sirolimus and Mucositis

Between 1993 and 2003, through experiments involving Drosophila sp., cancer biologists identified the protein kinase known as the mammalian target of rapamycin, its pathway, and its relationship to the genes responsible for tuberous sclerosis. Thereafter, clinical research has resulted in regulatory approval of mTOR inhibitors for four distinct manifestations of the disease: giant cell astrocytoma, angiomyolipoma, lymphangioleiomyomatosis, and epilepsy. These developments are summarized and the practical use of mTOR inhibitors to improve the lives of patients with tuberous sclerosis reviewed.

Topics: Angiomyolipoma; Clinical Trials as Topic; Epilepsy; Humans; Lymphangiomyoma; Mucositis; Protein Kinase Inhibitors; Sirolimus; TOR Serine-Threonine Kinases; Tuberous Sclerosis

Mammalian target of rapamycin (mTOR) has emerged as an important target for cancer therapy. Rapamycin has a distinct, well-documented toxicity profile and most of the toxicity data has been reported in patients with organ transplantation. Newer mTOR inhibitors have slightly different pharmacokinetic properties, yet they present toxicity profiles similar to rapamycin. Most of these toxicities are mild to moderate in severity and can be managed clinically by dose modification and supportive measures. Mucositis and pneumonitis are the most commonly reported toxicities, but they rarely lead to treatment discontinuation. Pathogenesis of pneumonitis is uncertain, but various hypotheses have been suggested, including cell-mediated immune response to the drug.

Topics: Animals; Antineoplastic Agents; Drug Hypersensitivity; Graft Rejection; Humans; Mucositis; Neoplasms; Organ Transplantation; Pneumonia; Prognosis; Protein Kinases; Sirolimus; Th1 Cells; Th2 Cells; TOR Serine-Threonine Kinases; Treatment Outcome

Desmoplastic small round cell tumor (DSRCT) is a rare mesenchymal tumor that typically presents with multiple abdominal masses. Initial treatment is multimodal in nature. Patients with relapsed DSRCT have a poor prognosis, and there are no standard therapies. We report our experience with five patients treated with vinorelbine, cyclophosphamide, and temsirolimus (VCT). Median number of VCT courses delivered was 7 (range 4-14 courses), and partial response was observed in all patients. Median time to progression or relapse was 8.5 months (range 7-16 months). Neutropenia and mucositis were most common toxicities (n = 4 each).

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Child; Cyclophosphamide; Desmoplastic Small Round Cell Tumor; Female; Humans; Male; Mucositis; Neoplasm Recurrence, Local; Neutropenia; Sirolimus; Vinblastine; Vinorelbine

Animal and cellular studies support the importance of autophagy inhibition in lymphangioleiomyomatosis (LAM). In a cohort of subjects with LAM, we tested the hypothesis that treatment with sirolimus and hydroxychloroquine (an autophagy inhibitor) at two different dose levels is safe and well tolerated. Secondary end points included changes in lung function.. This 48-week, two-center phase I trial evaluated the safety of escalating oral hydroxychloroquine doses (100-200 mg) given twice a day in combination with sirolimus to eligible patients ≥ 18 years old with LAM. Subjects received combination therapy for 24 weeks followed by an observation phase without taking study drugs for an additional 24 weeks.. Fourteen patients provided written informed consent. Thirteen were treated in cohorts of three patients each with escalating hydroxychloroquine doses (200 and 400 mg) and an extension phase at the 400-mg dose. The most common adverse events were mucositis, headache, and diarrhea. No drug-related serious adverse events were reported. Secondary end points showed improvement in lung function at 24 weeks, with a decrease in lung function at the 48-week time point. When the higher dose of hydroxychloroquine was analyzed separately, FEV. The combination of sirolimus and hydroxychloroquine is well tolerated, with no dose-limiting adverse events observed at 200 mg twice a day. Potential effects on lung function should be explored in larger trials.. ClinicalTrials.gov; No.: NCT01687179; URL: www.clinicaltrials.gov.

Topics: Adult; Aged; Autophagy; Diarrhea; Enzyme Inhibitors; Enzyme-Linked Immunosorbent Assay; Female; Forced Expiratory Volume; Headache; Humans; Hydroxychloroquine; Immunosuppressive Agents; Lymphangioleiomyomatosis; Middle Aged; Mucositis; Sirolimus; Treatment Outcome; Vascular Endothelial Growth Factor D; Vital Capacity; Walk Test

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Female; Humans; Male; Metformin; Middle Aged; Mucositis; Niacinamide; Protein Kinase Inhibitors; Retrospective Studies; Sirolimus; TOR Serine-Threonine Kinases; Treatment Outcome; Young Adult

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

This phase I study investigated the safety, dose-limiting toxicity, and efficacy in three cohorts all treated with the mTOR inhibitor everolimus that was delivered (1) in combination with 5-fluorouracil with leucovorin (5-FU/LV), (2) with mFOLFOX6 (5-FU/LV + oxaliplatin), and (3) with mFOLFOX6 + panitumumab in patients with refractory solid tumors.. Patients were accrued using a 3-patient cohort design consisting of two sub-trials in which the maximum tolerated combination (MTC) and dose-limiting toxicity (DLT) of everolimus and 5-FU/LV was established in Sub-trial A and of everolimus in combination with mFOLFOX6 and mFOLFOX6 plus panitumumab in Sub-trial B.. Thirty-six patients were evaluable for toxicity, 21 on Sub-trial A and 15 on Sub-trial B. In Sub-trial A, DLT was observed in 1/6 patients enrolled on dose level 1A and 2/3 patients in level 6A. In Sub-trial B, 2/3 patients experienced DLT on level 1B and subsequent patients were enrolled on level 1B-1 without DLT. Three of six patients in cohort 2B-1 experienced grade 3 mucositis, and further study of the combination of everolimus, mFOLFOX6 and panitumumab was aborted. Among the 24 patients enrolled with refractory metastatic colorectal cancer, the median time on treatment was 2.7 months with 45 % of patients remaining on treatment with stable disease for at least 3 months.. While a regimen of everolimus in addition to 5-FU/LV and mFOLFOX6 appears safe and tolerable, the further addition of panitumumab resulted in an unacceptable level of toxicity that cannot be recommended for further study. Further investigation is warranted to better elucidate the role which mTOR inhibitors play in patients with refractory solid tumors, with a specific focus on mCRC as a potential for the combination of this targeted and cytotoxic therapy in future studies.

Topics: Antibodies, Monoclonal; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cohort Studies; Colorectal Neoplasms; Dose-Response Relationship, Drug; Drug Monitoring; Early Termination of Clinical Trials; Everolimus; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Mucositis; Neoplasm Metastasis; Neoplasms; Organoplatinum Compounds; Oxaliplatin; Panitumumab; Protein Kinase Inhibitors; Severity of Illness Index; Sirolimus; TOR Serine-Threonine Kinases

Pegylated liposomal doxorubicin (PLD) is used to treat patients with breast and gynecological cancers. In order to optimize treatment with PLD, we assessed the prognostic and predictive factors for efficacy of PLD.. Seventeen patients treated with PLD 30 or 40 mg/m(2) underwent pharmacokinetic sampling during the first cycle of treatment. PLD exposure was calculated. An univariate analysis was performed with the variables: hand-foot syndrome, mucositis, rash, neutropenia, age, tumor type, number of previous therapies, ECOG performance status and progression-free survival (PFS). Candidate variables with p ≤ 0.1 were selected for the multivariate analysis.. Based on the results of the multivariate analysis, the PLD exposure (log AUC) was higher in patients who experienced rash (p = 0.002) and mucositis (p = 0.001) compared to those who did not have these adverse events. The development of hand-foot syndrome was significantly related to a lower risk of disease progression (HR 0.1; 95 % CI 0.02-0.64). Patients with an ECOG status of 0 had a longer PFS than the patients with an ECOG status of 1 (HR 5.4; 95 % CI 1.3-22.8). Moreover, PLD exposure (ln AUC) was also positively related to PFS (HR 0.001; 95 % CI 0.00-0.42).. The extent of the exposure to PLD was correlated with more adverse events and longer PFS. This has important clinical implications, since dose reductions or interruptions might thus negatively affect treatment outcomes. More attention should be paid to preventive and supportive measures of adverse events of PLD to keep the exposure to PLD as high as possible.

Topics: Adult; Aged; Antibiotics, Antineoplastic; Area Under Curve; Breast Neoplasms; Disease-Free Survival; Doxorubicin; Drug Administration Schedule; Endometrial Neoplasms; Female; Hand-Foot Syndrome; Humans; Middle Aged; Mucositis; Multivariate Analysis; Ovarian Neoplasms; Polyethylene Glycols; Sirolimus; Treatment Outcome; Young Adult

We tested the oral mammalian target of rapamycin (mTOR) inhibitor everolimus in addition to paclitaxel in patients with HER2-negative tumours not responding to initial neoadjuvant cytotoxic and anti-angiogenic treatment.. Patients with primary HER2-negative tumours received four neoadjuvant cycles of epirubicin/cyclophosphamide (EC) with or without bevacizumab. Patients without clinical response were randomised to receive weekly paclitaxel (80 mg/m(2)) with or without everolimus (5mg p.o. daily, after a step-wise dose-escalation starting from 2.5mg bid) for 12 weeks before surgery. To detect an increase in pathological complete response (pCR; ypT0 ypN0) from 5% to 12.1% (odds ratio 2.62) 566 patients had to be recruited. The trial was stopped prematurely due to completion of accrual in the main study.. Of 1948 patients initially starting neoadjuvant treatment 403 were randomised. A total of 18 (4.6%) patients, 7 (3.6%) treated with paclitaxel and everolimus and 11 (5.6%) treated with paclitaxel alone had a pCR (odds ratio 0.36 (OR) (95% confidence interval (CI), 0.24-1.6) p=0.34). Overall response rate in breast and lymph nodes at surgery was 52.2% after paclitaxel plus everolimus and 61.7% after paclitaxel alone (p=0.063). Breast conserving treatment was performed in 54.4% of patients with the combination treatment and 61.9% with paclitaxel alone (p=0.20). Mucosal inflammation, thrombocytopenia, neutropenia, infection, and skin rash were more frequent when everolimus was added to paclitaxel.. Neoadjuvant therapy with everolimus and paclitaxel for patients with HER2-negative disease unresponsive to EC with or without bevacizumab did not improve the pCR rate. Long-term outcome is awaited.. Novartis, Roche, and Sanofi-Aventis.

Topics: Adult; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Breast Neoplasms; Cyclophosphamide; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Resistance, Neoplasm; Epirubicin; Everolimus; Exanthema; Female; Humans; Mastectomy, Segmental; Middle Aged; Mucositis; Neoadjuvant Therapy; Neutropenia; Paclitaxel; Sirolimus; Thrombocytopenia; Treatment Outcome

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

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

Preclinical data suggest concurrent inhibition of VEGF, mTOR and EGFR pathways may augment antitumor and antiangiogenic effects compared to inhibition of each pathway alone. This study evaluated the maximum tolerated dose/recommended phase II dose and safety and tolerability of bevacizumab, everolimus and panitumumab drug combination.. Subjects with advanced solid tumors received escalating doses of everolimus and flat dosing of panitumumab at 4.8 mg/kg and bevacizumab at 10 mg/kg every 2 weeks. Dose-limiting toxicities (DLTs) were assessed in cycle 1; toxicity evaluation was closely monitored throughout treatment. Treatment continued until disease progression or undesirable toxicity.. Thirty-two subjects were evaluable for toxicity; 31 subjects were evaluable for tumor response. DLTs were observed in cohorts with everolimus at 10 and 5 mg daily and included grade 3 mucositis, skin rash and thrombocytopenia. Therefore, everolimus was dose-reduced to 5 mg three times weekly, which improved the tolerability of the treatment regimen. Common adverse events were skin rash/pruritus (91 %), mucositis/stomatitis (75 %), hypomagnesemia (72 %), hypocalcemia (56 %) and hypokalemia (50 %). There were 3 partial responses; an additional 10 subjects had stable disease ≥6 months. Three subjects with ovarian cancer and one with endometrial cancer achieved prolonged disease control ranging from 11 to >40 months.. The recommended phase II dose is everolimus at 5 mg three times weekly plus panitumumab at 4.8 mg/kg and bevacizumab at 10 mg/kg every 2 weeks. This dosing regimen has an acceptable safety and tolerability profile and appears to have moderate the clinical activity in refractory tumors.

Topics: Adult; Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Dose-Response Relationship, Drug; Drug Administration Schedule; Everolimus; Exanthema; Female; Humans; Hypocalcemia; Hypokalemia; Male; Middle Aged; Mucositis; Neoplasms; Panitumumab; Sirolimus; Treatment Outcome; Young Adult

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

Despite high initial remission rates, most lymphomas relapse and require further therapy. The mammalian target of rapamycin (mTOR) pathway is a validated target in mantle cell lymphoma, but has not been extensively evaluated in other lymphomas.. We performed a phase II trial of single-agent temsirolimus 25-mg weekly in patients with relapsed aggressive and indolent lymphomas. The primary objective was overall and complete response rate. Patients were stratified by histology: group A (diffuse large B-cell lymphoma, transformed follicular lymphoma), group B (follicular lymphoma), and group C (chronic lymphocytic leukemia/small lymphocytic lymphoma, and other indolent lymphomas).. Eighty-nine patients were treated, with outcome strongly dependent on histology. Group A had an overall and complete response rate of 28.1% and 12.5%, respectively, and median progression-free survival (PFS) of 2.6 months and median overall survival (OS) of 7.2 months. Group B had overall and complete response rates of 53.8% and 25.6%, respectively, and median PFS of 12.7 months; median OS has not yet been reached. Group C had a partial response rate of 11% with no complete responders. Toxicity was mainly mild and/or reversible myelosuppression and mucositis; however, four patients developed pneumonitis.. Single-agent temsirolimus has significant activity in both diffuse large B-cell lymphoma and follicular lymphoma, although the durability of responses and PFS are longer for patients with follicular lymphoma. This is the first report of substantial activity of temsirolimus in lymphomas other than mantle cell lymphoma, and supports further evaluation of mTOR as a target in these diseases.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Bone Marrow; Chicago; Disease-Free Survival; Female; Humans; Intracellular Signaling Peptides and Proteins; Kaplan-Meier Estimate; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Follicular; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Mantle-Cell; Lymphoma, Non-Hodgkin; Male; Middle Aged; Mucositis; Pneumonia; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Remission Induction; Sirolimus; TOR Serine-Threonine Kinases; Treatment Outcome

This was a phase I trial to determine the maximum tolerated dose and toxicity of deforolimus (AP23573, MK-8669), an inhibitor of mammalian target of rapamycin (mTOR). The pharmacokinetics, pharmacodynamics, and antineoplastic effects were also studied.. Deforolimus was administered intravenously over 30 min every 7 days according to a flat dosing schedule. Dose was escalated according to an accelerated titration design. Patients remained on study until disease progression as long as they tolerated the drug without significant toxicities.. Forty-six patients were enrolled on the study. Common side effects included fatigue, anorexia, and mucositis. The maximum tolerated dose was 75 mg and mucositis was the dose-limiting toxicity. Similar to other mTOR inhibitors, deforolimus exhibited nonlinear pharmacokinetics and a prolonged half-life. Among 34 patients evaluable for response, 1 patient had a partial response, 21 patients had stable disease, and 12 had progressed. Percent change in tumor size was significantly associated with AUC (P=0.015). A significant association was also detected for maximum change in cholesterol within the first two cycles of therapy and change in tumor size (r=-0.38; P=0.029).. Deforolimus was well tolerated on the schedule tested in this trial with toxicity and pharmacokinetic profiles that were similar to that of other mTOR inhibitors. Additional phase II studies are needed to determine if deforolimus is superior to other mTOR inhibitors in terms of efficacy. The change in serum cholesterol as a potential biomarker of activity should be studied further.

Topics: Adaptor Proteins, Signal Transducing; Adult; Aged; Cell Cycle Proteins; Female; Humans; Male; Maximum Tolerated Dose; Middle Aged; Mucositis; Neoplasms; Phosphoproteins; Phosphorylation; Protein Kinases; Sirolimus; TOR Serine-Threonine Kinases

Autoimmune cytopenia includes autoimmune hemolytic anemia (AIHA), immune thrombocytopenia (ITP), and Evans syndrome (ES) caused by abnormal activation of autoimmunity and has a considerable refractory/relapse rate. To evaluate the efficacy and toxicity of sirolimus of primary relapsed/refractory autoimmune cytopenia, records of 45 patients with primary relapsed/refractory AIHA, ES, or ITP from October 2016 to January 2019 in two institutions, were collected; there were 3 pediatric patients and 42 adult patients. The median age at diagnosis was 31 (1-84) years. Patients were treated for a median of 14 (6-39) months and followed-up for a median of 18 (10-40) months. Thirty-eight patients responded to sirolimus, with 28 complete responses (CRs) and a median of 2 (2-5) months to response. Five patients had mucositis; the incidences of other adverse events were all less than 5%. Four patients relapsed, making the CR and overall response rate 46.7% and 75.6% at the end of follow-up. There were no differences in patient age, sex, time from diagnosis to sirolimus, serum sirolimus concentration, and disease distribution between CR and non-CR patients, or between responders and nonresponders, though AIHA patients were likely to relapse less and respond better. In conclusion, sirolimus is effective for patients with primary relapsed/refractory autoimmune cytopenia with a low relapse rate and good tolerance.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anemia, Hemolytic, Autoimmune; Autoimmunity; Child; Child, Preschool; Drug Administration Schedule; Female; Humans; Immunosuppressive Agents; Infant; Infant, Newborn; Male; Middle Aged; Mucositis; Patient Safety; Purpura, Thrombocytopenic, Idiopathic; Recurrence; Retrospective Studies; Sirolimus; T-Lymphocytes, Regulatory; Thrombocytopenia; Treatment Outcome

Mucositis is often experienced in metastatic renal cell carcinoma (mRCC) patients treated with targeted therapies. This might impair daily quality of life and lead to dose reduction, discontinuation, or treatment shift. We assessed the effect of folic acid to reduce mucositis.. Patients treated with systemic therapy for mRCC who developed Grade ≥2 mucositis according to Common Terminology Criteria for Adverse Events version 4.0 (CTCAE) received oral folic acid to reduce mucositis. The medical charts were retrospectively reviewed.. A total of 77 patients had Grade ≥2 mucositis during therapy with sunitinib (n = 29), pazopanib (n = 24), everolimus (n = 10), axitinib (n = 4), temsirolimus (n = 3), interleukin-2/interferon-α (n = 3), cabozantinib (n = 2), bevacizumab (n = 1), and nivolumab (n = 1). Given in doses of 1 to 5 mg daily, folic acid significantly reduced mucositis, mean CTCAE grade 0.88 (95% confidence interval [CI], 0.74-1.03) versus 2.38 (95% CI, 2.26-2.54; P < .0001). Stratified according to treatment, folic acid significantly reduced mucositis grade for sunitinib (0.97 [95% CI, 0.75-1.18] vs. 2.45 [95% CI, 2.23-2.67], P < .0001), pazopanib (0.96 [95% CI, 0.67-1.25] vs. 2.20 [2.03-2.38], P < .0001), everolimus (0.60 [95% CI, 0.10-1.10] vs. 2.60 [95% CI, 2.23-2.97], P < .0001), and other treatments (0.79 [95% CI, 0.38-1.19] vs. 2.36 [95% CI, 2.07-2.64], P < .0001). Of the 77 patients, 8 (10%) patients received dose reduction. Overall progression-free survival was 14 months and overall survival was 31 months.. Folic acid reduced mucositis in mRCC patients receiving systemic therapy. This finding needs prospective validation. A double-blind, placebo-controlled prospective evaluation of folic acid is ongoing (NCT03581773).

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Axitinib; Carcinoma, Renal Cell; Everolimus; Female; Folic Acid; Humans; Indazoles; Kidney Neoplasms; Male; Middle Aged; Mucositis; Neoplasm Metastasis; Pyrimidines; Retrospective Studies; Sirolimus; Sulfonamides; Sunitinib; Treatment Outcome

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

The integrity of the epidermis and mucosal epithelia is highly dependent on resident self-renewing stem cells, which makes them vulnerable to physical and chemical insults compromising the repopulating capacity of the epithelial stem cell compartment. This is frequently the case in cancer patients receiving radiation or chemotherapy, many of whom develop mucositis, a debilitating condition involving painful and deep mucosal ulcerations. Here, we show that inhibiting the mammalian target of rapamycin (mTOR) with rapamycin increases the clonogenic capacity of primary human oral keratinocytes and their resident self-renewing cells by preventing stem cell senescence. This protective effect of rapamycin is mediated by the increase in expression of mitochondrial superoxide dismutase (MnSOD), and the consequent inhibition of ROS formation and oxidative stress. mTOR inhibition also protects from the loss of proliferative basal epithelial stem cells upon ionizing radiation in vivo, thereby preserving the integrity of the oral mucosa and protecting from radiation-induced mucositis.

Topics: Animals; Carcinoma, Squamous Cell; Cell Compartmentation; Cell Death; Cell Proliferation; Cells, Cultured; Cellular Senescence; Clone Cells; Cytoprotection; Epithelial Cells; Head and Neck Neoplasms; Humans; Keratinocytes; Mice; Mouth Mucosa; Mucositis; Oxidative Stress; Radiation Injuries; Radiation, Ionizing; Sirolimus; Stem Cells; Superoxide Dismutase; TOR Serine-Threonine Kinases

Mammalian target of rapamycin (mTOR) inhibitors may have efficacy as an intervention for advanced malignancies. Oral ulceration (OU), reported as mucositis, has been a dose-limiting toxicity for this new class of agents. An analysis of the appearance, course, and toxicity associations of mTOR inhibitor-associated stomatitis (mIAS) demonstrated that the condition is distinct from conventional mucositis (CM) and more closely resembles aphthous stomatitis.. Safety data from 78 solid tumor patients enrolled in 2 Phase 1, multicenter trials of the mTOR inhibitor deforolimus (AP23573, MK-8669) were evaluated. Adverse events (AEs) based on National Cancer Institute Common Toxicity Criteria for National Cancer Institute Common Terminology Criteria for Adverse Events (version 3.0) criteria were coded, consolidated, and stratified according to the presence or absence and duration of concordant OU. The relation between OU and other AEs was analyzed.. Treatment-emergent AEs were reported in 91% of 78 study participants. OUs were reported in 66%, appeared within 5 days of deforolimus administration, and were discrete, ovoid, superficial, well demarcated, and surrounded by an erythematous halo. Their clinical appearance and distribution were similar to that of aphthous stomatitis but inconsistent with CM. Patients with OU were more likely to have nonspecific rashes and acneiform dermatitis but not gastrointestinal AEs.. OU associated with mTOR inhibitor therapy differed from CM. Lesions more closely resembled those of aphthous stomatitis. The lack of other gastrointestinal involvement but the presence of a higher incidence of concomitant cutaneous AEs provided additional evidence to suggest a distinction between mIAS and CM. Treatment strategies for aphthous stomatitis may be a rational approach for the prevention and control of mIAS.

Topics: Adult; Aged; Antineoplastic Agents; Clinical Trials, Phase I as Topic; Female; Humans; Intracellular Signaling Peptides and Proteins; Male; Middle Aged; Mucositis; Neoplasms; Protein Serine-Threonine Kinases; Sirolimus; Stomatitis; TOR Serine-Threonine Kinases