Comuna De Recoleta, Chile

Cyclophosphamide and Sirolimus for the Treatment of Metastatic, RAI-refractory, Differentiated Thyroid Cancer

Safety and Durability of Sirolimus for Treatment of LAM

Lymphangioleiomyomatosis (LAM) is an uncommon disease affecting women. It is associated with cystic lung destruction and progressive respiratory failure. The Multicenter International LAM Efficacy of Sirolimus (MILES) Trial, led by the investigators' research team, demonstrated that mTOR (mammalian target of rapamycin) inhibition with sirolimus was an effective therapy that stabilized decline in FEV1 (forced expiratory volume). However, lung function decline resumed when the drug was stopped at the one year point in MILES, suggesting that therapy is suppressive rather than remission-inducing, and may need to be lifelong. There is therefore a need to understand whether long-term therapy with sirolimus is safe and effective. To accomplish this goal, the investigators will conduct the Multicenter International Durability and Safety of Sirolimus in LAM Trial (MIDAS). This is an observational, real world registry. The investigators propose to enroll 600 LAM patients who are on, have previously failed or been intolerant of or are considering taking sirolimus or everolimus for clinical reasons in a longitudinal observational study. This registry will follow lung function tests and adverse events that are obtained for clinical purposes over periods of at least 2 years. The decision to treat with mTOR inhibitor therapy is made by the clinician and the patient, and will be managed by the participant's clinician. This study will help us to refine treatment for patients with LAM and determine if long term suppressive therapy with sirolimus can prevent progression to later stages of disease. This research will be accomplished as part of the NIH/NCATS Rare Lung Disease Consortium, with data stored and analyzed by the Database Management Coordinating Center (DMCC) at the University of South Florida.

Study of Sirolimus in Idiopathic Retroperitoneal Fibrosis

Retroperitoneal fibrosis refers to a group of diseases characterized by hyperplasia of the fibrosclerotic tissues in the retroperitoneal space, which mostly involve the abdominal aorta and iliac artery distal to the kidneys. The hyperplastic tissues can compress the surrounding ureters and inferior vena cava and cause serious complications such as aortic aneurysm, renal failure, and even death. There is no clear boundary between the lesion and its surrounding tissues. The lesion is diffuse and difficult to resect. corticosteroid is the first-line medication, but the recurrence rate of the disease is high, especially after dose reduction of corticosteroid. Therefore, the combined use of immunosuppressants is very important in preventing disease recurrence and reducing the toxic and side effects of long-term high- and medium-dose corticosteroid. In recent years, as the immunological characteristics of retroperitoneal fibrosis have gradually been recognized, some rheumatologists and immunologists have attempted to use immunosuppressants commonly used for autoimmune diseases in this population, including biologics. However, high-level evidences of evidence-based medicine such as randomized controlled trials (RCTs) were still lacking. Sirolimus plays dual roles in inhibiting T lymphocyte activation and fibroblast proliferation. It is inferred from its mechanism that sirolimus is a good potential treatment option for idiopathic retroperitoneal fibrosis. Therefore, we conducted this RCT on patients with idiopathic retroperitoneal fibrosis to determine the efficacy and safety of sirolimus.

COAST Therapy in Advanced Solid Tumors and Prostate Cancer

This is a Phase I/II safety and efficacy study of COAST therapy in patients with advanced cancer for which no satisfactory therapy options exist. An initial Phase I cohort of 18-30 patients with advanced cancer will receive increasing components of the COAST regimen following a traditional 3+3 escalation design. The starting COAST combination includes hydroxychloroquine, sirolimus and metformin (DL1 - base combination). If this three-drug base combination is cleared for safety, two dose levels will be opened for enrollment exploring the safety of the base in combination with either dasatinib or nelfinavir. Patients will be assigned sequentially to DL2A (base + dasatinib) and DL2B (base + nelfinavir). If nelfinavir is deemed unsafe in combination with the base (DL2B is not cleared for safety, regardless of the safety of DL2A), no further drug combinations will be explored since all remaining combinations include nelfinavir. If both dasatinib and nelfinavir are individually safe in combination with the base (DL2A and DL2B are both cleared for safety), two additional dose levels will be explored, the first combining all five drugs and the second exploring nelfinavir at a higher dose. If dasatinib is not safe but nelfinavir is safe in combination with the base (DL2A but not DL2B cleared for safety), then only one additional dose level will be explored combining the base with a higher dose of nelfinavir. If neither DL2A nor DL2B are cleared for safety, then only the base combination may be considered safe. Once a given dose level is cleared for initial DLT evaluation (e.g., 0 of 3 patients have a DLT or at most 1 of 6 have a DLT), additional patients may be enrolled (i.e., 'backfilled') to that dose level while a higher dose level is being evaluated for safety. Prioritization for backfill will be given to dose levels proximal to the current dose level being explored, and to those dose levels with evidence of anti-tumor activity. Backfill patients who are DLT-evaluable will be included in making decisions on dose escalation. Accrual to a dose-level may be halted and additional patients enrolled to a lower dose level that was previously cleared for safety depending on the total number of DLTs observed among all DLT-evaluable patients at that lower dose level (initial and backfill patients). The maximum tolerated mixture is the highest dose level at which at most 1 of 6 patients experiences a DLT or, for a dose level sample size >6 due to additional backfill patients, the highest dose level at which the observed DLT rate is ≤16.7%. The recommended phase 2 dose (RP2D) will be determined based on the totality of data, including the maximum tolerated mixture, dose adjustments, all safety data including any DLT-equivalent events (safety events that meet the criteria for a DLT regardless of treatment cycle and trial phase), and any response data. The study team may recommend a dose level lower than the maximum tolerated mixture as the RP2D based on their review of the data in aggregate. However, the RP2D will not exceed the dose level corresponding to the maximum tolerated mixture. The phase II efficacy trial will evaluate the anti-tumor activity of the COAST RP2D combination in patients with advanced prostate cancer based on a Simon two stage optimum design. The primary endpoint is the16-week PSA progression-free rate following treatment initiation, where PSA progression is defined per PCWG3. A maximum of 29 patients will be enrolled. In the first stage, 10 patients will be accrued. If none of the first 10 patients are PSA progression-free at 16 weeks, we will halt registration. If one or more patients are PSA progression-free at 16 weeks, an additional 19 patients will be enrolled. If 4 or more out of the 29 patients are PSA progression-free at 16 weeks, the treatment will be declared promising. This study is powered at 80% with a one-sided type I error rate of 5%. Specifically, this study has an 80% chance of declaring promise if the true 16-week PSA progression-free rate is at least 20%. If instead the true 16-week PSA progression-free rate is at most 5%, then the study has a 5% chance of declaring promise and a 60% chance of early termination. Phase I patients treated at the RP2D who meet inclusion and exclusion criteria for phase II will be included in the phase II cohort. Treatment will continue until there is 1) unacceptable toxicity (grade 3 or 4 toxicity that does not resolve to grade 1 or less by 28 days after drug withdrawal), 2) institution of new additional cancer therapy, 3) withdrawal of consent, 4) any condition that, in the opinion of the treating physician, renders continued COAST treatment to not be in the patient's best interest, 5) lack of compliance with study procedures by the patient, or 6) PSA progression by 16 weeks of COAST therapy.

Nab-Sirolimus and Endocrine Therapy in Recurrent Low Grade Serous Ovarian Cancer (NARETO)

Patients with histologic confirmed Low Grade Serous Ovarian Cancer with measurable disease should have a pre-dose tumor biopsy. Patients will receive proposed treatment regimen of nab-sirolimus on days 1 and 8 and fulvestrant on days 1 and 15 of cycle 1 and then every 21-day cycle as long as there is evidence that tumor is not growing or spreading and they are not having any unacceptable, bad side effects. Patients will be monitored during treatment with tests and exams and after treatment completion for up to 2 years.

A Phase I Trial of Combination Gemcitabine and Nab-Sirolimus in Advanced Leiomyosarcomas or Advanced Soft-Tissue Sarcomas With TSC2 or TSC1 Loss-of-function Mutations or Deletions

Primary Objectives: - To estimate the Maximum Tolerated Dose (MTD) of gemcitabine and nab-sirolimus combination in patients with advanced leiomyosarcomas or advanced soft-tissue sarcomas with TSC2 or TSC1 loss-of-function mutations or deletions. Secondary Objectives - To estimate the rate of toxicity in the combination of gemcitabine and nab-sirolimus in participants with advanced leiomyosarcomas or advanced soft-tissue sarcomas with TSC2 or TSC1 loss-of-function mutations or deletions. - To describe anti-tumor activity (ORR) by radiographic evaluation (RECIST 1.1) - To describe Progression-Free Survival (PFS) and Overall Survival (OS). Exploratory Objectives - To estimate the rate of detection of ctDNA in blood samples of participants with advanced leiomyosarcomas or advanced soft-tissue sarcomas with TSC2 or TSC1 loss-of-function mutations or deletions. - To describe the relationship of ctDNA changes in blood samples and anti-tumor activity of gemcitabine and nab-sirolimus in patients with advanced leiomyosarcomas or advanced soft-tissue sarcomas with TSC2 or TSC1 loss-of-function mutations or deletions. - To describe the relationship between baseline expression of pERK1/2 by IHC on tumor samples and anti-tumor activity of gemcitabine and nab-sirolimus in participants with advanced leiomyosarcomas or advanced soft-tissue sarcomas with TSC2 or TSC1 loss-of-function mutations or deletions. - To describe the relationship between decreased expression of pAKT and pS6 after two cycles of gemcitabine and nab-sirolimus and anti-tumor activity in participants with advanced leiomyosarcomas or advanced soft-tissue sarcomas with TSC2 or TSC1 loss-of-function mutations or deletions. - To obtain discovery genomic data with RNA sequencing and whole genome sequencing for rare tumors (planned through the MD Anderson Cancer Center Patient Mosaic project). This will be part of a separate IRB-approved consent, which includes RNA sequencing and whole genome sequencing of the tumor and whole genome sequencing of the germline. The Patient Mosaic project takes a patient-centric approach to learn more about different cancer types, with a focus on rare cancers. This approach includes comprehensive molecular profiling including: germline whole genome sequencing, tumor whole genome sequencing, tumor transcriptome sequencing, and gut microbiome sequencing,

Hemorrhagic Brainstem Cavernous Malformations Treatment With Sirolimus: aSingle Centre, Randomized, Placebo-controlled Pilot Trial

SIROOP Registry - a Prospective Registry Study to Evaluate the Outcomes of Coronary Artery Disease Patients Treated with SIROlimus or Paclitaxel Eluting Balloon Catheters

Objectives in detail: - To evaluate procedural success, efficacy, performance and clinical outcomes among various patient cohorts, who undergo PCI using currently available DCBs: 1. Periprocedural outcomes/complications, which will be analyzed, include: final result (e.g. residual stenosis, TIMI flow), dissections, perforations, prevalence of thrombus (assessed by angiography and intravascular imaging) 2. Short and long-term clinical outcomes of interest comprise among others: new MI, unstable angina (UA), target lesion failure, target vessel revascularization, target lesion failure/ revascularization, repeat hospitalization, new/worsening heart failure, cardiogenic shock, stroke, bleedings, cardiovascular death and all-cause death. - To describe procedural and clinical performance of various DCB, either alone or in combination with other stent and coronary scaffold devices - To identify optimal strategies for lesion preparation in cases treated with DCB - To identify possible predictors for TLR after treatment with DCB - To describe early and late angiographic and OCT-findings among coronary artery disease (CAD) patients treated with DCB and/or various metallic stent and scaffold devices - To evaluate the impact of different antithrombotic regimens on patient's clinical outcomes - To study procedural and clinical outcomes among CAD patients requiring hemodynamic support using mechanical devices. - To describe economic implications (cost-effectiveness) of various interventional treatments for CAD.

Phase 1/2a Clinical Trial of PR001 (LY3884961) in Patients With Parkinson's Disease With at Least One GBA1 Mutation (PROPEL)

Role of Sirolimus in Treatment of Microcystic , Mixed Lymphatic and Vascular Malformations

Lympho-vascular malformations result from errors in embryologic vasculogenesis involving capillaries, veins, arteries, lymphatics, or a combination of these. Infantile haemangiomas & Vascular malformations like : Capillary malformations & Venous malformations : they increase in size and never regress on their own. & They are generally present at birth, they enlarge in response to infection, hormonal changes or trauma . Lymphatic malformations can be classified into macrocystic (cyst diameter >1cm), microcystic (cyst diameter <1 cm), or mixed , in macrocystic lymphatic malformations, surgery and sclerotherapy are effective . Surgery of microcystic lymphatic malformations remains challenging due to their infiltrative nature & Sclerotherapy is often impossible. As especially large microcystic and mixed malformations are still a therapeutic challenge, pharmaceutical treatment as sirolimus is used in last years as main line of treatment with great efficacy. Sirolimus is a natural macrolide isolated from a bacteria strain of the Streptomyces genus & Streptomyces hygroscopicus . It was initially used as an antibiotic and antifungal agent, subsequent studies have revealed impressive cytostatic, antiproliferative, and immunosuppressive properties . Sirolimus not only prevents the growth of abnormal lymphatics but also induces the partial regression of lesions, without apparent effects on normal lymphatics .