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

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ClinicalTrials.gov Identifier: NCT02923778
Recruitment Status : Recruiting
First Posted : October 5, 2016
Last Update Posted : May 12, 2020
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Tracking Information
First Submitted Date  ICMJE October 4, 2016
First Posted Date  ICMJE October 5, 2016
Last Update Posted Date May 12, 2020
Actual Study Start Date  ICMJE August 15, 2017
Estimated Primary Completion Date December 1, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 31, 2019)
  • Pathologic complete response (CR) rate [ Time Frame: Up to 5 years ]
    Will be defined as >= 95% of tumor having necrosis. The estimated pathologic CR rate and a 95% confidence interval will be reported.
  • Incidence of post-surgical wound complications [ Time Frame: Up to 4 months post-surgery ]
    Evaluated according to National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.
Original Primary Outcome Measures  ICMJE
 (submitted: October 4, 2016)
  • Incidence of post-surgical wound complications evaluated according to National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 [ Time Frame: Up to 4 months post-surgery ]
  • Pathologic complete response (CR) rate defined as >= 95% of tumor having necrosis [ Time Frame: Up to 5 years ]
    The estimated pathologic CR rate and a 95% confidence interval will be reported.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: May 31, 2019)
  • Incidence of toxicities of T-VEC in combination with radiation therapy [ Time Frame: Up to 5 years ]
    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.
  • Rate of radiologic response [ Time Frame: Up to 5 years ]
    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.
  • Rate of surgical response [ Time Frame: Up to 5 years ]
    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.
  • Time to surgery [ Time Frame: From registration date until surgery, assessed up to 5 years ]
    Will be estimated using Kaplan-Meier methodology.
  • Time to progression [ Time Frame: From registration date until disease progression, assessed up to 5 years ]
    Will be estimated using Kaplan-Meier methodology.
  • Time to recurrence [ Time Frame: From registration date until disease recurrence, assessed up to 5 years ]
    Will be estimated using Kaplan-Meier methodology in only those patients having achieved a complete surgical resection.
  • Time to death [ Time Frame: From registration date until death, assessed up to 5 years ]
    Will be estimated using Kaplan-Meier methodology.
Original Secondary Outcome Measures  ICMJE
 (submitted: October 4, 2016)
  • Incidence of toxicities of T-VEC in combination with radiation therapy evaluated according to NCI CTCAE version 4.0 [ Time Frame: Up to 5 years ]
    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.
  • Rate of radiologic response evaluated according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 [ Time Frame: Up to 5 years ]
    Estimates and confidence intervals will be used to summarize the observed rate of radiologic response.
  • Rate of surgical response evaluated according to RECIST version 1.1 [ Time Frame: Up to 5 years ]
    Estimates and confidence intervals will be used to summarize the observed rate of surgical response.
  • Time to death [ Time Frame: From registration date until death, assessed up to 5 years ]
    Will be estimated using Kaplan-Meier methodology.
  • Time to progression [ Time Frame: From registration date until disease progression, assessed up to 5 years ]
    Will be estimated using Kaplan-Meier methodology.
  • Time to recurrence [ Time Frame: From registration date until disease recurrence, assessed up to 5 years ]
    Will be estimated using Kaplan-Meier methodology in only those patients having achieved a complete surgical resection.
  • Time to surgery [ Time Frame: From registration date until surgery, assessed up to 5 years ]
    Will be estimated using Kaplan-Meier methodology.
Current Other Pre-specified Outcome Measures
 (submitted: May 31, 2019)
  • Clinical outcomes within liposarcoma, leiomyosarcoma, and undifferentiated pleomorphic sarcoma [ Time Frame: Up to 5 years ]
  • Percentage of tumor necrosis in treated tumors [ Time Frame: Up to 5 years ]
    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.
  • Change in PD-L1 expression [ Time Frame: Baseline to time of surgery ]
  • Change in tumor infiltrating and circulating immune cells [ Time Frame: Baseline to time of surgery ]
Original Other Pre-specified Outcome Measures
 (submitted: October 4, 2016)
  • Change in PD-L1 expression [ Time Frame: Baseline to time of surgery ]
  • Change in tumor infiltrating and circulating immune cells [ Time Frame: Baseline to time of surgery ]
  • Clinical outcomes within liposarcoma, leiomyosarcoma, and undifferentiated pleomorphic sarcoma [ Time Frame: Up to 5 years ]
  • Percentage of tumor necrosis in treated tumors [ Time Frame: Up to 5 years ]
    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.
 
Descriptive Information
Brief Title  ICMJE Talimogene Laherparepvec and Radiation Therapy in Treating Patients With Newly Diagnosed Soft Tissue Sarcoma That Can Be Removed by Surgery
Official Title  ICMJE A Phase 2 Study of Talimogene Laherparepvec (T-VEC) and Radiation in Localized Soft Tissue Sarcoma
Brief 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. 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.
Detailed 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 determine 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) at weeks 1, 4, 6 and 8. Beginning 8-10 days after start of talimogene laherparepvec, patients undergo radiation therapy at weeks 2-6.

After completion of study treatment, patients are followed up at 60 days, every 3 months for 2 years, every 6 months for 1 year, and then every year for up to 5 years.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • FNCLCC Sarcoma Grade 2
  • FNCLCC Sarcoma Grade 3
  • Leiomyosarcoma
  • Liposarcoma
  • Stage I Soft Tissue Sarcoma AJCC v7
  • Stage IA Soft Tissue Sarcoma AJCC v7
  • Stage IB Soft Tissue Sarcoma AJCC v7
  • Stage II Soft Tissue Sarcoma AJCC v7
  • Stage IIA Soft Tissue Sarcoma AJCC v7
  • Stage IIB Soft Tissue Sarcoma AJCC v7
  • Undifferentiated Pleomorphic Sarcoma
Intervention  ICMJE
  • Other: Laboratory Biomarker Analysis
    Correlative studies
  • Radiation: Radiation Therapy
    Undergo radiation therapy
    Other Names:
    • Cancer Radiotherapy
    • Irradiate
    • Irradiated
    • Irradiation
    • Radiation
    • Radiation Therapy, NOS
    • Radiotherapeutics
    • Radiotherapy
    • RT
    • Therapy, Radiation
  • Biological: Talimogene Laherparepvec
    Given IT
    Other Names:
    • ICP34.5-, ICP47-deleted Herpes Simplex Virus 1 (HSV-1) Incorporating the Human GM-CSF Gene
    • Imlygic
    • JS1 34.5-hGMCSF 47- pA-
    • T-VEC
Study Arms  ICMJE Experimental: Treatment (talimogene laherparepvec, radiation therapy)
Patients receive talimogene laherparepvec IT at weeks 1, 4, 6 and 8. Beginning 8-10 days after start of talimogene laherparepvec, patients undergo radiation therapy at weeks 2-6.
Interventions:
  • Other: Laboratory Biomarker Analysis
  • Radiation: Radiation Therapy
  • Biological: Talimogene Laherparepvec
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: October 4, 2016)
40
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 1, 2020
Estimated Primary Completion Date December 1, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • PRE-REGISTRATION ELIGIBILITY CRITERIA:
  • 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 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)
  • 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 FNCLCC sarcoma grading system
  • Ability to understand and the willingness to sign a written informed consent document.
  • ELIGIBILITY CRITERIA:
  • Patient has been confirmed (through the protocol specified central review process to have newly diagnosed and a histopathologically 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)
  • Patient must have a histologically determined grade 2 or 3 tumor (through the protocol specified central review process) by the French Federation of Comprehensive Cancer Centers (FNCLCC) sarcoma grading system
  • Patients must have localized disease with a primary tumor >= 5 cm by magnetic resonance imaging (MRI) or computed tomography (CT) scan
  • Patients must have a primary tumor that are 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 14 days prior to randomization 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
  • 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 therapeutic anticoagulation
  • Patients must have had no prior radiotherapy to tumor-involved sites
  • Patients with gross total resection of the primary tumor prior to enrollment are not eligible; patients who have experienced tumor recurrence after gross total tumor resection 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; 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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02923778
Other Study ID Numbers  ICMJE NCI-2016-01461
NCI-2016-01461 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
MC1678
10056 ( Other Identifier: Mayo Clinic Cancer Center LAO )
10056 ( Other Identifier: CTEP )
UM1CA186686 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party National Cancer Institute (NCI)
Study Sponsor  ICMJE National Cancer Institute (NCI)
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Steven I Robinson Mayo Clinic Cancer Center LAO
PRS Account National Cancer Institute (NCI)
Verification Date May 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP