Talimogene Laherparepvec and Radiation Therapy in Treating Patients With Newly Diagnosed Soft Tissue Sarcoma That Can Be Removed by Surgery

Soft Tissue Sarcoma Clinical Trial

Official title:

A Phase 2 Study of Talimogene Laherparepvec (T-VEC) and Radiation in Localized Soft Tissue Sarcoma

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT02923778
• Other study ID #: NCI-2016-01461
• Secondary ID: NCI-2016-01461MC
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: December 31, 2019
• Est. completion date: December 1, 2024

Study information

• Verified date: June 2024
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This phase II trial studies the side effects of talimogene laherparepvec and radiation therapy and to see how well they work in treating patients with newly diagnosed soft tissue sarcoma that can be removed by surgery (resectable). Biological therapies, such as talimogene laherparepvec, use substances made from living organisms that may stimulate or suppress the immune system in different ways and stop cancer cells from growing. Radiation therapy uses high energy x-rays, photons. electrons, or protons to kill tumor cells and shrink tumors. Giving talimogene laherparepvec and radiation therapy may work better in treating patients with soft tissue sarcoma.

Description:

PRIMARY OBJECTIVE:

I. To estimate the pathologic complete necrosis rate (the number of patients with >= 95% necrosis divided by the number of evaluable patients) following preoperative treatment with talimogene laherparepvec (T-VEC) in combination with radiation in patients with localized soft tissue sarcoma including a pre-planned interim safety analysis to assess post-surgical wound complications.

SECONDARY OBJECTIVES:

I. To estimate the toxicity of talimogene laherparepvec (T-VEC) in combination with radiation in localized soft tissue sarcomas, during neo-adjuvant treatment and post-surgical resection wound complications.

II. To estimate the rate of radiologic response, prior to surgery, and extent of surgical resection.

III. To estimate time to surgery, time to progression, time to recurrence, and death.

CORRELATIVE OBJECTIVES:

I. To characterize the clinical outcomes within three distinct histologic subtypes:

liposarcoma (excluding myxoid liposarcoma), leiomyosarcoma and undifferentiated pleomorphic sarcoma.

II. To characterize the percentage of tumor necrosis in treated tumors. III. To assess if the combination of preoperative talimogene laherparepvec (T-VEC) with radiation will increase the expression of PD-L1 in soft tissue sarcomas.

IV. To assess the impact of preoperative talimogene laherparepvec (T-VEC) with radiation on the tumor infiltrating and circulating immune cells in patients with soft tissue sarcomas.

OUTLINE:

Patients receive talimogene laherparepvec intratumorally (IT) or via intralesional injection at weeks 1, 4, 6 and 8. Beginning 1 week after the start of talimogene laherparepvec, patients undergo radiation therapy on Monday-Friday of weeks 2-6. Patients undergo collection of blood and a tumor biopsy on study and undergo magnetic resonance imaging (MRI) throughout the trial.

After completion of study treatment, patients are followed up every 3 months for 2 years, every 6 months for 3 years, and then every year for up to 5 years.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 40
• Est. completion date: December 1, 2024
• Est. primary completion date: December 1, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Age >= 18 years

• Note: Because no dosing or adverse event data are currently available on the use of talimogene laherparepvec (T-VEC) in patients < 18 years of age, children are excluded from this study, but will be eligible for future pediatric trials

• Newly diagnosed and a histopathologically confirmed potentially resectable soft tissue sarcoma of the extremity or trunk of the following subtypes:

• Cohort 1: liposarcoma (excluding myxoid liposarcoma)

• Cohort 2: leiomyosarcoma

• Cohort 3: undifferentiated pleomorphic sarcoma (UPS) (malignant fibrous histiosarcoma [MFH])

• NOTE: If local pathology report is suggestive of or suspicious for UPS, study chair and study pathologists may review for eligibility determination.

• NOTE: Sites permissible for biopsy include

• Extremities: upper (including shoulder) and lower (including hip)

• Trunk: Body wall

• Patients must have a histologically determined grade 2 or 3 tumor by the French Federation of Cancer Centers Sarcoma Group (FNCLCC) sarcoma grading system

• Patients must have localized disease with a primary tumor > 5 cm by MRI or computed tomography (CT) scan

• Patients must have a primary tumor that is determined by multidisciplinary team (medical oncology, orthopedic/surgical oncology, and radiation oncology) to require radiation therapy for optimal management prior to surgical resection

• Patients must have a sarcoma in the extremity or trunk in location, which is accessible to direct or ultrasound guided injections

• Karnofsky performance score >= 70

• Absolute neutrophil count (ANC) >= 1500/uL

• Absolute lymphocyte count (ALC) >= 800/uL

• Platelets >= 100,000/uL

• Hemoglobin >= 9 g/dL

• Total bilirubin =< 1.5 x institutional upper limit of normal (ULN)

• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x institutional ULN

• Calculated creatinine clearance > 70 mL/min/1.73 m^2

• Patient must have a life expectancy of at least 3 months with appropriate therapy

• Patients must agree to use contraception during study treatment and for 4 months after the end of treatment

• NOTE: Talimogene laherparepvec (T-VEC), as well as other therapeutic agents used in this trial, may cause fetal harm when administered to a pregnant woman; women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, during the study participation, and for four months after the last dose of the drug; women of child-bearing potential must have a negative serum pregnancy test within 7 days prior to registration and agree to use effective contraception throughout the treatment period and for 4 months after the last dose of study treatment; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately

• Ability to understand and the willingness to sign a written informed consent document

• Willingness to provide mandatory blood and tissue samples for correlative studies and central pathology confirmation of surgical specimens collected during study participation

• Willingness to provide a tissue sample that is mandatory at the time of surgery (if applicable) and the determination of the primary objective of the study

Exclusion Criteria:

• Patients with localized sarcomas that are not of the extremity or trunk wall (including head/neck, retroperitoneum, visceral organs, peritoneum, pelvis within the confines of the bony pelvis, and tumors arising in bone)

• Patients who have had prior treatment with anti-PD1 or anti-CTLA4 therapy

• Patients with grade 1 non-rhabdomyosarcoma soft tissue sarcomas (NRSTS) tumors of any size are not eligible

• Patients with evidence of active bleeding or bleeding diathesis will be excluded (patients with excess of 2.5 mL of hemoptysis are not eligible)

• Patients requiring any therapeutic anticoagulation

• Patients must have had no prior radiotherapy to tumor-involved sites

• Patients with gross total resection of the primary tumor or who have developed tumor recurrence after gross total tumor resection prior to enrollment are not eligible

• History of serious or non-healing wound, ulcer, or bone fracture

• Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities > grade 1)

• Use of other investigational drugs within 28 days (or five half-lives, whichever is shorter; with a minimum of 14 days from the last dose) preceding the first dose of talimogene laherparepvec (T-VEC) and during the study

• Previous treatment with talimogene laherparepvec (T-VEC) or any other oncolytic virus

• Patients with metastatic disease

• Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to talimogene laherparepvec (T-VEC) or any of its components

• History or evidence of active autoimmune disease (e.g., pneumonitis, glomerulonephritis, vasculitis, or other); or history of active autoimmune disease that has required systemic treatment (i.e., use of corticosteroids, immunosuppressive drugs or biological agents used for treatment of autoimmune diseases) within 2 months of enrollment; (replacement therapy [e.g., thyroxine for hypothyroidism, insulin for diabetes or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency] is not considered a form of systemic treatment for autoimmune disease)

• Evidence of clinically significant immunosuppression such as

• Primary immunodeficiency state such as severe combined immunodeficiency disease

• Concurrent opportunistic infection

• Receiving systemic immunosuppressive therapy (> 2 weeks) including oral steroid doses > 10 mg/day of prednisone or equivalent within 2 months prior to enrollment

• Active herpetic skin lesions or prior complications of herpetic infection (e.g., herpetic keratitis or encephalitis)

• Viral infections requiring intermittent or chronic systemic (intravenous or oral) treatment with an anti-herpetic drug, other than intermittent topical use (e.g., acyclovir)

• Other viral infections

• Known to have acute or chronic active hepatitis B or hepatitis C infection

• Known to have human immunodeficiency virus (HIV) infection

• Prior therapy with viral-based tumor vaccine

• Received live vaccine within 28 days prior to enrollment

• Patients who are unwilling to minimize exposure with his/her blood or other body fluids to individuals who are at higher risks for herpes simplex virus (HSV)-1 induced complications such as immunosuppressed individuals, individuals known to have HIV infection, pregnant women, or children under the age of 1 year, during talimogene laherparepvec (T-VEC) treatment and through 30 days after the last dose of talimogene laherparepvec (T-VEC)

• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements

• Patients who are pregnant, breastfeeding or plan to become pregnant

• NOTE: Although no effects on embryo-fetal development have been observed in animal studies, adequate and well-controlled studies with talimogene laherparepvec (T-VEC) have not been conducted in pregnant women; therefore, sexually active patients and their partners must be willing to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, during the study participation, and for four months after the last dose of T-VEC

Related Conditions & MeSH terms

• Histiocytoma, Malignant Fibrous
• Leiomyosarcoma
• Liposarcoma
• Sarcoma
• Soft Tissue Sarcoma
• Soft Tissue Sarcoma of the Trunk and Extremities
• Stage I Soft Tissue Sarcoma AJCC v7
• Stage II Soft Tissue Sarcoma AJCC v7
• Undifferentiated Pleomorphic Sarcoma

Intervention

Procedure:
• Biopsy
Undergo tumor biopsy
• Biospecimen Collection
Undergo collection of blood
• Magnetic Resonance Imaging
Undergo MRI

Radiation:
• Radiation Therapy
Undergo radiation therapy

Biological:
• Talimogene Laherparepvec
Given IT or via intralesional injection

Locations

Country	Name	City	State
Canada	University Health Network-Princess Margaret Hospital	Toronto	Ontario
United States	Ohio State University Comprehensive Cancer Center	Columbus	Ohio
United States	Siteman Cancer Center at West County Hospital	Creve Coeur	Missouri
United States	City of Hope Comprehensive Cancer Center	Duarte	California
United States	M D Anderson Cancer Center	Houston	Texas
United States	Mayo Clinic in Florida	Jacksonville	Florida
United States	Dartmouth Hitchcock Medical Center/Dartmouth Cancer Center	Lebanon	New Hampshire
United States	University of Miami Miller School of Medicine-Sylvester Cancer Center	Miami	Florida
United States	Vanderbilt University/Ingram Cancer Center	Nashville	Tennessee
United States	Laura and Isaac Perlmutter Cancer Center at NYU Langone	New York	New York
United States	UC Irvine Health/Chao Family Comprehensive Cancer Center	Orange	California
United States	Mayo Clinic Hospital in Arizona	Phoenix	Arizona
United States	Virginia Commonwealth University/Massey Cancer Center	Richmond	Virginia
United States	Mayo Clinic in Rochester	Rochester	Minnesota
United States	Siteman Cancer Center-South County	Saint Louis	Missouri
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	Moffitt Cancer Center	Tampa	Florida

Sponsors (1)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)

Countries where clinical trial is conducted

United States,  Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Clinical outcomes within liposarcoma, leiomyosarcoma, and undifferentiated pleomorphic sarcoma		Up to 5 years
Other	Percentage of tumor necrosis in treated tumors	Summary statistics and frequency tables will be used to describe tumor necrosis. T-tests, logistic regression, and non-parametric methods, if required, may be used.	Up to 5 years
Other	Change in PD-L1 expression		Baseline to time of surgery
Other	Change in tumor infiltrating and circulating immune cells		Baseline to time of surgery
Primary	Pathologic complete response (CR) rate	Will be defined as >= 95% of tumor having necrosis. The estimated pathologic CR rate and a 95% confidence interval will be reported.	Up to 5 years
Primary	Incidence of post-surgical wound complications	Evaluated according to National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.	Up to 4 months post-surgery
Secondary	Incidence of toxicities of T-VEC in combination with radiation therapy	Will be evaluated according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Summary statistics and frequency tables will be used to describe the distributions of the observed adverse events occurring pre-surgery and following surgery. All patients having initiated study treatment will be considered evaluable for toxicity analysis.	Up to 5 years
Secondary	Rate of radiologic response	Will be evaluated according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Estimates and confidence intervals will be used to summarize the observed rate of radiologic response.	Up to 5 years
Secondary	Rate of surgical response	Will be evaluated according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Estimates and confidence intervals will be used to summarize the observed rate of surgical response.	Up to 5 years
Secondary	Time to surgery	Will be estimated using Kaplan-Meier methodology.	From registration date until surgery, assessed up to 5 years
Secondary	Time to progression	Will be estimated using Kaplan-Meier methodology.	From registration date until disease progression, assessed up to 5 years
Secondary	Time to recurrence	Will be estimated using Kaplan-Meier methodology in only those patients having achieved a complete surgical resection.	From registration date until disease recurrence, assessed up to 5 years
Secondary	Time to death	Will be estimated using Kaplan-Meier methodology.	From registration date until death, assessed up to 5 years