Phase 1 study of intraventricular 131I-omburtamab targeting B7H3 (CD276)-expressing CNS malignancies.

BACKGROUND: The prognosis for metastatic and recurrent tumors of the central nervous system (CNS) remains dismal, and the need for newer therapeutic targets and modalities is critical. The cell surface glycoprotein B7H3 is expressed on a range of solid tumors with a restricted expression on normal tissues. We hypothesized that compartmental radioimmunotherapy (cRIT) with the anti-B7H3 murine monoclonal antibody omburtamab injected intraventricularly could safely target CNS malignancies. PATIENTS AND METHODS: We conducted a phase I trial of intraventricular 131I-omburtamab using a standard 3 + 3 design. Eligibility criteria included adequate cerebrospinal fluid (CSF) flow, no major organ toxicity, and for patients > dose level 6, availability of autologous stem cells. Patients initially received 74 MBq radioiodinated omburtamab to evaluate dosimetry and biodistribution followed by therapeutic 131I-omburtamab dose-escalated from 370 to 2960 MBq. Patients were monitored clinically and biochemically for toxicity graded using CTCAEv 3.0. Dosimetry was evaluated using serial CSF and blood sampling, and serial PET or gamma-camera scans. Patients could receive a second cycle in the absence of grade 3/4 non-hematologic toxicity or progressive disease. RESULTS: Thirty-eight patients received 100 radioiodinated omburtamab injections. Diagnoses included metastatic neuroblastoma (n = 16) and other B7H3-expressing solid tumors (n = 22). Thirty-five patients received at least 1 cycle of treatment with both dosimetry and therapy doses. Acute toxicities included < grade 4 self-limited headache, vomiting or fever, and biochemical abnormalities. Grade 3/4 thrombocytopenia was the most common hematologic toxicity. Recommended phase 2 dose was 1850 MBq/injection. The median radiation dose to the CSF and blood by sampling was 1.01 and 0.04 mGy/MBq, respectively, showing a consistently high therapeutic advantage for CSF. Major organ exposure was well below maximum tolerated levels. In patients developing antidrug antibodies, blood clearance, and therefore therapeutic index, was significantly increased. In patients receiving cRIT for neuroblastoma, survival was markedly increased (median PFS 7.5 years) compared to historical data. CONCLUSIONS: cRIT with 131I-omburtamab is safe, has favorable dosimetry and may have a therapeutic benefit as adjuvant therapy for B7-H3-expressing leptomeningeal metastases. TRIAL REGISTRATION: clinicaltrials.gov NCT00089245, August 5, 2004.

Endonasal endoscopic reoperation for residual or recurrent craniopharyngiomas.

OBJECTIVE Craniopharyngiomas can be difficult to remove completely based on their intimate relationship with surrounding visual and endocrine structures. Reoperations are not uncommon but have been associated with higher rates of complications and lower extents of resection. So radiation is often offered as an alternative to reoperation. The endonasal endoscopic transsphenoidal approach has been used in recent years for craniopharyngiomas previously removed with craniotomy. The impact of this approach on reoperations has not been widely investigated. METHODS The authors reviewed a prospectively acquired database of endonasal endoscopic resections of craniopharyngiomas over 11 years at Weill Cornell Medical College, NewYork-Presbyterian Hospital, performed by the senior authors. Reoperations were separated from first operations. Pre- and postoperative visual and endocrine function, tumor size, body mass index (BMI), quality of life (QOL), extent of resection (EOR), impact of prior radiation, and complications were compared between groups. EOR was divided into gross-total resection (GTR, 100%), near-total resection (NTR, > 95%), and subtotal resection (STR, < 95%). Univariate and multivariate analyses were performed. RESULTS Of the total 57 endonasal surgical procedures, 22 (39%) were reoperations. First-time operations and reoperations did not differ in tumor volume, radiological configuration, or patients' BMI. Hypopituitarism and diabetes insipidus (DI) were more common before reoperations (82% and 55%, respectively) compared with first operations (60% and 8.6%, respectively; p < 0.001). For the 46 patients in whom GTR was intended, rates of GTR and GTR+NTR were not significantly different between first operations (90% and 97%, respectively) and reoperations (80% and 100%, respectively). For reoperations, prior radiation and larger tumor volume had lower rates of GTR. Vision improved equally in first operations (80%) compared with reoperations (73%). New anterior pituitary deficits were more common in first operations compared with reoperations (51% vs 23%, respectively; p = 0.08), while new DI was more common in reoperations compared with first-time operations (80% vs 47%, respectively; p = 0.08). Nonendocrine complications occurred in 2 (3.6%) first-time operations and no reoperations. Tumor regrowth occurred in 6 patients (11%) over a median follow-up of 46 months and was not different between first versus reoperations, but was associated with STR (33%) compared with GTR+NTR (4%; p = 0.02) and with not receiving radiation after STR (67% vs 22%; p = 0.08). The overall BMI increased significantly from 28.7 to 34.8 kg/m2 over 10 years. Six months after surgery, there was a significant improvement in QOL, which was similar between first-time operations and reoperations, and negatively correlated with STR. CONCLUSIONS Endonasal endoscopic transsphenoidal reoperation results in similar EOR, visual outcome, and improvement in QOL as first-time operations, with no significant increase in complications. EOR is more impacted by tumor volume and prior radiation. Reoperations should be offered to patients with recurrent craniopharyngiomas and may be preferable to radiation in patients in whom GTR or NTR can be achieved.