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TLR4 Agonist GLA-SE and Radiation Therapy in Treating Patients With Soft Tissue Sarcoma That Is Metastatic or Cannot Be Removed by Surgery

Primary Purpose

Stage III Adult Soft Tissue Sarcoma, Stage IV Adult Soft Tissue Sarcoma

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Laboratory Biomarker Analysis
Radiation Therapy
TLR4 Agonist GLA-SE
Sponsored by
Fred Hutchinson Cancer Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Stage III Adult Soft Tissue Sarcoma

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • A diagnosis of metastatic or unresectable sarcoma
  • Patient must have a palpable, superficial tumor, safely accessible for bedside injection that will be radiated and can be accurately localized and stabilized if needed
  • Patient must have consulted with a radiation oncologist who is planning radiation; radiation should be completed within a 2-week window from start to finish
  • Patient must be willing to undergo biopsies as specified by the protocol; the biopsy requirement can only be waived if deemed unsafe by the patient's treating physician or the principal investigator (PI)
  • Zubrod (Eastern Cooperative Oncology Group [ECOG]) performance status of '0-2'
  • Serum creatinine =< 1.5 times the upper limit of normal
  • Total bilirubin =< 1.5 times the upper limit of normal
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 times the upper limit of normal
  • Prothrombin time (PT) =< 1.5 times the upper limit of normal
  • Partial thromboplastin time (PTT) =< 1.5 times the upper limit of normal
  • Absolute neutrophil > 1000/uL
  • Platelet count > 75,000/uL
  • For patients who will be entering the "expansion phase" of the trial, the patient must be able to safely delay radiation by at least 6 weeks

Exclusion Criteria:

  • Pregnant women, nursing women, men and women of reproductive ability who are unwilling to use effective contraception or abstinence; women of childbearing potential must have a negative pregnancy test within two weeks prior to study entry
  • Known active symptomatic congestive heart failure
  • Known clinically significant hypotension
  • Known newly diagnosed cardiac arrhythmia; patients with an arrhythmia that has been stable for at least 3 months will be allowed to participate
  • Known untreated central nervous system (CNS) metastasis
  • Patients with known systemic infections requiring antibiotics or chronic maintenance/suppressive therapy
  • Systemic anticancer therapy (chemotherapy, "biologics", immunotherapy) less than two weeks prior to starting radiation
  • Known clinically significant autoimmune disorders requiring on-going systemic immune-suppression for control
  • Current treatment with steroids
  • Patients who are known to be human immunodeficiency virus (HIV) positive must have a normal cluster of differentiation (CD)4 count and undetectable viral load
  • Current treatment with warfarin; for patients not on an anti-platelet agent such as aspirin, other anticoagulation is acceptable so long as the treating physician feels that it is safe to hold it on the day of the biopsy until after the biopsy has been safely completed
  • Known allergy(ies) to any component of the study agent GLA-SE including egg lecithin

Sites / Locations

  • Fred Hutch/University of Washington Cancer Consortium

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment (TLR4 agonist GLA-SE, radiation therapy)

Arm Description

Patients receive TLR4 agonist GLA-SE intratumorally once weekly for 8 weeks. Within 2 weeks of starting treatment, patients also undergo radiation therapy over 2 weeks for a total of 5-6 fractions.

Outcomes

Primary Outcome Measures

Incidence of severe adverse events, defined as any grade 3 or higher adverse event (AE) according to National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03
The highest toxicity grades per patient will be tabulated for AEs and laboratory measurements as will the numbers and percentages of patients reporting AEs.

Secondary Outcome Measures

Change in biomarker outcomes from the peripheral blood
Summary statistics will be used to describe changes across time. In addition, the time course of biomarker outcomes from the peripheral blood will be investigated graphically, by summary plots or individual patient plots. If there is suggestion of meaningful trend, methods such as linear mixed models may be used to characterize the pattern of change over time.
Clinical benefit based on RECIST v1.1 and iRRC evaluations
Categorical data analysis and logistic regression will be used to evaluate the associations between correlative measures and clinical outcome (e.g., response, clinical benefit, time to progression, progression-free survival, and survival).
Immune infiltrates, measured quantitatively as number of cells per unit area
Tumor infiltrating lymphocytes will be analyzed directly by flow and grown in vitro so that functional characteristics can be analyzed. Metrics based on flow cytometry (e.g. cell phenotype and inhibitory receptor expression) will be reported both with respect to the mean florescence intensity of the staining as well as the absolute and relative numbers of positive and negative cells compared with established controls.
Progression free survival
Categorical data analysis and logistic regression will be used to evaluate the associations between correlative measures and clinical outcome (e.g., response, clinical benefit, time to progression, progression-free survival, and survival). Kaplan-Meier methodology and Cox Proportional Hazards models will be used to evaluate time-to-event endpoints.
Response based on Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1 and immune-related-response criteria (iRRC) evaluations
Categorical data analysis and logistic regression will be used to evaluate the associations between correlative measures and clinical outcome (e.g., response, clinical benefit, time to progression, progression-free survival, and survival).
Survival
Categorical data analysis and logistic regression will be used to evaluate the associations between correlative measures and clinical outcome (e.g., response, clinical benefit, time to progression, progression-free survival, and survival). Kaplan-Meier methodology and Cox Proportional Hazards models will be used to evaluate time-to-event endpoints.
Time to progression
Categorical data analysis and logistic regression will be used to evaluate the associations between correlative measures and clinical outcome (e.g., response, clinical benefit, time to progression, progression-free survival, and survival). Kaplan-Meier methodology and Cox Proportional Hazards models will be used to evaluate time-to-event endpoints.

Full Information

First Posted
July 1, 2014
Last Updated
November 4, 2019
Sponsor
Fred Hutchinson Cancer Center
Collaborators
National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT02180698
Brief Title
TLR4 Agonist GLA-SE and Radiation Therapy in Treating Patients With Soft Tissue Sarcoma That Is Metastatic or Cannot Be Removed by Surgery
Official Title
A Phase I Study to Determine the Safety of the Combination of Stable-Emulsion Formulation of Glucopyranosyl Lipid A (GLA-SE) With Radiation in Patients With Metastatic Sarcoma
Study Type
Interventional

2. Study Status

Record Verification Date
November 2019
Overall Recruitment Status
Completed
Study Start Date
November 17, 2014 (Actual)
Primary Completion Date
October 7, 2016 (Actual)
Study Completion Date
October 7, 2016 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Fred Hutchinson Cancer Center
Collaborators
National Cancer Institute (NCI)

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This pilot phase I clinical trial studies the side effects and best dose of toll-like receptor 4 (TLR4) agonist glucopyranosyl lipid A (GLA)-stable-emulsion (SE) when given together with radiation therapy in treating patients with soft tissue sarcoma that has spread to other parts of the body (metastatic) or cannot be removed by surgery (unresectable). TLR4 agonist GLA-SE may stimulate the immune system to kill sarcoma cells. Radiation therapy uses high energy x rays to kill tumor cells. Giving TLR4 agonist GLA-SE with radiation therapy may be a better treatment to treat sarcoma that cannot be removed by surgery.
Detailed Description
PRIMARY OBJECTIVES: I. To evaluate the safety of weekly injections of GLA-SE (TLR4 agonist GLA-SE) in combination with palliative radiation in patients with metastatic sarcoma. SECONDARY OBJECTIVES: I. To look for preliminary evidence of efficacy at distant tumor sites following the combination of radiation and intra-tumor injection of GLA-SE. II. To analyze changes in tumor-immune infiltrates following radiation and intra-tumor injection of GLA-SE. OUTLINE: This is a dose-escalation study of TLR4 agonist GLA-SE. Patients receive TLR4 agonist GLA-SE intratumorally once weekly for 8 weeks. Within 2 weeks of starting treatment, patients also undergo radiation therapy over 2 weeks for a total of 5-6 fractions. After completion of study treatment, patients are followed up every 6 weeks for 6 months and then every 3 months for up to 1 year.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Stage III Adult Soft Tissue Sarcoma, Stage IV Adult Soft Tissue Sarcoma

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
16 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Treatment (TLR4 agonist GLA-SE, radiation therapy)
Arm Type
Experimental
Arm Description
Patients receive TLR4 agonist GLA-SE intratumorally once weekly for 8 weeks. Within 2 weeks of starting treatment, patients also undergo radiation therapy over 2 weeks for a total of 5-6 fractions.
Intervention Type
Other
Intervention Name(s)
Laboratory Biomarker Analysis
Intervention Description
Correlative studies
Intervention Type
Radiation
Intervention Name(s)
Radiation Therapy
Other Intervention Name(s)
Cancer Radiotherapy, Irradiate, Irradiated, Irradiation, RADIATION, Radiotherapeutics, Radiotherapy, RT, Therapy, Radiation
Intervention Description
Undergo radiation therapy
Intervention Type
Drug
Intervention Name(s)
TLR4 Agonist GLA-SE
Other Intervention Name(s)
GLA-SE, Glucopyranosyl Lipid A in Stable Emulsion, Glucopyranosyl Lipid Adjuvant-Stable Emulsion, Toll-like Receptor 4 Agonist GLA-SE
Intervention Description
Given intratumorally
Primary Outcome Measure Information:
Title
Incidence of severe adverse events, defined as any grade 3 or higher adverse event (AE) according to National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03
Description
The highest toxicity grades per patient will be tabulated for AEs and laboratory measurements as will the numbers and percentages of patients reporting AEs.
Time Frame
Up to week 9
Secondary Outcome Measure Information:
Title
Change in biomarker outcomes from the peripheral blood
Description
Summary statistics will be used to describe changes across time. In addition, the time course of biomarker outcomes from the peripheral blood will be investigated graphically, by summary plots or individual patient plots. If there is suggestion of meaningful trend, methods such as linear mixed models may be used to characterize the pattern of change over time.
Time Frame
Baseline up to 1 year
Title
Clinical benefit based on RECIST v1.1 and iRRC evaluations
Description
Categorical data analysis and logistic regression will be used to evaluate the associations between correlative measures and clinical outcome (e.g., response, clinical benefit, time to progression, progression-free survival, and survival).
Time Frame
Up to 1 year
Title
Immune infiltrates, measured quantitatively as number of cells per unit area
Description
Tumor infiltrating lymphocytes will be analyzed directly by flow and grown in vitro so that functional characteristics can be analyzed. Metrics based on flow cytometry (e.g. cell phenotype and inhibitory receptor expression) will be reported both with respect to the mean florescence intensity of the staining as well as the absolute and relative numbers of positive and negative cells compared with established controls.
Time Frame
Up to 1 year
Title
Progression free survival
Description
Categorical data analysis and logistic regression will be used to evaluate the associations between correlative measures and clinical outcome (e.g., response, clinical benefit, time to progression, progression-free survival, and survival). Kaplan-Meier methodology and Cox Proportional Hazards models will be used to evaluate time-to-event endpoints.
Time Frame
Up to 1 year
Title
Response based on Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1 and immune-related-response criteria (iRRC) evaluations
Description
Categorical data analysis and logistic regression will be used to evaluate the associations between correlative measures and clinical outcome (e.g., response, clinical benefit, time to progression, progression-free survival, and survival).
Time Frame
Up to 1 year
Title
Survival
Description
Categorical data analysis and logistic regression will be used to evaluate the associations between correlative measures and clinical outcome (e.g., response, clinical benefit, time to progression, progression-free survival, and survival). Kaplan-Meier methodology and Cox Proportional Hazards models will be used to evaluate time-to-event endpoints.
Time Frame
Up to 1 year
Title
Time to progression
Description
Categorical data analysis and logistic regression will be used to evaluate the associations between correlative measures and clinical outcome (e.g., response, clinical benefit, time to progression, progression-free survival, and survival). Kaplan-Meier methodology and Cox Proportional Hazards models will be used to evaluate time-to-event endpoints.
Time Frame
Up to 1 year

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: A diagnosis of metastatic or unresectable sarcoma Patient must have a palpable, superficial tumor, safely accessible for bedside injection that will be radiated and can be accurately localized and stabilized if needed Patient must have consulted with a radiation oncologist who is planning radiation; radiation should be completed within a 2-week window from start to finish Patient must be willing to undergo biopsies as specified by the protocol; the biopsy requirement can only be waived if deemed unsafe by the patient's treating physician or the principal investigator (PI) Zubrod (Eastern Cooperative Oncology Group [ECOG]) performance status of '0-2' Serum creatinine =< 1.5 times the upper limit of normal Total bilirubin =< 1.5 times the upper limit of normal Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 times the upper limit of normal Prothrombin time (PT) =< 1.5 times the upper limit of normal Partial thromboplastin time (PTT) =< 1.5 times the upper limit of normal Absolute neutrophil > 1000/uL Platelet count > 75,000/uL For patients who will be entering the "expansion phase" of the trial, the patient must be able to safely delay radiation by at least 6 weeks Exclusion Criteria: Pregnant women, nursing women, men and women of reproductive ability who are unwilling to use effective contraception or abstinence; women of childbearing potential must have a negative pregnancy test within two weeks prior to study entry Known active symptomatic congestive heart failure Known clinically significant hypotension Known newly diagnosed cardiac arrhythmia; patients with an arrhythmia that has been stable for at least 3 months will be allowed to participate Known untreated central nervous system (CNS) metastasis Patients with known systemic infections requiring antibiotics or chronic maintenance/suppressive therapy Systemic anticancer therapy (chemotherapy, "biologics", immunotherapy) less than two weeks prior to starting radiation Known clinically significant autoimmune disorders requiring on-going systemic immune-suppression for control Current treatment with steroids Patients who are known to be human immunodeficiency virus (HIV) positive must have a normal cluster of differentiation (CD)4 count and undetectable viral load Current treatment with warfarin; for patients not on an anti-platelet agent such as aspirin, other anticoagulation is acceptable so long as the treating physician feels that it is safe to hold it on the day of the biopsy until after the biopsy has been safely completed Known allergy(ies) to any component of the study agent GLA-SE including egg lecithin
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Seth Pollack
Organizational Affiliation
Fred Hutch/University of Washington Cancer Consortium
Official's Role
Principal Investigator
Facility Information:
Facility Name
Fred Hutch/University of Washington Cancer Consortium
City
Seattle
State/Province
Washington
ZIP/Postal Code
98109
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
35115306
Citation
Goff PH, Riolobos L, LaFleur BJ, Spraker MB, Seo YD, Smythe KS, Campbell JS, Pierce RH, Zhang Y, He Q, Kim EY, Schaub SK, Kane GM, Mantilla JG, Chen EY, Ricciotti R, Thompson MJ, Cranmer LD, Wagner MJ, Loggers ET, Jones RL, Murphy E, Blumenschein WM, McClanahan TK, Earls J, Flanagan KC, LaFranzo NA, Kim TS, Pollack SM. Neoadjuvant Therapy Induces a Potent Immune Response to Sarcoma, Dominated by Myeloid and B Cells. Clin Cancer Res. 2022 Apr 14;28(8):1701-1711. doi: 10.1158/1078-0432.CCR-21-4239.
Results Reference
derived

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TLR4 Agonist GLA-SE and Radiation Therapy in Treating Patients With Soft Tissue Sarcoma That Is Metastatic or Cannot Be Removed by Surgery

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