Soft Tissue Sarcoma
Conditions
Brief summary
The goal of this clinical research study is to look at the effectiveness of giving a combination of chemotherapy, immunotherapy, radiation therapy, and surgery to treat soft tissue sarcomas that can be removed by surgery. Researchers want to find out if this treatment combination can extend the time it takes for the disease to relapse (come back after treatment). The safety of this treatment combination will also be studied.
Detailed description
Primary Objective: The primary objective is to determine time-to relapse (TTR) for patients with high-risk localized, resectable soft tissue sarcomas treated with neoadjuvant doxorubicin chemotherapy with concurrent atezolizumab, followed by preoperative radiotherapy plus atezolizumab, followed by surgery and additional adjuvant atezolizumab. Secondary Objectives: To estimate TTR in each histologic type of disease included. To assess the pathologic response on pre-treatment (diagnostic biopsy), mid-treatment (afterneoadjuvant chemotherapy + immunotherapy), and surgical specimen (after pre-operative RT) in the overall cohort and each histologic type separately by percent viable tumor cells, percent tumor necrosis, and the presence of fibrosis and hyalinization. To assess the objective response rate (ORR) of neoadjuvant atezolizumab and doxorubicin combination therapy and preoperative radiation therapy with atezolizumab by imaging (RECIST 1.1) before surgical resection in the overall cohort and each histologic type separately. To assess the 12-, 24-month, and 60-month local recurrence-free survival (LRFS), distantmetastasis-free survival (DFMS), event-free survival (EFS) and overall survival (OS) of patients in the overall cohort and each histologic type separately. To evaluate the safety of atezolizumab combination therapy with doxorubicin in the neoadjuvant setting, with radiation in the preoperative setting, and as a monotherapy in the adjuvant setting by CTCAE version 5.0 criteria. To assess acute and late radiation toxicities as per the CTCAE, including the development of major wound complications (MWCs) following surgery. Peripheral limb edema will be documented according to the Late Limb Edema Scoring Criteria. Provider-scored extremity function and patient-scored functional assessment will be documented according to the Musculoskeletal Tumour Society Rating Scale (MSTS) and the Toronto Extremity Salvage Score (TESS), respectively. Exploratory Objective: We will aim to profile the tumor immune microenvironment by assessing the immune infiltrate at baseline and in response to neoadjuvant atezolizumab and doxorubicin combination therapy and preoperative radiation therapy with atezolizumab. Investigators will profile the tumor immune microenvironment by immunohistochemistry (IHC) and by performing multiplex immunofluorescence analyses (mIF) including quantitative assessment of tertiary lymphoid structures (TLS), CD20 B-cells, CD8 T cells and PD-L1 expression levels. Investigators will also use immune deconvolution of bulk RNA sequencing (RNAseq) to evaluate the Sarcoma Immune Classes (SIC) and other validated immune signatures. Investigators will also profile intratumoral CD4T, CD8T cell receptor diversity by TCR deep sequencing. Investigators will collaborate with our APOLLO and MOSAIQ rare tumors program here at MD Anderson to achieve the bulk of these exploratory aims as our patients will co-consent to protocol 2014-0938 (Longitudinal Biospecimen Acquisition for All Tumor Types And At-Risk Tissue) for tissue and blood collection. The workflow will be as per below.
Interventions
DRUGAtezolizumab
Given by IV
DRUGDoxorubicin Hydrochloride
Given by IV
Sponsors
M.D. Anderson Cancer Center
Genentech, Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Adult subjects (Age ≥18 years) with treatment-naïve de novo or locally recurrent soft tissue sarcomas of the extremity or superficial trunk * Histological diagnosis of grade 2 or grade 3 undifferentiated pleomorphic sarcoma (UPS), myxofibrosarcoma (MFS), de-differentiated/pleomorphic liposarcoma (DDLPS), unclassified sarcoma, and leiomyosarcoma. Pathologic terms for the "unclassified sarcoma" histology may include pleomorphic undifferentiated sarcoma, unclassified spindle cell sarcoma, spindle cell sarcoma not otherwise specified, pleomorphic spindle cell sarcoma, or pleomorphic fibroblastic sarcoma. * Patient must have recent imaging (CT or MRI, as appropriate) within 8 weeks of trial enrollment demonstrating measurable disease, defined as at least one lesion that can be ccurately measured in at least one dimension (longest diameter to be recorded) as \>5 cm. * Patients must have disease determined to be surgically resectable and candidates for upfront surgery as agreed upon by a multidisciplinary consensus (Surgical Oncology, Medical Oncology, Radiation Oncology) after presentation at sarcoma multidisciplinary conference. Resectable tumors are defined as having no significant vascular, neural, or bony involvement. Only cases where a complete surgical resection can safely be achieved are defined as resectable. * Patients must have life expectancy \> 6 months. * ECOG performance status ≤2 (Karnofsky ≥60%) * For patients receiving therapeutic anticoagulation: stable anticoagulant regimen * Patients must have adequate organ and marrow function as defined below: absolute neutrophil count ≥1,000/mcL platelets ≥100,000/mcL total bilirubin ≤ institutional upper limit of normal (ULN) AST(SGOT)/ALT(SGPT) ≤3 × institutional ULN creatinine ≤ eGFR ≥40 ml/min * Negative HIV test at screening, with the following exception: patients with a positive HIV test at screening are eligible provided they are stable on anti-retroviral therapy, have a CD4 count ≥ 200/L, and have an undetectable viral load * Negative hepatitis B surface antigen (HBsAg) test at screening (if relevant) * Negative hepatitis C virus (HCV) antibody test at screening, or positive HCV antibody test followed by a negative HCV RNA test at screening (if relevant) a. The HCV RNA test must be performed for patients who have a positive HCV antibody test. * Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2B or better. * The effects of Atezolizumab on the developing human fetus are unknown. For this reason and because doxorubicin as used in this trial is known to be teratogenic, women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. (Refer to Pregnancy Assessment Policy MD Anderson Institutional Policy # CLN1114). This includes all female patients, between the onset of menses (as early as 8 years of age) and 55 years unless the patient presents with an applicable exclusionary factor which may be one of the following: * Postmenopausal (no menses in greater than or equal to 12 consecutive months). * History of hysterectomy or bilateral salpingo-oophorectomy. * Ovarian failure (Follicle Stimulating Hormone and Estradiol in menopausal range) * History of bilateral tubal ligation or another surgical sterilization procedure. * For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods, and agreement to refrain from donating eggs, as defined below: * Women must remain abstinent or use contraceptive methods with a failure rate of 1% per year during the treatment period and for 5 months after the final dose of atezolizumab after the final dose of doxorubicin. Women must refrain from donating eggs during this same period. * A woman is considered to be of childbearing potential if she is post-menarchal, has not reached a postmenopausal state (≥ 12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (removal of ovaries, fallopian tubes and/or uterus) or another cause as determined by the investigator (e.g., Müllerian agenesis). Per this definition, a woman with a tubal ligation is considered to be of childbearing potential. The definition of childbearing potential may be adapted for alignment with local guidelines or requirements. a. Examples of contraceptive methods with a failure rate of 1% per year include: i. bilateral tubal ligation ii. male sterilization iii. hormonal contraceptives that inhibit ovulation iv. hormone-releasing intrauterine devices v. copper intrauterine devices. * The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or post ovulation methods) and withdrawal are not adequate methods of contraception. If required per local guidelines or regulations, locally recognized adequate methods of contraception and information about the reliability of abstinence will be described in the local Informed Consent Form. * Ability to understand and the willingness to sign a written informed consent document.
Exclusion criteria
* Disease that is considered surgically unresectable, including, but not limited to significant vascular, neural, or bone involvement, and in cases where a complete surgical resection cannot be safely performed. * Prior chemotherapy or targeted small molecule therapy for the current sarcoma. History of previous systemic treatments for other cancers is allowable. This
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Safety and Adverse Events (AEs) | Through study completion; an average of 1 year. | Incidence of Adverse Events, Graded According to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version (v) 5.0 |
Countries
United States
Contacts
CONTACTAhsan S Farooqi, MD, PHD
PRINCIPAL_INVESTIGATORAhsan S Farooqi, MD, PHD
M.D. Anderson Cancer Center
Outcome results
None listed