Neoplasms

Symptoms and General Pathology

All Conditions

Rare Diseases

Neoplasm Metastasis

Sarcoma

Neoplasms, Connective and Soft Tissue

Neoplasms by Histologic Type

Soft Tissue Sarcoma

Antineoplastic Agents

All Drugs and Chemicals

Anti-Infective Agents

Doxorubicin

Liposomal doxorubicin

Molgramostim

Sargramostim

Cisplatin

Ifosfamide

Mitomycins

Mitomycin

Isophosphamide mustard

Anti-Bacterial Agents

Antibiotics, Antitubercular

Enzyme Inhibitors

Antineoplastic Agents, Alkylating

Alkylating Agents

Immunologic Factors

aerosol sargramostim

sargramostim

cisplatin

doxorubicin hydrochloride

ifosfamide

mitomycin C

flow cytometry

immunological diagnostic method

laboratory biomarker analysis

adjuvant therapy

multimodality therapy

neoadjuvant therapy

therapeutic conventional surgery

intraoperative radiation therapy

selective external radiation therapy

Scott Okuno, MD

RATIONALE: Drugs used in chemotherapy work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. GM-CSF may stimulate the immune system in different ways and stop tumor cells from growing. GM-CSF, given by inhalation, may interfere with the growth of tumor cells and prevent metastases from forming. Radiation therapy uses high energy x rays to kill tumor cells. Giving combination chemotherapy together with radiation therapy and GM-CSF before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. Giving these treatments after surgery may kill any tumor cells that remain after surgery.

PURPOSE: This phase II trial is studying how well giving combination chemotherapy together with radiation therapy and GM-CSF before and after surgery works in treating patients with stage III soft tissue sarcoma that can be removed by surgery.

OBJECTIVES:

Primary

* To evaluate 2-year pulmonary metastatic progression rates in patients with primary high-grade extremity soft tissue sarcoma who have received preoperative I-MAP, plus aerosol GM-CSF, plus irradiation with concomitant MAP followed by post-operative aerosol GM-CSF.

Secondary

* To evaluate survival of these patients.
* To evaluate time to progression in these patients.
* To evaluate toxicity in these patients.
* To evaluate tumor response in these patients.

Translational

* To observe and describe sequentially before treatment, after treatment, and after recovery from treatment the frequency of skin test anergy and cellular immunity in extremity soft tissue sarcoma receiving systemic GM-CSF preoperatively and aerosol GM-CSF as part of both preoperative and postoperative treatment.

OUTLINE:

* Neoadjuvant treatment: Patients receive ifosfamide IV over 2 hours on days 0 and 1 and cisplatin IV over 4 hours, mitomycin IV and doxorubicin IV on day 1. Treatment repeats every 28 days for 2 courses in the absence of disease progression or unacceptable toxicity. Patients also receive sargramostim (GM-CSF) subcutaneously (SC) every 12 hours on days -6 to -3, 2-14, and 22-25. Beginning on day 84 patients also undergo radiotherapy once daily, five days a week, continuing for five weeks. Patients also receive GM-CSF SC twice daily on days -3 and 2 -15 and aerosol GM-CSF twice daily on days 85 - 91, 99 -105, and 113 - 119.
* Chemoradiotherapy: Beginning 4 weeks after completion of neoadjuvant chemotherapy, patients undergo radiotherapy (RT) once daily, 5 days a week, for 5 weeks. Patients also receive aerosolized GM-CSF twice daily on days 2-8, 16-22, and 30-38 and mitomycin C IV, doxorubicin hydrochloride IV, and cisplatin IV over 2 hours on days 1 and 29.
* Surgery: Four weeks after completion of chemotherapy, patients undergo surgery. Patients may also undergo intraoperative RT electron boost or intraoperative high-dose brachytherapy.
* Adjuvant treatment: Beginning 4 weeks after surgery, patients receive aerosol GM-CSF twice daily on days -7, 15-21, 35-42, 56-63, and 77-84. Some patients may undergo external beam RT 2-4 weeks after surgery.

Blood samples are collected at baseline and at 4 and 14 weeks after surgery. Samples are tested for NY-ESO-1 by staining, for T-cell subset by flow cytometry, and for autologous lymphocyte proliferation. Patients may also be tested for delayed-type hypersensitivity and skin test anergy.

After completion of study therapy, patients are followed every 3 months for 1 year, every 4 months for 1 year, every 6 months for 2 years, and at 5 years.

Combination Chemotherapy, Radiation Therapy, and Sargramostim Before and After Surgery in Treating Patients With Soft Tissue Sarcoma That Can Be Removed By Surgery

Chemotherapy, Irradiation, and Surgery for Function-Preserving Curative Therapy of Primary Extremity Soft Tissue Sarcomas: Initial Treatment With I-MAP and GM-CSF; Aerosol GM-CSF During Preoperative Irradiation and Postoperatively

National Cancer Institute (NCI)

Mayo Clinic

Scott Okuno, M.D.

Skin and Connective Tissue Diseases

Recurrence

Melanoma

Melanoma, Cutaneous Malignant

Neuroendocrine Tumors

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms, Nerve Tissue

Nevus, Pigmented

Nevus

Nevi and Melanomas

Skin Neoplasms

Skin Diseases

Neuroendocrine Tumor

Neuroepithelioma

Adjuvants, Anesthesia

Anticonvulsants

Antiemetics

Central Nervous System Depressants

Muscle Relaxants, Central

Psychotropic Drugs

Gastrointestinal Agents

Immunomodulating Agents

Nivolumab

Diazepam

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

Patients receive aerosolized sargramostim via inhalation using the Aerogen Solo nebulization device and receive nivolumab IV on study. Patients also undergo collection of blood samples on study and undergo CT or MRI at screening and on study.

Aerosol Sargramostim

Biospecimen Collection

Computed Tomography

Magnetic Resonance Imaging

Medical Device Usage and Evaluation

Clinical Trials Referral Office

Svetomir N. Markovic, M.D., Ph.D.

This phase II trial tests the safety, best dose, and effectiveness of inhaled aerosolized sargramostim in combination with standard immunotherapy (nivolumab) for the treatment of patients with melanoma that has spread from where it first started (primary site) to the lung (metastatic to the lung). Sargramostim works to stimulate the immune system by prompting the bone marrow to produce more white blood cells. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. In this study, an aerosolized form of sargramostim is inhaled using a device called a nebulizer, which can deliver the drug directly to the lungs. Inhalation of aerosolized sargramostim in combination with nivolumab may be more effective at treating patients melanoma metastatic to the lung.

PRIMARY OBJECTIVE:

I. To determine feasibility, safety (maximum tolerated dose, MTD), and/or the maximally immunologically effective dose of aerosolized sargramostim (aSAR) administered as an inhalation in combination with nivolumab for the treatment of patients with metastatic malignant melanoma with evidence of pulmonary metastases.

SECONDARY OBJECTIVES:

I. To assess the pharmacodynamics of inhaled aSAR administered in combination with nivolumab for the treatment of metastatic malignant melanoma.

II. To gather preliminary data on the clinical efficacy of aSAR + nivolumab therapy as 2nd line treatment for patients with metastatic melanoma.

OUTLINE: This is a dose escalation study of aerosolized sargramostim.

Patients receive aerosolized sargramostim via inhalation using the Aerogen Solo nebulization device and receive nivolumab intravenously (IV) on study. Patients also undergo collection of blood samples on study and undergo computed tomography (CT) or magnetic resonance imaging (MRI) at screening and on study.

Aerosolized Sargramostim Added to Immunotherapy for the Treatment of Patients With Metastatic Melanoma to the Lung

Aerosolized Granulocyte-Macrophage Colony Stimulating Factor (Sargramostim) in Combination With Anti-PD1 Therapy for the Treatment of Metastatic Melanoma to the Lung

The MRD is the dose level where at most 1 of the 6 patients treated at that dose level develops a dose-limiting event during the first cycle of treatment.

Adverse events will be identified using Common Terminology Criteria for Adverse Events version 5.0. The maximum grade of each type of adverse event will be recorded for each patient. For each adverse event reported by dose level, the percentage of patients developing any degree of that adverse event as well as the percentage of patients developing a severe degree (grade 3 or higher) will be determined.

PFS distribution will be estimated using the Kaplan-Meier method.

OS distribution will be estimated using the Kaplan-Meier method.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Combination Chemotherapy, Radiation Therapy, and Sargramostim Before and After Surgery in Treating Patients With Soft Tissue Sarcoma That Can Be Removed By Surgery	NCT00652860	Metastatic Canc... Sarcoma	aerosol sargram... sargramostim cisplatin doxorubicin hyd... ifosfamide mitomycin C flow cytometry immunological d... laboratory biom... adjuvant therap... multimodality t... neoadjuvant the... therapeutic con... intraoperative ... selective exter...	18 Years -	Mayo Clinic
Aerosolized Sargramostim Added to Immunotherapy for the Treatment of Patients With Metastatic Melanoma to the Lung	NCT05717140	Clinical Stage ... Metastatic Mali... Metastatic Mela... Recurrent Melan... Unresectable Me...	Aerosol Sargram... Biospecimen Col... Computed Tomogr... Magnetic Resona... Medical Device ... Nivolumab	18 Years -	Mayo Clinic
Aerosolized Sargramostim Added to Immunotherapy for the Treatment of Patients With Metastatic Melanoma to the Lung	NCT05717140	Clinical Stage ... Metastatic Mali... Metastatic Mela... Recurrent Melan... Unresectable Me...	Aerosol Sargram... Biospecimen Col... Computed Tomogr... Magnetic Resona... Medical Device ... Nivolumab	18 Years -	Mayo Clinic
Aerosolized Sargramostim Added to Immunotherapy for the Treatment of Patients With Metastatic Melanoma to the Lung	NCT05717140	Clinical Stage ... Metastatic Mali... Metastatic Mela... Recurrent Melan... Unresectable Me...	Aerosol Sargram... Biospecimen Col... Computed Tomogr... Magnetic Resona... Medical Device ... Nivolumab	18 Years -	Mayo Clinic

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