Patient case: 78-year-old female with sarcoma; genetic feature: MDM2

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

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 OBJECTIVES:
  I. To determine the pathologic complete response 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 safety analysis.
  SECONDARY OBJECTIVES:
  I. To determine the toxicity of T-VEC in combination with radiation in localized soft tissue sarcomas, during neo-adjuvant treatment and post-surgical resection wound complications.
  II. To determine 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.
  TERTIARY OBJECTIVES:
  I. To characterize the clinical outcomes within three distinct histologic subtypes: liposarcoma, leiomyosarcoma and undifferentiated pleomorphic sarcoma.
  II. To characterize the percentage of tumor necrosis in treated tumors. III. To determine if the combination of preoperative T-VEC with radiation will increase the expression of PD-L1 in soft tissue sarcomas.
  IV. To determine the impact of preoperative 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, 3, 5, 7, 9, and 11. 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.

Eligibility: Inclusion Criteria:
  -  Newly diagnosed and histopathologically confirmed (by central pathology review) potentially resectable soft tissue sarcomas of the extremity and trunk of the following subtypes: liposarcoma (excluding myxoid liposarcoma), leiomyosarcoma and undifferentiated pleomorphic sarcoma
  -  An incisional or core biopsy is the preferred method for diagnosis; fine needle aspiration is not acceptable
  -  Sites permissible for biopsy include
  -  Extremities: upper (including shoulder) and lower (including hip)
  -  Trunk: body wall
  -  Sites not permissible for biopsy include
  -  Head and neck, visceral organs, retroperitoneum, peritoneum, pelvis within confines of the bony pelvis
  -  Tumors arising in bone will not be eligible for this study
  -  Patients must have a primary tumor >= 5 cm by magnetic resonance imaging (MRI) or computed tomography (CT) scan
  -  Patients must have histologically confirmed grade 2 or 3 tumors by the French Federation of Cancer Centers Sarcoma Group (FNCLCC) sarcoma grading system
  -  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/L
  -  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
  -  Serum creatinine =< 1.5 x institutional ULN or creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 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
  -  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 tissue and blood samples for correlative studies
  Exclusion Criteria:
  -  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 T-VEC and during the study
  -  Previous treatment with T-VEC or any other oncolytic virus
  -  Known active central nervous system (CNS) metastases; patients with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids > 10 mg/day of prednisone or equivalent
  -  Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to 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 (e.g., acyclovir), other than intermittent topical use
  -  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 T-VEC treatment and through 30 days after the last dose of 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; sexually active patients and their partners must be willing to use male or female latex condoms to avoid potential viral transmission while on treatment and within 30 days after treatment with T-VEC

Relevance to patient case: not relevant