sirolimus and Fatigue

Mammalian target of rapamycin (mTOR) inhibitors, everolimus and temsirolimus, are approved for the treatment of a variety of malignancies. Fatigue has been described with these agents as a common side effect, although the overall incidence and risk remain unclear. We performed a meta-analysis to calculate the overall incidence of fatigue in cancer patients treated with everolimus and temsirolimus and to compare the differences in incidence with placebo. The electronic databases PubMed, Embase, Web of Science, and Cochrane databases were searched for studies to include in the meta-analysis. Eligible studies were phase II and III prospective clinical trials of cancer patients treated with single drug everolimus or temsirolimus with toxicity data on fatigue. Overall incidence rates, relative risk (RR), and 95% confidence intervals (CI) were calculated employing fixed or random effects models depending on the heterogeneity of the included studies. A total of 9,760 patients with a variety of malignancies from 56 prospective clinical trials were included for the meta-analysis. The overall incidences of all-grade and high-grade fatigue in cancer patients treated with mTOR inhibitor (everolimus or temsirolimus) were 45.4% (95% CI 36.9-55.8%) and 8.7% (95% CI 7.2-10.4%), respectively. The relative risks of fatigue of mTOR inhibitor compared to placebo were increased for all-grade (RR = 1.22, 95% CI 1.08-1.38, P = 0.002) and high-grade (RR = 1.82, 95% CI 1.24-2.69, P = 0.002) fatigue. The incidence of all-grade fatigue of patients treated with everolimus was higher than those with temsirolimus (RR = 1.85, 95% CI 1.71-2.01, P < 0.001). No significant difference was detected with between everolimus and temsirolimus in terms of high-grade fatigue (RR = 1.15, 95% CI 0.94-1.41, P = 0.18). Treatment with mTOR inhibitor, everolimus and temsirolimus, is associated with an increased incidence of fatigue in patients with cancer. Early detection and management of fatigue is needed.

Topics: Clinical Trials as Topic; Everolimus; Fatigue; Humans; Neoplasms; Prospective Studies; Protein Kinase Inhibitors; Risk; Sirolimus; TOR Serine-Threonine Kinases

We performed a systematic review and meta-analysis of fatigue, hepatic and metabolic toxicities associated with everolimus intake in patients with solid tumors.. Eligible studies included randomized trials of patients with solid tumors on everolimus describing events of fatigue, hyperlipidemia, hyperglycemia and elevated alanine aminotransferase (ALT).. After the exclusion of ineligible studies, a total of ten clinical trials were considered eligible for the meta-analysis. The relative risks of all-grade fatigue, hyperglycemia, hyperlipidemia and elevated ALT were 1.31 (p < 0.002), 3.06 (p < 0.0001), 2.54 (p = 0.0001) and 2.96 (p < 0.003), respectively.. Our meta-analysis demonstrates that everolimus is associated with a significantly increased risk of all-grade fatigue, hyperglycemia, hyperlipidemia and elevated ALT.

Topics: Chemical and Drug Induced Liver Injury; Everolimus; Fatigue; Humans; Neoplasms; Protein Kinase Inhibitors; Risk Factors; Sirolimus

We performed a meta-analysis of fatigue associated with the use of everolimus, temsirolimus or ridaforolimus in patients with solid tumors. Eligible studies included randomized trials of patients with solid tumors on everolimus, temsirolimus or ridaforolimus describing events of fatigue. A total of 18 clinical trials including 8143 patients were considered eligible for the meta-analysis. On the basis of random-effects model, we found that the relative risk of all-grade and high-grade fatigue were 1.26 [95% CI: 1.09-1.46; p < 0.0001], 1.49 [95% CI: 0.99, 2.24; p = 0.05], respectively. On subgroup analysis, we cannot identify any difference between everolimus and temsirolimus in the risk of fatigue. Thus, our meta-analysis has demonstrated that regimens containing everolimus, temsirolimus or ridaforolimus for the treatment of solid tumors are associated with an increased risk of all-grade fatigue, whereas the risk of high-grade fatigue did not reach the threshold of statistical significance. Close clinical monitoring and pre-emptive treatment for fatigue are recommended.

Topics: Antineoplastic Agents; Everolimus; Fatigue; Humans; Neoplasms; Protein Kinase Inhibitors; Randomized Controlled Trials as Topic; Risk; Sirolimus

The combination of exemestane and everolimus is a new treatment option for metastatic hormone-sensitive breast cancer. This treatment is used after progression on non-steroidal aromatase inhibitors. The treatment is generally well tolerated, but sometimes leads to minor or even serious side effects. It is important to be aware of these side effects and to treat them. We describe two patients who had to cope with various forms of toxicity: a 73-year-old woman with aphthous mouth lesions and a 49-year-old woman with pneumonitis. We then discuss the efficacy of the combination exemestane and everolimus and its positioning in the treatment of metastatic hormone-sensitive breast cancer. Finally, some common and some potentially serious side effects will be discussed, along with recommendations for their management and indications for distinguishing side effects from disease progression.

Topics: Aged; Androstadienes; Antineoplastic Agents; Breast Neoplasms; Drug Therapy, Combination; Everolimus; Fatigue; Female; Humans; Sirolimus

Everolimus is an orally available inhibitor of the mammalian target of rapamycin (mTOR), which has been approved in combination with exemestane for hormone receptor-positive (HR) breast cancer after failure of treatment with non-steroidal aromatase inhibitors. Everolimus is generally very well tolerated with most common side effects including stomatitis, rash, fatigue, hyperglycemia, hyperlipidemia, and myelosuppression. Most of these side effects are mild and resolve with dose interruptions or dose reductions. Symptomatic non-infectious pneumonitis is a relatively uncommon class effect of mTOR inhibitors, which can be life threatening. Given the efficacy of everolimus in HR-positive metastatic breast cancer, it is crucial for physicians to recognize toxicities related to everolimus and start timely interventions. This review will focus on the adverse events reported with everolimus in breast cancer trials and will provide practical guidelines for the management of these adverse events.

Topics: Antineoplastic Agents; Breast Neoplasms; Everolimus; Fatigue; Female; Humans; Hyperglycemia; Hyperlipidemias; Pneumonia; Sirolimus; Stomatitis; TOR Serine-Threonine Kinases

A phase II study was conducted to ascertain whether sequential exposure to decitabine followed by rapamycin, an mTOR (mechanistic target of rapamycin) inhibitor would result in better responses than decitabine alone. Newly diagnosed acute myelogenous leukemia (AML) patients who were >65 years old and not eligible for intensive induction regimens or patients with relapsed or refractory AML received 10 days of decitabine followed by 12 days of rapamycin in cycle 1 and 5 days of decitabine followed by 17 days of rapamycin in subsequent cycles. The composite complete remission rate (CR) was 33 % (CR plus CR with incomplete count recovery). Median overall survival was 7.7 months in newly diagnosed elderly AML patients and 6.6 months in relapsed/refractory AML patients. Twenty-four evaluable patients were enrolled, and the study did not meet its primary endpoint of demonstrating a significant improvement in composite CR rate with the combination as compared to an established historical CR rate of 25 % with decitabine alone. Despite that, the survival rates in relapsed/refractory cases appear comparable to what is reported with other salvage regimens, and no significant patterns of non-hematologic toxicity were noted. 50 % of subjects in the de novo group achieved a composite CR which is significantly higher (p = 0.02) than the rate of 25 % with decitabine alone. This trial is registered at clinical trials.gov as NCT02109744.

Topics: Acute Disease; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Decitabine; Disease-Free Survival; Fatigue; Febrile Neutropenia; Female; Humans; Leukemia, Myeloid; Leukopenia; Male; Middle Aged; Remission Induction; Sirolimus; Treatment Outcome

Ridaforolimus is a mammalian target of rapamycin inhibitor that has activity in solid tumors. Paclitaxel and carboplatin have broad antineoplastic activity in many cancers. This phase I trial was conducted to determine the safety profile, maximal tolerated dose, and recommended phase II dose and schedule of oral ridaforolimus combined with paclitaxel and carboplatin in patients with solid tumor cancers.. Thirty-one patients were consented, 28 patients were screened, and 24 patients met eligibility requirements and received treatment. Two patients were replaced for events unrelated to drug-related toxicity, resulting in 22 DLT-evaluable patients. Two grade 4 DLTs due to neutropenia were observed at dose level 1. The next cohort was changed to a predefined alternate dosing schedule (days 1-5 and 8-12). DLTs were neutropenia, sepsis, mucositis, and thrombocytopenia. The most common adverse events were neutropenia, anemia, thrombocytopenia, fatigue, alopecia, nausea, pain, and leukopenia. Twenty-four patients received a median of 4 cycles (range, 1-12). Evaluable patients for response (n = 18) demonstrated a median tumor measurement decrease of 25%. The best response in these 18 patients included 9 patients with partial response (50%), 6 with stable disease (33%), and 3 with progressive disease (17%). Thirteen of these patients received treatment for 4 or more cycles.. ClinicalTrials.gov Identifier: NCT01256268 (trial registration date: December 1, 2010).

Topics: Administration, Oral; Adult; Aged; Anemia; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Dose-Response Relationship, Drug; Drug Administration Schedule; Fatigue; Female; Humans; Male; Maximum Tolerated Dose; Middle Aged; Neoplasms; Neutropenia; Paclitaxel; Research Design; Sirolimus; Thrombocytopenia

There is crosstalk between the ANG-Tie2 and the PI3K/Akt/mTOR pathways. Combined ANG1/2 and mTOR blockade may have additive anti-cancer activity. The combination of trebananib, an inhibitor of ANG1/2-Tie2 interaction, with temsirolimus was evaluated in patients with advanced solid tumors to determine tolerability, maximum tolerated dose (MTD), and preliminary antitumor activity.. Patients were enrolled using 3 + 3 design, and were given intravenous trebananib and temsirolimus on Day 1, 8, 15 and 22 of a 28-day cycle. Dose limiting toxicities (DLTs) were evaluated during cycle 1. Peripheral blood was collected for evaluation of Tie2-expressing monocytes (TEMs) and thymidine phosphorylase (TP). Sparse pharmacokinetic (PK) sampling for trebananib drug levels was performed on Day 1 and 8 of cycle 2.. Twenty-one patients were enrolled, 6 at dose level (DL) 1, 7 at DL -1, and 8 at DL -2. No effect of temsirolimus on trebananib PK was observed. The most common treatment-related adverse events (AEs) were: fatigue (81 %), edema (62 %), anorexia (57 %), nausea (52 %), rash (43 %) and mucositis (43 %). The most common grade ≥ 3 AEs included lymphopenia (28 %) and fatigue (28 %). The MTD was exceeded at DL-2. Of 18 response evaluable patients, 1 partial response was observed (ER+/HER2-/PIK3CA mutant breast cancer) and 4 patients had prolonged SD ≥ 24 weeks. No correlation with clinical benefit was observed with change in number TEMs or TP expression in TEMs with treatment.. The MTD was exceeded at trebananib 10 mg/kg weekly and temsirolimus 20 mg weekly, with frequent overlapping toxicities including fatigue, edema, and anorexia.

Topics: Adult; Aged; Anorexia; Antineoplastic Combined Chemotherapy Protocols; Edema; Fatigue; Female; Humans; Male; Maximum Tolerated Dose; Middle Aged; Neoplasms; Recombinant Fusion Proteins; Sirolimus; Treatment Outcome

With an increasing choice of new treatment options, the management of side effects to maintain a chosen treatment if likely to be effective on the tumor remains important. The perception of side effects however varies between the physician and the patient, leading to possible wrong assumptions on tolerability that result in dose modifications, which may ultimately affect effectiveness. The aim was to assess fatigue in patients with advanced or metastatic renal cell carcinoma (RCC) by comparing the evaluation of the physician to the one provided by their respective patient. In addition, we aimed to assess possible influences of fatigue on parameters of quality of life.. Patients receiving systemic treatment for advanced RCC and their physicians were questioned independently regarding incidence and severity of fatigue and its effect on quality of life.. Both physicians and patients completed 98 matching questionnaires. Patients were treated with sunitinib, sorafenib, bevacizumab combined with interferon alpha, temsirolimus, everolimus, or interferon alpha alone. Incidence and severity of fatigue was differently assessed by patients and physicians, with fatigue being more severe when reported by the patient. The severity of fatigue increased with progressing treatment lines. Quality of life was significantly lower in patients experiencing fatigue compared with patients without fatigue. Emotional, functional, and physical well-being were all affected by fatigue, the latter being the most affected subscale. Social well-being was least affected.. Fatigue is a complex and cumulative condition of patients treated for advanced RCC, and it considerably affects patient's quality of life. As many of its underlying causes may be treated, the divergent perception of occurrence and severity of fatigue should be integrated in treatment concepts. The active role of the patient in helping to manage ailments through assessment should be implemented when optimizing treatment of RCC.

Topics: Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Bevacizumab; Carcinoma, Renal Cell; Cross-Sectional Studies; Everolimus; Fatigue; Female; Humans; Incidence; Indoles; Interferon-alpha; Kidney Neoplasms; Male; Middle Aged; Niacinamide; Phenylurea Compounds; Physicians; Pyrroles; Quality of Life; Self Report; Sirolimus; Sorafenib; Sunitinib; Surveys and Questionnaires

Myelodysplastic syndrome (MDS) continues to cause major morbidity and mortality; thus, novel treatments are needed. The mammalian target of rapamycin (mTOR) inhibitor RAD001 (everolimus) inhibits cellular pathways important to MYC protein stability and cell growth. Pharmacodynamic biomarkers could be useful in distinguishing between (1) disease resistance that occurs even though mTOR is successfully inhibited (suggesting a need for a different treatment strategy) and (2) resistance that might respond to changes in drug dosage or schedule.. This was a small phase II trial of RAD001 in patients with low- and intermediate-1-risk MDS (n = 7). Protein S6K1 (S6) is downstream of mTOR, whereas protein kinase B (AKT) is upstream of mTOR. Therefore, to evaluate the pharmacodynamic effects of RAD001, S6 and AKT phosphorylation (pS6, pAKT) were measured by peripheral blood flow cytometry.. Sequential weeks of RAD001 produced a decrease in pS6, whereas pAKT was maintained or increased. There were no clinical responses despite the biomarker evidence of intended pharmacodynamic effect.. The pS6:pAKT ratio could be useful as a biomarker of target inhibition by RAD001 (clinicaltrials.gov identifier: NCT00809185).

Topics: Aged; Aged, 80 and over; Biomarkers; Cell Line, Tumor; Drug Administration Schedule; Dyspnea; Everolimus; Fatigue; Female; Fever; Flow Cytometry; Humans; Immunosuppressive Agents; Male; Middle Aged; Myelodysplastic Syndromes; Neutropenia; Phosphorylation; Proto-Oncogene Proteins c-akt; Ribosomal Protein S6 Kinases; Sirolimus; TOR Serine-Threonine Kinases; Treatment Outcome

LY2584702 tosylate (hereafter referred to as LY2584702) is an oral, selective ATP competitive inhibitor of p70 S6 kinase. Preclinical studies with LY2584702 demonstrated significant synergistic activity with erlotinib and everolimus. The primary objective was to determine a phase II dose and schedule. Secondary objectives included evaluation of safety, toxicity and pharmacokinetics of LY2584702 in combination with erlotinib or everolimus.. Patients with advanced solid tumours were treated with a total daily dose of 50-200mg of LY2584702 in combination with erlotinib 150 mg once daily (Arm A) or everolimus 10mg once daily (Arm B). Dose escalation was based on 3+3 design and used the Common Terminology Criteria for Adverse Events Version 4.0.. Twenty-nine patients were enrolled, 17 in Arm A and 12 in Arm B. Dose limiting toxicities (DLTs) in cycle 1 were observed in Arm A in four patients and consisted of Grade 3 vomiting, hypophosphataemia, pulmonary embolism and decreased clotting factor V. No DLTs were observed in Arm B at cycle 1, and the most frequent treatment-emergent adverse events related to study drug were: fatigue, anorexia, diarrhoea, nausea and vomiting. Seven patients received ≥4 cycles (3 in A, 4 in B). Best overall response was stable disease. Exposure accumulation of LY2584702 occurred with BID (twice daily) dosing. Exposure of erlotinib increased when administered in combination with LY2584702.. LY2584702 was not well tolerated when administered with erlotinib, therefore this combination is not feasible. The combination with everolimus was better tolerated but yielded very limited clinical benefit.

Topics: Adaptor Proteins, Signal Transducing; Adult; Aged; Anorexia; Antineoplastic Combined Chemotherapy Protocols; Area Under Curve; Diarrhea; Dose-Response Relationship, Drug; Drug Administration Schedule; Erlotinib Hydrochloride; Everolimus; Fatigue; Female; Humans; Male; Metabolic Clearance Rate; Middle Aged; Neoplasms; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Pyrazoles; Pyrimidines; Quinazolines; Ribosomal Protein S6 Kinases, 70-kDa; Sirolimus; Time Factors; Treatment Outcome; Vomiting

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

Topics: Anemia; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Dose-Response Relationship, Drug; Drug Administration Schedule; Everolimus; Exanthema; Fatigue; Female; Humans; Kaplan-Meier Estimate; Middle Aged; Nausea; Remission Induction; Sirolimus; Thrombocytopenia; Treatment Outcome; Triple Negative Breast Neoplasms

Everolimus is an oral raptor mTOR inhibitor and has shown activity in patients with Waldenstrom's macroglobulinemia (WM). This study examines a large cohort of patients with relapsed/refractory WM with long-term follow up for survival. Patients were eligible if they had measurable disease, a platelet count >75,000 x 10(6)/L, an absolute neutrophil count >1,000 x 10(6)/L. Patients received everolimus 10 mg PO daily and were evaluated monthly. A success was defined as a complete or partial response (PR); minor responses (MR) were recorded and considered to be of clinical benefit. Sixty patients were enrolled and treated. The overall response rate (ORR) was 50% (all PR); the clinical benefit rate including MR or better was 73% (95% CI: 60-84%) with 23% MR. The median time to response for patients who achieved PR was 2 months (range, 1-26). The median duration of response has not been reached and median progression-free survival (PFS) was 21 months. Grade 3 or higher toxicities (at least possibly related to everolimus) were observed in 67% of patients. The most common grade 3 or 4 toxicities were anemia (27%), leukopenia (22%), and thrombocytopenia (20%). Other nonhematological toxicities were diarrhea (5%), fatigue (8%), stomatitis (8%) and pulmonary toxicity (5%). Everolimus has a high single-agent activity of 73% including MR, with a progression free survival of 21 months, indicating that this agent is active in relapsed/refractory WM.

Topics: Adult; Aged; Aged, 80 and over; Alkylating Agents; Angiogenesis Inhibitors; Antibodies, Monoclonal, Murine-Derived; Antimetabolites; Bone Marrow; Diarrhea; Disease-Free Survival; Drug Resistance; Everolimus; Fatigue; Female; Hematologic Diseases; Humans; Immunoglobulin M; Kaplan-Meier Estimate; Male; Middle Aged; Pain; Paraproteins; Recurrence; Rituximab; Sirolimus; Stomatitis; TOR Serine-Threonine Kinases; Treatment Outcome; Waldenstrom Macroglobulinemia

Bevacizumab and temsirolimus are active agents in gynecologic tumors. Temsirolimus attenuates upregulation of HIF-1α levels, a resistance mechanism for antiangiogenics, and targets the PI3-kinase/AKT/mTOR axis, commonly aberrant in these tumors.. We analyzed safety and responses in 41 patients with gynecologic cancers treated as part of a Phase I study of bevacizumab and temsirolimus.. Median age of the 41 women was 60 years (range, 33-80 years); median number of prior systemic therapies was 4 (1-11). Grade 3 or 4 treatment-related toxicities included: thrombocytopenia (10%), mucositis (2%), hypertension (2%), hypercholesterolemia (2%), fatigue (7%), elevated aspartate aminotransferase (2%), and neutropenia (2%). Twenty-nine patients (71%) experienced no treatment-related toxicity greater than grade 2. Full FDA-approved doses of both drugs (bevacizumab 15mg/kg IV Q3weeks and temsirolimus 25mg IV weekly) were administered without dose-limiting toxicity. Eight patients (20%) achieved stable disease (SD) > 6 months and 7 patients (17%), a partial response (PR) [total = 15/41 patients (37%)]. Eight of 13 patients (62%) with high-grade serous histology (ovarian or primary peritoneal) achieved SD > 6 months/PR.. Bevacizumab and temsirolimus was well tolerated. Thirty-seven percent of heavily-pretreated patients achieved SD > 6 months/PR, suggesting that this combination warrants further study.

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Aspartate Aminotransferases; Bevacizumab; Carcinoma; Fatigue; Female; Humans; Hypercholesterolemia; Hypertension; Male; Middle Aged; Mucositis; Neutropenia; Ovarian Neoplasms; Sirolimus; Thrombocytopenia; Uterine Cervical Neoplasms

Everolimus (mammalian target of rapmaycin (mTOR) inhibitor) and dovitinib (vascular endothelial growth factor (VEGF) and fibroblast growth factor 2 (FGF-2) inhibitor) demonstrate activity in metastatic clear cell renal cancer. The combination of these agents has a broad spectrum of relevant activity. The combination is explored in this phase Ib study.. Patients with metastatic clear cell renal cancer who have failed VEGF targeted therapy were eligible. Up to four cohorts of three to six patients (3+3 design) were treated with escalating doses of everolimus and dovitinib. Dose-limiting toxicities (DLTs) were assessed to determine the maximum tolerated dose (MTD). An expansion cohort (n=15) was investigated to obtain additional efficacy information. Sequential fluorodeoxyglucose positron emission tomography (FDG-PET) was used as a surrogate marker of response.. Overall 18 patients were recruited into the study. Fifteen patients received the MTD, which was everolimus 5mg orally (PO) once daily (OD) and dovitinib 200mg PO day 1-5/7. The MTD was associated with toxicity, which included fatigue, mucositis and diarrhoea in 73%, 53% and 53% (Common Toxicity Criteria (CTC) grade 1-4) of patients, respectively. Frequent biochemical abnormalities occurred (such as hypertriglyceridaemia in 67%). Higher doses of the combination were not tolerable due to grade 3 fatigue in 2/3 patients and grade 3 nausea in 1/3 patients within 1 month of therapy. The response rate at the MDT was 1/15 (7%) while the progression free survival for the MTD was 7 months (95% confidence interval (CI) 2.2-11 months). Pharmacokinetic data at the MTD showed stable kinetics with time.. Dovitinib and everolimus had modest activity, but did not meet all of the planned efficacy end-points. Fatigue was the dose limiting toxicity.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Carcinoma, Renal Cell; Cohort Studies; Disease-Free Survival; Dose-Response Relationship, Drug; Everolimus; Fatigue; Female; Humans; Kaplan-Meier Estimate; Kidney Neoplasms; Male; Middle Aged; Quinolones; Sirolimus

To determine the recommended phase II dose (RP2D) and assess the safety, pharmacokinetics (PKs) and pharmacodynamics of RO4929097in combination with temsirolimus.. Escalating doses of RO4929097 and temsirolimus were administered at three dose levels. Patients received once daily oral RO4929097 on a 3 days on/4 days off schedule every week, and weekly intravenous temsirolimus. Blood samples were collected for PK analysis. Archival tissue specimens were collected for Notch pathway biomarker analysis and genotyping of frequent oncogenic mutations.. Seventeen patients with refractory advanced solid tumors were enrolled in three dose levels (DLs): DL1 (RO4929097 10 mg; Temsirolimus 25 mg), DL2 (RO4929097 20 mg; Temsirolimus 25 mg), and DL3 (RO4929097 20 mg; Temsirolimus 37.5 mg). The most common toxicities related to the study drug combination included: fatigue (82 %; grade 3 6 %), mucositis, (71 %; grade 3 6 %), neutropenia (59 %; grade 3 12 %), anemia (59 %; grade 3 0 %), and hypertriglyceridemia (59 %; grade 3 0 %). Two dose-limiting toxicities, grade 3 rash and grade 3 mucositis, were observed in the same patient in the first dose level prompting dose expansion. Eleven patients (73 %) had stable disease as their best response. Co-administration of RO4929097 was associated with increased clearance and reduced exposure to temsirolimus, suggestive of drug-drug interaction via CYP3A4 induction. No correlation between the expression of Notch pathway biomarkers or genotype and time to progression was noted.. RO4929097 can be safely combined with temsirolimus in patients with advanced solid tumors. The RP2D was established at 20 mg of RO4929097 combined with 37.5 mg of temsirolimus.

Topics: Adult; Aged; Aged, 80 and over; Amyloid Precursor Protein Secretases; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Benzazepines; Calcium-Binding Proteins; Fatigue; Female; Humans; Intercellular Signaling Peptides and Proteins; Male; Membrane Proteins; Middle Aged; Mucositis; Neoplasms; Protein Kinase Inhibitors; Receptor, Notch3; Receptors, Notch; Serrate-Jagged Proteins; Sirolimus

Diffuse large B-cell lymphoma is an aggressive non-Hodgkin's lymphoma without a standard therapy for patients who relapse after or are not eligible for salvage autologous stem cell transplantation. In vitro analysis of lymphoma cell lines has shown that everolimus can inhibit cell cycle progression in vitro and inhibitors of the mammalian target of rapamycin have already demonstrated single-agent activity in relapsed non-Hodgkin's lymphomas including diffuse large B-cell lymphoma, validating mammalian target of rapamycin as a viable therapeutic target. We performed an open label phase II study of everolimus, an inhibitor of mammalian target of rapamycin, in combination with rituximab to examine efficacy and tolerability in patients with relapsed/refractory diffuse large B-cell lymphoma. Eligible patients were treated with everolimus 10 mg by mouth once daily on days 1-28 of a 28-day cycle with rituximab administered weekly during cycle one and then on day one of subsequent cycles. Patients were treated for a total of 12 cycles or until disease progression. The primary end-point was objective response rate, with secondary end-points being toxicity, progression-free survival, duration of response, and overall survival. Twenty-six patients (24 evaluable) were enrolled and had an overall response rate of 38% [90% CI (21%-56%)] with three complete responses and six partial responses among these 24 patients. The median duration of response among responders was 8.1 months. At a median follow-up of 12 months, the overall survival rate was 37% [90% CI (20%-54%)]. The most common grade 3 to 4 toxicities were neutropenia, anemia, and thrombocytopenia. In conclusion, everolimus in combination with rituximab is well tolerated and demonstrates activity in relapsed diffuse large B-cell lymphoma. Further studies of this combination are warranted.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Anemia; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Drug Administration Schedule; Everolimus; Fatigue; Female; Humans; Lymphoma, Large B-Cell, Diffuse; Male; Middle Aged; Neutropenia; Remission Induction; Rituximab; Sirolimus; Treatment Outcome

To retrospectively analyze the effects of treatment duration on outcomes of everolimus treatment of patients in the RAD001 Expanded-Access Clinical Trial in RCC (REACT) program.. Patients with metastatic renal cell carcinoma refractory to vascular endothelial growth factor receptor-tyrosine kinase inhibitor received everolimus (10 mg once daily), with dosing interruption or modifications allowed for toxicity. All serious and grade 3/4 adverse events and grade 1/2 adverse events leading to a change in drug administration were reported. Tumor response was evaluated using Response Evaluation Criteria In Solid Tumors.. The study stratified 1367 evaluable patients into treatment duration groups of <3 months, ≥3 and <6 months, ≥6 months and <1 year, and ≥1 year. Pneumonia, noninfectious pneumonitis, and hyperglycemia occurred more frequently in patients receiving everolimus for ≥1 year but did not result in treatment discontinuations. First occurrence of adverse events presented early in the treatment course for most patients. Treatment duration of ≥6 months was associated with improved disease control rates.. Everolimus is well tolerated in patients with metastatic renal cell carcinoma for treatment durations≥1 year and not associated with cumulative toxicity.

Topics: Aged; Anemia; Antineoplastic Agents; Carcinoma, Renal Cell; Disease Progression; Dyspnea; Everolimus; Fatigue; Female; Humans; Hyperglycemia; Kidney Neoplasms; Male; Middle Aged; Pneumonia; Sirolimus; Stomatitis; Time Factors; Treatment Outcome

A pediatric study has established a maximum tolerated dose (MTD) for temsirolimus (Tem) of more than 150 mg/m intravenously/week. A phase I trial was conducted to establish the MTD for Tem in combination with valproic acid (VPA) in children and adolescents with refractory solid tumors. The secondary aims included expression of mammalian target of rapamycin (mTOR) markers on archival tumor tissue; Tem pharmacokinetics; assessment of histone acetylation (HA); and tumor response. Patients were treated with VPA (5 mg/kg orally three times daily) with a target serum level of 75-100 mcg/ml. Tem was started at an initial dose of 60 mg/m/week. Pharmacokinetics and HA measurements were performed during weeks 1 and 5. Two of the first three patients experienced dose-limiting toxicity (grade 3 mucositis). Tem at 35 mg/m/week was found to be tolerable. Peak Tem concentrations were higher in all patients compared with those in previously published reports of single agent Tem. Increases in HA are correlated with VPA levels. All tumor samples expressed mTORC1 and mTORC2. An objective response was observed in one patient (melanoma), whereas transient stable disease was observed in four other patients (spinal cord ependymoma, alveolar soft part sarcoma, medullary thyroid carcinoma, and hepatocellular carcinoma). The MTD of Tem when administered with VPA is considerably lower than when used as a single agent, with mucositis the major dose-limiting toxicity. The combination merits further study and may have activity in melanoma. Attention to drug-drug interactions will be important in future multiagent trials including Tem.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Diphenhydramine; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Eruptions; Early Termination of Clinical Trials; Fatigue; Female; Hematologic Diseases; Histone Deacetylase Inhibitors; Humans; Infusions, Intravenous; Male; Mucositis; Neoplasms; Pain; Sirolimus; Valproic Acid

Rapalogs are emerging as promising targeted anticancer drugs. Activation of the PI3K/Akt/mTOR pathway has been observed in 15-50% of hepatocellular carcinomas.. In this phase II study, patients with advanced hepatocellular carcinoma and underlying cirrhosis received sirolimus (20 mg/week for 1 month then 30 mg/week). Tumour response was assessed every 8 weeks. The primary endpoint was the objective tumour response rate according to the Response Evaluation Criteria in Solid Tumours criteria. Secondary endpoints included the objective response according to the modified Response Evaluation Criteria in Solid Tumours criteria, safety, and pharmacokinetic parameters.. Twenty-five patients received sirolimus for a median of 20.6 weeks. Two patients had an objective response (8%, 95CI: 0.98-26.03), including one complete response, and 8 patients had stable disease. There were 2 cases of grade 5 toxicity (infections) and 5 cases of grade 3 toxicity. The main grade 1/2 toxicity was mild transient fatigue (76%). Median time to radiological progression and overall survival were 15.3 weeks (range: 8.2-173.9) and 26.4 weeks (range: 8.2-173.9) respectively. Use of the modified Response Evaluation Criteria in Solid Tumours criteria did not identify any further responders.. These data suggest that first-line sirolimus shows antitumoural efficacy in advanced hepatocellular carcinoma. Larger trials with Child A patients are needed.

Topics: Acne Vulgaris; Adult; Aged; Carcinoma, Hepatocellular; Disease Progression; Epistaxis; Fatigue; Female; Humans; Immunosuppressive Agents; Infections; Kaplan-Meier Estimate; Liver Cirrhosis; Liver Neoplasms; Male; Middle Aged; Mucositis; Multimodal Imaging; Positron-Emission Tomography; Sirolimus; Tomography, X-Ray Computed; TOR Serine-Threonine Kinases; Treatment Outcome

KIT D816V mutation has been observed in more than 90% of patients with systemic mastocytosis (SM). This mutation constitutively activates the mammalian target of rapamycin (mTOR) signaling pathway. We tested the efficacy of everolimus (RAD001), a novel oral mTOR inhibitor, at a dose of 10 mg daily in an open label, non-comparative Phase II trial for patients with SM. Ten patients were enrolled from April 2007 to October 2008. Median age was 55 years, four were males, seven had indolent and three aggressive SM, and six were previously treated with other agents. Median duration of therapy was 4 months (range 0.2-18). No objective responses were noted. Four patients had a short-lasting subjective improvement in symptoms for a median duration of 3 months (range 3-15). Grade 1-3 diarrhea, mucositis, and neutropenia were the most common adverse effects. No Grade 4 toxicity was noted. In conclusion, everolimus does not result in appreciable clinical activity in patients with SM.

Topics: Administration, Oral; Adult; Aged; Diarrhea; Everolimus; Fatigue; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Intracellular Signaling Peptides and Proteins; Male; Mastocytosis, Systemic; Middle Aged; Mucositis; Mutation; Neutropenia; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins c-kit; Sirolimus; TOR Serine-Threonine Kinases; Treatment Outcome

Standard cytotoxic treatments for neuroendocrine tumours have been associated with limited activity and remarkable toxicity. A phase II study was designed to evaluate the efficacy, safety and pharmacodynamics of temsirolimus in patients with advanced neuroendocrine carcinoma (NEC). Thirty-seven patients with advanced progressive NEC received intravenous weekly doses of 25 mg of temsirolimus. Patients were evaluated for tumour response, time to progression (TTP), overall survival (OS) and adverse events (AE). Twenty-two archival specimens, as well as 13 paired tumour biopsies obtained pretreatment and after 2 weeks of temsirolimus were assessed for potential predictive and correlative markers. The intent-to-treat response rate was 5.6% (95% CI 0.6-18.7%), median TTP 6 months and 1-year OS rate 71.5%. The most frequent drug-related AE of all grades as percentage of patients were: fatigue (78%), hyperglycaemia (69%) and rash/desquamation (64%). Temsirolimus effectively inhibited the phosphorylation of S6 (P=0.02). Higher baseline levels of pmTOR (phosphorylated mammalian target of rapamycin) (P=0.01) predicted for a better response. Increases in pAKT (P=0.041) and decreases in pmTOR (P=0.048) after treatment were associated with an increased TTP. Temsirolimus appears to have little activity and does not warrant further single-agent evaluation in advanced NEC. Pharmacodynamic analysis revealed effective mTOR pathway downregulation.

Topics: Adult; Aged; Antineoplastic Agents; Carcinoid Tumor; Carcinoma, Neuroendocrine; Disease Progression; Exanthema; Fatigue; Female; Follow-Up Studies; Humans; Hyperglycemia; Infusions, Intravenous; Male; Middle Aged; Pancreatic Neoplasms; Phosphorylation; Protein Kinases; Proto-Oncogene Proteins c-akt; Ribosomal Protein S6; Sirolimus; Survival Analysis; TOR Serine-Threonine Kinases; Treatment Outcome

This study compared 2-year health-related quality-of-life (HRQL) outcomes of sirolimus (SRL)-treated kidney transplant patients after elimination of cyclosporine A (CsA) to patients continuing on a combined CsA and SRL regimen.. A randomized, open-label, clinical trial was performed in Europe, Australia, and Canada. Four hundred thirty kidney transplant patients were randomly assigned to sirolimus plus steroids (ST) (n=215) or SRL and CsA+ST (n=215) therapy after 3 months of combined SRL+CsA+ST treatment. HRQL was measured using the Kidney Transplant Questionnaire (KTQ) and the SF-36 Health Survey at month 3 (time of randomization) and months 12 and 24 after transplantation. Repeated-measures analysis of covariance was used to evaluate treatment differences in HRQL scores over the 2-year period.. HRQL scores were available for 361 (86%) eligible study patients. Statistically significant treatment-by-assessment time interactions, favoring SRL+ST, were found on KTQ Fatigue (P=0.0158) and Appearance scores (P=0.0007). No treatment differences were observed in KTQ Physical Symptom, Uncertainty-Fear, and Emotion scores. Statistically significant treatment-by-assessment time interactions were observed for SF-36 Vitality scores (P=0.0203) but not other SF-36 scores (P>0.05). For Vitality scores, the SRL+ST group remained stable (mean, 0.4-point change) from month 3 to month 24 compared with decreases in the SRL+CsA+ST group (mean, -6.5-point change).. SRL-based therapy with early elimination of CsA results in fewer appearance-related problems, less fatigue, and better vitality compared with continuous treatment with SRL, CsA, and ST.

Topics: Adult; Analysis of Variance; Cyclosporine; Drug Administration Schedule; Drug Therapy, Combination; Emotions; Fatigue; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Quality of Life; Sirolimus; Steroids; Surveys and Questionnaires

The aim of this study was to evaluate the association between axitinib, sunitinib and temsirolimus toxicities and patient survival in metastatic renal cell cancer patients. Overall survival (OS) and progression-free survival (PFS) of metastatic renal cell cancer patients from the prospective multicenter STAR-TOR study were assessed using multivariable Cox models. A total of 1195 patients were included (n = 149 axitinib; n = 546 sunitinib; n = 500 temsirolimus). The following toxicities significantly predicted outcomes: hand-foot skin reaction (hazard ratio [HR] = 0.29) for PFS with axitinib; stomatitis (HR = 0.62) and pneumonitis (HR = 0.23) for PFS with temsirolimus; stomatitis (HR = 0.52) and thrombocytopenia (HR = 0.6) for OS with temsirolimus; fatigue (HR = 0.71) for PFS with sunitinib; hand-foot skin reaction (HR = 0.56) and fatigue (HR = 0.58) for OS with sunitinib. In conclusion, in metastatic renal cell cancer, axitinib, sunitinib and temsirolimus demonstrate specific toxicities that are protective OS/PFS predictors.

Topics: Aged; Axitinib; Carcinoma, Renal Cell; Chemotherapy, Adjuvant; Disease Progression; Fatigue; Female; Hand-Foot Syndrome; Humans; Incidence; Kidney Neoplasms; Male; Middle Aged; Nephrectomy; Pneumonia; Prognosis; Progression-Free Survival; Prospective Studies; Protective Factors; Risk Assessment; Sirolimus; Stomatitis; Sunitinib; Thrombocytopenia

Background Signal transduction inhibitors (STIs) have considerably improved treatment of advanced/metastasized renal cell carcinoma (mRCC). Most safety data for these drugs are derived from clinical trials. The purpose of this study was to evaluate which adverse drug reactions are documented during first-line treatments in routine clinical practice. Patients and methods The ongoing prospective German mRCC clinical registry is recruiting patients in 110 oncology and urology outpatient centers. Data from the first 250 patients who had completed first-line treatment were analyzed regarding adverse drug reactions (ADRs) documented in patients' medical records. Results Patients were older than in clinical trials and had comorbidities. Patients were treated with the STIs sunitinib (61%), temsirolimus (14%), sorafenib (10%), or bevacizumab combined with interferon (6%). About 520 ADRs were documented, of which 29% resulted in treatment modifications. The most frequently affected organ system was the gastrointestinal system. The most frequently documented ADRs were mucositis/stomatitis (14%), fatigue (14%), diarrhea (12%), and nausea (12%). Conclusions In routine practice, mRCC first-line treatments using STIs frequently lead to ADRs partly necessitating treatment modifications. The pattern of reported ADRs is similar to that reported in clinical trials, but frequencies of events differ, especially for symptoms of multifactorial origin that are not immediately associated with the treatment. These results indicate that perception and documentation of adverse reactions is different between clinical trials and routine practice, and that reviews of patients' medical records might not be the best method to assess safety in routine practice.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Carcinoma, Renal Cell; Diarrhea; Documentation; Fatigue; Female; Germany; Humans; Indoles; Interferons; Kidney Neoplasms; Male; Medical Oncology; Middle Aged; Nausea; Niacinamide; Phenylurea Compounds; Prospective Studies; Pyrroles; Registries; Sirolimus; Sorafenib; Stomatitis; Sunitinib

Metastatic renal cell carcinoma (mRCC) has historically been refractory to cytotoxic and hormonal agents. IL-2 and IFN-α provide response in a minority of patients. Small molecule tyrosine kinase inhibitors and monoclonal antibodies have established a role in the setting of mRCC. However, there is a lack of data from the Indian subcontinent. The aim of this study was to look whether our patients behave similarly as reported in the Western data to targeted agents, especially sunitinib.. The study was a prospective observational study conducted for a period of 5 years from 2011 to 2016. Sixty-three patients received targeted agents and were recruited in the study. Five patients were excluded for various reasons, and three were lost to follow-up. Fifty-five patients were properly studied and followed up. Fifty patients received sunitinib, four patients received sorafenib, and one patient received parenteral temsirolimus. Patients were followed for AEs and survival.. The most common AEs in patients taking sunitinib were fatigue (70 %), hand-foot syndrome (62 %), skin rash (58 %), mucosal inflammation (58 %), anorexia (42 %), skin discoloration (42 %), followed by dry mouth, dysgeusia, dyspepsia, dry skin, dry mouth, hair color changes, hypothyroidism, alopecia, oral pain/stomatitis, hypertension, decreased weight, photosensitivity, peripheral edema, erythema, and others. The median overall survival in our patients was 13.2 (95 % CI 10.1-16.5), progression-free survival was 8.1 months (95 % CI 6.4-10.5), and objective response was seen in 36 %.. Non-Western patients behave differently with sunitinib therapy compared to Western patients. Our patients have more mucocutaneous side effects and lesser overall survival.

Topics: Adult; Aged; Aged, 80 and over; Anorexia; Antineoplastic Agents; Carcinoma, Renal Cell; Developing Countries; Disease-Free Survival; Fatigue; Female; Follow-Up Studies; Hand-Foot Syndrome; Humans; India; Indoles; Kidney Neoplasms; Male; Middle Aged; Mucositis; Niacinamide; Phenylurea Compounds; Pigmentation Disorders; Prospective Studies; Pyrroles; Response Evaluation Criteria in Solid Tumors; Sirolimus; Sorafenib; Sunitinib; Survival Rate; White People; Young Adult

Everolimus (EVE; an inhibitor of mammalian target of rapamycin [mTOR]) enhances treatment options for postmenopausal women with hormone-receptor-positive (HR(+)), human epidermal growth factor receptor-2-negative (HER2(-)) advanced breast cancer (ABC) who progress on a non-steroidal aromatase inhibitor (NSAI). This is especially true for patients with visceral disease, which is associated with poor prognosis. The BOLERO-2 (Breast cancer trial of OraLEveROlimus-2) trial showed that combination treatment with EVE and exemestane (EXE) versus placebo (PBO)+EXE prolonged progression-free survival (PFS) by both investigator (7.8 versus 3.2 months, respectively) and independent (11.0 versus 4.1 months, respectively) central assessment in postmenopausal women with HR(+), HER2(-) ABC recurring/progressing during/after NSAI therapy. The BOLERO-2 trial included a substantial proportion of patients with visceral metastases (56%).. Prespecified exploratory subgroup analysis conducted to evaluate the efficacy and safety of EVE+EXE versus PBO+EXE in a prospectively defined subgroup of patients with visceral metastases.. At a median follow-up of 18 months, EVE+EXE significantly prolonged median PFS compared with PBO+EXE both in patients with visceral metastases (N=406; 6.8 versus 2.8 months) and in those without visceral metastases (N=318; 9.9 versus 4.2 months). Improvements in PFS with EVE+EXE versus PBO+EXE were also observed in patients with visceral metastases regardless of Eastern Cooperative Oncology Group performance status (ECOG PS). Patients with visceral metastases and ECOG PS 0 had a median PFS of 6.8 months with EVE+EXE versus 2.8 months with PBO+EXE. Among patients with visceral metastases and ECOG PS ≥1, EVE+EXE treatment more than tripled median PFS compared with PBO+EXE (6.8 versus 1.5 months).. Adding EVE to EXE markedly extended PFS by ≥4 months among patients with HR(+) HER2(-) ABC regardless of the presence of visceral metastases.

Topics: Aged; Androstadienes; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Clinical Trials, Phase III as Topic; Everolimus; Exanthema; Fatigue; Female; Follow-Up Studies; Humans; Kaplan-Meier Estimate; Middle Aged; Multicenter Studies as Topic; Neoplasm Metastasis; Placebos; Postmenopause; Prognosis; Randomized Controlled Trials as Topic; Receptor, ErbB-2; Receptors, Steroid; Sirolimus; Stomatitis; Treatment Outcome; Viscera

Treatment options are scarce in pretreated advanced non-small-cell lung cancer (NSCLC) patients. RAD001, an oral inhibitor of the mammalian target of rapamycin (mTOR), has shown phase I efficacy in NSCLC.. Stage IIIb or IV NSCLC patients, with two or fewer prior chemotherapy regimens, one platinum based (stratum 1) or both chemotherapy and epidermal growth factor receptor tyrosine kinase inhibitors (stratum 2), received RAD001 10 mg/day until progression or unacceptable toxicity. Primary objective was overall response rate (ORR). Analyses of markers associated with the mTOR pathway were carried out on archival tumor from a subgroup using immunohistochemistry (IHC) and direct mutation sequencing.. Eighty-five patients were enrolled, 42 in stratum 1 and 43 in stratum. ORR was 4.7% (7.1% stratum 1; 2.3% stratum 2). Overall disease control rate was 47.1%. Median progression-free survivals (PFSs) were 2.6 (stratum 1) and 2.7 months (stratum 2). Common > or =grade 3 events were fatigue, dyspnea, stomatitis, anemia, and thrombocytopenia. Pneumonitis, probably or possibly related, mainly grade 1/2, occurred in 25%. Cox regression analysis of IHC scores found that only phospho AKT (pAKT) was a significant independent predictor of worse PFS.. RAD001 10 mg/day was well tolerated, showing modest clinical activity in pretreated NSCLC. Evaluation of RAD001 plus standard therapy for metastatic NSCLC continues.

Topics: Adult; Aged; Anemia; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Disease-Free Survival; Dyspnea; ErbB Receptors; Everolimus; Fatigue; Female; Follow-Up Studies; Humans; Immunohistochemistry; Immunosuppressive Agents; Lung Neoplasms; Male; Middle Aged; Neoplasm Staging; Pneumonia; Proto-Oncogene Proteins c-akt; Regression Analysis; Sirolimus; Stomatitis; Thrombocytopenia; Time Factors; Treatment Outcome