Phase I Study of Ipilimumab Combined with Whole Brain Radiation Therapy or Radiosurgery for Melanoma Patients with Brain Metastases

Purpose: We performed a phase I study to determine the maximum tolerable dose (MTD) and safety of ipilimumab with stereotactic radiosurgery (SRS) or whole brain radiotherapy (WBRT) in patients with brain metastases (BM) from melanoma. Methods: Based on intracranial (IC) disease burden, patients were treated with WBRT (Arm A) or SRS (Arm B). Ipilimumab starting dose was 3 mg/kg (every 3 weeks, starting on day 3 of WBRT or 2 days after SRS). Ipilimumab was escalated to 10 mg/kg using a two-stage, 3+3 design. The primary endpoint was to determine the MTD of ipilimumab combined with radiotherapy. Secondary endpoints were overall survival (OS), IC and extracranial (EC) control, progression free survival (PFS), and toxicity. This trial is regis- tered with ClinicalTrials.gov, number NCT01703507. Results: Characteristics of the 16 patients enrolled between 2011 and 2014 were: mean age, 60; median BM, 2 (1 to \u3e10); number with EC disease, 13 (81%). Treatment included WBRT (n=5), SRS (n=11), ipilimumab 3mg/kg (n=7), 10 mg/kg (n=9). Median follow-up was 8 months (Arm A) and 10.5 months (Arm B). There were 21 grade 1-2 neuro- toxic effects with no dose-limiting toxicities (DLTs). One patient experienced grade 3 neurotoxicity prior to ipilimumab administration. Ten additional grade 3 toxicities were reported with gastrointestinal (n=5, 31%) as the most common. There were no grade 4/5 toxicities. Median PFS and OS, respectively, in Arm A were 2.5 months and 8 months, and in Arm B were 2.1 months and not reached. Conclusion: Concurrent ipilimumab 10 mg/kg with SRS is safe. The WBRT arm was closed early due to slow accrual, but demonstrated safety with ipilimumab 3 mg/kg. No patient experienced DLT. Larger studies with ipilimumab 10 mg/kg and SRS are warranted

Transformation of facial basal cell carcinoma to squamous cell carcinoma following vismodegib

Objective(s): Vismodegib, a unique hedgehog pathway inhibitor, has been demonstrated to be effective in the treatment of non-operable and metastatic basal cell carcinoma (BCC). While effective, concerns regarding its role in the development of cutaneous squamous cell carcinoma (CSCC) remain. The primary objective is to describe a unique case of locally advanced BCC of the face and subsequent transformation to CSCC following treatment with vismodegib. Methods: Case report. Results: A 64-year-old Caucasian female presented with a 3-year history of a progressive and erosive lesion involving the entirety of her forehead with involvement of the left medial canthus and upper eyelid. Biopsies performed at the periphery of the lesion demonstrated superficial and nodular BCC. As surgical management would result in significant morbidity, the patient elected for treatment with oral vismodegib, 150 mg daily, with curative intent. Dramatic tumor response was experienced over an 18-month period; however, surveillance MRI demonstrated concern for tumor progression at the periphery of the mass without evidence of intracranial extension or metastases. Subsequent biopsies at the superior and left supraorbital margins demonstrated invasive SCC. Following immunohistochemistry analysis, intravenous nivolumab, 480 mg monthly was initiated; the patient remains progression-free after 18 months of therapy. Conclusion: This case highlights the importance of close surveillance in patients treated with vismodegib for non-operable BCC. Serial biopsies of new or suspicious appearing tumors should be performed given the potential for CSCC transformation

Phase I Study of GC1008 (Fresolimumab): A Human Anti-Transforming Growth Factor-Beta (TGFβ) Monoclonal Antibody in Patients with Advanced Malignant Melanoma or Renal Cell Carcinoma

<div><p>Background</p><p>In advanced cancers, transforming growth factor-beta (TGFβ) promotes tumor growth and metastases and suppresses host antitumor immunity. GC1008 is a human anti-TGFβ monoclonal antibody that neutralizes all isoforms of TGFβ. Here, the safety and activity of GC1008 was evaluated in patients with advanced malignant melanoma and renal cell carcinoma.</p><p>Methods</p><p>In this multi-center phase I trial, cohorts of patients with previously treated malignant melanoma or renal cell carcinoma received intravenous GC1008 at 0.1, 0.3, 1, 3, 10, or 15 mg/kg on days 0, 28, 42, and 56. Patients achieving at least stable disease were eligible to receive Extended Treatment consisting of 4 doses of GC1008 every 2 weeks for up to 2 additional courses. Pharmacokinetic and exploratory biomarker assessments were performed.</p><p>Results</p><p>Twenty-nine patients, 28 with malignant melanoma and 1 with renal cell carcinoma, were enrolled and treated, 22 in the dose-escalation part and 7 in a safety cohort expansion. No dose-limiting toxicity was observed, and the maximum dose, 15 mg/kg, was determined to be safe. The development of reversible cutaneous keratoacanthomas/squamous-cell carcinomas (4 patients) and hyperkeratosis was the major adverse event observed. One malignant melanoma patient achieved a partial response, and six had stable disease with a median progression-free survival of 24 weeks for these 7 patients (range, 16.4–44.4 weeks).</p><p>Conclusions</p><p>GC1008 had no dose-limiting toxicity up to 15 mg/kg. In patients with advanced malignant melanoma and renal cell carcinoma, multiple doses of GC1008 demonstrated acceptable safety and preliminary evidence of antitumor activity, warranting further studies of single agent and combination treatments.</p><p>Trial Registration</p><p>Clinicaltrials.gov <a href="http://clinicaltrials.gov/ct2/show/NCT00356460?term=NCT00356460&rank=1" target="_blank">NCT00356460</a></p></div

Patient Flow Chart.

<p>Patient Flow Chart.</p