sirolimus and Soft-Tissue-Neoplasms

Patient outcomes remain poor for advanced or metastatic soft tissue sarcomas (STS) and bone sarcomas despite a growing number of clinical trials involving single- and multi-agent chemotherapy. mTOR is an intracellular kinase that plays a central role in regulating cell growth, metabolism, survival and proliferation. mTOR inhibitors including temsirolimus, everolimus and ridaforolimus have demonstrated broad anticancer activity. Ridaforolimus is a non-prodrug analog of rapamycin (sirolimus) with conserved affinity for mTOR but improved solubility, stability and bioavailability when compared with sirolimus. Early clinical trials reveal a reproducible and predictable pharmacokinetic profile, a potent, rapid and prolonged target inhibition and an acceptable safety and tolerability profile. Phase II and III trials of ridaforolimus have produced promising clinical activity against advanced sarcomas and will be presented.

Topics: Antineoplastic Agents; Bone Neoplasms; Clinical Trials as Topic; Humans; Neoplasm Invasiveness; Neoplasm Metastasis; Sarcoma; Sirolimus; Soft Tissue Neoplasms; TOR Serine-Threonine Kinases; Treatment Outcome

Despite the use of recommended chemotherapy regimens, patients with metastatic sarcomas have a poor prognosis. To date, the median overall survival for metastatic disease remains less than 18 months. First-line treatment of most metastatic sarcomas consists of chemotherapy with or without surgical excision of residual disease, followed by "watchful waiting" until disease progression or recurrence. According to the current treatment paradigm, recommended by United States and European clinical guidelines, chemotherapy is administered for a fixed number of cycles, and then a watchful waiting approach is taken once a best response is achieved. Single-agent doxorubicin remains the standard for treatment of most soft-tissue sarcomas (STS), as combination and dose-intense regimens have largely failed to improve survival. Combination chemotherapy is the standard treatment approach for osteosarcoma and Ewing's sarcoma, but outcomes are poor for patients with recurrent disease. In order to improve outcomes (in particular, progression-free survival [PFS] and overall survival [OS]), strategies shown to be effective in other solid malignancies, such as maintenance therapy and long-term treatment with targeted therapy, are being investigated in patients with advanced sarcomas. One potential promising approach is the use of mammalian target of rapamycin (mTOR) inhibitors for maintenance therapy. One such mTOR inhibitor, ridaforolimus (AP23573, MK-8669), is currently being evaluated in patients with advanced bone and STS in the ongoing Sarcoma mUlti-Center Clinical Evaluation of the Efficacy of riDaforolimus (SUCCEED) trial.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Carcinoma, Non-Small-Cell Lung; Disease-Free Survival; Doxorubicin; Female; Humans; Lung Neoplasms; Osteosarcoma; Ovarian Neoplasms; Sarcoma; Sarcoma, Ewing; Sirolimus; Soft Tissue Neoplasms; TOR Serine-Threonine Kinases

Topics: Administration, Oral; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials, Phase III as Topic; Combined Modality Therapy; Dacarbazine; Deoxycytidine; Disease-Free Survival; Dose-Response Relationship, Drug; Gemcitabine; Humans; Hyperthermia, Induced; Indazoles; Multimodal Imaging; Neoadjuvant Therapy; Positron-Emission Tomography; Pyrimidines; Randomized Controlled Trials as Topic; Sarcoma; Sirolimus; Soft Tissue Neoplasms; Sulfonamides; Tomography, X-Ray Computed; Treatment Outcome

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma of childhood. The two most common histologic variants are the embryonal and alveolar subtypes. Although successive collaborative group clinical trials have improved survival rates for many RMS patients, the outcome for those patients with metastatic or recurrent disease remains poor. Recent studies have pointed to a possible mesenchymal stem cell as the progenitor for alveolar RMS. Other studies have implicated several cellular mechanisms and pathways being involved in RMS pathogenesis and survival, such as the cyclin-dependent kinase inhibitors, insulin-like growth factor pathway, and the mammalian target of rapamycin pathway, thus providing potential avenues for targeted therapy. Recent clinical trials have tried to improve risk stratification and prediction of clinical outcome based upon clinical or radiographic response to initial therapy and also to determine the role of high-dose chemotherapy with stem cell rescue in high-risk RMS patients.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Clinical Trials as Topic; Combined Modality Therapy; Disease Progression; Female; Humans; Male; Mesenchymal Stem Cells; Mice; Neoplasm Metastasis; Neoplasm Staging; Neoplastic Stem Cells; Prognosis; Protein Kinase Inhibitors; Rhabdomyosarcoma, Alveolar; Rhabdomyosarcoma, Embryonal; Risk Factors; Secondary Prevention; Signal Transduction; Sirolimus; Soft Tissue Neoplasms; Survival Rate; Tomography; TOR Serine-Threonine Kinases

Bone and soft tissue sarcomas represent rare tumors that can be cured by local treatment at early stages of disease. However, advanced or metastatic disease is rarely cured, and very few drugs have shown efficacy in this setting. Early studies with mTOR inhibitors have demonstrated antitumor activity in patients with metastatic sarcoma who failed previous chemotherapies. The response rate and durable stable disease in early studies, as well as the tolerability profile, recommend these drugs as promising candidates for further clinical studies. This article discusses preliminary results from clinical trials in patients with advanced or metastatic sarcoma as well as future perspectives.

Topics: Antineoplastic Agents; Bone Neoplasms; Drug Therapy, Combination; Everolimus; Gastrointestinal Stromal Tumors; Humans; Protein Kinase Inhibitors; Protein Kinases; Sarcoma; Sirolimus; Soft Tissue Neoplasms; TOR Serine-Threonine Kinases

Patients with Neurofibromatosis Type 1 (NF1) have an increased risk of developing tumors of the central and peripheral nervous system, including plexiform neurofibromas (PN), which are benign nerve sheath tumors that are among the most debilitating complications of NF1. There are no standard treatment options for PN other than surgery, which is often difficult due to the extensive growth and invasion of surrounding tissues. Mammalian Target of Rapamycin (mTOR) acts as a master switch of cellular catabolism and anabolism and controls protein translation, angiogenesis, cell motility, and proliferation. The NF1 tumor suppressor, neurofibromin, regulates the mTOR pathway activity. Sirolimus is a macrolide antibiotic that inhibits mTOR activity.. We conducted a 2-stratum phase II clinical trial. In stratum 2, we sought to determine whether the mTOR inhibitor sirolimus in subjects with NF1 results in objective radiographic responses in inoperable PNs in the absence of documented radiographic progression at trial entry.. No subjects had better than stable disease by the end of six courses. However, the children's self-report responses on health-related quality of life questionnaires indicated a significant improvement in the mean scores of the Emotional and School domains from baseline to 6 months of sirolimus.. This study efficiently documented that sirolimus does not cause shrinkage of non-progressive PNs, and thus should not be considered as a treatment option for these tumors. This study also supports the inclusion of patient-reported outcome measures in clinical trials to assess areas of benefit that are not addressed by the medical outcomes.

Topics: Adolescent; Child; Child, Preschool; Diarrhea; Emotions; Female; Humans; Magnetic Resonance Imaging; Male; Neurofibroma, Plexiform; Neurofibromatosis 1; Pain Measurement; Protein Kinase Inhibitors; Quality of Life; Sirolimus; Soft Tissue Neoplasms; Surveys and Questionnaires; TOR Serine-Threonine Kinases; Treatment Outcome; Tumor Burden

This multicenter, phase II trial evaluated the efficacy and safety of everolimus, an mTOR inhibitor, in patients with metastatic or recurrent bone and soft-tissue sarcoma after the failure of anthracycline- and ifosfamide-containing regimens. Everolimus was administered orally as 10 mg once daily. The primary endpoint was the progression-free rate (PFR) at 16 weeks, assessed by computed tomography scan according to RECIST v1.0. Between July 2010 and May 2011, 41 patients were enrolled in this study. Among them, 83% received two or more regimens of chemotherapy prior to study entry. In 38 patients who the primary endpoint was evaluable, 11 patients reached 16 weeks progression-free (one with partial response and 10 with stable disease), indicating a PFR at 16 weeks of 27% (95% confidence interval [CI], 16-42%). The PFR at 16 weeks was highest in patients with angiosarcoma (2 of 3, 67%). With a median follow-up of 10.9 months (range, 2.3-23.9 months) in living patients, the median progression-free survival was 1.9 months (95% CI, 1.3-2.4 months) and the median overall survival was 5.8 months (95% CI, 3.6-8.0 months). Most adverse events were generally mild and tolerable. Grade 3/4 toxicities included hyperglycemia (15%), stomatitis (7%), pain (5%), and asthenia (5%). Everolimus shows modest antitumor activity with manageable toxicities in heavily pretreated patients with bone and soft-tissue sarcoma.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anthracyclines; Antineoplastic Agents; Bone Neoplasms; Everolimus; Female; Humans; Ifosfamide; Male; Middle Aged; Sarcoma; Sirolimus; Soft Tissue Neoplasms; Tomography, X-Ray Computed; Treatment Outcome; Young Adult

In this study, two doses of temsirolimus (CCI-779), a novel inhibitor of the mammalian target of rapamycin, were evaluated for efficacy, safety, and pharmacokinetics in patients with locally advanced or metastatic breast cancer who had been heavily pretreated.. Patients (n = 109) were randomly assigned to receive 75 or 250 mg of temsirolimus weekly as a 30-minute intravenous infusion. Patients were evaluated for tumor response, time to tumor progression, adverse events, and pharmacokinetics of temsirolimus.. Temsirolimus produced an objective response rate of 9.2% (10 partial responses) in the intent-to-treat population. Median time to tumor progression was 12.0 weeks. Efficacy was similar for both dose levels but toxicity was more common with the higher dose level, especially grade 3 or 4 depression (10% of patients at the 250-mg dose level, 0% at the 75-mg dose level). The most common temsirolimus-related adverse events of all grades were mucositis (70%), maculopapular rash (51%), and nausea (43%). The most common, clinically important grade 3 or 4 adverse events were mucositis (9%), leukopenia (7%), hyperglycemia (7%), somnolence (6%), thrombocytopenia (5%), and depression (5%).. In heavily pretreated patients with locally advanced or metastatic breast cancer, 75 and 250 mg temsirolimus showed antitumor activity and 75 mg temsirolimus showed a generally tolerable safety profile.

Topics: Adult; Aged; Antineoplastic Agents; Area Under Curve; Bone Neoplasms; Breast Neoplasms; Female; Humans; Male; Middle Aged; Protein Kinase Inhibitors; Protein Kinases; Safety; Salvage Therapy; Sirolimus; Soft Tissue Neoplasms; TOR Serine-Threonine Kinases; Treatment Outcome

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Everolimus; Giant Cell Tumors; Humans; Joint Capsule; Male; Middle Aged; Neoplasm Metastasis; Receptors, Somatomedin; Shoulder Joint; Sirolimus; Soft Tissue Neoplasms; Tendons; TOR Serine-Threonine Kinases; Treatment Outcome

Topics: Adolescent; Antibiotics, Antineoplastic; Humans; Lymphangioma; Male; Sirolimus; Soft Tissue Neoplasms

We describe herein the current concepts tested in clinical trials dedicated to patients with metastatic soft tissue sarcomas: identify predictive factors under anthracyclin-based regimens, identify patients beneficing from polychemotherapy, benefit of maintenance treatment, use of non-progression rate rather than response rate for selecting new drugs, histology-tailored or biological target-tailored second-line treatment.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Doxorubicin; Humans; Sarcoma; Sirolimus; Soft Tissue Neoplasms

Skin manifestations of Tuberous Sclerosis Complex (TSC) cause significant morbidity. The molecular mechanism underlying TSC is understood and there is evidence that systemic treatment with rapamycin or other mTOR inhibitors may be a useful approach to targeted therapy for the kidney and brain manifestations. Here we investigate topical rapamycin in a mouse model for TSC-related tumors.. 0.4% and 0.8% rapamycin ointments were applied to nude mice bearing subcutaneous, TSC-related tumors. Topical treatments were compared with injected rapamycin and topical vehicle. Rapamycin levels in blood and tumors were measured to assess systemic drug levels in all cohorts.. Treatment with topical rapamycin improved survival and reduced tumor growth. Topical rapamycin treatment resulted in systemic drug levels within the known therapeutic range and was not as effective as injected rapamycin.. Topical rapamycin inhibits TSC-related tumor growth. These findings could lead to a novel treatment approach for facial angiofibromas and other TSC skin lesions.

Topics: Administration, Cutaneous; Animals; Antibiotics, Antineoplastic; Cell Line, Tumor; Disease Models, Animal; Enzyme Inhibitors; Mice; Mice, Nude; Neoplasm Transplantation; Protein Kinases; Sirolimus; Skin Absorption; Soft Tissue Neoplasms; Survival Analysis; TOR Serine-Threonine Kinases; Tuberous Sclerosis