Glembatumumab Vedotin, Nivolumab, and Ipilimumab in Treating Patients With Advanced Metastatic Solid Tumors That Cannot Be Removed by Surgery
Glembatumumab Vedotin, Nivolumab, and Ipilimumab in Treating Patients With Advanced Metastatic Solid Tumors That Cannot Be Removed by Surgery
This phase Ib/II trial studies the best dose of glembatumumab vedotin when giving together
 with nivolumab and ipilimumab in treating patients with solid tumor that has spread to other
 places in the body and cannot be removed by surgery. Monoclonal antibodies, such as
 glembatumumab vedotin, nivolumab, and ipilimumab, may interfere with the ability of tumor
 cells to grow and spread.
PRIMARY OBJECTIVES:

 I. To determine the recommended phase 2 dose (RP2D) for the combination of glembatumumab
 vedotin and nivolumab in patients with solid tumors. (Phase Ib) II. To evaluate the antitumor
 activity of the combination in 4 expansion cohorts (melanoma, uveal melanoma, GPNMB
 overexpressing triple negative breast cancer [TNBC], other GPNMB overexpressing solid tumors)
 as measured by overall response by Immune-Modified Response Evaluation Criteria in Solid
 Tumors (iRECIST)/Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. (Phase II)

 SECONDARY OBJECTIVES:

 I. To characterize the safety and toxicity profile of the combination. II. To evaluate the
 clinical benefit rate (no disease progression within 6 months), progression free survival
 (PFS), and overall survival (OS) in patients receiving the combination treatment.

 III. To evaluate the pharmacokinetics (PK) of glembatumumab vedotin and nivolumab in
 combination in serum and in mononuclear phagocyte system (MPS) cells in peripheral blood
 mononuclear cells.

 IV. Profile differences in the type, number and density of Fc-receptors (FcgammaR) on MPS
 cells in blood of patients prior to and after administration of glembatumumab vedotin and
 nivolumab as a method to evaluate the factors affecting PK and pharmacodynamics (PD)
 variability and mechanisms of drug-drug interactions.

 V. Characterize differences in chemokines (CCL2 and CCL5) and other cytokines in blood of
 patients prior to and after administration of glembatumumab vedotin and nivolumab as a method
 to evaluate the factors affecting PK and PD variability and mechanisms of drug-drug
 interactions.

 VI. To evaluate the pharmacodynamic (PD) effects of the combination in plasma and tissue
 biomarkers.

 OUTLINE:

 Patients receive glembatumumab vedotin intravenously (IV) over 90 minutes and nivolumab IV
 over 60 minutes on day 8 of course 1 and on day 1 of subsequent courses. Patients in melanoma
 expanded cohort also receive ipilimumab IV over 90 minutes on day 1. Treatment with
 ipilimumab repeats every 21 days for 4 courses in the absence of disease progression or
 unaccepted toxicity and courses with glembatumumab vedotin and nivolumab repeat every 21 days
 in the absence of disease progression or unaccepted toxicity.

 After completion of study treatment, patients are followed up for 4 weeks and then at 30 and
 70 days.
Inclusion Criteria:

 -  Patients must have histologically confirmed malignancy that is metastatic or
 unresectable and for which standard curative measures do not exist or are no longer
 effective

 -  For TNBC and solid tumors other than melanoma: GPNMB expression as defined by at least
 25% of malignant epithelial cells or tumor stromal cells expression GPNMB at any
 intensity via central immunohistochemistry on archived or biopsied tumor tissue (as
 per standard clinical care) from an advanced/metastatic disease site; for melanoma or
 uveal melanoma cohort: GPNMB testing results will not be required for eligibility
 assessment

 -  Patients must have measurable disease, in addition to at least one lesion in a
 reasonably safe location for study-related biopsies; measurable disease is 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) by chest x-ray or as >= 10 mm (>= 1 cm) with computed tomography (CT)
 scan, magnetic resonance imaging (MRI), or calipers by clinical exam

 -  Willing to undergo study-related biopsies as noted in study calendar: before
 treatment, after glembatumumab-only, and after combination therapy

 -  Prior treatment with immune checkpoint inhibitors or antibody drug conjugates are
 allowed.

 -  For cutaneous melanoma cohort, patients should have received PD-1/CTLA-4
 targeting therapy in combination and had disease progression

 -  For all other cohorts including phase Ib dose-finding, patients should have
 received at least one line of standard non-immunotherapy treatment

 -  Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 80%)

 -  Life expectancy of greater than 12 weeks

 -  Leukocytes >= 2,000/mcL

 -  Absolute neutrophil count >= 1,500/mcL

 -  Platelets >= 75,000/mcL

 -  Hemoglobin >= 9.0 g/dL

 -  Total bilirubin =< 1.5 x institutional upper limit of normal (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])
 =< 3.0 x institutional upper limit of normal (or =< 5.0 x institutional upper limit of
 normal in presence of metastatic liver disease)

 -  Serum creatinine =< 1.5 x institutional upper limit of normal OR creatinine clearance
 >= 50 mL/min (if using the Cockcroft-Gault formula)

 -  Women of childbearing potential (WOCBP) 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; WOCBP should use an adequate method
 to avoid pregnancy for 32 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 HCG) within 24 hours prior to the start of
 nivolumab; women must not be breastfeeding; men who are sexually active with WOCBP
 must use any contraceptive method with a failure rate of less than 1% per year; men
 receiving nivolumab and who are sexually active with WOCBP will be instructed to
 adhere to contraception for a period of 31 weeks after the last dose of
 investigational product; women who are not of childbearing potential (i.e., who are
 postmenopausal or surgically sterile as well as azoospermic men) 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;
 should a woman become pregnant or suspect she is pregnant while she or her partner is
 participating in this study, she (or the participating partner) should inform the
 treating physician immediately

 -  Ability to understand and the willingness to sign a written informed consent document

 Exclusion Criteria:

 -  Patients who have had systemic therapy within 2 weeks (6 weeks for nitrosoureas or
 mitomycin C) or radiotherapy within 2 weeks prior to entering the study

 -  Patients who have not recovered from adverse events due to prior anti-cancer therapy
 (i.e., have residual toxicities >= grade 2 other than alopecia)

 -  Patients who are receiving any other concurrent investigational agents; those with
 history of receiving investigational cancer treatment are allowed as long as washout
 period is fulfilled

 -  Symptomatic or untreated leptomeningeal or brain metastases or spinal cord
 compression; patients with treated and stable brain metastases will be allowed;
 controlled brain metastases are defined as no radiographic progression for at least 4
 weeks following radiation and/or surgical treatment (or 4 weeks of observation if no
 intervention is clinically indicated), and off of steroids for at least 2 weeks, and
 no new or progressive neurological signs and symptoms

 -  History of allergic reactions attributed to compounds of similar chemical or biologic
 composition to nivolumab, glembatumumab vedotin, or other agents used in study; this
 includes sensitivity to the drugs dolastatin or auristatin

 -  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

 -  Participants must not have a history of life-threatening toxicity related to prior IO
 treatment (eg, anti-CTLA-4 or anti-PD-1/PD-L1 treatment or any other antibody or
 treatment specifically targeting T-cell co-stimulation or immune checkpoint pathways);
 i) participants with toxicities that are unlikely to recur with standard
 countermeasures (eg, hormone replacement treatment after adrenal crisis) are eligible

 -  Pregnant women are excluded from this study; breastfeeding should be discontinued if
 the mother is treated with nivolumab and glembatumumab vedotin

 -  Human immunodeficiency virus (HIV) patients should be allowed if otherwise eligible,
 with the following caveats:

 -  Undetectable HIV viral load by standard clinical assay

 -  Willing to remain adherent with antiretroviral therapy that has minimal
 overlapping toxicity or pharmacokinetic interactions with protocol therapy

 -  CD4+ T cell counts of 200/mm^3 or greater

 -  No acquired immunodeficiency syndrome (AIDS)-defining events other within the
 past 12 months

 -  Near normal life expectancy if not for presence of the cancer

 -  Not taking antiviral agents that are otherwise prohibited because of CYP
 interactions

 -  Patients should be excluded if they have a positive test for hepatitis B virus surface
 antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV RNA) 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, should be 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 because of the risk of recurrence or exacerbation of disease; 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 and abdominal carcinomatosis which are
 known risk factors for bowel perforation should be evaluated for the potential need
 for additional treatment before coming on study

 -  Use of any vaccines against infectious diseases (e.g. influenza, varicella,
 pneumococcus) within 4 weeks of initiation of study treatment