Radiation and Dostarlimab after Surgery for the Treatment of Endometrial Cancer
This phase II trial studies the effects of radiation therapy and dostarlimab in treating patients with endometrial cancer after they receive surgery. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. TSR-042 (also called dostarlimab) is an antibody, like the proteins made by the immune system to protect the body from harm. TSR-042 blocks the protein PD-1 (programmed cell death receptor 1) that usually acts as a “brake” on the immune system. Blocking this protein is like releasing the brakes, so that the immune system can target cancer cells and destroy them. Giving radiation therapy and dostarlimab in combination may work better than standard of care radiation therapy and chemotherapy in treating patients with endometrial cancer.
Inclusion Criteria
- Age 18 years or older
- Eastern Cooperative Oncology Group (ECOG) performance status 0-1
- Endometrial cancer: all histologies (submission of pathology report is required for all patients who underwent surgery outside of Memorial Sloan Kettering [MSK])
- MMR-D or MSI-H (submission of report[s] required for patients who underwent testing outside of MSK) * Patients with hypermethylation of MMR gene promoters (MLH1, MSH2, MSH6 or PMS2) will be included * POLE-mutated endometrial cancers will be included
- Must have undergone a complete surgical staging and have stage III/IVA disease. * Patients with measurable disease (Response Evaluation Criteria in Solid Tumors [RECIST] 1.1) after surgery are NOT eligible. * Patients with stage IIIB and IIIC2 are not eligible * Patients with isolated tumor cells in lymph nodes found on surgery will be counted as clinical stage III disease
- Surgery completed between 3 weeks and 12 weeks (inclusive) before cycle 1 day 1 of therapy, and must have adequately recovered from surgery and any complications of surgery
- Has a negative serum pregnancy test within 7 days prior to taking study treatment if of childbearing potential, and agrees use an adequate method of contraception from screening through 150 days after the last dose of study treatment, or is of nonchildbearing potential. Nonchildbearing potential is defined as follows (by other than medical reasons): * >= 45 years of age and has not had menses for > 1 year * Patients who have been amenorrhoeic for < 2 years without history of a hysterectomy and oophorectomy must have a follicle stimulating hormone value in the postmenopausal range upon screening evaluation * Post-hysterectomy, post-bilateral oophorectomy, or post-tubal ligation. Documented hysterectomy or oophorectomy must be confirmed with medical records of the actual procedure or confirmed by an ultrasound. Tubal ligation must be confirmed with medical records of the actual procedure, otherwise the patient must be willing to use an adequate birth control method throughout the study, starting with the screening visit through 150 days after the last dose of study treatment. See list of acceptable birth control methods. Information must be captured appropriately within the site's source documents. Note: Abstinence is acceptable if this is the established and preferred contraception for the patient
- Participant must agree to not breastfeed during the study or for 150 days after the last dose of study treatment
- Absolute neutrophil count (ANC) >= 1,500 /mcL (within 14 days of treatment initiation)
- Platelets >= 100,000 / mcL (within 14 days of treatment initiation)
- Hemoglobin >= 9 g/dL (within 14 days of treatment initiation)
- Creatinine clearance glomerular filtration rate (GFR) >= 45 (within 14 days of treatment initiation)
- Serum total bilirubin =< 1.5 x upper limit of normal (ULN) (patients with known Gilbert’s disease who have bilirubin level =< 3 x ULN may be enrolled)
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3 ULN
- Thyroid stimulating hormone (TSH) within normal limits. If TSH is not within normal range despite no symptoms of thyroid dysfunction, normal free T4 level is required.
Exclusion Criteria
- Has had prior chemotherapy, targeted therapy, or investigational therapy for endometrial cancer * Patients who have received prior chemotherapy, targeted therapy, or other investigational therapies for other cancers and are in remission/cured may be included at the discretion of the treating investigator in consultation with the study PI
- Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-CTLA-4 agent for endometrial cancer
- Unfit for radiation therapy due to the following: * Has had radiation therapy encompassing > 20% of the bone marrow within 2 weeks; or any radiation therapy within 1 week prior to day 1 of protocol therapy * Patients with a prior history of pelvic radiation * Patients with a prior known history or current diagnosis of a vesicovaginal, enterovaginal, or colovaginal fistula * Any hematological abnormality or disorder that would be a contraindication to radiation per the treating physician
- Hypersensitivity to TSR-042 or any of its excipients
- Patients with diagnosis of immunodeficiency or patients receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment
- Patients who have received acute, low dose, systemic immunosuppressant medications (e.g., dexamethasone containing antiemetic regimen or steroids as computed tomography [CT] scan contrast premedication) may be enrolled * The use of inhaled corticosteroids and mineralocorticoids (e.g., fludrocortisone) for patients with orthostatic hypotension or adrenocortical insufficiency is allowed * Total systemic steroid dose cannot exceed an equivalent of 10 mg of prednisone daily and dose must be stable for at least 4 weeks prior to initiating protocol therapy
- Has a history of active TB (Bacillus tuberculosis)
- Has evidence of active, non-infectious pneumonitis
- Has history of interstitial lung disease
- Has an active infection requiring systemic therapy with intravenous antibiotics
- Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject’s participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator. This includes but is not limited to: uncontrolled ventricular arrhythmia, recent (within 90 days) myocardial infarction, chronic obstructive pulmonary disease, uncontrolled major seizure disorder, unstable spinal cord compression, and superior vena cava syndrome
- Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial * Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial
- Patients with prior allogeneic bone marrow transplantation or prior solid organ transplantation
- Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease; systemic lupus erythematosus; Wegener syndrome [granulomatosis with polyangiitis]; myasthenia gravis; Graves’ disease; rheumatoid arthritis, hypophysitis, uveitis) within the past 3 years prior to the start of treatment or patients requiring immunosuppressive therapy for the autoimmune disease. The following are exceptions to this criterion: * Subjects with vitiligo or alopecia * Subjects with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement * Subjects with psoriasis not requiring systemic treatment * Subjects with history of immune-related hyperthyroidism with total thyroidectomy currently in remission * Select situations after approval of study PI
- Known human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
- For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated
- Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load
- Has received a live vaccine within 30 days of planned start of study therapy * Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist) are live attenuated vaccines, and are not allowed
- Is unwilling to give written informed consent, unwillingness to participate, or inability to comply with the protocol for the duration of the study. The use of legally authorized representative (LAR) for cognitively impaired patients is not permitted
Additional locations may be listed on ClinicalTrials.gov for NCT04774419.
Locations matching your search criteria
United States
New Jersey
Basking Ridge
Middletown
Montvale
New York
Commack
New York
Uniondale
West Harrison
PRIMARY OBJECTIVES:
I. To evaluate safety and feasibility of concurrent checkpoint blockade and radiation in a safety run-in.
II. To evaluate progression-free survival (PFS) at 2 years in women with mismatch repair deficiency/microsatellite instability-high (MMR-D/MSI-H), locally advanced, endometrial cancer receiving adjuvant checkpoint blockade as an immune primer with radiation therapy.
SECONDARY OBJECTIVES:
I. To determine the kinetics of cell free deoxyribonucleic acid (cfDNA) levels obtained pre and post-treatment to correlate with clinical outcomes.
II. To determine overall survival (OS) of patients with MMR-D/MSI-H, locally advanced endometrial cancer treated with adjuvant checkpoint blockade and radiation.
III. To assess the tolerability of checkpoint blockade and radiation using physician reported adverse events (AE) (Common Terminology Criteria for Adverse Events [CTCAE]).
IV. To evaluate changes in quality of life during treatment using patient-reported outcomes (Functional Assessment of Cancer Therapy-Endometrial Cancer [FACT-En]).
TRANSLATIONAL OBJECTIVES:
I. To evaluate the intra-tumoral immune microenvironment at baseline and assess the immune response to combination checkpoint blockade and radiation using changes in peripheral T-Cell receptor (TCR) clonality over time.
II. To identify genomic predictors of immune response and clinical benefit.
III. To assess the stool microbiome at baseline and any changes with immunotherapy and radiation.
IV. To evaluate post-treatment changes in tumor microenvironment (TME) and genomic signatures in a subset of patients who undergo post-progression biopsies.
OUTLINE: Patients are assigned to 1 of 2 arms.
ARM I: Patients undergo intensity-modulated radiation therapy (IMRT) 5 days per week for 5-6 weeks for a total of 25-28 fractions and receive dostarlimab (TSR-042) intravenously (IV) over 30 minutes every 3 weeks (Q3W) of each cycle. Cycles repeat every 21 days for up to 5 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo tissue collection at time of biopsy during screening, computed tomography (CT) scans and collection of blood samples throughout the study, and may undergo an optional biopsy at the end of treatment.
ARM II: Patients receive TSR-042 IV over 30 minutes Q3W for 2 cycles prior to undergoing hypofractionated IMRT once daily (QD) for 5 days and receive 3 additional doses of TSR-042 IV over 30 minutes Q3W of each subsequent cycle after IMRT is completed. Cycles repeat every 21 days for up to 5 cycles in the absence of disease progression or unacceptable toxicity. Patients who have delays in cycle 2 of TSR-042 and/or are unable to receive the second dose of TSR-042 may undergo hypofractionated IMRT independently per the discretion of treating and principal investigators. Patients also undergo collection of tissue at biopsy during screening, kilovoltage (KV) imaging, cone-beam CT and/or CT scans and collection of blood samples throughout the study, and may undergo an optional biopsy at the end of treatment.
After completion of study treatment, patients are followed up every 3 months for 24 months and then every 6 months for up to 5 years.
Trial PhasePhase II
Trial Typetreatment
Lead OrganizationMemorial Sloan Kettering Cancer Center
Principal InvestigatorYing Liu
- Primary ID20-491
- Secondary IDsNCI-2021-03138
- ClinicalTrials.gov IDNCT04774419