Accepting New Patients
This is an MSKCC investigator-initiated, single-center, non-randomized, open-label, phase 2 study to evaluate the activity of nivolumab in patients with recurrent or persistent hypermutated, MMR-D, or MSI-H uterine cancer. Activity of nivolumab will be assessed by determining the percentage of patients who remain progression-free at 24 weeks (primary endpoint) or who have objective RECIST response (co-primary endpoint). The safety and tolerability of single-agent nivolumab in this population will also be evaluated.
- Histologically confirmed diagnosis of metastatic or recurrent uterine cancer (endometrial carcinoma, carcinosarcoma, clear cell carcinoma, leiomyosarcoma, undifferentiated sarcoma, high grade endometrial stromal sarcoma) by Memorial Sloan Kettering Cancer Center. Carcinosarcomas, endometrioid and clear cell carcinomas that appears to have arisen in the ovary/fallopian tube or peritoneum are also eligible. Recurrence should not be amenable to curative approaches such as surgical resection or chemoradiotherapy.
- Tumor is confirmed to be one of the following: 1. MSI-high, or 2. MMR-deficient, or 3. Hypermutated defined as ≥20 somatic mutations in the tumor by MSK-IMPACT
- One or more prior lines of cytotoxic treatment for advanced disease (prior hormonal therapy is not considered to count as prior lines of therapy)
- Measurable disease by RECIST 1.1 criteria
- No known CNS metastases
- ECOG Performance status 0-1
- WBC > 2000/uL, ANC > 1500/uL, PLT > 100,000/uL, HGB > 8 g/dL
- Serum creatinine < 1.5 x ULN or creatinine clearance of > 40mL/min by Cockroft-Gault formula
- AST (SGOT) and ALT (SGPT) < 3 x ULN
- Total bilirubin < 1.5 x ULN, except subjects with Gilbert’s syndrome who can have total bilirubin < 3.0 mg/dL 11. Able to sign voluntary written informed consent
- Female, 18 years of age or older
- Available archival tumor tissue or patient is willing to undergo new biopsy
- Premenopausal women of child bearing potential must have a normal urine or serum betaHCG prior to enrollment, and must agree to use effective contraception during treatment with nivolumab and for at least 5 months following the last dose of nivolumab.
Acute promyelocytic leukemia (APL, M3 subtype of AML) or patients with a t(9:22) cytogenetic translocation.
Hyperleukocytosis (leukocytes ≥25 x 109/L) at study entry. These patients may be treated with hydroxyurea according to routine practice, and enroll in the study when the leukocyte count falls below 25 x 109/L.
Patients known to be refractory to platelet or packed red cell transfusions per Institutional Guidelines, or a patient who refuses blood product support.
Prior treatment with all-trans retinoic acid (ATRA) or systemic retinoid for the treatment of hematologic malignancy.
SY-1425 and daratumumab combination only - Prior or concurrent exposure to daratumumab or other CD38 therapies5.
SY-1425 and daratumumab combination only - Subject has either of the following:
- Known chronic obstructive pulmonary disease (COPD) with a forced expiratory volume in 1 second (FEV1) <50% of predicted normal. Note that FEV1 testing is required for subjects suspected of having COPD and subjects must be excluded if FEV1 is <50% of predicted normal.
- Known moderate or severe persistent asthma within the past 2 years, or uncontrolled asthma of any classification. Note that subjects who currently have controlled intermittent asthma or controlled mild persistent asthma are allowed to participate in the study.
Patients with active malignancy (not including basal cell carcinoma, non-melanoma skin cancer, cervical carcinoma in situ, localized prostate cancer treated with hormone therapy). Patients with history of other cancers should be free of disease for at least 2 years.
Patients with hypertriglyceridemia defined as >1000 mg/dL (CTCAE Grade 4).
Patients with clinically significant cardiac disease including one of the following currently or in the previous 6 months: myocardial infarction, unstable cardiac function due to unstable angina or congestive heart failure, congenital long QT syndrome, torsades de pointes or significant ventricular arrhythmias .
Patients with known active uncontrolled central nervous system (CNS) leukemia.
Patients taking Vitamin A supplements (>10,000 IU/d) unless discontinued prior to first dose of study drug, or having hypervitaminosis A.
Pregnant females; breastfeeding females; and males and females of childbearing potential not willing to use two highly effective methods of birth control, one being barrier method. Intrauterine Devices (IUD) and birth control pills are not barrier methods, but are highly effective especially when combined with a barrier method (e.g. latex condom or a diaphragm or cervical cap) while taking investigational product (SY-1425) and continuing contraception use for at least 90 days after the last dose of study drug. Men/women should not donate sperm or ova during this time frame.