A phase I/II study of intrathecal trastuzumab in human epidermal growth factor receptor 2-positive (HER2-positive) cancer with leptomeningeal metastases: Safety, efficacy, and cerebrospinal fluid pharmacokinetics.

BACKGROUND: Patients with human epidermal growth factor receptor 2-positive (HER2-positive) cancers have a high incidence of central nervous system (CNS) spread, but unfortunately systemic trastuzumab which targets the HER2 receptor has little CNS penetration. The purpose of this study was to determine the maximum-tolerated dose of intrathecal trastuzumab and its efficacy in patients with HER2-positive leptomeningeal disease (LMD). METHODS: This multicenter study enrolled 34 LMD patients in a combined phase I/II study in treating patients with intrathecal trastuzumab. Any HER2-positive histology was allowed in the phase I; the phase II was limited to HER2-positive breast cancer. RESULTS: Intrathecal trastuzumab was well-tolerated, with one dose limiting toxicity of grade 4 (arachnoiditis) occurring at the 80 mg twice weekly dose. The recommended phase II dose was 80 mg intrathecally twice weekly. Twenty-six patients at dose level 80 mg were included in evaluation for efficacy: partial response was seen in 5 (19.2%) patients, stable disease was observed in 13 (50.0%), and 8 (30.8%) of the patients had progressive disease. Median overall survival (OS) for phase II dose treated patients was 8.3 months (95% CI 5.2-19.6). The phase II HER2-positive breast cancer patients median OS was 10.5 months (95% CI 5.2-20.9). Pharmacokinetic (PK) studies were limited in the setting of concurrent systemic trastuzumab administration, however, did show stable cerebrospinal fluid (CSF) concentrations with repeated dosing suggest that trastuzumab does not accumulate in the CSF in toxic concentrations. CONCLUSION: This study suggests promise for potentially improved outcomes of HER-positive LMD patients when treated with intrathecal trastuzumab while remaining safe and well-tolerated for patients.

Phase I clinical trial of temsirolimus and perifosine for recurrent glioblastoma.

PURPOSE: Malignant glioma (MG) is the most deadly primary brain cancer. Signaling though the PI3K/AKT/mTOR axis is activated in most MGs and therefore a potential therapeutic target. The mTOR inhibitor temsirolimus and the AKT inhibitor perifosine are each well-tolerated as single agents but with limited activity reclinical data demonstrate synergistic anti-tumor effects from combined treatment. Therefore, we initiated a phase I trial of combined therapy in recurrent MGs to determine safety and a recommended phase II dose. METHODS: Adults with recurrent MG, Karnofsky Performance Status ≥ 60 were enrolled, with no limit on the number of prior therapies. Temsirolimus dose was escalated using standard 3 + 3 design from 15 mg to 170 mg administered once weekly. Perifosine was fixed as a 600 mg load on day 1 followed by 100 mg nightly (single agent MTD) until dose level 7 when the load increased to 900 mg. RESULTS: We treated 35 patients with with glioblastoma (17) or other MGs (18; including nine anaplastic astrocytoma, nine anaplastic oligodendroglioma, one anaplastic oligoastrocytoma, and two low grade astrocytomas with radiographic transformation to MG). We observed five dose-limiting toxicities (DLTs): one at dose level 3 (50mg temsirolimus), then two at dose level 7 expansion (170 mg temsirolimus), and then two more at dose level 6 expansion (170 mg temsirolimus). DLTs included thrombocytopenia (n = 3), intracerebral hemorrhage (n = 1) and lung infection (n = 1). CONCLUSION: Combining the mTOR inhibitor temsirolimus dosed at 115 mg weekly and the AKT inhibitor perifosine dosed at 100 mg daily (following 600 mg load) is tolerable in heavily pretreated adults with recurrent MGs.

Tracking tumour evolution in glioma through liquid biopsies of cerebrospinal fluid.

Diffuse gliomas are the most common malignant brain tumours in adults and include glioblastomas and World Health Organization (WHO) grade II and grade III tumours (sometimes referred to as lower-grade gliomas). Genetic tumour profiling is used to classify disease and guide therapy1,2, but involves brain surgery for tissue collection; repeated tumour biopsies may be necessary for accurate genotyping over the course of the disease3-10. While the detection of circulating tumour DNA (ctDNA) in the blood of patients with primary brain tumours remains challenging11,12, sequencing of ctDNA from the cerebrospinal fluid (CSF) may provide an alternative way to genotype gliomas with lower morbidity and cost13,14. We therefore evaluated the representation of the glioma genome in CSF from 85 patients with gliomas who underwent a lumbar puncture because they showed neurological signs or symptoms. Here we show that tumour-derived DNA was detected in CSF from 42 out of 85 patients (49.4%) and was associated with disease burden and adverse outcome. The genomic landscape of glioma in the CSF included a broad spectrum of genetic alterations and closely resembled the genomes of tumour biopsies. Alterations that occur early during tumorigenesis, such as co-deletion of chromosome arms 1p and 19q (1p/19q codeletion) and mutations in the metabolic genes isocitrate dehydrogenase 1 (IDH1) or IDH21,2, were shared in all matched ctDNA-positive CSF-tumour pairs, whereas growth factor receptor signalling pathways showed considerable evolution. The ability to monitor the evolution of the glioma genome through a minimally invasive technique could advance the clinical development and use of genotype-directed therapies for glioma, one of the most aggressive human cancers.

Phase 1b trial of an ibrutinib-based combination therapy in recurrent/refractory CNS lymphoma.

Ibrutinib is a first-in-class inhibitor of Bruton tyrosine kinase (BTK) and has shown single-agent activity in recurrent/refractory central nervous system (CNS) lymphoma. Clinical responses are often transient or incomplete, suggesting a need for a combination therapy approach. We conducted a phase 1b clinical trial to explore the sequential combination of ibrutinib (560 or 840 mg daily dosing) with high-dose methotrexate (HD-MTX) and rituximab in patients with CNS lymphoma (CNSL). HD-MTX was given at 3.5 g/m2 every 2 weeks for a total of 8 doses (4 cycles; 1 cycle = 28 days). Ibrutinib was held on days of HD-MTX infusion and resumed 5 days after HD-MTX infusion or after HD-MTX clearance. Single-agent daily ibrutinib was administered continuously after completion of induction therapy until disease progression, intolerable toxicity, or death. We also explored next-generation sequencing of circulating tumor DNA (ctDNA) in cerebrospinal fluid (CSF) before and during treatment. The combination of ibrutinib, HD-MTX, and rituximab was tolerated with an acceptable safety profile (no grade 5 events, 3 grade 4 events). No dose-limiting toxicity was observed. Eleven of 15 patients proceeded to maintenance ibrutinib after completing 4 cycles of the ibrutinib/HD-MTX/rituximab combination. Clinical responses occurred in 12 of 15 patients (80%). Sustained tumor responses were associated with clearance of ctDNA from the CSF. This trial was registered at www.clinicaltrials.gov as #NCT02315326.

Cerebrospinal fluid circulating tumor cells: a novel tool to diagnose leptomeningeal metastases from epithelial tumors.

BACKGROUND: Diagnosis of leptomeningeal metastasis (LM) remains challenging due to low sensitivity of CSF cytology and infrequent unequivocal MRI findings. In a previous pilot study, we showed that rare cell capture technology (RCCT) could be used to detect circulating tumor cells (CTC) in the CSF of patients with LM from epithelial tumors. To establish the diagnostic accuracy of CSF-CTC in the diagnosis of LM, we applied this technique in a distinct, larger cohort of patients. METHODS: In this institutional review board-approved prospective study, patients with epithelial tumors and clinical suspicion of LM underwent CSF-CTC evaluation and standard MRI and CSF cytology examination. CSF-CTC enumeration was performed through an FDA-approved epithelial cell adhesion molecule-based RCCT immunomagnetic platform. LM was defined by either positive CSF cytology or imaging positive for LM. ROC analysis was utilized to define an optimal cutoff for CSF-CTC enumeration. RESULTS: Ninety-five patients were enrolled (36 breast, 31 lung, 28 others). LM was diagnosed in 30 patients (32%) based on CSF cytology (n = 12), MRI findings (n = 2), or both (n = 16). CSF-CTC were detected in 43/95 samples (median 19.3 CSF-CTC/mL, range 0.3 to 66.7). Based on ROC analysis, 1 CSF-CTC/mL provided the best threshold to diagnose LM, achieving a sensitivity of 93%, specificity of 95%, positive predictive value 90%, and negative predictive value 97%. CONCLUSIONS: We defined ≥1 CSF-CTC/mL as the optimal cutoff for diagnosis of LM. CSF-CTC enumeration through RCCT is a robust tool to diagnose LM and should be considered in the routine LM workup in solid tumor patients.

Evaluating Cancer of the Central Nervous System Through Next-Generation Sequencing of Cerebrospinal Fluid.

PURPOSE: Cancer spread to the central nervous system (CNS) often is diagnosed late and is unresponsive to therapy. Mechanisms of tumor dissemination and evolution within the CNS are largely unknown because of limited access to tumor tissue. MATERIALS AND METHODS: We sequenced 341 cancer-associated genes in cell-free DNA from cerebrospinal fluid (CSF) obtained through routine lumbar puncture in 53 patients with suspected or known CNS involvement by cancer. RESULTS: We detected high-confidence somatic alterations in 63% (20 of 32) of patients with CNS metastases of solid tumors, 50% (six of 12) of patients with primary brain tumors, and 0% (zero of nine) of patients without CNS involvement by cancer. Several patients with tumor progression in the CNS during therapy with inhibitors of oncogenic kinases harbored mutations in the kinase target or kinase bypass pathways. In patients with glioma, the most common malignant primary brain tumor in adults, examination of cell-free DNA uncovered patterns of tumor evolution, including temozolomide-associated mutations. CONCLUSION: The study shows that CSF harbors clinically relevant genomic alterations in patients with CNS cancers and should be considered for liquid biopsies to monitor tumor evolution in the CNS.

Anaplastic astrocytoma and non-1p/19q co-deleted anaplastic oligoastrocytoma: long-term survival, employment, and performance status of survivors.

BACKGROUND: Despite optimal treatment for patients with anaplastic gliomas, median survival is 2 to 5 years, but some young adults survive longer. We sought to evaluate the functional and employment status of long-term survivors (5 years or more) diagnosed with anaplastic astrocytoma or non-1p/19q co-deleted anaplastic oligoastrocytoma. METHODS: We retrospectively identified patients with a diagnosis of anaplastic glioma at Memorial Sloan Kettering Cancer Center from 1999 to 2005. We reviewed demographics, pathology, 1p/19q status, survival, and treatment. Overall survival was estimated by the Kaplan-Meier method. RESULTS: There were 195 patients; 167 with anaplastic astrocytoma and 28 with anaplastic oligoastrocytoma. All patients were observed either to death or last follow-up. Sixty-four patients (33%) were identified as long-term survivors; 58% of these were men. The median age of the long-term survivors was 39 years and the median Karnofsky Performance Score was 100 at diagnosis. Thirteen patients underwent stereotactic biopsy, 7 had a gross total resection, and 44 a subtotal resection. Fifty-four patients completed radiation therapy as initial treatment; 54 received chemotherapy. Five years following diagnosis, median KPS was 90 and 55% of long-term survivors were employed and remained fully functional. CONCLUSIONS: One-third of patients with non-co-deleted anaplastic glioma were long-term survivors, and more than one-half of long-term survivors resumed their prior level of employment and activity. However, a significant proportion could not return to normal function. These findings have serious implications for the social and financial status of these predominantly young adult survivors.