Neoplasms

All Conditions

Mouth and Tooth Diseases

Rare Diseases

Carcinoma

Carcinoma, Squamous Cell

Head and Neck Neoplasms

Mouth Neoplasms

Tongue Neoplasms

Squamous Cell Carcinoma of Head and Neck

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Neoplasms, Squamous Cell

Mouth Diseases

Stomatognathic Diseases

Tongue Diseases

Oral Cancer

Lip and Oral Cavity Cancer

Tongue Cancer

Anti-Infective Agents

Antineoplastic Agents

All Drugs and Chemicals

Sirolimus

Temsirolimus

MTOR Inhibitors

Anti-Bacterial Agents

Antibiotics, Antitubercular

Clotrimazole

Miconazole

Antifungal Agents

Immunosuppressive Agents

Immunologic Factors

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

Blood and Lymph Conditions

Immune System Diseases

Symptoms and General Pathology

Leukemia

Leukemia, Lymphoid

Leukemia, Lymphocytic, Chronic, B-Cell

Hematologic Diseases

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

Leukemia, B-Cell

Chronic Disease

Disease Attributes

Chronic Graft Versus Host Disease

Chronic Lymphocytic Leukemia

Chromosome 17p Deletion

Ruxolitinib will be administered over a 28-day cycle, which will be repeated 6 more times in the absence of intolerable toxicity, disease progression, patient withdrawal of consent, or investigator decision to end therapy. The dose and schedule have been adapted from the product monograph for myelofibrosis. The starting dose will be 20 mg orally twice a day with normal .platelet and absolute neutrophil counts and no hepatic and renal impairment.

20 mg orally on day 1 to 21 of each 28 day cycle. Number of Cycles: 7 or until progression or unacceptable toxicity develops.

Ruxolitinib

David E Spaner, MD, PhD

The purpose of this study is to determine if Ruxolitinib, an inhibitor of cytokine-signaling, is effective in the treatment of patients with Chronic Lymphocytic Leukemia for whom conventional chemotherapy is either too toxic or ineffective.

Chronic lymphocytic leukemia (CLL) is the commonest leukemia in adults and, until recently, had limited treatment options. However, the combination of fludarabine, cyclophosphamide, and rituximab (FCR) produces impressive clinical responses and prolongs survival of many CLL patients with symptomatic disease. Unfortunately, FCR is a toxic regimen that cannot generally be tolerated by patients over the age of 65 years who constitute more than 70% of the CLL patient population. In addition, FCR is contraindicated in patients whose leukemia cells harbor deletions of chromosome 17, where the tumor suppressor p53 is located, because such cells are intrinsically resistant to genotoxic drugs. This group constitutes 10-15% of patients of all ages who require first-line therapy. Better therapies for these two large groups of patients are needed.

The initiating event in CLL is thought to be genetic damage to a class of B lymphocytes that prevents proper functioning of apoptotic pathways. However, disease progression is driven by signals from the proliferation centers in tumor microenvironments where circulating CLL cells originate. Signals that cause CLL cells to proliferate include antigens that activate B-cell receptors (BCRs), Toll-like receptor ligands, chemokines, and cytokines. CLL cells that respond strongly to these microenvironmental signals exhibit more aggressive clinical behavior and resistance to cytotoxic drugs. These observations have motivated the use of signal transduction inhibitors to treat CLL and initial results of targeting kinases in the BCR-signaling cascade, such as Bruton's Tyrosine Kinase (BTK), suggest this strategy is effective and likely to change the treatment paradigm for CLL.

BCR signaling is not the only driver of CLL proliferation in vivo. Cytokines and chemokines in the tumor microenvironment activate Janus Kinases (JAKs) and mediate many of the pathological features of CLL cells. Cytokine signaling pathways have been shown to be rewired in aggressive tumor cells to support rapid growth and will eventually overcome the effects of inhibiting BCR-signaling. Preclinical findings suggest that JAK inhibitors will also have a place in the treatment of CLL.

Based on this strong theoretical rationale and pre-clinical evidence, along with its known toxicity profile, Ruxolitinib is expected to have significant activity with limited toxicity as a single agent in CLL. This trial is designed to investigate the efficacy and toxicity of Ruxolitinib in patients who are otherwise unfit for first-line therapy with FCR.

Ruxolitinib in the Treatment of Chronic Lymphocytic Leukemia

A Phase I/II Trial of Ruxolitinib (Jakafi) in Patients With Chronic Lymphocytic Leukemia Who Are Unfit for Conventional First-line Therapy Due to Age or 17p Deletions

Novartis

Sunnybrook Health Sciences Centre

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
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)
Ruxolitinib in the Treatment of Chronic Lymphocytic Leukemia	NCT02015208	Chronic Lymphoc...	Ruxolitinib	65 Years -	Sunnybrook Health Sciences Centre
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)
Ruxolitinib in the Treatment of Chronic Lymphocytic Leukemia	NCT02015208	Chronic Lymphoc...	Ruxolitinib	65 Years -	Sunnybrook Health Sciences Centre

Spots Global Cancer Trial Database for signal transduction inhibitors