Trial Of Everolimus Research Articles

Everolimus.

Everolimus (RAD001) is an oral protein kinase inhibitor of the mTOR (mammalian target of rapamycin) serine/threonine kinase signal transduction pathway. The mTOR pathway regulates cell growth, proliferation and survival, and is frequently deregulated in cancer.The EMA has approved Everolimus as Afinitor® for the treatment of hormone receptor-positive, HER2/neu-negative advanced breast cancer, in combination with exemestane, in postmenopausal women without symptomatic visceral disease after recurrence or progression following a nonsteroidal aromatase inhibitor, for the treatment of unresectable or metastatic, well- or moderately differentiated neuroendocrine tumors of pancreatic origin in adults with progressive disease, and for the treatment of unresectable or metastatic, well-differentiated (Grade 1 or Grade 2) nonfunctional neuroendocrine tumors of gastrointestinal or lung origin in adults with progressive disease, and for the treatment of patients with advanced renal cell carcinoma, whose disease has progressed on or after treatment with VEGF-targeted therapy And as Votubia® for the treatment of adult patients with renal angiomyolipoma associated with tuberous sclerosis complex (TSC), who are at risk of complications (based on factors such as tumor size or presence of aneurysm, or presence of multiple or bilateral tumors) but who do not require immediate surgery, and for the treatment of patients with subependymal giant cell astrocytoma (SEGA) associated with TSC who require therapeutic intervention but are not amenable to surgery, and as an add-on treatment in patients from 2years of age with seizures related to TSC that have not responded to other treatments ( https://www.novartis.com/news/media-releases/novartis-drug-votubiar-receives-eu-approval-treat-refractory-partial-onset ). The FDA has approved Everolimus as Afinitor® for the treatment of postmenopausal women with advanced hormone receptor-positive, HER2-negative breast cancer in combination with exemestane, after the failure of treatment with letrozole or anastrozole, for the treatment of adult patients with progressive neuroendocrine tumors of pancreatic origin (PNET) with unresectable, locally advanced or metastatic disease, for the treatment of adult patients with advanced RCC after failure of treatment with sunitinib or sorafenib, for the treatment of adult patients with renal angiomyolipoma and tuberous sclerosis complex (TSC), not requiring immediate surgery. for the treatment of adult and pediatric patients, 3years of age or older, with SEGA associated with TSC who require therapeutic intervention but are not candidates for curative surgical resection. Everolimus shows promising clinical activity in additional indications. Multiple Phase II and Phase III trials of everolimus alone or in combination and will help to further elucidate the role of mTOR in oncology. For a review on everolimus as immunosuppressant, please consult other sources.

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

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

Pharmacokinetically-targeted dosed everolimus maintenance therapy in lymphoma patients.

Everolimus, an mTOR inhibitor, is active in refractory lymphomas. However, toxicity with flat dosing limits its usage. Speculatively, pharmacokinetically-targeted dosing could improve tolerability. Therefore, we studied serum-trough dosing with rituximab as maintenance after high-dose cyclophosphamide (HDC) consolidation in lymphoma patients. After HDC, everolimus was dosed to serum trough levels (goal 3-15ng/mL), with quarterly rituximab infusions for 1year while maintaining < grade II non-hematologic and < grade III hematologic toxicities. Adult patients in first PR/CR with: mantle cell, transformed, double-hit, or high risk chronic lymphocytic leukemia or in second PR for any relapsed B cell lymphoma were eligible. Prophylaxis was given for encapsulated organisms, HSV and PCP. Serum IgG levels were maintained > 500mg/dL. 49 patients, median age: 59.0years enrolled; MCL (26), CLL (10), transformed lymphoma (7), and other histologies (6). During the life of the study, the most frequent everolimus dosing has been 2.5mg daily or 2.5mg every other day; at these doses, serum levels are within the therapeutic range and non-hematologic toxicity is rare. At a median follow-up of 27.1months, three patients remain on active therapy. Two patients withdrew secondary to potentially-attributable adverse events including a bacterial pneumonia and a viral pneumonia; this low rate of discontinuation compares well to other long-term everolimus trials. While a 58 and 76% EFS at 30months for the entire cohort and MCL cohort, respectively, compares similarly to previously published HDC/rituximab data, longer follow-up is required. Pharmacokinetically-targeted dosing appears to increase everolimus tolerability. This finding may be applicable to other patient populations.

MS 07.03 Novel Systemic Therapy for Carcinoid of the Lung

Carcinoid tumors of the lung belong to a broad group of neoplasms called neuroendocrine tumors (NETs). These tumors are highly heterogeneous and represent a broad spectrum of phenotypes and clinical behavior. Often, the clinical behavior of these tumors corresponds with their underlying pathologic features. For example, in those tumors deemed as “typical carcinoid/NETs”, clinical behavior is often very indolent. At the other end of the spectrum, NETs can present as small cell lung cancer (SCLC) which is characterized by virulent and highly metastatic behavior. Those tumors deemed as “atypical carcinoid/NETs” usually have an intermediate clinical phenotype. Lung NETs are rare: the annual incidence rate is estimated to be approximately 1 in 100,000. In those patients whose lung NETs are no longer surgically resectable and/or have metastasized distantly, the treatment goals are principally disease control and symptom palliation. Because of their rarity, there are very limited prospective Level 1 data to guide optimal management of lung NETs. Treatment recommendations are often based on extrapolation from clinical experience in gastrointestinal NETs (especially pancreatic NET), subset analyses from other NET trials, anecdotal reports (case series), and expert opinion (e.g., consensus panels). Thus, the optimal management strategy for Lung NETs is not yet fully defined. Systemic therapy options range from somatostatin analog therapy, mTOR inhibitor therapy, and cytotoxic chemotherapy. Somatostatin analog therapy is offered in selected patient subsets that have slowly progressing disease and whose tumors express somatostatin receptors as detected by nuclear medicine scanning (Octreoscan). Somatostatin analog therapy is only modestly efficacious, with disease stabilization as the expected clinical benefit. Inhibition of the mTOR with everolimus has demonstrated efficacy in randomized trials. In the RADIANT-2 trial of everolimus+octreotide vs. placebo+octreotide in NETs, a small subset of patients with lung NETs (n=44) was analyzed. This showed an improvement in progression free survival with everolimus+octreotide vs. the control arm (median PFS8.8 months vs 2.8; Hazard Ratio (HR) = 0.62; p=0.1). Subsequently, the phase III RADIANT-4 trial of everolimus vs placebo in non-functional lung and GI NETs was conducted. In this trial, approximately 30% of the 302 randomized patients had lung NETs. RADIANT-4 showed a PFS and overall survival (OS) benefit in favor of everolimus (PFS HR=0.39, p<0.0001; OS HR=0.64, p=0.037). More recently, a randomized phase II trial (LUNA) of pasitreotide alone, everolimus alone, or the combination showed a trend for improved PFS for the combination arm (PFS at 9 months was 39.0% for pasitreotide alone, 33.3% for everolimus alone, and 58.5% for the combination). In patients who are not candidates for somatostatin analog therapy or everolimus, or have failed these therapies, cytotoxic chemotherapy is often considered. The most commonly used regimens include platinum-etoposide (similar to that employed for SCLC) and temozolomide. Response rates to chemotherapy are reportedly much lower in lung NETs (vs SCLC) in retrospective studies; for example, platinum-etoposide is reported to yield response rates of 20-30% in lung NETs compared to rates greater than 50% in SCLC. It is thought that tumor responses are possibly influenced by the degree of tumor de-differentiation. Other agents with anecdotal activity include 5FU, capecitabine, oxaliplatin, and anthracyclines. Prospective trials of systemic therapy in lung NETs are essential to define the optimal standards of care. 1. Hendifar, AE et al. J Thor Oncol 2016; 12(3):425-436 2. Yao, J. et al. Lancet 2016; 387: 968-77 3. Fazio N, et al. Chest 2013; 143(4):955-962. carcinoid, neuroendocrine tumors, NETs

Pooled analysis of menstrual irregularities from three major clinical studies evaluating everolimus for the treatment of tuberous sclerosis complex.

ObjectivesTo determine the impact of everolimus on female fertility, including menstrual irregularities, secondary amenorrhea, and luteinizing and follicle stimulating hormone levels in female patients.DesignA pooled analysis from 3 prospective studies consisting of a core phase (≥6 months) and a long-term follow-up open-label extension.SettingOne phase 2 single-center and two phase 3 multicenter studies.ParticipantsData were obtained from female participants, restricted to those between 10 and 55 years of age, during 1 of 3 of the described clinical trials of everolimus. Patients had received ≥ 1 dose of everolimus.Main outcome measuresIncidence of fertility events.ResultsA total of 43/112 patients (38.4%) experienced at least 1 menstrual irregularity. The most common events were amenorrhea (24.1%) and irregular menstruation (17.0%). Seven patients (6.3%) experienced grade 3/4 amenorrhea. When only the longest duration period of amenorrhea for each patient was considered, the median duration was 291 days. Fifteen patients attained menarche during the treatment period in any of the pooled studies. The mean age of menarche for this group was 12.4 years, similar to that of patients who were postmenarche at study entry (12.2 years). A total of 19/92 patients (20.7%) who were postmenarche at baseline or during the study experienced an irregular menstruation event. An increased luteinizing hormone level was reported as an adverse event in 3/112 patients (3%), and follicle-stimulating hormone levels were within normal limits for these patients.ConclusionsNo new safety concerns emerged regarding endocrine function and menstruation in female patients with tuberous sclerosis complex–associated subependymal giant cell astrocytoma or angiomyolipoma, who were receiving everolimus.Trial registrationClinicalTrials.gov NCT00411619, NCT00789828, NCT00790400

K-Ras mutation and amplification status is predictive of resistance and high basal pAKT is predictive of sensitivity to everolimus in biliary tract cancer cell lines.

Advanced biliary tract cancer (BTC) has a poor prognosis and limited treatment options. The PI3K/Akt/mTOR signalling pathway is hyperactivated in a subset of BTCs, and clinical activity of the mTOR inhibitor everolimus has been observed in some patients with BTC. The goal of this study was to identify biomarkers predictive of everolimus response. Twenty BTC cell lines were assessed for everolimus sensitivity with a spectrum of growth inhibitory responses observed. Molecular biomarkers of sensitivity and resistance were identified by interrogation of the activation status of the Ras/MAPK and PI3K/Akt/mTOR pathways. K‐Ras mutations and/or amplifications were identified in 45% of cell lines and were associated with resistance to everolimus. Activating mutations in PIK3CA or loss of PTEN was not predictive of everolimus response; however, high basal levels of pAKT were associated with sensitivity, independent of Ras/MAPK pathway activation status. Notably, everolimus inhibited mTOR signalling to a similar extent in sensitive and resistant cell lines, suggesting that relative dependence on the mTOR pathway rather than the magnitude of pathway inhibition determines everolimus response. Consistent with the known limitations of rapalogs, everolimus induced feedback‐mediated activation of AKT in BTC cell lines, which could be overcome by cotreatment with an AKT inhibitor or ATP‐competitive mTORC1/mTORC2 inhibitors. However, both approaches failed to induce greater apoptosis compared to everolimus, and mTORC1/mTORC2 kinase inhibitors induced compensatory activation of pERK, identifying an inherent limitation of these agents in BTC cell lines. These findings suggest that future trials of everolimus in BTC would benefit from preselecting patients based on their K‐Ras and PI3K/mTOR pathway activation status. The study also identifies strategies for enhancing inhibition of the PI3K/mTOR pathway in BTC cell lines.

Phase 2 trial of everolimus and letrozole in relapsed estrogen receptor-positive high-grade ovarian cancers

ObjectivesWe report the results of a phase 2 clinical trial of the combination of everolimus and letrozole in patients with relapsed estrogen receptor-positive high-grade ovarian cancer. The trial's primary endpoint was the proportion of patients alive and progression-free after 12weeks of therapy with the combination of everolimus and letrozole. A 12-week PFS of 45% or greater was considered a positive result. The feasibility of generating patient-derived xenograft (PDX) models from biopsy specimens was also evaluated. MethodsEligibility criteria included relapsed estrogen receptor-positive ovarian, fallopian tube or primary peritoneal carcinomas with measurable disease, not previously treated with everolimus or AIs. Both platinum-resistant and sensitive tumors were included. Xenografts were created from image-guided tumor biopsies at baseline. Patients received oral everolimus 10mg daily and letrozole 2.5mg daily. ResultsTwenty patients were enrolled, 19 were evaluable. Nine out of 19 were alive, progression-free, and still on treatment at the 12week evaluation time-point (12-week PFS of 47%) with a median PFS of 3.9months (95% CI: 2.8–11.0). The median overall survival was 13.0months. Twelve patients (63%) experienced at least one grade 3 or worse adverse events. PDX tumor engraftment was feasible in the majority of patients (9 out of 17, 52.9%). ConclusionsThe combination of everolimus and letrozole is associated with a promising 47% 12-week PFS rate in patients with ER-positive relapsed high-grade ovarian cancer with acceptable toxicity. PDX tumor models can be generated from biopsies of ovarian tumors.

Phase I Clinical Trial of Everolimus Combined with Trimodality Therapy in Patients with Muscle-Invasive Bladder Cancer.

Background: Local control following trimodality therapy (TMT) for muscle-invasive bladder cancer (MIBC) requires further optimization.Objective: Evaluating the biologic endpoint, feasibility, and toxicity of integrating everolimus to TMT in patients with MIBC.Methods: This was a phase I trial in patients with MIBC who were not surgical candidates or who refused cystectomy. Following maximal transurethral tumor resection, patients were treated by radiotherapy (50 Gy/20 fractions), gemcitabine (100 mg/m2/weekly) and escalating doses of everolimus (2.5–5.0 mg/day). Everolimus was given daily for one month prior to radiation, during treatment, and one month post-radiation. Toxicity assessment followed the Radiation Therapy Oncology Group Acute Radiation Morbidity Scoring Criteria. Biologic endpoint with downregulation of phospho-S6 (pS6) was assessed using immunohistochemistry. Local response was evaluated with imaging and bladder biopsy post-therapy.Results: 10 patients were recruited; 8 males, 2 females. Median age was 78 years (range: 63–85). Four patients entered everolimus 2.5 mg cohort. Six other patients entered everolimus 5.0 mg cohort. Toxicities were encountered in 2 patients (Grade I), 6 patients (Grade II), 9 patients (Grade III) and 1 patient (Grade IV), with some experiencing more than one toxicity. Most Grade III and IV toxicities were encountered from everolimus alone prior to combination testing. Trial was terminated early due to toxicity. Interestingly, 6/10 patients (60%) achieved a complete response with negative post-treatment biopsies. Significant decrease of pS6 was demonstrated post-therapy (p = 0.03).Conclusions: Although combining everolimus with TMT achieved a biological endpoint and complete response in a significant number of patients with MIBC and negative prognostic factors, it was associated with unacceptable increased toxicity.

Prospective phase II trial of everolimus in PIK3CA amplification/mutation and/or PTEN loss patients with advanced solid tumors refractory to standard therapy

BackgroundWe designed a single-arm, open-label phase II trial of everolimus in PIK3CA amplification/mutation and/or PTEN loss patients with advanced solid tumors refractory to standard therapy (#NCT02449538).MethodsEverolimus was administered orally at a daily dose of 10 mg continuously (28-day cycles). Treatment was continued until progression of the disease or intolerable toxicity was observed. Based on Simon’s two-stage optimal design, 10 patients were treated with everolimus during the first stage.ResultsThe median age of the patients was 55.5 years (range, 42–72), and the median Eastern Cooperative Oncology Group (ECOG) performance status (PS) was 2 (range, 1–2). Most of the patients (50.0%) had gastric cancer (GC) as the site of their primary tumor followed by colorectal cancer (CRC), pancreatic cancer, and cholangiocarcinoma. Patients received everolimus as a third-line (3 patients), fourth-line (4 patients), fifth-line (1 patient) or sixth-line (2 patients) treatment. Complete or partial responses were not observed in any of the patients. Four patients showed stable disease, resulting in a disease control rate of 40%. The median PFS was 1.6 months (95% CI, 0.8–2.4 months). Grade 3 or greater hematologic/non-hematologic toxicity was not observed. Grade 2 diarrhea and stomatitis were reported in one patient each. There were no treatment-related deaths. There was less than one response out of the 10 initial patients during the first stage, and the study did not progress to the second stage.ConclusionsThe study did not meet its primary objective of demonstrating the anti-tumor activity of everolimus in PIK3CA amplification/mutation and/or PTEN loss patients with advanced solid tumors refractory to standard therapy. Further investigation using other genomic candidates and new-generation mTOR inhibitors is warranted in patients with treatment-refractory cancer.Trial registration#NCT02449538, April 2015.

Phase I Trial of Everolimus and Capecitabine in Metastatic HER2− Breast Cancer

BackgroundThe mammalian target of rapamycin (mTOR) pathway is a driver of breast tumorigenesis. The mTOR inhibitor everolimus reverses antihormonal therapy resistance and is an approved therapy for metastatic breast cancer. A synergistic effect with fluoropyrimidine has been suggested. The present study evaluated the safety and tolerability of an all-oral combination of everolimus and capecitabine for metastatic breast cancer (MBC). Patients and MethodsMBC patients naive to capecitabine and mTOR inhibitors who had received ≤ 3 previous chemotherapy regimens in the metastatic setting were eligible for the present study. The patients were scheduled to receive capecitabine 825 mg/m2 twice daily for 14 days in a 21-day cycle, combined with everolimus in 5 separate dose cohorts: 2.5 mg every other day, 2.5 mg daily, 5 mg daily, 7.5 mg daily, and 10 mg daily. A 3+3 design was used. The maximum tolerated dose was based on the dose-limiting toxicity of everolimus plus capecitabine. ResultsA total of 18 patients were enrolled in the present trial. The median age was 58 years. Most had received previous anthracycline (83%) and taxane (94%) therapy. The maximum tolerated dose was everolimus 7.5 mg daily and capecitabine 825 mg/m2. The incidence of grade 3 events was low and mainly hematologic in nature. One incident each of grade 4 neutropenia, thrombocytopenia, hyperglycemia, and mucositis occurred. No grade 5 events occurred. The clinical benefit rate was 50%. The median progression-free survival was 196 days, and the median overall survival was 569 days. ConclusionThe all-oral regimen of everolimus with capecitabine is active and well tolerated, with encouraging results for progression-free survival, overall survival, and clinical benefit rate in patients with MBC.

Abstract P6-16-03: Phase 2 trial of everolimus and/or trastuzumab in hormone refractory, hormone receptor (HR)-positive, HER2-normal metastatic breast cancer (MBC)

Abstract Background: Increased signaling through growth factor pathways including PI3K/Akt/mTOR and HER2 have been implicated in hormone resistance. Everolimus (EVE) improves outcomes when added to endocrine therapy for patients with HR-positive MBC. This study evaluated the efficacy of everolimus (EVE) and trastuzumab (TRAS) in hormone refractory HER2-normal metastatic breast cancer. Methods: Eligible patients had HR-positive, HER2/neu-negative (IHC +1 or +2, HER2-non-amplified) MBC that had progressed within 6 months of the most recent endocrine therapy. Patients continued on the most recent endocrine therapy they received and were randomized to receive EVE 10 mg oral daily or TRAS IV (8 mg/kg loading dose followed by 6 mg/kg every 3 weeks). At progression, the other agent was added (TRAS in the EVE arm and EVE in the TRAS arm). Patients were followed until disease progression or death. Results: 54 eligible patients were included in the analysis, and were randomized to EVE (n=30) or TRAS (n=24). 33% of patients were on fulvestrant, 31% exemestane, 22% tamoxifen and 7% letrozole, which were continued. The median PFS was 5.7 months for EVE vs. 2 months for TRAS until first progression or death with hazard ratio of 0.45 (95% CI 0.25-0.81, p=0.008). Among 48 patients who had disease progression, EVE was added to 16 patients who were originally treated by TRAS, and TRAS was added to 12 patients who were originally treated by EVE; the median time to the second progression was 6.3 months for the arm where EVE was added vs. 3.1 months in the arm where TRAS was added. Three patients were taken off study due to decrease in ejection fraction. Conclusions: This trial demonstrates the efficacy of EVE alone or in combination with TRAS in patients with hormone refractory HR-positive, HER2-negative metastatic breast cancer, who remained on the endocrine therapy they had experienced disease progression on. This suggests that mTOR inhibition has the potential of restoring sensitivity to endocrine therapy and potentially allows the re-use of endocrine agents. Updated results and correlative studies will be presented. Clinical trial information: NCT00912340. Citation Format: Paplomata E, Gogineni K, Meisel J, Santa-Maria C, Yuan L, Kramer J, Bill Li X, Zelnak A, Pakkala S, Kaklamani V, O'Regan R. Phase 2 trial of everolimus and/or trastuzumab in hormone refractory, hormone receptor (HR)-positive, HER2-normal metastatic breast cancer (MBC) [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-16-03.

Phase 1 Trial of Everolimus and Radiation Therapy for Salvage Treatment of Biochemical Recurrence in Prostate Cancer Patients Following Prostatectomy

In up to half of patients treated with salvage radiation therapy (SRT) for rising prostate-specific antigen levels, a second biochemical recurrence ultimately develops.Phosphatase and tensin homolog inactivation is implicated in prostate cancer progression, and upregulation of the mammalian target of rapamycin pathway can lead to tumor hypoxia and radioresistance. Everolimus is a mammalian target of rapamycin inhibitor with both antitumor and radiosensitizing effects. We performed a phase 1 study using a modified 3+3 dose-escalation design to evaluate the safety and tolerability of everolimus in combination with standard SRT for the treatment of biochemical recurrence following prostatectomy.After a 2-week run-in period of everolimus daily therapy, patients received prostate bed irradiation with daily cone beam computed tomography localization in 37 fractions of 1.8Gy each (total dose, 66.6Gy). Patients were monitored for both acute (≤90days) and chronic (>90days) treatment-related toxicities. Eighteen patients received everolimus at dose levels of 5mg (n=6), 7.5mg (n=6), or 10mg (n=6) daily in conjunction with SRT. No dose-limiting toxicities were observed. Common acute treatment-related toxicities included grade 1 or 2 mucositis (55.6%), grade 1 or 2 fatigue (38.9%), grade 1 or 2 rash (61.1%), and grade 1 urinary symptoms (61.1%). A grade 3 acute toxicity occurred in 4 patients (22.2%) (n=1 for rash, anemia, lymphopenia, and neutropenia), and no patients had a chronic toxicity of grade 3 or greater. After a median follow-up time of 17.8months (range, 1.2-46.0months), an undetectable prostate-specific antigen nadir was achieved in 9 patients (56.3%) and a second biochemical recurrence developed in 5 patients (31.3%). Everolimus at a dose of ≤10mg daily appears to be safe and tolerable in combination with fractionated post-prostatectomy radiation therapy.

Phase I Trial of Everolimus in Combination with Salvage Radiation Therapy (RT) for Post-prostatectomy Biochemical Recurrence (BCR) in Prostate Cancer (PC) Patients

Phase I Trial of Everolimus in Combination with Salvage Radiation Therapy (RT) for Post-prostatectomy Biochemical Recurrence (BCR) in Prostate Cancer (PC) Patients

Phase I trial of everolimus plus radiation therapy for salvage treatment of biochemical recurrence in prostate cancer patients following prostatectomy.

e16617Background: Up to half of patients treated with salvage radiation therapy (RT) for rising PSA ultimately develop a second biochemical recurrence (sBCR). Phosphatase and tensin homolog inactiv...

Meta-analysis of stomatitis in clinical studies of everolimus: incidence and relationship with efficacy

Everolimus, an oral mammalian target of rapamycin (mTOR) inhibitor, is used to treat solid tumors and tuberous sclerosis complex (TSC). Stomatitis, an inflammation of the mucous membranes of the mouth, is a common adverse event associated with mTOR inhibitors, including everolimus. We conducted a meta-analysis of data from seven randomized, double-blind phase 3 clinical trials of everolimus to determine the clinical impact of stomatitis on efficacy and safety. Data were pooled from the safety sets of solid tumor [breast cancer (BOLERO-2 and BOLERO-3), renal cell carcinoma (RECORD-1), carcinoid tumors (RADIANT-2), and pancreatic neuroendocrine tumors (RADIANT-3)] and TSC studies (EXIST-1 and EXIST-2). Data from solid tumor trials and TSC trials were analyzed separately. The rate of stomatitis was 67% in the solid tumor trials (973/1455 patients) and 70% in the TSC trials (110/157 patients). Most stomatitis events were grade 1/2, with grade 3/4 events reported in only 9% (solid tumor trials) and 8% (TSC trials) of patients. Low TSC patient numbers prevented an in-depth evaluation of stomatitis and response. In the solid tumor trials, most first stomatitis episodes (89%; n = 870) were observed within 8 weeks of starting everolimus. Patients with stomatitis occurring within 8 weeks of everolimus initiation had longer progression-free survival (PFS) than everolimus-treated patients without stomatitis in BOLERO-2 {8.5 versus 6.9 months, respectively; hazard ratio (HR), 0.78 [95% confidence interval (CI), 0.62-1.00]} and RADIANT-3 [13.9 versus 8.3 months, respectively; HR, 0.70 (95% CI, 0.48-1.04)]. A similar trend was observed in RECORD-1 [HR, 0.90 (95% CI, 0.66-1.22)] and RADIANT-2 [HR, 0.87 (95% CI, 0.61-1.22)] but not in BOLERO-3 [HR, 1.01 (95% CI, 0.75-1.36)]. Stomatitis did not adversely affect PFS, supporting the administration of everolimus in accordance with standard management guidelines.

ATNT-20A PHASE I-II TRIAL EVEROLIMUS AND SORAFENIB IN PATIENTS WITH RECURRENT HIGH-GRADE GLIOMAS: BRAIN TUMOR TREATMENT COLLABORATIVE TRIAL 09-01

BACKGROUND: Limited treatment options exist for patients with recurrent Malignant Gliomas (rMG), especially after Bevacizumab (BEV). Everolimus targets mTOR and sorafenib targets Raf, VEGF and PDFG. Combining these agents can block two parallel pathways simultaneously. We performed a phase I trial of Everolimus and Sorafenib in patients with rMG in preparation for a phase II study. METHODS: Patients with rMG > 18 yrs, KPS ≥ 60, normal laboratory data and no history of HIV or hepatitis were eligible. No limit on prior relapses and BEV exposure was allowed. Enzyme inducing seizure drugs were not allowed. A 3 + 3 dose escalation was used to determine the MTD. The starting dose was Everolimus 5 mg a day + Sorafenib 400 mg twice a day with a dose de-escalation level of Everolimus 5 mg/day + Sorafenib 400 mg twice a day for 7 days on and 7 days off. RESULTS: 11 men and 2 women were enrolled with a median age of 50 years (19-66) and median KPS of 80 (70-100). All patients had a GBM with 7 receiving prior BEV. In cohort 1, 3 of 6 patients experienced a DLT which were grade 3: fatigue, chest pain, HTN, elevated ALT, hypercholesterolemia and hyperglycemia and one grade 4 hypertriglyceridemia. Dose de-escalation occurred with 1 of 7patients having a DLT of myositis, nausea, fatigue, hypertension and hypercholesterolemia-all grade 3. All patients died due to disease progression with a median PFS of 4 weeks and OS of 20.9 weeks. CONCLUSION: This phase I study determined a phase II dose of Everolimus at 5 mg daily and Sorafenib at 400 mg BID 7 days on and 7 days off. A phase II trial is on-going for Bev naive recurrent anaplastic gliomas and GBMs as well as recurrent GBM who failed BEV.

Phase II trial of everolimus and erlotinib in patients with platinum-resistant recurrent and/or metastatic head and neck squamous cell carcinoma

Enhanced phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway is one of the key adaptive changes accounting for epidermal growth factor receptor (EGFR) inhibitor-resistant growth in head and neck squamous cell carcinoma (HNSCC). We designed a phase II clinical trial of EGFR tyrosine kinase inhibitor (TKI), erlotinib, in association with the mTOR inhibitor, everolimus, based on the hypothesis that the downstream effects of Akt through inhibition of mTOR may enhance the effectiveness of the EGFR-TKI in patients with recurrent/metastatic HNSCC. Patients with histologically or cytologically confirmed platinum-resistant HNSCC received everolimus 5 mg and erlotinib 150 mg daily orally until disease progression, intolerable toxicity, investigator or patient decision. Cytokines and angiogenic factors profile, limited mutation analysis and p16 immunohistochemistry status were included in the biomarker analysis. Of the 35 assessable patients, 3 (8%) achieved partial response at 4 weeks, 1 confirmed at 12 weeks; overall response rate at 12 weeks was 2.8%. Twenty-seven (77%) patients achieved disease stabilization at 4 weeks, 11 (31%) confirmed at 12 weeks. Twelve-week progression-free survival (PFS) was 49%, median PFS 11.9 weeks and median overall survival (OS) 10.25 months. High neutrophil gelatinase lipocalin (P = 0.01) and vascular endothelial growth factor (VEGF) (P = 0.04) plasma levels were significantly associated with worse OS. The combination of erlotinib and everolimus did not show significant benefit in unselected patients with platinum-resistant metastatic HNSCC despite a manageable toxicity profile. Markers of tumor invasion and hypoxia identify a group of patients with particularly poor prognosis. NCT00942734.

Abstract A01: Exploring phosphatase and tensin homolog (PTEN) loss as a potential predictive marker for response to everolimus in patients with pancreatic neuroendocrine tumors (PNETs)

Abstract Introduction: Identification of patients with exquisite sensitivity and/or durable responses to targeted therapies may lead to improved patient selection and allow for more rational treatment designs. Loss of PTEN tumor suppressor gene function, usually due to deletion, leads to activation of phosphatidylinositol 3-kinase/Akt and mammalian target of rapamycin (mTOR) signaling. The RADIANT-3 trial of everolimus in advanced PNETs demonstrated a significant prolongation of progression-free survival (PFS) from 4.6 months with placebo versus 11 months with everolimus. Despite the improvement in PFS, the response rate was only 5% among patients receiving everolimus. The index case for our study was an exceptional responder who had a significant radiological response as well as a PFS of 24 months, which were both better than expected from the literature. This led to the hypothesis that there may be mutational changes in genes affecting the mTOR pathway that could predict sensitivity to mTOR inhibitors. In this study, we specifically explored the role of PTEN loss as a potential predictive marker. Methods and Materials: Between 2010 and 2014, patients with well-differentiated unresectable and metastatic PNETs treated at the University of Miami/Sylvester Comprehensive Cancer Center and Jackson Memorial Hospital with everolimus were identified. Eight patients had pathology specimens available for testing. PTEN loss detected by Fluorescence In Situ Hybridization (FISH) was carried out using a commercially available probe for cytoband 10q23. Patients' response to everolimus was evaluated through June 2014. The primary outcome was PFS. PTEN expression by immunohistochemistry (IHC) will also be performed and the results will be compared to those obtained by FISH. Results: The median age was 60 years (range 45-78). 50% of the patients were females and 50% were males. Two patients had gastrinomas, 1 patient had an insulinoma, and five patients had non-functional PNETs. All patients had unresectable metastases to the liver. In addition to sandostatin LAR, the patients received everolimus starting at a dose of 10mg daily. Three patients were found to have deletion of PTEN. Of those, one patient did not tolerate everolimus and the PFS for the other two was 8 and 24 months respectively. Detection of PTEN loss by FISH yielded no results in 2 patients due to insufficient tumor left in the specimen. PFS in these 2 patients was 24 and 4 months respectively. Testing is ongoing in the last 3 patients and the PFS for these patients is 3, 10 and 13 months. PTEN expression by IHC is also ongoing and will be reported at the meeting. Conclusion: The index case for this study had a PTEN deletion and had a partial response to treatment and prolonged disease control for 2 years with everolimus. Testing is ongoing in additional cases to determine if there is a consistent correlation between PTEN loss by FISH and PFS. Citation Format: Moh'd Khushman, Joyce Slingerland, Yao-Shan Fan, Monica Garcia-Buitrago, Ernesto Bustinza, Maria Restrepo, Daniel Sussman, Caio Rocha-Lima, Peter Hosein. Exploring phosphatase and tensin homolog (PTEN) loss as a potential predictive marker for response to everolimus in patients with pancreatic neuroendocrine tumors (PNETs). [abstract]. In: Proceedings of the AACR Special Conference: Targeting the PI3K-mTOR Network in Cancer; Sep 14-17, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(7 Suppl):Abstract nr A01.

Everolimus in patients with metastatic renal cell carcinoma previously treated with bevacizumab: a prospective multicenter study CRAD001LRU02T⃰

Everolimus is an orally administered inhibitor of the mammalian target of rapamycin (mTOR) recommended for patients with metastatic renal cell carcinoma (mRCC) who progressed on previous vascular endothelial growth factor (VEGF) receptor-tyrosine kinase inhibitor therapy. Efficacy of everolimus in patients who progressed on anti-VEGF monoclonal antibody bevacizumab is unknown. We did a multicenter prospective trial of everolimus in patients with mRCC whose disease had progressed on bevacizumab ± interferon alpha (IFN). Patients with clear-cell mRCC which had progressed on bevacizumab ± IFN received everolimus 10 mg once daily. The primary end point was the proportion of patients remaining progression-free for 56 days, and a two-stage Simon design was used, with 80 % power and an alpha risk of 5 %. This study is registered with ClinicalTrials.gov, number NCT02056587. From December 2011 to October 2013, a total of 37 patients (28 M, 9 F) were enrolled. Median age was 60.5 years (range 41-66), 11 % had Eastern Cooperative Oncology Group Performance Status (ECOG PS) &gt; 2, and Memorial Sloan-Kettering Cancer Center (MSKCC) favorable/intermediate risk was 38/62 %. Five (14 %) patients had a confirmed partial response and 26 (70 %) patients had a stable disease. Median progression-free survival was 11.5 months (95 % CI, 8.8–14.2). Median overall survival was not reached. No grade 3 or 4 treatment-related toxicities were observed. The most common grade 2 adverse events were fatigue (19 %) and pneumonitis (8 %). Everolimus demonstrated a favorable toxicity profile and promising anti-tumor activity as a second-line therapy in metastatic renal cell carcinoma (RCC) patients previously treated with bevacizumab ± IFN.

Phase I trial of everolimus in combination with thoracic radiotherapy in non-small-cell lung cancer

This phase I study evaluated the safety and efficacy of the oral mTOR inhibitor everolimus in combination with thoracic radiotherapy followed by consolidation chemotherapy in locally advanced or oligometastatic untreated non-small-cell lung cancer (NSCLC). Everolimus dose was escalated in incremental steps [sequential cohorts of three patients until the occurrence of dose-limiting toxicity (DLT)] and administered orally weekly (weekly group: dose of 10, 20 or 50 mg) or daily (daily group: 2.5, 5 or 10 mg), 1 week before, and during radiotherapy until 3.5 weeks after the end of radiotherapy. Two cycles of chemotherapy (cisplatin-navelbine) were administrated 4.5 weeks after the end of radiotherapy. Twenty-six patients were included in two centers, 56% had adenocarcinoma and 84% had stage III disease. In the weekly group (12 assessable patients), everolimus could be administered safely up to the maximum planned weekly dose of 50 mg; however, one patient experienced a DLT of interstitial pneumonitis at the weekly dose level of 20 mg. In the daily group (9 assessable patients): one DLT of interstitial pneumonitis with a fatal outcome was observed at the daily dose level of 2.5 mg; two other DLTs (one grade 3 esophagitis and one bilateral interstitial pneumonitis) were found at the daily dose level of 5 mg. Overall there were five patients with G3-4 interstitial pneumonitis related to treatment. Among 22 assessable patients for response, there were 9 (41%) partial response and 7 (32%) stable disease. At a median follow-up of 29 months, the 2-year overall survival and progression-free survival actuarial rates were 31% and 12%, respectively. In previously untreated and unselected NSCLC patients, the recommended phase II dose of everolimus in combination with thoracic radiotherapy is 50 mg/week. Pulmonary toxicity is of concern and should be carefully monitored to establish the potential role of mTOR inhibitor with concomitant radiotherapy. 2007-001698-27.