Durvalumab, Tremelimumab, and Radiation Therapy in Treating Participants with High Risk Soft-Tissue Sarcoma
- Written informed consent and any locally-required authorization (e.g., Health Insurance Portability and Accountability Act [HIPAA]) obtained from the subject prior to performing any protocol-related procedures, including screening evaluations
- Patients with a biopsy-proven adult-type high-risk soft tissue sarcoma (STS) in the trunk (non-retroperitoneal) or extremities. Histologies will include the most common adult-type STS such as undifferentiated pleomorphic sarcoma, liposarcoma, leiomyosarcoma, fibrosarcoma, synovial sarcoma, angiosarcoma, epithelioid sarcoma and malignant peripheral nerve sheath tumor. STS considered high-risk as defined below: * Tumors greater than or equal to 5 cm, intermediate or high grade according to French Federation of Comprehensive Cancer Centers (FNCLCC) criteria, and a location deep or superficial to fascia * Intermediate or high-grade tumors that are locally recurrent, metastatic or have had prior inadequate resections * Intermediate and high grade tumors shall be grade 2 or 3 based on FNCLCC parameters (Trojani et al, 1984; Coindre 2006) ** Tumor differentiation *** Score 1 (sarcomas closely resembling normal adult mesenchymal tissue) *** Score 2 (sarcomas for which histological typing is certain) *** Score 3 (embryonal and undifferentiated sarcomas) ** Mitotic count (HPF – high power field – 0.17 mm squared) *** Score 1 (0-9 mitoses per 10 HPF) *** Score 2 (10-19 mitoses per 10 HPF) *** Score 3 (greater than or equal to 20 mitoses per 10 HPF) ** Tumor necrosis *** Score 0 (no necrosis) *** Score 1 (less than 50% tumor necrosis) *** Score 2 (greater than or equal to 50% tumor necrosis) ** Histological grade *** Grade 1 – total score 2 or 3 *** Grade 2 – total score 4 or 5 *** Grade 3 – total score 6, 7 or 8
- Patients must have measurable disease as defined by RECIST v1.1
- Eastern Cooperative Oncology Group (ECOG) performance status 0-1
- Life expectancy of >= 12 weeks based on investigator estimate
- Hemoglobin >= 9.0 g/dL
- Absolute neutrophil count (ANC) >= 1.5 x 10^9/L (>= 1500 per mm^3)
- Platelet count >= 100 x 10^9/L (>= 100,000 per mm^3)
- Serum bilirubin =< 1.5 x institutional upper limit of normal (ULN). (This will not apply to subjects with confirmed Gilbert’s syndrome [persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis or hepatic pathology], who will be allowed only in consultation with their physician)
- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal unless liver metastases are present, in which case it must be =< 5 x ULN
- Serum creatinine clearance (CL) > 40 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of creatinine clearance: * Males: Creatinine CL (mL/min) = Weight (kg) x (140 - Age) / 72 x serum creatinine (mg/dL) * Females: Creatinine CL (mL/min) = (Weight [kg] x [140 - Age] / 72 x serum creatinine [mg/dL]) x 0.85
- Female subjects must either be of non-reproductive potential (i.e., post-menopausal by history: >= 60 years old and no menses for >= 1 year without an alternative medical cause; OR history of hysterectomy, OR history of bilateral tubal ligation, OR history of bilateral oophorectomy) or must have a negative serum pregnancy test upon study entry. If unsure postmenopausal status, hormone levels will be employed to verify
- Females of childbearing potential who are sexually active with a non-sterilized male partner and non-sterilized male subjects who are sexually active with a female partner of childbearing potential must be willing to use 2 methods of effective contraception from time of screening through 180 days after receipt of the final dose of durvalumab + tremelimumab combination therapy or 90 days after receipt of the final dose of durvalumab monotherapy, whichever is the longer time period
- Subject is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up
- To limit the heterogeneity of the tumor population and reduce the risk of masking any clinical effect of the treatment regimen, multiple categories of STS subtypes will be excluded: * Patients with primarily bone-based sarcomas that can occur in the soft tissues, such as: ** Extraskeletal Ewing sarcoma ** Extraskeletal osteosarcoma ** Peripheral chordoma ** Extraskeletal myxoid chondrosarcoma ** Mesenchymal chondrosarcoma * Patients with predominantly low-grade STS, such as: ** Solitary fibrous tumor / hemangiopericytoma ** Well-differentiated liposarcoma ** Dermatofibrosarcoma protuberans ** Kaposi’s sarcoma * Pediatric-type STS such as rhabdomyosarcoma * Gastrointestinal stromal tumors (GIST)
- Retroperitoneal soft tissue sarcomas
- Patients with extra-pulmonary metastases aside from lymph node involvement or with a surgically unresectable primary lesion
- Symptomatic or uncontrolled brain metastases requiring concurrent treatment, inclusive of but not limited to surgery, radiation and/or corticosteroids
- Any previous treatment with an anti-PD-1, anti-PD-L1 or anti-CTLA-4 therapy, including durvalumab and tremelimumab
- History of hypersensitivity to durvalumab or any excipient
- History of hypersensitivity to tremelimumab or any excipient
- History of hypersensitivity to the combination or comparator agent
- History or clinically confirmed pneumonitis or interstitial lung disease
- Receipt of the last dose of anti-cancer therapy (cytotoxic chemotherapy, immunotherapy, endocrine therapy, targeted therapy, biologic therapy, tumor embolization, monoclonal antibodies, other investigational agent) =< 28 days prior to the first dose of study drug (28 days prior to the first dose of study drug for subjects who have received prior tyrosine kinase inhibitors [TKIs] [e.g., erlotinib, gefitinib and crizotinib] and within 6 weeks for nitrosourea or mitomycin C [if sufficient wash-out time has not occurred due to the schedule or pharmacokinetic [PK] properties of an agent, a longer wash-out period may be required])
- Current or prior use of immunosuppressive medication within 28 days before the first dose of durvalumab or tremelimumab, with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid
- Any unresolved toxicity (˃ Common Terminology Criteria for Adverse Events [CTCAE] grade 2) from previous anti-cancer therapy. NOTE: Subjects with irreversible toxicity that is not reasonably expected to be exacerbated by the investigational product may be included (e.g., hearing loss, peripherally neuropathy)
- Any prior immune-related adverse event (irAE) >= grade 2 while receiving any previous immunotherapy agent, or any unresolved irAE > grade 1
- Active or prior documented autoimmune disease within the past 2 years. NOTE: Subjects with vitiligo, Grave’s disease, or psoriasis not requiring systemic treatment (within the past 2 years) are not excluded
- History of primary immunodeficiency
- History of allogeneic organ transplant (e.g. solid organ/bone marrow transplant patients)
- Uncontrolled intercurrent illness including, but not limited to: * Ongoing or active infections * Cardiac conditions, such as: ** Symptomatic congestive heart failure ** Uncontrolled hypertension ** Unstable angina pectoris ** Cardiac arrhythmia * Active peptic ulcer disease or gastritis * History of inflammatory bowel disease, ulcerative colitis or Crohn’s disease * Active bleeding diatheses * Any subject known to have evidence of acute or chronic hepatitis B or hepatitis C. Patients with undetectable viral levels will be allowed * Any subject known to have evidence of human immunodeficiency virus (HIV) or acquired immune deficiency syndrome (AIDS) * Uncontrolled seizures
- Mean QT interval corrected for heart rate (QTc) >= 470 ms calculated from 3 electrocardiograms (ECGs) using Fredericia’s correction
- Known history of current or recent clinical diagnosis of tuberculosis (within 6 months prior to enrollment). A chest XR will be performed to screen for active TB for patients who have a history of treated TB. A chest XR will be performed in all patients to screen for active TB unless there has been a prior chest XR or CT scan of chest within 1 month of entry
- Active or prior documented inflammatory bowel disease (e.g., Crohn’s disease, ulcerative colitis)
- Any signs or symptoms of bowel obstruction within 28 days prior to study entry
- History of leptomeningeal carcinomatosis
- Receipt of live attenuated vaccination within 30 days prior to study entry or within 30 days of receiving durvalumab or tremelimumab, or active infection
- History of psychiatric illness/social situations that would limit compliance with study requirements or compromise the ability of the subject to give written informed consent
- Any condition that, in the opinion of the investigator, would interfere with evaluation of study treatment or interpretation of patient safety or study results
- Previously enrolled in the present study
- Participation in another clinical study with an investigational product during the last 6 months
- Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site)
- Female patients who are pregnant or breastfeeding or male or female patients of reproductive potential who are not willing to employ effective birth control from screening to 180 days after the last dose of durvalumab + tremelimumab combination therapy or 90 days after the last dose of durvalumab monotherapy, whichever is the longer time period
(1) Objective: Phase I component:To evaluate the safety and tolerability of neoadjuvant durvalumab/tremelimumab and radiation therapy in patients with high-risk soft-tissue sarcoma (STS).
(2) Objective: Phase II component: To evaluate the proportion of patients achieving an excellent response (>= 90% necrosis/treatment response) on histopathologic examination of the surgical specimen.
(3) Objective: To evaluate the clinical outcomes of distant relapse, progression of disease, and disease-specific survival with neoadjuvant durvalumab/tremelimumab and radiation therapy (RT) followed by surgical resection.
(4) Objective: To evaluate the histopathologic effect of neoadjuvant durvalumab/tremelimumab and radiation therapy on the primary tumor.
(5) Objective: To evaluate the effect of neoadjuvant durvalumab/tremelimumab and radiation therapy on the primary tumor using Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1 criteria and the immune-related response criteria (irRC).
(6) Objective: To evaluate whether neoadjuvant durvalumab/tremelimumab and radiation therapy produces tumor-specific immune responses within the tumor, the infiltrative margins and surrounding reactive zone, and in the peripheral blood, and whether the strength of these responses correlate with the extent of tumor microsatellite instability and mutagenic burden.
(7) Objective: To evaluate the effect of neoadjuvant durvalumab/tremelimumab and radiation therapy on the primary tumor using Positron Emission Tomography Response Criteria in Solid Tumors (PERCIST) criteria.
Radiation treatment will be given over 5-7 weeks. Tremelimumab is given as a 60 minute infusion followed by an hour break. Then Durvalumab is given, as a 60 minute infusion into a vein (IV). You will receive this combination infusion three times (each time separated by 4 weeks) prior to surgery. One time will be before radiation, one time during the 5-7 weeks of radiation, and one time after radiation. After surgery, you will receive Durvalumab only. Those patients with no detectable tumor will receive 4 doses (separated by 4 weeks each time). Those with detectable tumor will receive 9 doses (separated by 4 weeks each time). If your cancer is getting worse, if you need different treatment, or if you have bad side effects, your immunotherapy treatment may be stopped in favor of different treatment. Researchers will follow you for up to two years after you stop study treatment (your doctor will follow you for longer periods of time for routine monitoring of the cancer) and after you stop taking the immunotherapy drugs, the study staff will continue to contact you to see how you are doing.
This is an open-label study, which means that everyone in the study will get radiation and Durvalumab/Tremelimumab followed by surgical tumor removal and then Durvalumab after surgery.
Trial Phase Phase I/II
Trial Type Treatment
University of Maryland / Greenebaum Cancer Center
Vincent Y. Ng
- Primary ID 1711GCCC
- Secondary IDs NCI-2018-01048
- Clinicaltrials.gov ID NCT03116529