Neoplasms

All Conditions

Infections

Symptoms and General Pathology

Rare Diseases

Sarcoma

Sarcoma, Kaposi

Neoplasms, Connective and Soft Tissue

Neoplasms by Histologic Type

Communicable Diseases

Herpesviridae Infections

Virus Diseases

DNA Virus Infections

Neoplasms, Vascular Tissue

Soft Tissue Sarcoma

Kaposi Sarcoma

Endemic Kaposi Sarcoma

Antineoplastic Agents

All Drugs and Chemicals

Anti-Infective Agents

Everolimus

Sirolimus

Temsirolimus

MTOR Inhibitors

Protein Kinase Inhibitors

Enzyme Inhibitors

Immunosuppressive Agents

Immunologic Factors

everolimus

Celeste Lebbé, MD, PhD

Classic Kaposi's sarcoma (CKS) is an angioproliferation associated with human herpes virus 8 (HHV8), which sometimes requires systemic treatment. Rapamycin and everolimus are mTOR inhibitors. The PI3K-AKT-mTOR pathway is activated in CKS.The aim of this study is to evaluate the rate of clinical response and tolerance to everolimus 10mg/d in CKS. Patients suffering from CKS will be enrolled in a multicenter two-stage phase II trial. At inclusion, all patients will have at least 10 lesions or more than one limb or 3% of body surface affected, in the absence of symptomatic visceral CKS. The primary endpoint is objective response to everolimus after 6 months therapy (complete or partial response per ACTG criteria). The trial is planned using Simon's minimax two-stage design to demonstrate a response rate of 50% as compared to 20% with type I error rate 2.5% and power of 90%. Accordingly, 11 patients will to be enrolled in the first stage and provided at least 3 patients responded, 15 patients will be accrued in a second stage.

The primary endpoint is objective response to everolimus after 6 months therapy (complete or partial response per ACTG criteria).

Secondary endpoints are response according to physician global assessment, lesions size , lesions infiltration, lymphedema, tolerance, pharmacodynamic (pathologic, angiogenic and lymphangiogenic biomarkers, HHV8 viral load sequential evaluation in the lesions, pharmacokinetic evaluation.

A Phase II Study With Tumor Molecular Pharmacodynamic (MPD) Evaluation of Oral mTOR-inhibitor Everolimus (RAD001) 10 mg Daily in Patients Suffering From Classic or Endemic Kaposi's Sarcoma

objective response to everolimus after 6 months therapy (complete or partial response per ACTG criteria).

response according to physician global assessment, lesions size , lesions infiltration

Institut National de la Santé Et de la Recherche Médicale, France

Digestive System Diseases

Carcinoma

Gallbladder Neoplasms

Biliary Tract Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Biliary Tract Diseases

Gastrointestinal Diseases

Gallbladder Diseases

Gallbladder Cancer

Gemcitabine

Oxaliplatin

Capecitabine

Everolimus 10 mg. PO/day in addition to standard of care

Standard of care alone i.e Capecitabine and Oxaliplatin or Gemcitabine and oxaliplatin

Oral Everolimus 10 mg daily in addition to standard of care i.e. GemOx or CapOx

Everolimus 10 mg

Standard of care

Manoj Pandey

Madhumita Tripathi

Gallbladder cancer (GBC) is the most common malignant tumour of the biliary tract. It is also the most aggressive cancer of the biliary tract with the shortest median survival from the time of diagnosis. Currently, radical resection is the most effective strategy to potentially cure GBC. Chemotherapy and radiotherapy have been employed as adjuvant and palliative setting, however, the overall survival is still dismal. This study aim to evaluate the addition of Everolimus in addition to standard of care in gallbladder cancer.

Gallbladder cancer is the most common malignant tumour of the biliary tract. It is also the most aggressive cancer of the biliary tract with the shortest median survival from the time of diagnosis. While the incidence rate of GBC varies widely, it has a unique distribution pattern in some regions, where Chile, India, some other Asian countries, Eastern European, and Latin American countries have reported more cases than the rest of the world every year. The other factors, which associated with chronic inflammation and disease pathogenesis, such as hepatobiliary stones, liver flukes, and Salmonella frequently observed in these areas, also constitute the other high-risk factors of bile tract cancer (BTC) including GBC.

Currently, radical resection is the most effective strategy to potentially cure GBC. The non-surgical therapies engaged in patients were primarily composed of chemotherapy and radiotherapy. additional therapeutic strategies including next-generation sequencing (NGS), whole-exome sequencing (WES), RNA-sequencing (RNAseq), and single-cell isolation, as well as characterization that have fundamentally opened a novel view enabled to globally identify genetic and epigenetic features and key molecules as potential therapeutic target.

Advanced or unrespectable locally advanced disease has a poor prognosis with limited systemic treatment options. Combination platinum-gemcitabine chemotherapy is an active first-line treatment regimen.in particular, specific target treatment, immune therapy, vaccine therapy, biotherapy and nanoparticles have been intensively developed in preclinical and clinical trials.

One of target treatment is Mammalian target of rapamycin (mTOR) inhibitors, as The mTOR signaling pathway has critical roles in mammalian metabolism and physiology. The de-regulated activity of mTOR is involved in many pathophysiological conditions, such as aging, Alzheimer's disease, diabetes, obesity, and cancer.

Everolimus is a derivative of rapamycin that selectively inhibits mTORC1 (mammalian target of rapamycin complex 1), a key protein kinase complex which regulates cell growth, proliferation and survival. Activation of mTORC1 is mediated by the phosphatidylinositol 3-kinase (PI3K) pathway through activation of AKT/ PKB and subsequent inhibition of the tuberous sclerosis complex.

Addition of Everolimus to Standard of Care in Carcinoma Gallbladder

A Randomized Controlled, Open Labeled, Two Arm, Study of Addition of Everolimus to Standard of Care in Carcinoma Gallbladder

Progression free survival from diagnosis to disease progression or death

Survival time from the enrollment till the study closure

Toxicity of addition of Everolimus to standard of care as measured by WHO toxicity criteria

Banaras Hindu University

Professor

Mouth and Tooth Diseases

Carcinoma, Squamous Cell

Head and Neck Neoplasms

Mouth Neoplasms

Tongue Neoplasms

Squamous Cell Carcinoma of Head and Neck

Neoplasms, Glandular and Epithelial

Neoplasms, Squamous Cell

Mouth Diseases

Stomatognathic Diseases

Tongue Diseases

Oral Cancer

Lip and Oral Cavity Cancer

Tongue Cancer

Anti-Bacterial Agents

Antibiotics, Antitubercular

Clotrimazole

Miconazole

Antifungal Agents

Subjects will be treated with sirolimus 21 days

21 evaluable subjects will take rapamycin (sirolimus) orally once per day for 21 days. Before and after dosing tumor assessments to include: photographs, CT \& amp; PET scans will be done for tumor measurement.

Janice S Lee, DDS, MD

Background:

- Advanced-stage head and neck cancer (head and neck squamous cell carcinoma \[HNSCC\]) has moderately successful treatment outcomes, usually involving surgery as part of the standard treatment. Researchers are investigating the use of the drug rapamycin to prevent tumor growth in HNSCC, and are interested in using it to treat individuals with HNSCC that has not been treated previously with other drugs, radiation, or surgery.

Objectives:

- To evaluate the usefulness of rapamycin in decreasing tumor size prior to surgery for head and neck squamous cell carcinoma.

Eligibility:

- Individuals at least 18 years of age who have been diagnosed with advanced head and neck squamous cell carcinoma that has not yet been treated.

Design:

* Participants will be screened with a physical examination, medical history, blood tests, and imaging studies.
* Approximately 1 month before scheduled surgery, participants will begin to receive rapamycin. Participants will take rapamycin once daily for 21 days, followed by a 7-day period without the drug.
* During the 21-day rapamycin treatment, participants will have weekly study visits to provide blood and urine samples and have possible tumor biopsies and imaging studies such as x-rays or tumor photographs. Participants will have additional study visits for tests 1 day and 1 week after the end of rapamycin treatment, followed by HNSCC surgery.
* Participants will have a final visit to provide blood samples 30 days after surgery.
* Participants medical records will be reviewed 1 year after surgery; however, participants will not need to have further study visits at this time.

BACKGROUND:

* The five-year survival rate for head and neck squamous cell carcinoma (HNSCC) has remained at approximately 50% for more than three decades.
* In HNSCC, the AKT-mTOR-pS6 pathway is aberrantly activated and promotes tumorigenesis and metastasis.
* Rapamycin is the most extensively studied mTOR inhibitor for which therapeutic daily oral dose and schedule, pharmacologic levels in blood, and safety have been established.
* Inhibition of mTOR by rapamycin causes the rapid apoptotic death of HNSCC tumor xenografts and decreases the tumor burden and prolongs the survival of mice harboring early and advanced oral and skin SCC lesions in a variety of experimental cancer models.
* Preliminary evidence suggests that mTOR inhibitors cause tumor shrinkage and improved tumor margins in HNSCC patients.

OBJECTIVES:

* The primary objectives are to evaluate the following for patients with HNSCC given rapamycin as neoadjuvant treatment prior to surgery or chemoradiation:

  * Whether therapeutic activities of rapamycin lead to inhibition of mTOR complexes, mTORC1 and mTORC2, as assessed by the change in levels of pS6 and pAkt473 measured by immunohistochemistry (IHC) in tumor samples and by Western blotting in peripheral blood mononuclear cells (PBMCs) and reduce tumor cell proliferation, as judged by IHC for Ki-67 in tumor samples.
  * Antitumor activity in terms of objective response.
* Secondary objectives include safety evaluation of rapamycin therapy, exploratory studies of possible effects of rapamycin on tumor size, dynamic CT perfusion, and FDG-PET; and evaluation of tumor proliferation, apoptosis, microvessel density, and molecular changes associated with these effects. Survival status, recurrence of disease, metastases, and adverse events/serious adverse events, including complications of wound healing, which are related to rapamycin therapy will also be assessed for 360 days after surgery or chemoradiation through medical record review.

ELIGIBILITY:

* Males and females age 18 years and older
* Previously untreated HNSCC of the oral cavity or oropharynx
* Clinical stage II, III, or IVA disease without distant metastasis
* Definitive therapy to include surgical resection or chemoradiation for curative purposes
* Life expectancy greater than six months

STUDY DESIGN:

* Pilot, single arm, open-label, interventional neoadjuvant clinical trial.
* Twenty one evaluable subjects will take rapamycin (sirolimus) orally once per day for 21 days.
* Before and after dosing, the tumor will be photographed and biopsied, peripheral blood mononuclear cells (PBMCs) will be collected, and computed tomography and positron emission tomography scans will be performed.
* Surgical or chemoradiation treatment, which is being provided outside of this protocol, will be conducted after Day 28 and when rapamycin levels are less than or equal to 3 nanograms per milliter.
* Subjects will be followed by medical record review for 360 days after surgery or chemoradiation to assess 1) survival, 2) recurrence of disease, 3) metastases, and 4) adverse events/serious adverse events that are related to rapamycin therapy, including complications of wound healing and infections due to immune compromise.
* Levels of pS6 and pAkt473 in tumor tissue and PBMCs and Ki-67 in tumor tissue before and after rapamycin therapy will be determined by immunohistochemistry and by Western blotting. Computed tomography (CT) and positron emission tomography (PET) scans of the head, neck, and chest region with and without contrast will be performed within 7 days prior to the first rapamycin administration. One day after the last administration of rapamycin the CT and PET scans (head and neck region only) with contrast will be repeated.
* A single stage design will be used based on response defined as \> 25% tumor shrinkage. A Wilcoxon signed rank test will be used to compare levels of pS6, pAkt473, and Ki-67 before and after rapamycin therapy. As part of secondary analysis, the number of subjects achieving a best response of complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD) according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 will also be summarized.

Rapamycin Therapy in Head and Neck Squamous Cell Carcinoma

A Pilot Trial Targeting mTOR as a Novel Mechanism-Based Neoadjuvant Therapy for Head and Neck Cancer

National Institute of Dental and Craniofacial Research (NIDCR)

Subjects were followed 360 days after treatment, surgical or chemo radiation, to assess survival, recurrence of disease, metastases and adverse events that were related to rapamycin therapy including complications of wound healing, infections due to immune compromise and late radiation toxicities.

Rapamycin (sirolimus), which will be dispensed as either tablets or an oral solution for patients with dysphagia (see Section 0), will be administered orally as a single loading dose of 15 mg on the first day and 5 mg once a day for the next 20 days. Serum rapamycin levels will be obtained on Days 8, 15, 22, and 28 (if rapamycin is \> 3 ng/ml at Day 28, the subject will return daily, or as is convenient, for testing until rapamycin is ≤ 3 ng/ml). Dose reduction to 3 mg by mouth once per day will occur if trough levels of rapamycin \> 20 ng/ml occur on Days 8 or 15 (see Appendix A, Study Calendar for visit windows). If a dose is decreased at Day 8, it will not be increased at Day 15 regardless of serum rapamycin levels. If subjects receiving 3 mg have levels \> 20 ng/ml at Day 15, rapamycin will be reduced to 2 mg once per day. Rapamycin will cease on Day 21 regardless of level.

Age, Continuous

Sex: Female, Male

United States

Region of Enrollment

D. J. Silvio Gutkind

pAKt473

Ki-67

pERK

paraffin embedded formalin fixed tissues including head and neck cancer lesion were not available for 2 participants

Percent (%) Change in Levels of pS6, pAKt473, and Ki-67

Tumor size by CT

SUV non-nodal target lesions

SUV lymph nodes

It was not possible to obtain appropriate CT scans or SUV measurement from all participants

Percent (%) Changes in Tumor Size, Blood Flow, and Standardized Uptake Value

MCHC

PLAT

CREATININE

GLUCOSE

PHOSPHOR

Same sample loss during processing for phosphor and magnesium

Percent (%) Change in Clinical and Laboratory Evaluations for Safety

Rapamycin (sirolimus), dispensed as either tablets or an oral solution for patients with dysphagia was administered orally as a single loading dose of 15 mg on the first day and 5 mg once a day for the next 20 days. Dose reductions to 3 mg by mouth once per day were implemented if levels of rapamycin \> 20 ng/ml occurred on Days 8 or 15.

Overall Study

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
A Phase II Study With Tumor Molecular Pharmacodynamic (MPD) Evaluation of Oral mTOR-inhibitor Everolimus (RAD001) 10 mg Daily in Patients Suffering From Classic or Endemic Kaposi's Sarcoma	NCT01412515	Kaposi Sarcoma	everolimus	18 Years -	Institut National de la Santé Et de la Recherche Médicale, France
Addition of Everolimus to Standard of Care in Carcinoma Gallbladder	NCT05833815	Gallbladder Can...	Everolimus 10 m... Standard of car...	18 Years - 99 Years	Banaras Hindu University
Rapamycin Therapy in Head and Neck Squamous Cell Carcinoma	NCT01195922	Mouth Neoplasms Head and Neck N... Tongue Neoplasm... Carcinoma, Squa...	Sirolimus	18 Years - 80 Years	National Institutes of Health Clinical Center (CC)
Addition of Everolimus to Standard of Care in Carcinoma Gallbladder	NCT05833815	Gallbladder Can...	Everolimus 10 m... Standard of car...	18 Years - 99 Years	Banaras Hindu University
Rapamycin Therapy in Head and Neck Squamous Cell Carcinoma	NCT01195922	Mouth Neoplasms Head and Neck N... Tongue Neoplasm... Carcinoma, Squa...	Sirolimus	18 Years - 80 Years	National Institutes of Health Clinical Center (CC)

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