To further characterize the safety of this drug, the protocol was modified and additional three patients were added to cohort 1 for a total of nine patients at 1.90 mg/kg dose. A second DLT was observed in cohort 1. The patient experienced grade 3 treatment-related pruritus requiring hospital admission. The dose was de-escalated to dose level 1. No DLT was observed at dose level 1 of 1.30 mg/kg.

Stage III or IV, histologically confirmed melanoma. Patients must had previously received no more than one prior chemotherapy-containing treatment regimen for advanced disease, at least one checkpoint inhibitor (ie, antiCTLA-4, PD-1, PD-L1targeted immunotherapy), and at least one BRAF-targeted and/or MEK-targeted therapy if melanoma harbored a BRAFV600 mutation, unless it was not clinically indicated or was refused by the patient.

Glembatumumab vedotin was administered as a 90 minute intravenous infusion, once every 3 weeks (day 1 of repeated 21 day cycles). Delays of up to 3 weeks and up to two dose reductions (to dose levels of 1.34, 1.00, and 0.75 mg/kg, as applicable) were permitted for toxicity. Dosing continued until unmanageable treatment-related toxicities, disease progression, or death.

Patients must have histologically or cytologically confirmed metastatic or locally recurrent uveal melanoma; because histologic or cytologic confirmation of primary uveal melanoma is not always possible, confirmation of the clinical diagnosis of uveal melanoma by the treating investigator is allowed; clinical diagnosis of uveal melanoma is often made by an ophthalmologist, not by tissue diagnosis; if an ophthalmologist diagnosed and treated a patient for uveal melanoma in the past, it is sufficient for a clinical diagnosis

Patients must have histologically or cytologically confirmed metastatic or locally recurrent uveal melanoma; because histologic or cytologic confirmation of primary uveal melanoma is not always possible, confirmation of the clinical diagnosis of uveal melanoma by the treating investigator is allowed; clinical diagnosis of uveal melanoma is often made by an ophthalmologist, not by tissue diagnosis; if an ophthalmologist diagnosed and treated a patient for uveal melanoma in the past, it is sufficient for a clinical diagnosis

18 years of age or older.Locally advanced or metastatic breast cancer.Previous treatment with at least two but no more than seven prior chemotherapy treatments for progressive, recurrent or metastatic breast cancer.Unless not a candidate for these agents, prior therapies must have included a taxane, an anthracycline, and capecitabine, as well as trastuzumab and lapatinib for patients whose tumors are positive for the human epidermal growth factor receptor 2 (HER2). (Patients who received incomplete courses of therapy with these agents due to intolerance will be eligible.)Breast cancer tumor confirmed to express GPNMB. This will be determined by submitting a tissue sample (obtained during a diagnostic biopsy or surgery) to a central laboratory for analysis.

Glembatumumab vedotin was well tolerated as compared with IC chemotherapy (less hematologic toxicity; more rash, pruritus, neuropathy, and alopecia). ORR was 6% (five of 83) for glembatumumab vedotin versus 7% (three of 41) for IC, without significant intertreatment differences for predefined strata. Secondary end point revealed ORR of 12% (10 of 83) versus 12% (five of 41) overall, and 30% (seven of 23) versus 9% (one of 11) for gpNMB overexpression (≥ 25% of tumor cells). Unplanned analysis showed ORR of 18% (five of 28) versus 0% (0 of 11) in patients with triple-negative breast cancer (TNBC), and 40% (four of 10) versus 0% (zero of six) in gpNMB-overexpressing TNBC.

In the breast cancer study, this dose resulted in an ORR of 12% (four of 33) and median progression-free survival (PFS) of 2.1 months. In the subset of patients with triple-negative breast cancer (TNBC), defined by the lack of overexpression of estrogen, progesterone, and human epidermal growth factor receptor 2 (HER2), ORR was 20% (two of 10), and median PFS was 4.1 months. For the small subset of patients with TNBC who also had gpNMB-expressing tumors (≥ 5% of epithelial or stromal cells were positive), ORR was 25% (one of four), and median PFS was 5.1 months..

Unresectable, histologically-confirmed advanced (Stage III or Stage IV) melanoma.Disease progression during or after the last anticancer therapy received. For Cohort 3, progression must have occurred during the PD-1 targeted CPI (checkpoint inhibitor) treatment and the investigator has deemed it appropriate to continue treatment with the PD-1 targeted CPI beyond confirmed disease progression. No more than one prior chemotherapy-containing regimen for advanced disease. Prior treatments received must include at least one CPI inhibitor (e.g., anti-CTLA-4, PD-1-, PD-L1-targeted immunotherapy) and for patients with a BRAF mutation at least one BRAF- or MEK-targeted therapy, unless patients are not candidates for, or refused, these therapies. For cohort 3, prior treatment received must include a PD-1 targeted CPI administered during the most recent disease progression and for patients with BRAF mutation at least one BRAF- or MEK-targeted therapy when appropriate. The study site will submit paraffin-embedded tumor tissue obtained from the patient for gpNMB analysis. Patients may require a biopsy if recent tumor tissue is not available. Patients in cohort 2 and 3 must submit a recently obtained biopsy of the skin fold for gpNMB analysis. Patients in Cohort 4 will submit a tumor tissue sample while on study. Eastern Cooperative Oncology Group (ECOG) Performance Status 0 to 1. Adequate bone marrow, liver and renal function.

Patients must have histologically or cytologically confirmed metastatic or locally recurrent uveal melanoma; because histologic or cytologic confirmation of primary uveal melanoma is not always possible, confirmation of the clinical diagnosis of uveal melanoma by the treating investigator is allowed; clinical diagnosis of uveal melanoma is often made by an ophthalmologist, not by tissue diagnosis; if an ophthalmologist diagnosed and treated a patient for uveal melanoma in the past, it is sufficient for a clinical diagnosis

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 receive glembatumumab vedotin 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.

Patients must have had histologic verification of osteosarcoma at original diagnosis or relapse, Patients must have measurable disease according to RECIST 1.1, and have relapsed or become refractory to conventional therapy, Patient must have archival tumor specimen available for submission, Patients must have a performance status corresponding to Eastern Cooperative Oncology Group (ECOG) scores of 0, 1 or 2; use Karnofsky for patients > 16 years of age and Lansky for patients =< 16 years of age.

Twenty-two patients were enrolled, and all were evaluable for response. Antibody-drug conjugate levels were detectable in patients, although small numbers limit comparison to adult data. The toxicities observed were similar to the previous studies with GV. The most common grade III adverse event was rash. One death from end organ failure occurred possibly related to GV. Of the 22 patients, one patient had a partial response, and two had stable disease. There was no correlation between gpNMB expression and response to GV.