gt;90% PSA decline. Of 19 pts with MD, 8 had stable disease and no objective responses were observed. The median TTP and OS were 2.5 months (90% CI: 1.8 - 4.3), and 12.5 months (90% CI: 6.7 - 16.1), respectively. Correlative studies including pharmacokinetic and pharmacodynamic evaluations are ongoing, and will be reported. Conclusions: The combination was tolerable but revealed modest clinical efficacy. Biomarker evaluation may help identify a subset likely to benefit from mTOR inhibition strategy in mCRPC. Clinical trial information: NCT01051570.