Neoplasms

Skin and Connective Tissue Diseases

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Rare Diseases

Melanoma

Neuroendocrine Tumors

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Nerve Tissue

Nevus, Pigmented

Nevus

Nevi and Melanomas

Skin Neoplasms

Skin Diseases

Neuroendocrine Tumor

Neuroepithelioma

All Drugs and Chemicals

Antineoplastic Agents

Antibodies

Molgramostim

Sargramostim

Immunoglobulins

Immunologic Factors

Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF)

Lynn E. Spitler, MD

This is a pilot study to describe the immunological responses and clinical outcome associated with administration of recombinant human Granulocyte Macrophage Colony Stimulating Factor (GM-CSF) as surgical adjuvant therapy in patients with malignant melanoma who are at high risk for recurrence (Stage II T4, III and IV).

This is a pilot study to describe the immunological responses and clinical outcome associated with administration of recombinant human Granulocyte Macrophage Colony Stimulating Factor (GM-CSF) as surgical adjuvant therapy in patients with malignant melanoma who are at high risk for recurrence (Stage II T4, III and IV). The immunological responses include serum neopterin levels. In a sub-set of study participants, additional immunologic testing will be done, including monocyte cytotoxicity to a melanoma cell line and phenotypic and functional markers of dendritic and T cell activation in peripheral blood mononuclear cells. The clinical end points of the study include safety, time to disease recurrence, time to disseminated disease, and survival. Eligible patients are those with high-risk melanoma who are clinically tumor free following surgery. Treatment will consist of GM-CSF at 125 g/m2 once daily (maximum dose 250 g) for 14 days followed by 14 days of rest (28 day cycle) for 1 year. Clinical status will be monitored until death or until the patient has been tumor free for five years, whichever event occurs first. Immunologic responses will be determined pretreatment, at the end of the first 14 days of dosing (Day 15), after the 14-day rest period (Day 29) and at the end of 14 days of dosing in cycles 6 (Day 155) and 13 (Day 351). Clinical outcome will be determined according to patient risk group (ultra-high risk Stage IIIC or IV versus high-risk Stage II T4, Stage IIIA and Stage IIIB). The pilot study will also assess the association of the immunological responses with clinical response and safety by patient risk group.

GM-CSF as Adjuvant Therapy of Melanoma

Immunologic and Antibody Responses in Patients Receiving GM-CSF, (Leukine, Sargramostim) as Adjuvant Therapy of Stage II (T4), III and IV Melanoma.

Bayer

Melanoma Research Institute

Northern California Melanoma Center

Symptoms and General Pathology

Blood and Lymph Conditions

Immune System Diseases

Carcinoma

Neoplasm Metastasis

Lymphoma

Lymphosarcoma

Immunomodulating Agents

Maximum tolerated dose (MTD) determination in subjects with metastatic cancers receiving recombinant human Interleukin-15 (rhIL-15) intravenous (IV) for 10 consecutive days

Clinical activity evaluation in subjects with metastatic cancers receiving recombinant human Interleukin-15 (rhIL-15) intravenous (IV) for 10 consecutive days

Maximum tolerated dose (MTD) determination in subjects with metastatic unresectable cancers receiving recombinant human Interleukin-15 (rhIL-15) intravenous (IV) for 5 consecutive days

Clinical activity evaluation in subjects with metastatic cancers receiving recombinant human Interleukin-15 (rhIL-15) intravenous (IV) for 5 consecutive days

Continuous infusion of recombinant human Interleukin-15 (rh IL-15) intravenous (IV) for first 10 days of each cycle

rh IL-15 (10 DAYS)

Continuous infusion of recombinant human Interleukin-15 (rh IL-15) for first 5 days of each cycle

rh IL-15 (5 DAYS)

Kevin C Conlon, M.D.

Background:

- People with cancer can have a weak immune system as a result of the cancer itself, or from prior treatments. Still, treatments that stimulate the immune system have been shown to be effective against a number of different cancers. Recombinant human interleukin-15 (rhIL-15) is a drug that is designed to boost the immune system. Researchers are interested in seeing if rhIL-15 can strengthen the immune system's response against cancer. The drug will be given through a vein without a break for 10 days (240 hours).

Objectives:

* To see rhIL-15 given as a continuous infusion over 10 days can be used to treat advanced cancer
* Identify the side effects associated with this treatment.

Eligibility:

- Individuals at least 18 years of age with advanced cancer for which there are no effective treatments.

Design:

* Participants screening procedures will include a physical exam and medical history, laboratory (blood) tests and x-rays (Imaging studies) to determine suitability for the protocol.
* Appropriate participants with easily accessible tumor deposits may also be asked to have one pretreatment and one post (cycle 1) treatment tumor biopsy.
* Eligible participants will be admitted to the hospital for the rhIL-15 treatment and will spend about 12 days in the hospital.
* Participants will receive one 10 day infusion each cycle (about every 42 days) for as long as there are no serious side effects and the disease does not progress.
* Participants will continue treatment as long as imaging studies show that the tumor continues to shrink or for two additional cycles after it has disappeared from the x-rays to make that the cancer is completely gone.
* Participants who stop treatment for side effects or because their tumor did not shrink or stopped responding to the treatment will continue to have follow-up visits to monitor the outcome of the rhIL-15 treatment until there is evidence their cancer has progress or they begin another treatment.

BACKGROUND:

* Interleukin-15 (IL-15) is a stimulatory cytokine with a number of desirable immunotherapeutic features, and clinical trials evaluating recombinant human interleukin-15 (rhIL-15) are underway.
* In contrast to IL-2, IL-15 treatment does not stimulate activation-induced cell death of T-cells; potentially inhibits immunosuppressive cluster of differentiation 4 (CD4) + Interleukin-2 receptor alpha chain (CD25) + T regulatory cells, contributes to the proliferation, differentiation and activation of CD8+ T-cells and NK-cells and the maintenance of long-term cluster of differentiation 8 (CD8) + memory T-cells.
* IL-15 is active in a number of syngeneic mouse preclinical tumor models, and vaccinia-based constructs expressing IL-15 induced long-lasting, high-avidity cytotoxic CD8+ T-lymphocyte response that appears to be more effective than similar IL-2 expressing vaccines.
* Pharmacology/toxicology (pharm/tox) experiments in non-human primate (NHP) rhesus macaques and preliminary results from the first-in-human phase I trial examining rhIL-15 given as an intravenous (IV) bolus (IVB) for 12 consecutive days indicate significant stimulation and expansion of NK-cells and CD8+ T-cells.
* rhIL-15 given as an IVB at 1 mcg/kg dose level appears to be well tolerated despite the presence of some common cytokine-related side effects indicating that 0.1 mcg/kg/day is an appropriate initial dose level for a phase I safety trial of continuous intravenous infusion (CIV) of rhIL-15.
* Comparison of the pharmacokinetic and immunologic assessments from the IVB phase I trial with the data from both sets of NHP pharm/tox experiments suggest that continuous intravenous (CIV) of rhIL-15 may have greater potential for stimulating an anticancer cellular immune response with a more manageable safety profile.

OBJECTIVES:

Primary Objective:

- Determine the safety, toxicity profile, dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) of rhIL-15 administered as a CIV for 10 consecutive days (240 hours) in subjects with metastatic unresectable cancers for which curative or palliative measures either do not exist or are not associated with a survival advantage.

ELIGIBILITY CRITERIA:

* Patients greater than or equal to18 years-old, Eastern Cooperative Oncology Group (ECOG) performance status (PS) less than or equal to 1, with pathologically confirmed metastatic unresectable cancers for which curative or palliative measures either do not exist or are not associated with a survival advantage.
* Patients with measurable or evaluable disease, normal organ and bone marrow function.

DESIGN:

* This is a single-institution, open-label, non-randomized 3 + 3 design phase I dose escalation study.
* Groups of 3 to 6 subjects will receive CIV rhIL-15 at doses of 0.1, 0.25, 0.5 1, 2, 4, 6 and 8 mcg/kg/day for 10 days provided that DLT has not been observed.
* After assessments of the 10-day dosing cohorts have been completed, new groups of 3 to 6 subjects will receive CIV rhIL-15 at doses of 3, 4 and 5 mcg/kg/day for 5 days provided that a DLT has not been observed.
* Patients with evidence of response and the absence of significant toxicities will be eligible for repeat cycles of treatment.
* Samples for correlative studies will be obtained prior to treatment and at specific times points during and after treatment to assess pharmacokinetics of rhIL-15, the effect of rhIL-15 on immune cell subset populations and pro-inflammatory cytokine levels in the peripheral blood and for the development of neutralizing anti-rhIL-15 antibodies.

Continuous Infusion of rhIL-15 for Adults With Advanced Cancer

A Phase I Study of a Continuous Intravenous Infusion of Recombinant Human Interleukin IL-15 (rhIL-15) in Adults With Metastatic Cancers

Here is the number of participants with serious and/or non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.

The MTD is the dose level at which less than one-third of patients (0/3 or 0-1/6 participants) treated at that dose experience a dose-limiting toxicity (DLT), with the next higher dose level demonstrating a one-third or greater number of participants (≥ 2/3 or ≥ 2/6 participants) having DLT. A DLT is Grade 2 diarrhea lasting more than 24 hours or any grade 3 or 4 toxicity, if deemed possibly, probably or definitely related to the study drug by the principal investigator during the first cycle of treatment. Toxicities were assessed by the Common Terminology Criteria for Adverse Events (CTCAE)v4. Grade 3 is severe, and Grade 4 is life-threatening.

A DLT is Grade 2 diarrhea lasting more than 24 hours or any grade 3 or 4 toxicity, if deemed possibly, probable or definitely related to the study drug by the principal investigator during the first cycle of treatment; and/or Grade 5 death related to adverse event. Toxicities were assessed by the Common Terminology Criteria for Adverse Events (CTCAE)v4. Grade 3 is severe, and Grade 4 is life-threatening.

Response was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1). Complete response (CR) is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. Partial response (PR) is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. Progressive disease (PD) is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study, and the appearance of one or more new lesions. Stable disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD.

TTP is defined as the date of protocol consent until date of progressive disease is documented. Progressive disease was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1). Progressive disease (PD) is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study, and the appearance of one or more new lesions.

The maximum observed analyte concentration in serum was reported.

Concentration of drug in plasma at steady state (Css).

AUClast is from dosing to the time of the last measured concentration \>/= lower limit of quantitation (LLOQ)(Clast) of that dosing period.

Serum samples was obtained from participants and inflammatory cytokine analyses was performed by flow cytometry to determine levels of Interleukin - 1, Interferon γ, Interleukin-6 and Tumor Necrosis Factor ἁ.

National Cancer Institute (NCI)

Principal Investigator

Dose Escalation Level 1 - 0.1 mcg/kg/Day x 10 Days

Dose Escalation Level 2 - 0.25 mcg/kg/Day x 10 Days

Dose Escalation Level 3 - 0.5 mcg/kg/Day x 10 Days

Dose Escalation Level 4 - 1 mcg/kg/Day x 10 Days

Dose Escalation Level 5 - 2 mcg/kg/Day x 10 Days

Dose Escalation Level 6 - 4 mcg/kg/Day x 10 Days

Dose Escalation Level 7 - 3 mcg/kg/Day x 5 Days

Dose Escalation Level 8 - 4 mcg/kg/Day x 5 Days

Dose Escalation Level 9 - 5 mcg/kg/Day x 5 Days

Total

Age, Categorical

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Head and Neck cancer

Sarcoma

Renal Cell carcinoma

Pancreatic cancer

Colorectal cancer

Metastatic Melanoma

Non-Small Cell Lung cancer (NSCLC)

Endometrial

Adrenal

Adenoid Cystic

Cholangiocarcinoma

Gastric neuro-ectodermal

Prostate

Gastrointestinal Stromal Tumor

Small bowel

Esophageal

Diagnosis

Performance status ECOG 0 is normal activity, and 1 is symptoms, but ambulatory.

Performance Status - Eastern Cooperative Oncology Group (ECOG)

Surgery

Chemotherapy

Radiation Therapy

Molecular Therapy

Immunotherapy

Checkpoint Inhibitors

Hormonal Therapy

Prior Therapy

Dr. Kevin C. Conlon

All participants on the following dose levels:

Level 1 - 0.1 mcg/kg/day x 10 Days Level 2 - 0.25 mcg/kg/day x 10 Days Level 3 - 0.5 mcg/kg/day x 10 Days Level 4 - 1 mcg/kg/day x 10 Days Level 5 - 2 mcg/kg/day x 10 Days Level 6 - 4 mcg/kg/day x 10 Days

All Participants

Maximum Tolerated Dose (MTD) of Recombinant Human Interleukin-15 (rhIL-15) for 10 Day Dosing

All participants on the following dose levels:

Level 7 - 3 mcg/kg/day x 5 Days Level 8 - 4 mcg/kg/day x 5 Days Level 9 - 5 mcg/kg/day x 5 Days

Maximum Tolerated Dose (MTD) of Recombinant Human Interleukin-15 (rhIL-15) for 5 Day Dosing

Grade 3

Grade 4

Grade 5

Number of Participants With Grades 3, 4 or 5 Dose-Limiting Toxicity (DLT) Related to Study Drug

Complete Response

Partial Response

Progressive Disease

Stable Disease

Not Assessed

Clinical Response Rate

Dose Escalation Dose Escalation Level 7 - 3 mcg/kg/Day x 5 Days

One participant in dose level 1 and dose level 2, two participants in dose level 3, three participants in dose level 4, two participants in dose level 5, one participant in dose level 6 and dose level 7, and one participant in dose level 9 were not evaluable.

Time to Progression (TTP)

3/4 participants in dose level 1, and 2/3 participants in dose level 2 were not evaluable for this outcome measure. Cmax was only performed for the 10 day dosing cohorts.

Maximum Observed Plasma Concentration (Cmax) of Recombinant Human Interleukin-15 (rhIL-15)

3/4 participants in dose level 1, and 2/3 participants in dose level 2 were not evaluable for this outcome measure. Css was only performed for the 10 day dosing cohorts.

Concentration of Drug in Plasma at Steady State (Css)

3/4 participants in dose level 1, and 2/3 participants in dose level 2 were not evaluable for this outcome measure. AUClast was only performed for the 10 day dosing cohorts.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
GM-CSF as Adjuvant Therapy of Melanoma	NCT00350597	Malignant Melan...	Granulocyte-Mac...	14 Years -	Northern California Melanoma Center
Continuous Infusion of rhIL-15 for Adults With Advanced Cancer	NCT01572493	Lymphoma Carcinoma	rh IL-15 (10 DA... rh IL-15 (5 DAY...	18 Years -	National Institutes of Health Clinical Center (CC)
Biological Therapy in Treating Women With Metastatic Breast Cancer	NCT00002780	Breast Cancer	aldesleukin cytokine therap... sargramostim carboplatin cyclophosphamid... thiotepa peripheral bloo...	18 Years -	National Cancer Institute (NCI)
Biological Therapy in Treating Women With Metastatic Breast Cancer	NCT00002780	Breast Cancer	aldesleukin cytokine therap... sargramostim carboplatin cyclophosphamid... thiotepa peripheral bloo...	18 Years -	National Cancer Institute (NCI)

Spots Global Cancer Trial Database for cytokine therapy