Entinostat, nivolumab and ipilimumab for women with advanced HER2-negative breast cancer: a phase Ib trial.

We report the results of 24 women, 50% (N = 12) with hormone receptor-positive breast cancer and 50% (N = 12) with advanced triple-negative breast cancer, treated with entinostat + nivolumab + ipilimumab from the dose escalation (N = 6) and expansion cohort (N = 18) of ETCTN-9844 ( NCT02453620 ). The primary endpoint was safety. Secondary endpoints were overall response rate, clinical benefit rate, progression-free survival and change in tumor CD8:FoxP3 ratio. There were no dose-limiting toxicities. Among evaluable participants (N = 20), the overall response rate was 25% (N = 5), with 40% (N = 4) in triple-negative breast cancer and 10% (N = 1) in hormone receptor-positive breast cancer. The clinical benefit rate was 40% (N = 8), and progression-free survival at 6 months was 50%. Exploratory analyses revealed that changes in myeloid cells may contribute to responses; however, no correlation was noted between changes in CD8:FoxP3 ratio, PD-L1 status and tumor mutational burden and response. These findings support further investigation of this treatment in a phase II trial.

Intraarterial delivery of bevacizumab and cetuximab utilizing blood-brain barrier disruption in children with high-grade glioma and diffuse intrinsic pontine glioma: results of a phase I trial.

OBJECTIVE: Delivery of drugs intraarterially to brain tumors has been demonstrated in adults. In this study, the authors initiated a phase I trial of superselective intraarterial cerebral infusion (SIACI) of bevacizumab and cetuximab in pediatric patients with refractory high-grade glioma (diffuse intrinsic pontine glioma [DIPG] and glioblastoma) to determine the safety and efficacy in this population. METHODS: SIACI was used to deliver mannitol (12.5 ml of 20% mannitol) to disrupt the blood-brain barrier (BBB), followed by bevacizumab (15 mg/kg) and cetuximab (200 mg/m2) to target VEGF and EGFR, respectively. Patients with brainstem tumors had a balloon inflated in the distal basilar artery during mannitol infusion. RESULTS: Thirteen patients were treated (10 with DIPG and 3 with high-grade glioma). Toxicities included grade I epistaxis (2 patients) and grade I rash (2 patients). There were no dose-limiting toxicities. Of the 10 symptomatic patients, 6 exhibited subjective improvement; 92% showed decreased enhancement on day 1 posttreatment MRI. Of 10 patients who underwent MRI at 1 month, 5 had progressive disease and 5 had stable disease on FLAIR, whereas contrast-enhanced scans demonstrated progressive disease in 4 patients, stable disease in 2, partial response in 2, and complete response in 1. The mean overall survival for the 10 DIPG patients was 519 days (17.3 months), with a mean posttreatment survival of 214.8 days (7.2 months). CONCLUSIONS: SIACI of bevacizumab and cetuximab was well tolerated in all 13 children. The authors' results demonstrate safety of this method and warrant further study to determine efficacy. As molecular targets are clarified, novel means of bypassing the BBB, such as intraarterial therapy and convection-enhanced delivery, become more critical. Clinical trial registration no.: NCT01884740 (clinicaltrials.gov).

Analysis of the Sonopet Ultrasonic Bone Aspirator to Traditional Instrumentation for Endoscopic Suturectomy for Craniosynostosis.

OBJECTIVE: The goal of endoscopic treatment for craniosynostosis is to remove the fused suture and achieve calvarial remodeling with external orthosis. To reduce the need for secondary surgery and to minimize blood loss, instruments that maximize bone removal while minimizing blood loss and risk of dural injury are evolving. The authors therefore assess the safety and efficacy of the Sonopet Ultrasonic Bone Aspirator (UBA) (Stryker, Kalamazoo, MI) for endoscopic suturectomy compared to traditional instrumentation at our institution. METHODS: Retrospective chart review of consecutive endoscopic suturectomies performed from 2011 to 2019 at Weill Cornell Medical Center was conducted, including demographics, cephalic index, surgical indications, operative time, cosmetic and functional results, complications, estimated blood loss (EBL), re-operation rate, length of stay, and length of helmet therapy. These variables were then compared between the Sonopet and non-Sonopet cohorts. RESULTS: Of the 60 patients who underwent endoscopic suturectomy, 16 cases (26.7%) utilized the Sonopet. Mean operative time was 2.8 ±â€Š0.4 hours in the Sonopet group, compared to 3.2 ±â€Š1.2 hours (P = 0.05) without the Sonopet. EBL was 17.8 ±â€Š23.9 cc versus 34.7 ±â€Š75.5 cc (P = 0.20) with versus without the Sonopet respectively. Length of stay and duration of helmet therapy were similar in both groups, ranging from 1 to 3 days (P = 0.68) and 7.25 to 12 months (P = 0.30) respectively. There were no reoperations in the Sonopet group with a mean follow up of 9.18 months. There were 3 reoperations in the non-Sonopet group with a mean follow up of 11.3 months. Among the cases utilizing the Sonopet, 13 (81%) were metopic and three (19%) were coronal synostoses. Of the non-Sonopet cases, 27 (61%) were sagittal, 8 (18%) were metopic, 7 (16%) were coronal, and 2 (5%) were lambdoid synostoses. CONCLUSIONS: The use of the Sonopet resulted in a mean decrease in operative time at our institution (P = 0.18). Lower EBL and reoperation rates with comparable LOS and helmet therapy duration were also seen. This modality should be considered a safe and effective adjunct in appropriate endoscopic craniosynostosis cases.

Phase I and Pharmacokinetic Study of Romidepsin in Patients with Cancer and Hepatic Dysfunction: A National Cancer Institute Organ Dysfunction Working Group Study.

PURPOSE: Romidepsin dosing recommendations for patients with malignancy and varying degrees of hepatic dysfunction was lacking at the time of regulatory approval for T-cell lymphoma. We conducted a multicenter phase I clinical trial (ETCTN-9008) via the NCI Organ Dysfunction Working Group to investigate safety, first cycle MTD, and pharmacokinetic profile of romidepsin in this setting. PATIENTS AND METHODS: Patients with select advanced solid tumors or hematologic malignancies were stratified according to hepatic function. Romidepsin was administered intravenously on days 1, 8, and 15 of a 28-day cycle and escalation followed a 3 + 3 design in moderate and severe impairment cohorts. Blood samples for detailed pharmacokinetic analyses were collected after the first dose. RESULTS: Thirty-one patients received one dose of romidepsin and were evaluable for pharmacokinetic analyses in normal (n = 12), mild (n = 8), moderate (n = 5), and severe (n = 6) cohorts. Adverse events across cohorts were similar, and dose-limiting toxicity occurred in two patients (mild and severe impairment cohorts). The MTD was not determined because the geometric mean AUC values of romidepsin in moderate (7 mg/m2) and severe (5 mg/m2) impairment cohort were 114% and 116% of the normal cohort (14 mg/m2). CONCLUSIONS: Data from the ETCTN-9008 trial led to changes in the romidepsin labeling to reflect starting dose adjustment for patients with cancer and moderate and severe hepatic impairment, with no adjustment for mild hepatic impairment.

Impact of a Multidisciplinary Craniofacial Clinic for Patients With Craniofacial Syndromes on Patient Satisfaction and Outcome.

OBJECTIVE: Multidisciplinary clinics are becoming widely utilized. Given the number of patients with craniofacial syndromes evaluated at our institution, and the burden of assessment by multiple subspecialists, we created an American Cleft Palate-Craniofacial Association-certified Craniofacial Multidisciplinary Clinic (CMC) composed of a nurse practitioner, neurosurgeon, plastic surgeon, otolaryngologist, oromaxillofacial surgeon, geneticist, pulmonologist, occupational therapist, dentist, and child life specialist to improve patient experience, lessen the burden of assessment, decrease time to surgery, and improve patients' understanding of the diagnosis and treatment plan specifically for patients with complex craniofacial syndromes. We reviewed the impact of this clinic after 1 year of implementation. DESIGN: Retrospective review was performed to identify patients with craniofacial syndromic diagnoses seen by the neurosurgery department before and after implementation of the CMC from February 2017 to present. SETTING: The CMC is an outpatient clinic based in a tertiary care academic institution. PATIENTS: Chart review was performed to identify demographic, diagnostic, clinical, and treatment data. We assessed clinic experience, and the impact on quality of clinical and surgical care was assessed via survey. We compared this cohort to patients with similar craniofacial syndromes treated prior to the CMC. Thirty patients seen at the CMC were identified, and data from a comparable cohort of 30 patients seen prior to the clinic's inception was reviewed. RESULTS: Our CMC survey response rate was 67% (n = 20/30) for the CMC patients. Second opinions sought by parents prior to CMC was higher (mean = 0.85, range: 0-3) than for patients seen at the CMC (mean = 0.16, range: 0-1). Mean time to surgery before the CMC was 10.1 months (range: 1-15) compared to 4 months (range: 3-5) after implementation. Parents agreed that they felt well-informed about their diagnosis (n = 18/20, 90%), and that the presence of a plastic surgeon (19/20, 95%) and a nurse practitioner (17/20, 85%) were valuable in coordination of their care. Following surgery, 76% (n = 13/17) of patients who received surgery were happy with the outcome, 76% (n = 13/17) were happy with the appearance of the scar, and 95% (n = 19/20) would recommend the CMC to others. CONCLUSION: Multidisciplinary evaluation of patients with complex craniofacial conditions provides comprehensive, efficient, and effective care, as well as improved parent satisfaction and knowledge base.

Surgical Management of Complex Syndromic Craniosynostosis: Experience With a Rare Genetic Variant.

Patients with syndromic craniosynostosis (CS) can present with both intracranial and extracranial manifestations. Extracranial features include proptosis, exorbitism, and midface hypoplasia. Intracranial manifestations can include elevated intracranial pressure (ICP), brainstem compression, foramen magnum stenosis or jugular foramen hypoplasia with resultant venous hypertension and anomalous drainage. While fronto-orbital advancement, cranial vault remodeling, and posterior fossa decompression are standard surgical approaches to normalizing orbito-cranial volume and morphology, associated hydrocephalus, anomalous venous drainage, and tonsillar herniation often affect the timing, safety, and selection of corrective interventions. The surgical decision-making to circumvent venous emissaries, effectively time treatment of hydrocephalus, and address posterior versus anterior pathology primarily has not been widely described in the literature, and is important in the development of guidelines in these complex cases. In this report, we describe the surgical management of a patient with Jackson-Weiss syndrome presenting with delayed, but rapidly progressive bilateral lambdoid CS, severe proptosis, midface hypoplasia, elevated ICP, hydrocephalus, tonsillar ectopia, and severe venous hypertension with anomalous drainage. We review the literature related to management of complex synostosis and present our surgical decision-making in the setting of complex syndromic synostosis to aid in the formation of guidelines toward approaching these cases.

A Phase I Trial of the VEGF Receptor Tyrosine Kinase Inhibitor Pazopanib in Combination with the MEK Inhibitor Trametinib in Advanced Solid Tumors and Differentiated Thyroid Cancers.

PURPOSE: Differentiated thyroid cancer (DTC) responds to VEGF receptor inhibitors. VEGF signals through RAS/RAF/MEK signaling. We evaluated the safety and efficacy of the VEGF receptor inhibitor pazopanib and MEK inhibitor trametinib in advanced solid tumors and DTC. PATIENTS AND METHODS: Patients with advanced solid tumors were enrolled in a phase I, multicenter trial with a DTC expansion cohort. Patients received pazopanib 400-800 mg and trametinib 1-2 mg daily. Efficacy in the expansion cohort was assessed with objective response (OR) at 6 months of treatment. RESULTS: Twenty-six patients were enrolled in five dose levels. MTD was not reached; the recommended phase II dose was pazopanib 800 mg orally and trametinib 2 mg orally every day. There was one dose-limiting toxicity on dose level 1 with grade 3 fatigue and muscle weakness. Common grade 3 adverse events were elevated transaminases (19%), diarrhea (15%), hypertension (12%), and fatigue (8%). Thirteen patients were enrolled in the DTC cohort; OR was 33% (95% confidence interval, 9.9, 65.1%) and median progression-free survival was 10.7 months. The cohort was terminated after planned interim analysis suggested insufficiently increased activity against the historical control of pazopanib alone. Reduction in tumor diameter negatively correlated with p-ERK change in tumor (Spearman ρ = -0.71; P = 0.05). NRAS mutation was associated with response (Fisher exact P = 0.008). CONCLUSIONS: Pazopanib + trametinib was tolerable at full single-agent doses with clinical activity in DTC but did not achieve the prespecified response rate target.

The oral VEGF receptor tyrosine kinase inhibitor pazopanib in combination with the MEK inhibitor trametinib in advanced cholangiocarcinoma.

BACKGROUND: Cholangiocarcinoma is an aggressive malignancy with limited therapeutic options. MEK inhibition and antiangiogenic therapies have individually shown modest activity in advanced cholangiocarcinoma, whereas dual inhibition of these pathways has not been previously evaluated. We evaluated the safety and efficacy of combination therapy with the oral VEGF receptor tyrosine kinase inhibitor pazopanib plus the MEK inhibitor trametinib in patients with advanced cholangiocarcinoma. METHODS: In this open-label, multicentre, single-arm trial, adults with advanced unresectable cholangiocarcinoma received pazopanib 800 mg daily and trametinib 2 mg daily until disease progression or unacceptable toxicity. The primary end point was progression-free survival (PFS) with secondary end points including overall survival (OS), response rate, and disease control rate (DCR). RESULTS: A total of 25 patients were enrolled and had received a median of 2 prior systemic therapies (range 1-7). Median PFS was 3.6 months (95% CI: 2.7-5.1) and the 4-month PFS was 40% (95% CI: 24.7-64.6%). There was a trend towards increased 4-month PFS as compared with the prespecified null hypothesised 4-month PFS of 25%, but this difference did not reach statistical significance (P=0.063). The median survival was 6.4 months (95% CI: 4.3-10.2). The objective response rate was 5% (95% CI: 0.13-24.9%) and the DCR was 75% (95% CI: 51%, 91%). Grade 3/4 adverse events attributable to study drugs were observed in 14 (56%) and included thrombocytopenia, abnormal liver enzymes, rash, and hypertension. CONCLUSIONS: Although the combination of pazopanib plus trametinib had acceptable toxicity with evidence of clinical activity, it did not achieve a statistically significant improvement in 4-month PFS over the prespecified null hypothesised 4-month PFS.

Phase Ib/II Study of the Safety and Efficacy of Combination Therapy with Multikinase VEGF Inhibitor Pazopanib and MEK Inhibitor Trametinib In Advanced Soft Tissue Sarcoma.

Purpose: Pazopanib, a multireceptor tyrosine kinase inhibitor targeting primarily VEGFRs1-3, is approved for advanced soft tissue sarcoma (STS) and renal cell cancer. Downstream of VEGFR, trametinib is an FDA-approved MEK inhibitor used for melanoma. We hypothesized that vertical pathway inhibition using trametinib would synergize with pazopanib in advanced STS.Experimental Design: In an open-label, multicenter, investigator-initiated National Comprehensive Cancer Network (NCCN)-sponsored trial, patients with metastatic or advanced STS received pazopanib 800 mg and 2 mg of trametinib continuously for 28-day cycles. The primary endpoint was 4-month progression-free survival (PFS). Secondary endpoints were overall survival, response rate, and disease control rate.Results: Twenty-five patients were enrolled. The median age was 49 years (range, 22-77 years) and 52% were male. Median PFS was 2.27 months [95% confidence interval (CI), 1.9-3.9], and the 4-month PFS rate was 21.1% (95% CI, 9.7-45.9), which was not an improvement over the hypothesized null 4-month PFS rate of 28.3% (P = 0.79). Median overall survival was 9.0 months (95% CI, 5.7-17.7). A partial response occurred in 2 (8%) of the evaluable patients (95% CI, 1.0-26.0), one with PIK3CA E542K-mutant embryonal rhabdomyosarcoma and another with spindle cell sarcoma. The disease control rate was 14/25 (56%; 95% CI, 34.9-75.6). The most common adverse events were diarrhea (84%), nausea (64%), fatigue (56%), and hypertension (52%).Conclusions: The combination of pazopanib and trametinib was tolerable without indication of added activity of the combination in STS. Further study may be warranted in RAS/RAF aberrant sarcomas. Clin Cancer Res; 23(15); 4027-34. ©2017 AACR.