Neoplasms

All Conditions

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Hematinics

All Drugs and Chemicals

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Cola

colloidal gold-bound tumor necrosis factor

electron microscopy

pharmacological study

conventional surgery

Steven A. Rosenberg, MD, PhD

RATIONALE: Biological therapies, such as tumor necrosis factor, may stimulate the immune system in different ways and stop tumor cells from growing. Studying tumor necrosis factor in samples of tumor tissue and healthy tissue from patients with cancer in the laboratory may help doctors learn how tumor necrosis factor works in tumor tissue and healthy tissue.

PURPOSE: This clinical trial is studying tumor necrosis factor in patients undergoing surgery for primary cancer or metastatic cancer .

OBJECTIVES:

Primary

* Determine the tumor tissue and normal tissue distribution of colloidal gold-bound tumor necrosis factor in patients with primary or metastatic cancer undergoing surgery.

Secondary

* Determine, by histological examination of resected tumor tissue, the acute antitumor effects of this treatment in these patients.
* Determine the long-term toxicities of this treatment in these patients.
* Determine the response to this treatment in these patients.

OUTLINE: This is a cohort study. Patients are stratified according to disease type (colorectal cancer vs hepatocellular cancer vs pancreatic exocrine cancer vs pancreatic endocrine cancer vs breast cancer vs melanoma vs primary adrenal tumors vs renal cell carcinoma).

Patients receive colloidal gold-bound tumor necrosis factor IV over 15-30 seconds 12-78 hours prior to surgery. Patients then undergo standard-care surgery.

Tumor and normal tissues are removed during surgery for analysis of antitumor effects and tissue distribution of colloidal gold-bound tumor necrosis factor by electron microscopy.

After completion of study treatment, patients are followed every 3 months for 1 year, every 4 months for 1 year, and then every 6 months for 1 year.

PROJECTED ACCRUAL: A total of 108 patients will be accrued for this study.

Tumor Necrosis Factor in Patients Undergoing Surgery for Primary Cancer or Metastatic Cancer

An Evaluation of the Tissue Distribution and the Selective Tumor Trafficking of TNF-Bound Colloidal Gold (CYT-6091) Following Intravenous Administration in Subjects With Primary and Metastatic Cancer Undergoing Surgical Resection

National Cancer Institute (NCI)

National Institutes of Health Clinical Center (CC)

Anti-Infective Agents

Antirheumatic Agents

Antineoplastic Agents

Hydroxychloroquine

Temozolomide

Antineoplastic Agents, Alkylating

Alkylating Agents

Antimalarials

Antiprotozoal Agents

Antiparasitic Agents

Enzyme Inhibitors

hydroxychloroquine

temozolomide

TdT-mediated dUTP nick end labeling assay

western blotting

high performance liquid chromatography

immunoenzyme technique

immunohistochemistry staining method

laboratory biomarker analysis

mass spectrometry

Ravi Amaravadi, MD

RATIONALE: Drugs used in chemotherapy, such as hydroxychloroquine and temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more tumor cells.

PURPOSE: This phase I trial is studying the side effects and best dose of hydroxychloroquine when given together with temozolomide in treating patients with metastatic or unresectable solid tumors.

OBJECTIVES:

Primary

* To determine the maximum tolerated dose (MTD) of hydroxychloroquine (HCQ) when administered in combination with temozolomide (TMZ) in patients with metastatic or unresectable solid tumors.

Secondary

* To determine the toxicity and toxicity rate of HCQ when administered at the MTD in combination with TMZ in these patients.

Tertiary

* To construct a population pharmacokinetic (PK) model using a limited sampling of whole blood to determine the drug exposure of HCQ and HCQ metabolites in these patients.
* To measure changes in autophagic vesicle accumulation by immunoblotting against the autophagy marker LC3 in protein lysates prepared from peripheral blood mononuclear cells (PBMC) collected from patients treated with HCQ and TMZ.
* To measure changes in median number of autophagic vesicles by electron microscopy in PBMC collected from patients treated with HCQ and TMZ.
* To assess tumor changes in LC3 and caspase 3 cleavage by western blotting.
* To assess tumor cell death characteristics by immunohistochemical methods (Ki67, TUNEL staining, cleaved caspase 3).
* To evaluate autophagy by electron microscopy.
* To define associations between changes in LC3 levels from baseline in PBMC with HCQ exposure.
* To measure the levels of HMGB1 in the serum of patients treated with HCQ and TMZ.

OUTLINE: This is a dose-escalation study of hydroxychloroquine (HCQ).

Patients receive oral HCQ alone once or twice daily for 14 days. Patients then receive oral HCQ once or twice daily on days 1-28 and oral temozolomide once daily on days 1-7 and 15-21. Treatment with HCQ and temozolomide repeats every 28 days in the absence of disease progression or unacceptable toxicity.

Patients undergo blood sample collection periodically for pharmacodynamic and pharmacokinetic correlative studies. Autophagic vesicles in blood samples are quantified by immunoblotting against the autophagy protein LC3 and by electron microscopy. Pharmacokinetics are analyzed by high-performance liquid chromatography with tandem mass spectrometry. Patients with tumors amenable to biopsy also undergo serial biopsies. Tumor tissue samples are assessed for tumor cell apoptosis and proliferation using Ki67 and TUNEL staining and for the number of autophagic vesicles and nuclear changes characteristic of apoptotic, autophagic, or necrotic cell death by western blotting and electron microscopy.

After completion of study treatment, patients are followed periodically.

Hydroxychloroquine and Temozolomide in Treating Patients With Metastatic or Unresectable Solid Tumors

A Phase I Study of Hydroxychloroquine in Combination With Temozolomide in Patients With Advanced Solid Tumors

Abramson Cancer Center at Penn Medicine

Eye Diseases

Heart and Blood Diseases

Glaucoma

Uveitis

Hypertension

Ocular Hypertension

Neoplastic Processes

Uveal Diseases

Ultrastructural analysis of trabeculectomy specimens of patients with uveitic secondary glaucoma.

To evaluate morphological changes and to compare to primary open angle glaucoma patients.

trabeculectomy specimens including trabecular meshwork and Schlemms canal

Ultrastructural Changes of Trabeculectomy Specimens in Patients With Uveitic Secondary Glaucoma

University of Erlangen-Nürnberg Medical School

St. Franziskus Hospital

Department of Ophthalmology at St. Franziskus Hospital

Sirolimus

Temsirolimus

MTOR Inhibitors

Protein Kinase Inhibitors

Immunosuppressive Agents

Immunologic Factors

Anti-Bacterial Agents

Antibiotics, Antitubercular

Clotrimazole

Miconazole

Antifungal Agents

temsirolimus

immunologic technique

autophagy inhibition therapy

RATIONALE: Drugs used in chemotherapy, such as hydroxychloroquine, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Temsirolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving hydroxychloroquine together with temsirolimus may kill more tumor cells.

PURPOSE: This phase I trial is studying the side effects and best dose of hydroxychloroquine when given together with temsirolimus in treating patients with metastatic solid tumors that have not responded to treatment.

OBJECTIVES:

Primary

* Determine the maximum tolerated dose of hydroxychloroquine (HCQ) in combination with temsirolimus (TEM) in patients with metastatic refractory solid tumors.

Secondary

* Describe the toxicity of this regimen in these patients.
* Measure the response rate in patients treated with this regimen.

Tertiary

* Establish a population pharmacokinetic (PK) model for HCQ and its metabolites in combination with TEM.
* Use the population PK model to estimate the exposure of HCQ in individual patients.
* Compare PK parameters for this regimen to data from published single agent studies.
* Measure the change in median number of autophagic vesicles/cell in peripheral blood mononuclear cells with TEM alone and with TEM and HCQ and correlate these changes with HCQ exposure.

OUTLINE: This is a dose-escalation study of hydroxychloroquine.

Patients receive temsirolimus IV over 30 minutes once a week beginning in week 1 and oral hydroxychloroquine twice daily beginning in week 2. Courses repeat every 8 weeks in the absence of disease progression or unacceptable toxicity.

Blood samples are collected at baseline and periodically during study for pharmacokinetic and pharmacodynamic studies and measurement of autophagy inhibition. Samples are analyzed via HPLC and tandem mass spectrometry, immunoblotting assays, and electron microscopy.

Hydroxychloroquine and Temsirolimus in Treating Patients With Metastatic Solid Tumors That Have Not Responded to Treatment

A Phase I Trial of Hydroxychloroquine in Combination With Temsirolimus in Patients With Refractory Solid Tumors

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Tumor Necrosis Factor in Patients Undergoing Surgery for Primary Cancer or Metastatic Cancer	NCT00436410	Adrenocortical ... Breast Cancer Colorectal Canc... Gastrointestina... Kidney Cancer Liver Cancer Melanoma (Skin) Ovarian Cancer Pancreatic Canc... Sarcoma	colloidal gold-... electron micros... pharmacological... conventional su...	18 Years -	National Institutes of Health Clinical Center (CC)
Hydroxychloroquine and Temozolomide in Treating Patients With Metastatic or Unresectable Solid Tumors	NCT00714181	Unspecified Adu...	hydroxychloroqu... temozolomide TdT-mediated dU... western blottin... electron micros... high performanc... immunoenzyme te... immunohistochem... laboratory biom... mass spectromet... pharmacological...	18 Years - 120 Years	Abramson Cancer Center at Penn Medicine
Hydroxychloroquine and Temozolomide in Treating Patients With Metastatic or Unresectable Solid Tumors	NCT00714181	Unspecified Adu...	hydroxychloroqu... temozolomide TdT-mediated dU... western blottin... electron micros... high performanc... immunoenzyme te... immunohistochem... laboratory biom... mass spectromet... pharmacological...	18 Years - 120 Years	Abramson Cancer Center at Penn Medicine
Ultrastructural Changes of Trabeculectomy Specimens in Patients With Uveitic Secondary Glaucoma	NCT00917670	Uveitis Secondary Glauc...		-	St. Franziskus Hospital
Hydroxychloroquine and Temsirolimus in Treating Patients With Metastatic Solid Tumors That Have Not Responded to Treatment	NCT00909831	Unspecified Adu...	hydroxychloroqu... temsirolimus electron micros... high performanc... immunologic tec... laboratory biom... mass spectromet... pharmacological... autophagy inhib...	18 Years - 120 Years	Abramson Cancer Center at Penn Medicine

Spots Global Cancer Trial Database for electron microscopy