Nivolumab Alone or in Combination With Ipilimumab in Treating Patients With Advanced Uterine Leiomyosarcoma
Condition: Metastatic Leiomyosarcoma; Unresectable Leiomyosarcoma; Uterine Corpus Leiomyosarcoma
MeSH terms: Leiomyosarcoma
Intervention: Ipilimumab; Laboratory Biomarker Analysis; Nivolumab
Intervention description: Given IV; Correlative studies; Given IV
Intervention MeSH terms: Nivolumab; Ipilimumab
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 20.0
Sex: Female
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      This phase II trial studies how well nivolumab alone or in combination with ipilimumab works
      in treating patients with uterine cancer that has spread to other places in the body and
      usually cannot be cured or controlled with treatment. Monoclonal antibodies, such as
      nivolumab and ipilimumab, may interfere with the ability of tumor cells to grow and spread.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Patients must have histologically or cytologically confirmed advanced leiomyosarcoma
             of the uterus (ULMS); advanced ULMS is defined as metastatic ULMS or unresectable
             primary ULMS

          -  Patients must have measurable disease, defined as at least one lesion that can be
             accurately measured in at least one dimension (longest diameter to be recorded for
             non-nodal lesions and short axis for nodal lesions) as >= 20 mm (>= 2 cm) with
             conventional techniques or as >= 10 mm (>= 1 cm) with spiral computed tomography (CT)
             scan, magnetic resonance imaging (MRI), or calipers by clinical exam

          -  Patients must have received at least one prior line of chemotherapy, for ULMS (either
             in the adjuvant or metastatic setting)

          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

          -  Life expectancy of greater than 9 months

          -  Absolute neutrophil count >= 1,500/mcL

          -  Platelets >= 100,000/mcL

          -  Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (except patients
             with Gilbert syndrome, who can have total bilirubin < 3.0 mg/dL)

          -  Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
             [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
             =< 2.5 x ULN/ =< 5 x ULN for subjects with liver metastases

          -  Serum creatinine =< 1.5 x ULN OR creatinine clearance (CrCl) >= 50 mL/min (if using
             the Cockcroft-Gault formula)

          -  Patients with a requirement for steroid treatment or other immunosuppressive
             treatment: patients should be excluded if they have a condition requiring systemic
             treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other
             immunosuppressive medications within 14 days of study drug administration; inhaled or
             topical steroids and adrenal replacement doses > 10 mg daily prednisone equivalents
             are permitted in the absence of active autoimmune disease

          -  Women of child-bearing potential (WOCBP) 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; WOCBP should use an adequate method to avoid
             pregnancy for 31 weeks after the last dose of investigational drug; women of
             childbearing potential must have a negative serum or urine pregnancy test (minimum
             sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin [HCG]) within
             24 hours prior to the start of nivolumab; women must not be breastfeeding; women who
             are not of childbearing potential (i.e., who are postmenopausal or surgically sterile)
             do not require contraception

               -  Women of childbearing potential (WOCBP) is defined as any female who has
                  experienced menarche and who has not undergone surgical sterilization
                  (hysterectomy or bilateral oophorectomy) or who is not postmenopausal; menopause
                  is defined clinically as 12 months of amenorrhea in a woman over 45 in the
                  absence of other biological or physiological causes; in addition, women under the
                  age of 55 must have a documented serum follicle stimulating hormone (FSH) level
                  less than 40 mIU/mL

               -  WOCBP receiving nivolumab will be instructed to adhere to contraception for a
                  period of 31 weeks after the last dose of investigational product; these
                  durations have been calculated using the upper limit of the half-life for
                  nivolumab (25 days) and are based on the protocol requirement that WOCBP use
                  contraception for 5 half-lives plus 30 days

               -  Should a woman become pregnant or suspect she is pregnant while participating in
                  this study, she should inform the treating physician immediately

          -  Ability to understand and the willingness to sign a written informed consent document

          -  For enrollment in the first stage of Cohort B, patients must have accessible
             pre-treatment and post-treatment (4-6 weeks) tumor for biopsy

        Exclusion Criteria:

          -  Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for
             nitrosoureas or mitomycin C) prior to entering the study or those who have not
             recovered from adverse events (AEs) due to agents administered more than 3 weeks
             earlier; patients who have had prior pelvic radiation may be at increased risk for
             bowel perforation, and therefore may not have residual inflammatory disease of the
             bowel or residual bowel toxicity based on baseline imaging and clinical assessment;
             palliative (limited-field) radiation therapy is permitted, if all of the following
             criteria are met:

               -  Repeat imaging demonstrates no new sites of bone metastases

               -  The lesion being considered for palliative radiation is not a target lesion

               -  Bowel toxicity is not expected from the target field due to increased risk of
                  perforation

          -  Patients who are receiving any other investigational agents

          -  Patients are excluded if they have had prior treatment with an anti-PD-1, anti-PD-L1,
             anti-PD-ligand 2 (L2), anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4)
             antibody, or any other antibody or drug specifically targeting T-cell co-stimulation
             or immune checkpoint pathways

          -  Active brain metastasis or leptomeningeal disease; patients with known brain
             metastases are allowed if metastases have been treated and there is no magnetic
             resonance imaging (MRI) evidence of progression for at least 12 weeks after treatment
             is complete and within 28 days prior to the first dose of nivolumab administration;
             there must also be no requirement for immunosuppressive doses of systemic
             corticosteroids (> 10 mg/day prednisone equivalents) for at least 2 weeks prior to
             study drug administration

          -  History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to nivolumab

          -  History of severe hypersensitivity reaction to any monoclonal antibody

          -  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

          -  Pregnant women are excluded from this study; breastfeeding should be discontinued if
             the mother is treated with nivolumab

          -  Patients should be excluded if they have known history of testing positive for human
             immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS) or if
             they have a positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis
             C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection

          -  Patients with active autoimmune disease or history of autoimmune disease that might
             recur, which may affect vital organ function or require immune suppressive treatment
             including systemic corticosteroids, are excluded; these include but are not limited to
             patients with a history of immune related neurologic disease, multiple sclerosis,
             autoimmune (demyelinating) neuropathy, Guillain-Barre syndrome, myasthenia gravis;
             systemic autoimmune disease such as systemic lupus erythematosus (SLE), connective
             tissue diseases, scleroderma, inflammatory bowel disease (IBD), Crohn's, ulcerative
             colitis, hepatitis; and patients with a history of toxic epidermal necrolysis (TEN),
             Stevens-Johnson syndrome, or phospholipid syndrome should be excluded; patients with
             vitiligo, endocrine deficiencies including thyroiditis managed with replacement
             hormones including physiologic corticosteroids are eligible; patients with rheumatoid
             arthritis and other arthropathies, Sjogren's syndrome and psoriasis controlled with
             topical medication and patients with positive serology, such as antinuclear antibodies
             (ANA), anti-thyroid antibodies should be evaluated for the presence of target organ
             involvement and potential need for systemic treatment but should otherwise be eligible

          -  Patients are permitted to enroll if they have vitiligo, type I diabetes mellitus,
             residual hypothyroidism due to autoimmune condition only requiring hormone
             replacement, psoriasis not requiring systemic treatment, or conditions not expected to
             recur in the absence of an external trigger (precipitating event)

          -  Patients should be excluded if they have a condition requiring systemic treatment with
             either corticosteroids (> 10 mg daily prednisone equivalents) or other
             immunosuppressive medications within 14 days of study drug administration; inhaled or
             topical steroids and adrenal replacement doses =< 10 mg daily prednisone equivalents
             are permitted in the absence of active autoimmune disease; patients are permitted to
             use topical, ocular, intra-articular, intranasal, and inhalational corticosteroids
             (with minimal systemic absorption); physiologic replacement doses of systemic
             corticosteroids are permitted, even if =< 10 mg/day prednisone equivalents; a brief
             course of corticosteroids for prophylaxis (e.g., contrast dye allergy) or for
             treatment of non-autoimmune conditions (e.g., delayed-type hypersensitivity reaction
             caused by contact allergen) is permitted

          -  Patients who have had evidence of active or acute diverticulitis, intra-abdominal
             abscess, gastrointestinal (GI) obstruction, fistula and abdominal carcinomatosis
             should be evaluated for the potential need for additional treatment before coming on
             study