A patient with metastatic melanoma who experienced a durable complete response after treatment with a patient-specific vaccine has been described in this article. This 59-year-old woman presented with cervical spine metastases and, within the year, had experienced local disease progression and, despite various therapies, metastases to the axilla, rectum, gall bladder, and multiple soft-tissue sites. She had previously received radiation therapy, combination chemotherapy, interleukin-2 plus interferon biotherapy, and gamma knife radiosurgery, and undergone multiple surgical resections. At the time vaccine therapy was initiated, she had multiple, new, measurable, soft-tissue metastases that were increasing in size. She was treated with a vaccine consisting of autologous dendritic cells incubated with irradiated tumor cells from an autologous tumor cell line and suspended in granulocyte-macrophage colony stimulating factor (GM-CSF), with subcutaneous injections once a week for 3 weeks and monthly for 5 months. There was evidence of disease regression by the completion of therapy. A few months later a complete response was documented by radiologic scans, and subsequently reconfirmed at 6-month intervals. She remains in complete remission >2.5 years after starting the vaccine, and >2 years after completing the vaccine, and survives >4 years after her initial presentation with bone, bowel, and lymph node metastases. This is the first time she has been in a complete remission since her initial diagnosis. Patient-specific vaccines can sometimes induce durable complete regression of progressing soft-tissue melanoma metastases.
2038 Background: BI 2536 is a novel highly potent and selective inhibitor of the serine-threonine kinase polo-like kinase 1 (Plk1), which is a key regulator of cell cycle progression. Objectives of this trial were the assessment of the maximum tolerated dose (MTD), overall safety, pharmacokinetics and efficacy of BI 2536 given intravenously. Methods: Sequential cohorts of 3 to 6 patients (pts) with pretreated advanced or metastatic solid tumours received intravenous infusions of BI 2536 on days 1 and 8 of a 3-week treatment course following a toxicity guided dose escalation design. Further treatment courses were administered to pts in the absence of disease progression and if toxicity after a 3-week treatment course had resolved. Results: A total of 42 pts was treated at doses of 25 mg (n=3), 50 mg (n=3), 100 mg (n=22), 125 mg (n=5), 150 mg (n=6) and 200 mg (n=3). Reversible CTCAE grade ≥ 3 neutropenia in 14/42 pts represented the main drug related toxicity with an incidence of 3/5 in the 125 mg cohort, 4/6 in the 150 mg and 2/2 in the 200 mg dose cohorts. Dose limiting toxicity (DLT) was defined as drug related toxicity prohibiting administration of the day 8 dose of BI 2536 (hematologic: CTCAE ≥ 3 grade, non-hematologic toxicity: CTCAE ≥ 2). No DLT other than d8 neutropenia was observed. The MTD was defined at 100 mg for the given day 1 and 8 schedule. Further related adverse events (AE’s) were of mild to moderate intensity (CTCAE grade ≤ 2). There were no related AEs resulting in study discontinuation. Preliminary PK analysis showed dose proportionality of Cmax and AUC0-∞ with a high clearance (∼ 1500 mL/min) and a high volume of distribution (∼ 2000 L). No accumulation from d1 to d8 occurred. Patients were treated for up to 8 courses without evidence of accumulating toxicity. No objective responses were observed according to RECIST criteria in this heavily pretreated patient population. Conclusions: In summary BI 2536 is a Plk1 inhibitor with a favorable PK and safety profile at the tested dose and schedule. Neutropenia as a mechanism-related toxicity indicates target inhibition in vivo. [Table: see text]
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