Neoplasms

Symptoms and General Pathology

All Conditions

Skin and Connective Tissue Diseases

Rare Diseases

Neoplasm Metastasis

Osteosarcoma

Neoplasms, Bone Tissue

Neoplasms, Connective Tissue

Neoplasms, Connective and Soft Tissue

Neoplasms by Histologic Type

Sarcoma

Soft Tissue Sarcoma

All Drugs and Chemicals

Anti-Infective Agents

Gastrointestinal Agents

Bone Density Conservation Agents

Calcium

Plerixafor

Lenograstim

Calcium Carbonate

Calcium, Dietary

Radiopharmaceuticals

Hormones

Antacids

Anti-Ulcer Agents

Anti-HIV Agents

Anti-Retroviral Agents

Antiviral Agents

Dose Levels 1-3 will consist of treatment with radiopharmaceutical (153Sm-DOTMP) alone. If the maximally tolerated dose (MTD) has not been reached at Level 3, external beam radiotherapy will be added to each of Levels 4-6. Participants enrolled on Dose Levels 4-6 will be treated with external beam radiotherapy to all radiographically evident sites of disease. If an MTD has not been determined at Level 6, the study will end and Dose Level 6 will be declared the Recommended Phase 2 Dose.

Participants will be given prophylactic / supportive treatment protocols including Calcium Carbonate, mozobil, and neupogen injectable product.

For Levels 1- 3, the Day 1 dosages will be the same (0.5 millicurie (mCi)/kg 153Sm-DOTMP) for all levels but the Day 8 dosages will be 0.5, 1.0 and 3.0 mCi/kg respectively. For Levels 4, 5 \& 6, the Day 1 dosages will be the same (0.5 mCi/kg 153Sm-DOTMP) for all levels but the Day 8 dosages will be 3, 6, then 10 mCi/kg 153Sm-DOTMP respectively.

153Sm-DOTMP

The amount of radiation will be determined based on how much radiation was delivered to each tumor by the 153Sm-DOTMP, and will be targeted to 70 Gray (Gy)

External beam radiotherapy.

Calcium carbonate will be given to participants as prophylaxis against hypocalcemia..

Participants who require stem cell collection will be given Mozobil to help mobilize hematopoietic stem cells into the circulation for collection.

Mozobil

Participants who require stem cell collection will be given Neupogen to help mobilize hematopoietic stem cells into the circulation for collection.

Neupogen Injectable Product

David Loeb, MD, PhD

This is a dose finding study of a novel radiopharmaceutical agent, 153Sm-DOTMP. It will be studied alone and then in combination with external beam radiotherapy. The study design includes six cohorts, Levels 1-6. The first three cohorts of participants will receive 153Sm-DOTMP alone, and if this is determined to be safe, subsequent cohorts will receive the radiopharmaceutical followed by external beam radiotherapy.

This is a dose escalation study of a new radiopharmaceutical agent, 153Sm-DOTMP. Eligible participants will have osteosarcoma metastatic to bone, other solid tumors with bone metastases, or an unresectable localized osteosarcoma. Because of anticipated prolonged myelosuppression, participants will have a peripheral blood stem cell harvest. They will then be treated with 2 doses of 153Sm-DOTMP given 7 days apart. Twenty-four days after the initial dose, stem cells will be reinfused if needed. The first three cohorts of participants will receive only radiopharmaceutical. If Dose Level 3 is not the maximally tolerated dose (MTD), subsequent dose levels will include external beam radiotherapy, administered beginning on Day 15. The dose of external beam radiotherapy will be determined by dosimetry studies performed after each administration of study agent, and will be targeted to a tumoricidal dose of radiation. All participants will have disease re-evaluation 30 days following completion of all study treatments, and then at 4, 6, 8, and 12 months, unless they experience disease progression.

A Dose Finding Study of CycloSam® Combined With External Beam Radiotherapy

A Dose Finding Study of CycloSam® (153Sm-DOTMP) Combined With External Beam Radiotherapy to Treat High Risk Osteosarcoma and Other Solid Tumors Metastatic to Bone

The maximally tolerated dose (MTD) of 153Sm-DOTMP will be determined. The MTD will be defined as the dose that produces a dose limiting toxicity (DLT) in 30% of the participants. The dose limiting toxicity is the dosage at which side effects are serious enough to prevent an increase in dose or level of that treatment. DLTs will be defined as any grade 3, 4, or 5 non-hematologic toxicity experienced during a 42-70 day observation window.

The overall survival of participants with bone metastatic osteosarcoma will be determined. Overall survival is defined as the time from enrollment in the study until death. Observation begins at study enrollment and terminates upon death of the subject.

The time to progression of participants with bone metastatic osteosarcoma will be determined. Time to progression is defined as the time from study enrollment until the first radiographic evidence of progressive disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST). RECIST is a set of published rules that help define whether cancer patients improve, stay the same, or get worse with treatment. This study uses the revised RECIST 1.1 guidelines.

Participants will undergo radiographic evaluation 30 days after completion of all protocol therapy. The response of each tumor to treatment will be determined based on RECIST 1.1 criteria. Clinical response will be defined as either stable disease or a decrease in the size of the tumor by radiographic imaging (which may include CT or MRI) using RECIST 1.1 criteria.

Participants will undergo radiographic evaluation 4 months after completion of all protocol therapy. The response of each tumor to treatment will be determined based on RECIST 1.1 criteria. Clinical response will be defined as either stable disease or a decrease in the size of the tumor by radiographic imaging (which may include CT or MRI) using RECIST 1.1 criteria.

Participants will undergo radiographic evaluation 8 months after completion of all protocol therapy. The response of each tumor to treatment will be determined based on RECIST 1.1 criteria. Clinical response will be defined as either stable disease or a decrease in the size of the tumor by radiographic imaging (which may include CT or MRI) using RECIST 1.1 criteria

Participants will undergo radiographic evaluation 12 months after completion of all protocol therapy. The response of each tumor to treatment will be determined based on RECIST 1.1 criteria. Clinical response will be defined as either stable disease or a decrease in the size of the tumor by radiographic imaging (which may include CT or MRI) using RECIST 1.1 criteria.

National Cancer Institute (NCI)

Albert Einstein College of Medicine

Digestive System Diseases

Respiratory Tract (Lung and Bronchial) Diseases

Esophageal Neoplasms

Carcinoma

Small Cell Lung Carcinoma

Carcinoma, Non-Small-Cell Lung

Carcinoma, Small Cell

Lung Neoplasms

Mesothelioma

Mesothelioma, Malignant

Neoplasms, Glandular and Epithelial

Adenoma

Neoplasms, Mesothelial

Respiratory Tract Neoplasms

Thoracic Neoplasms

Pleural Neoplasms

Lung Diseases

Respiratory Tract Diseases

Carcinoma, Bronchogenic

Bronchial Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Head and Neck Neoplasms

Gastrointestinal Diseases

Esophageal Diseases

Esophageal Cancer

Small Cell Lung Cancer

Malignant Mesothelioma

Antineoplastic Agents

Romidepsin

Alvocidib

Growth Inhibitors

Protein Kinase Inhibitors

Enzyme Inhibitors

Anti-Bacterial Agents

Antibiotics, Antitubercular

Histone Deacetylase Inhibitors

Depsipeptide

Flavopiridol (alvocidib)

David S Schrump, M.D.

This study will test the safety and effectiveness of two experimental medicines - depsipeptide and flavopiridol - given together to treat cancers of the lung, esophagus, and pleura. It will determine the highest dose that these drugs can safely be given together and will test whether giving them together works better at shrinking tumors than giving either one alone.

Patients 18 years of age and older with cancer of the lung, esophagus, or pleura, or other cancers that have spread to the lungs or pleura may be eligible for this study. Candidates are screened with a medical history and physical examination, blood tests, electrocardiogram (EKG), x-rays and scans, pulmonary function tests, and a tumor biopsy (removal of a small piece of tumor tissue for microscopic examination).

Participants are admitted to the hospital for treatment for approximately 10 days during each 28-day treatment cycle. Depsipeptide is infused through an arm vein or central venous catheter (tube placed in a large vein in the neck or chest) for 4 hours. When this infusion is complete, flavopiridol is infused over 72 hours. The dose of depsipeptide is increased four times over the period of the study with successive groups of patients, and flavopiridol is increased once to determine the maximum safe dose of giving these drugs together.

Blood tests are done before and after each depsipeptide infusion and 3 more times for the next 24 hours, and at various times over 4 days during the flavopiridol infusion to evaluate the effects of the medicines. Samples are also drawn periodically throughout the treatment cycle to evaluate safety. Heart function is monitored with several EKGs before and during the depsipeptide doses. The drug has shown effects on EKG tracings, but does not appear to injure the heart muscle.

Tumor biopsies are done before treatment begins and on the fifth day of the first treatment cycle. The biopsies may be done either in the operating room by passing a tube (bronchoscope) down the throat and into the lungs or in the Radiology Department using a thin needle put through the chest wall into the tumor. For the bronchoscopy, numbing medicine is sprayed into the back of the throat to reduce discomfort, and for the needle biopsy, the skin over the biopsy area is numbed. Optional repeat biopsies may be requested before the start of the second treatment cycle and on day 5 of that cycle. (The repeat biopsies are not required for participation in the study.) At the time of each tumor biopsy, a buccal mucosal biopsy is also done. This involves scraping a tongue depressor along the inside of the mouth to collect cells for examination.

At the end of the first treatment cycle, patients return to NIH for evaluation with a physical examination, blood work, x-rays, and scans of the chest, abdomen, pelvis, and brain. Patients who are not experiencing significant drug side effects are offered a second cycle, exactly like the first. The two cycles complete one course of treatment, after which patients once again return to NIH for evaluation. Additional treatment cycles may be offered to patients whose tumors have shrunk or remained stable with therapy. Patients whose tumors have not responded to therapy or who have developed severe drug side effects are taken off the study.

Background:

In preclinical studies we have demonstrated that the histone deacetylase (HDAC) inhibitor Depsipeptide FR901228 (DP) mediates cell cycle arrest and apoptosis in cultured lung and esophageal cancer, and malignant pleural mesothelioma cells.

We have observed that the cdk inhibitor Flavopiridol (FLA) markedly potentiates Depsipeptide-mediated apoptosis in cultured cancer cells, but not cultured normal epithelial cells.

Patients with advanced malignancies involving lungs, esophagus, or pleura will receive 4-hour Depsipeptide infusion followed by 72-hour FLA infusion using a phase I study design.

Tumor and buccal mucosa biopsies as well as PBMC may be obtained prior to, and after therapy to evaluate gene expression using cDNA array long-oligo and protein lysate array techniques, and determine if sequential DP/FLA mediates apoptosis in target tissues.

Results of these studies may provide the rationale for phase II evaluation of sequential DP/FLA infusion in thoracic oncology patients.

Objectives:\<TAB\>

Primary objectives:

To define the maximum tolerated dose (MTD) and dose limiting toxicities (DLT) of sequential 4 hour Depsipeptide(DP)/72 hour Flavopiridol (FLA)

To evaluate the pharmacokinetics of sequential DP/FLA infusion

Secondary objectives

To analyze gene expression profiles in laser-captured tumor cells, buccal mucosa, and PBMC before and after sequential DP/FLA exposure.

To analyze mcl-1 protein expression and apoptosis in tumor biopsies before and after sequential DP/FLA treatment.

Tertiary objectives:

The development of tissue and serum proteomic techniques to assess treatment response in patients receiving sequential DP/FLA infusions.

Eligibility:

Patients with histologically or cytologically proven primary small cell or non-small cell lung cancers, esophageal cancers, malignant pleural mesotheliomas or chest wall sarcoma, or thymomas are eligible for evaluation. In addition, patients with cancers of nonthoracic origin with metastases to the lungs or pleura, or germ cell tumors refractory to standard therapy are eligible for evaluation.

Patients must have an ECOG performance status of 0 - 2.

Patients must have adequate pulmonary reserve evidenced by FEV1 and DLCO greater than the 30 percent predicted, and pCO2 less than 50 mm Hg and pO2 greater than 60 mm Hg on room air ABG.

Patients must be 18 years of age or older.

Adequate organ function as evidenced by standard laboratory parameters.

The patient must be willing to sign an informed consent.

Design:\<TAB\>\<TAB\>

A phase 1 study where patient cohorts will receive escalating doses of Depsipeptide, administered on day 1 and day 21, and a dose of flavopiridol (either 40 mg/m2/d or 50 mg/m2/d) administered on days 1-3, and 21-24 of a 42-day course.

Pharmacokinetics, systemic toxicity, and response to therapy will be recorded.

Two cycles of therapy (one course) will be administered, following which treatment evaluation will be performed using standard clinical criteria.

48 patients will be enrolled over a period of 2-4 years.

Depsipeptide/Flavopiridol Infusion for Cancers of the Lungs, Esophagus, Pleura, Thymus or Mediastinum

Phase I Study of Sequential Depsipeptide/Flavopiridol Infusion for Malignancies Involving Lungs, Esophagus, Pleura, Thymus or Mediastinum

Nervous System Diseases

Brain Neoplasms

Neuroblastoma

Neuroectodermal Tumors, Primitive, Peripheral

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Neuroepithelial

Neoplasms, Germ Cell and Embryonal

Neoplasms, Nerve Tissue

Central Nervous System Neoplasms

Nervous System Neoplasms

Brain Diseases

Central Nervous System Diseases

Neuroepithelioma

4-phenylbutyric acid

Phenylacetic acid

phenylbutyrate

This is a pharmacokinetic trial. Patients receive phenylbutyrate through a central venous catheter for each 28 day cycle. The first several days of drug administration should be inpatient. Cycles may be repeated if there is no tumor progression or dose limiting toxicities (DLT). There are no breaks between cycles.

Once a minimum of 3 patients have completed at least 4 weeks of therapy without DLT, new patients will be entered at the next dose level.

Phenylbutyrate is an aromatic fatty acid that is converted to phenylacetate in vivo by mitochondrial beta-oxidation to phenylacetate. Preclinical studies have shown that continuous exposure to phenylacetate or phenylbutyrate can induce tumor cytostasis and differentiation in a wide variety of cell lines including malignant gliomas and neuroblastomas. However, phenylbutyrate has been shown to be a more potent differentiating agent than phenylacetate in a variety of tumor cell lines. In addition, phenylbutyrate appears to have molecular activities that are distinct from phenylacetate. The objective of this trial is to determine the maximum tolerated dose and the toxicities of phenylbutyrate administered as a continuous intravenous infusion for 28 days. In addition, the pharmacokinetics of phenylbutyrate and its metabolite, phenylacetate, will be studied using both model-dependent and model-independent parameters.

Phase I and Pharmacokinetic Trial of Phenylbutyrate Given as a Continuous Infusion in Pediatric Patients With Refractory Malignancy

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
A Dose Finding Study of CycloSam® Combined With External Beam Radiotherapy	NCT03612466	Osteosarcoma Bone Metastases	153Sm-DOTMP External beam r... Calcium Carbona... Mozobil Neupogen Inject...	15 Years - 65 Years	Albert Einstein College of Medicine
Depsipeptide/Flavopiridol Infusion for Cancers of the Lungs, Esophagus, Pleura, Thymus or Mediastinum	NCT00094978	Carcinoma, Smal... Carcinoma, Non-... Esophageal Neop... Mesothelioma	Depsipeptide Flavopiridol (a...	18 Years -	National Institutes of Health Clinical Center (CC)
Phase I and Pharmacokinetic Trial of Phenylbutyrate Given as a Continuous Infusion in Pediatric Patients With Refractory Malignancy	NCT00001565	Brain Neoplasms Neuroblastoma	phenylbutyrate	-	National Institutes of Health Clinical Center (CC)

Spots Global Cancer Trial Database for maximally tolerated dose