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Background Several multitargeted tyrosine kinase inhibitors (TKIs) have demonstrated activity in patients with thyroid cancer that is refractory to radioactive iodine (RAI). The antitumor effect is attributed at least in part to the ability of these TKIs to inhibit angiogenesis in these vascular tumors. Vascular endothelial growth factor (VEGF) Trap (VT) is a recombinantly produced fusion protein consisting solely of human sequences for VEGF receptors 1 and 2 extracellular domains and human immunoglobulin 1. Evaluating VT in patients with thyroid cancer is reasonable considering the activity observed with TKIs targeting VEGF. Methods The current study was a single-institution, phase 2, Simon 2-stage design (21 to >41 patients) study based on the objective response rate and/or 6-month progression-free survival as the primary endpoints. Eligible patients were required to have progressive, RAI-refractory and/or [18 F]fludeoxyglucose-avid, recurrent and/or metastatic, nonmedullary, nonanaplastic thyroid cancer; disease that was measurable using Response Evaluation Criteria In Solid Tumors (RECIST) criteria; and adequate organ and bone marrow function. VT at a dose of 4 mg/kg intravenously was administered every 14 days. Results A total of 40 patients were included in the analysis. Of these patients, 24 had papillary thyroid cancer, 2 had follicular thyroid cancer, and 11 had Hurthle cell thyroid cancer. The final 3 tumors were classified as poorly differentiated. There were no complete and/or partial responses noted; 34 patients achieved stable disease and 6 patients experienced disease progression as their best response. Of the 34 patients with stable disease, 16 remained on the study for >6 months and 6 patients remained on the study for >12 months. The median duration on treatment was 4.1 months (range, 0.6-30.8 months). Conclusions Unlike TKIs, which have shown responses in this setting, to the authors' knowledge there have been no responses observed with the use of single-agent VT to date. It does not appear to be a promising drug for the treatment of patients with thyroid cancer.

BACKGROUND: The incidence of large congenital melanocytic nevi (LCMN) is 1/20,000 with 25% of children diagnosed with neurocutaneous melanocytosis (NCM), characterized by excessive proliferation of melanocytes in the leptomeninges and brain parenchyma. Specifically the disorder represents abnormal migration of melanocyte precursors due to abnormal melanin-producing genes in primitive leptomeningeal cells. While NCM can transform to melanoma, the molecular drivers involved in NCM related melanoma are different from the drivers in patients with non-NCM related melanoma. Children who become symptomatic from NCM may have a poor prognosis overall with 25–60% developing melanoma. While melanoma typically harbors mutations in the BRAF gene, NCM has a distinct molecular signature comprised primarily of mutations in the NRAS gene. METHODS: We reviewed our institutional database from 2003–2018 and identified 47 patients with large congenital melanocytic nevi (LCMN) and NCM. Fifteen were female and 16/47 died. Five had molecular testing which revealed an NRAS mutation in the affected tissues. Four patients who developed melanoma, received targeted therapy including off label trametinib, nivolumab and/or ipilumumab. While none of these patient were longterm survivors, one patient lived for 12 months after receiving radiation therapy, nivolumab and ipilumumab. One patient with a VP shunt developed intraperitoneal melanoma, malignant ascites and subsequently died. CONCLUSIONS: While NCM which transforms to melanoma is typically fatal, new targeted therapies may offer prolonged survival. Further efforts to identify which patients are high risk are needed in an attempt to offer earlier treatment.

Context BRAFV600E mutant thyroid cancers are often refractory to radioiodine (RAI). Objectives To investigate the utility and molecular underpinnings of enhancing lesional iodide uptake with the BRAF inhibitor vemurafenib in patients with RAI-refractory (RAIR). Design This was a pilot trial that enrolled from June 2014 to January 2016. Setting Academic cancer center. Patients Patients with RAIR, BRAF mutant thyroid cancer. Intervention Patients underwent thyrotropin-stimulated iodine-124 (124I) positron emission tomography scans before and after ~4 weeks of vemurafenib. Those with increased RAI concentration exceeding a predefined lesional dosimetry threshold (124I responders) were treated with iodine-131 (131I). Response was evaluated with imaging and serum thyroglobulin. Three patients underwent research biopsies to evaluate the impact of vemurafenib on mitogen-activated protein kinase (MAPK) signaling and thyroid differentiation. Main outcome measure The proportion of patients in whom vemurafenib increased RAI incorporation to warrant 131I. Results Twelve BRAF mutant patients were enrolled; 10 were evaluable. Four patients were 124I responders on vemurafenib and treated with 131I, resulting in tumor regressions at 6 months. Analysis of research tumor biopsies demonstrated that vemurafenib inhibition of the MAPK pathway was associated with increased thyroid gene expression and RAI uptake. The mean pretreatment serum thyroglobulin value was higher among 124I responders than among nonresponders (30.6 vs 1.0 ng/mL; P = 0.0048). Conclusions Vemurafenib restores RAI uptake and efficacy in a subset of BRAF mutant RAIR patients, probably by upregulating thyroid-specific gene expression via MAPK pathway inhibition. Higher baseline thyroglobulin values among responders suggest that tumor differentiation status may be a predictor of vemurafenib benefit.

PURPOSE: Novel treatment strategies are needed for children with recurrent ependymoma. We explored the use of intraventricular targeted immunotherapy with monoclonal antibodies (cRIT-mAb) using (131)I-8H9 and (131)I-3F8 targeting B7-H3 or G(D2), respectively. METHODS: Patients received 2 mCi cRIT- (131)I- mAb for dosimetry with serial CSF sampling and region of interest (ROI) on nuclear scans. Therapy injections were 40 -100 mCi (131)I-8H9 or up to 40 mCi (131)I-3F8. Brain and spine MRIs, CSF cytology were routinely assessed. Acute toxicities and survival were noted. RESULTS: 11 patients with anaplastic ependymoma (median age 8.5 years, 1–32) suffered 1- 7 recurrences (median 2.9); median age at cRIT was 12.3 years (3–35). 39 injections were delivered (13 (131)I-3F8; 26 (131)I-8H9). Transient headache, nausea and vomiting was observed following (131)I-3F8; (131)I-8H9 was well-tolerated. Mean CSF cGy/mCi by sampling was 37.6 (131)I-8H9 and 40.1 (131)I-3F8. Mean ventricular ROI dose was 75.3 cGy/mCi (131)I-8H9 and 111 cGy/mCi (131)I-3F8 and to spine 20.2 cGy/mCi (131)I-8H9 and 18.9 cGy/mCi (131)I-3F8. 4/5 patients with radiographic evidence of disease progressed; 1 had spinal disease improvement. Of 5 patients treated in radiographic remission, 2 remain in remission 2.5 and 8 years since cRIT, 1 is alive with disease 2.5 years post; 2 patients died of disease 7 and 13 years post cRIT. CONCLUSIONS: cRIT mAb appear safe with a favorable dosimetry therapeutic index and may be considered as a viable therapeutic option for patients with recurrent ependymoma.

Background The purpose of this study was to evaluate the efficacy and tolerability of the addition of 2 monoclonal antibodies, bevacizumab and cetuximab, to 2 cycles of high-dose cisplatin administered concurrently with intensity-modulated radiation therapy (IMRT) for head and neck squamous cell carcinoma (HNSCC). Methods Patients with newly diagnosed stage III/IVB (M0) HNSCC received cetuximab (400 mg/m2 loading dose, followed by 250 mg/m2 weekly), bevacizumab (15 mg/kg, days 1 and 22), and cisplatin (50 mg/m2, days 1, 2, 22, and 23) concurrently with IMRT (70 Gy). The primary endpoint was progression-free survival (PFS). Secondary endpoints were overall survival (OS) and safety and tolerability. Results Among 30 patients enrolled in this study, the primary tumor site was the oropharynx in 24 patients (p16 immunohistochemistry was positive in 17, negative in 1, and not done in 6 of the oropharyngeal tumors). Median age was 57 years (range, 38–77 years) and 27 patients had clinical stage IVA disease. All patients completed the full planned dose of radiation therapy. The most common ≥ grade 3 adverse events were lymphopenia, mucositis (functional), and dysphagia. With a median follow-up of 33.8 months, 2-year PFS was 88.5% (95% confidence interval [CI] = 68.1–96.1) and 2-year OS was 92.8% (95% CI = 74.2–98.1). Conclusion The addition of bevacizumab and cetuximab to 2 cycles of cisplatin, given concurrently with IMRT, was well-tolerated and was associated with favorable efficacy outcomes in this patient population. © 2015 Wiley Periodicals, Inc. Head Neck, 2015

Introduction: Targeted therapies in HER2+ metastatic breast cancer (MBC) have significantly improved survival, however efficacy is limited by development of therapeutic resistance. HSP90 is a molecular chaperone involved in the stability and function of multiple signaling onco-proteins. HER2 is an acutely sensitive HSP90 client and HSP90 inhibition can overcome trastuzumab resistance. Ganetespib is a novel, synthetic HSP90 inhibitor with increased potency and tolerability compared with earlier agents. Our group has conducted a single agent ganetespib trial in unselected patients which showed anti-tumor activity in HER2+ and triple negative breast cancer. In addition, preclinical data suggests HSP90 inhibition is synergistic with taxanes with potential for significant clinical activity. Ganetespib has been combined with docetaxel in non-small cell lung cancer, it has not previously been combined with paclitaxel and trastuzumab. This study will define the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of ganetespib when given with paclitaxel and trastuzumab for patients with HER2+ MBC. Methods: In this 3+3 phase I dose escalation study, patients with trastuzumab resistant HER2+ MBC receive trastuzumab (4mg/kg loading dose, then 2mg/kg) and paclitaxel weekly (80mg/m2) with ganetespib day 1, 8 ,15 of 28 day cycle. Patients are required to have prior pertuzumab and T-DM1 (prior pertuzumab and T-DM1 are not mandated if heavily pretreated prior to their respective FDA approvals). Hormone receptor positive patients are required to have at least one prior line of endocrine therapy. The single agent dose limiting toxicity (DLT) of ganetespib is diarrhea and therefore patients receive prophylactic anti-motility agents. The anticipated MTD of ganetespib in this combination has been informed by experience with docetaxel and based on this only three dose levels of ganetespib are being explored 100mg/m2, 150mg/m2 and a third intermediate cohort of 125mg/m2, if needed. Secondary endpoints include evaluation of effects of ganetespib on the pharmacokinetics of paclitaxel and preliminary assessment of efficacy of the combination (scans at 8 weeks and every 12 weeks thereafter, RECIST 1.1). Results: The first dosing cohort has fully enrolled and there were no significant toxicities or DLTs reported. Median age was 48 years (range 39-49), median prior lines of chemotherapy were 4 (range 3-7) and included prior pertuzumab and T-DM1 in all 3 patients. 5 adverse events have been defined as possibly/probably related to ganetespib – grade 2 anemia and leukopenia, grade 1 diarrhea (2 patients), fatigue, and rash. Enrollment to the second and potentially final cohort is underway. Conclusion: This study will define the RP2D of ganetespib in combination with paclitaxel and trastuzumab. Final safety, pharmacokinetic and preliminary response data for all patients will be presented. This combination, with a novel anti-HER2 agent, has encouraging potential for activity in HER2+ breast cancer which is refractory to other HER2 targeting agents. Citation Format: Komal Jhaveri, Karen Cadoo, Sarat Chandarlapaty, Eleonora Teplinsky, James Speyer, Gabriella D' Andrea, Sujata Patil, Sofia Haque, Kent Friedman, Scott Heese, Deirdre Neville, Francisco Esteva, Clifford Hudis, Shanu Modi. A phase I clinical trial of ganetespib (heat shock protein 90 inhibitor) in combination with paclitaxel and trastuzumab in human epidermal growth factor receptor-2 positive (HER2+) metastatic breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-19-23.

Orbital metastasis is an uncommon and atypical presentation of recurrent esophageal cancer that has been only seldom reported in literature. F-FDG PET/CT is routinely performed for staging and response assessment in patients with esophageal carcinoma. This case demonstrates use of follow-up FDG PET/CT scans in characterizing solitary metastatic disease in orbit and in evaluating response to therapy. It also highlights a key teaching point that postradiation-related inflammatory/infective changes may interfere in accurate assessment of PET/CT scan; however, frequently used clinical and radiological correlation may not be entirely sufficient to rule out pathological involvement.

BRAF

BACKGROUND: High-risk and recurrent medulloblastoma is associated with significant mortality. The murine monoclonal antibody 3F8 targets the cell-surface disialoganglioside GD2 on medulloblastoma. We tested the efficacy, toxicity, and dosimetry of compartmental radioimmunotherapy (cRIT) with intraventricular 131Ilabeled 3F8 in patients with medulloblastoma on a phase II clinical trial. METHODS: Patients with histopathologically confirmed high-risk or recurrent medulloblastoma were eligible for cRIT. After determining adequate cerebral spinal fluid (CSF) flow, patients received 2 mCi 124I-3F8 or 131I-3F8 with nuclear imaging for dosimetry, followed by a maximum of 4 therapeutic (10 mCi /dose)131I-3F8 injections. Dosimetry estimates were based on serial CSF and blood samplings over 48 hours plus region-of-interest analyses on serial imaging scans. Disease evaluation included pre- and post-therapy brain/spine MRI approximately every 3 months for the first year after treatment, and every 6–12 months thereafter. RESULTS: Forty-three patients received a total of 167 injections; 42 patients were evaluable for outcome. No treatment-related deaths occurred. Toxicities included acute bradycardia with somnolence, headache, fatigue and CSF pleocytosis consistent with chemical meningitis, and dystonic reaction. Total CSF absorbed dose was 1453 (350.0–2784) cGy. Median OS from first dose of cRIT was 24.9 months (95% CI: 16.3–55.8). Patients treated in radiographic and cytologic remission were at a lower risk of death compared to patients with radiographically measurable disease (HR: 0.40, 95%CI: 0.18–0.88, p=0.024). CONCLUSIONS: cRIT with 131I-3F8 is safe, has favorable dosimetry to CSF and when added to salvage therapy using conventional modalities, may have clinical utility in maintaining remission in high-risk or recurrent medulloblastoma.

Background Targeted therapies in HER2-positive metastatic breast cancer significantly improve outcomes but efficacy is limited by therapeutic resistance. HER2 is an acutely sensitive Heat Shock Protein 90 (HSP90) client and HSP90 inhibition can overcome trastuzumab resistance. Preclinical data suggest that HSP90 inhibition is synergistic with taxanes with the potential for significant clinical activity. We therefore tested ganetespib, a HSP90 inhibitor, in combination with paclitaxel and trastuzumab in patients with trastuzumab-refractory HER2-positive metastatic breast cancer. Methods In this phase I dose-escalation study, patients with trastuzumab-resistant HER2-positive metastatic breast cancer received weekly trastuzumab (2 mg/kg) and paclitaxel (80 mg/m2) on days 1, 8, 15, and 22 of a 28-day cycle with escalating doses of ganetespib (100 mg/m2, 150 mg/m2, and a third cohort of 125 mg/m2 if needed) on days 1, 8, and 15. Therapy was continued until disease progression or toxicity. The primary objective was to establish the safety and maximum tolerated dose and/or recommended phase II dose (RP2D) of this therapy. The secondary objectives included evaluation of the effects of ganetespib on the pharmacokinetics of paclitaxel, and to make a preliminary assessment of the efficacy of the combination therapy. Results Dose escalation was completed for the two main cohorts without any observed dose-limiting toxicities. Nine patients received treatment. The median prior lines of anti-HER2 therapy numbered three (range 2–4), including prior pertuzumab in 9/9 patients and ado-trastuzumab emtansine (T-DM1) in 8/9 patients. The most common grade 1/2 adverse events (AEs) were diarrhea, fatigue, anemia, and rash. There were no grade 4 AEs related to ganetespib. The overall response rate was 22% (2/9 patients had partial response) and stable disease was seen in 56% (5/9 patients). The clinical benefit rate was 44% (4/9 patients). The median progression-free survival was 20 weeks (range 8–55). Conclusion The RP2D of ganetespib is 150 mg/m2 in combination with weekly paclitaxel plus trastuzumab. The combination was safe and well tolerated. Despite prior taxanes, pertuzumab, and T-DM1, clinical activity of this triplet regimen in this heavily pretreated cohort is promising and warrants further study in HER2-positive metastatic breast cancer. Trial registration ClinicalTrials.gov NCT02060253 . Registered 30 January 2014.

Background Ganetespib is a small molecule, nongeldanamycin HSP90 inhibitor with potent inhibitory effects on HSP90-dependent oncoproteins of relevance to breast cancer pathogenesis. We therefore tested ganetespib in an unselected cohort of patients with MBC. Patients and Methods Patients were treated with single agent ganetespib at 200 mg/m2 once weekly for 3 weeks, on a 28-day cycle. Therapy was continued until disease progression. The primary end point was ORR using Reponse Evaluation Criteria in Solid Tumors version 1.1. Results Twenty-two patients were enrolled with a median age of 51(range, 38-70) years and a median Eastern Cooperative Oncology Group performance status of 0 (range, 0-1). Most patients had at least 2 previous lines of chemotherapy in the metastatic setting. Most common toxicities, largely grade 1/2, were diarrhea, fatigue, nausea, and hypersensitivity reaction. The ORR in this unselected population was 9%, with all responses coming from the subset of patients with HER2-positive MBC (2/13; 15%). One patient with TNBC had objective tumor regression in the lung metastases. The clinical benefit rate (complete response + partial response + stable disease > 6 months) was 9%, median progression-free survival was 7 weeks (95% confidence interval [CI], 7-19), and median overall survival was 46 weeks (95% CI, 27-not applicable). Conclusion The study did not meet the prespecified criteria for ORR in the first stage of the Simon 2-stage model in this heavily pretreated unselected population of MBC. However, activity was observed in trastuzumab-refractory HER2-positive and TNBC. Ganetespib was well tolerated and responses in more targeted populations harboring specific HSP90-dependent oncoproteins justifies its further study, particularly as part of rational combinations.

Background The human papillomavirus (HPV) E6 oncoprotein enhances the oncogenic potential of ErbB proteins in HPV-related malignancies. This phase I study evaluates the addition of afatinib, an ErbB family inhibitor, and ribavirin to paclitaxel and carboplatin induction chemotherapy in HPV-associated, locally advanced oropharyngeal squamous cell carcinoma (SCC). Methods This dose escalation study included 2 doses of oral afatinib: 30 and 40 mg daily. Ribavirin dosing was weight based. Paclitaxel (80 mg/m2) and carboplatin (area under the curve [AUC] 1.5) were administered on days 1 and 8 of each 21-day cycle. After 3 cycles, patients were removed from protocol to receive definitive treatment. Results Among 10 patients, there were no dose-limiting toxicities. Six patients (67%) had unconfirmed objective partial responses. The 2-year progression-free survival rate was 75%. Conclusion Afatinib, ribavirin, paclitaxel, and carboplatin induction chemotherapy is safe and well tolerated. The phase II recommended dose of afatinib is 40 mg oral daily in this combination regimen.

2008 Background: Diffuse intrinsic pontine glioma (DIPG) represents one of the most deadly central nervous system tumors of childhood with a median survival of less than 12 months. Convection-enhanced delivery (CED) has been recently hypothesized as a means for efficiently distributing therapeutic agents within the brain stem. We conducted this study to evaluate CED in children with DIPG. Methods: We performed a standard phase I dose escalation study in patients with non-progressive DIPG 4 to 14 weeks post-completion of radiation therapy. Seven dose levels of a single injection of 124I-8H9 (Omburtamab) (range 0.25 to 4.0 mCi) were studied. Results: 37 children were treated with 34 evaluable for primary and secondary endpoints. The median age at enrollment was 6.8 years old (range 3.2 - 17.9). There was no dose limiting toxicity (DLT). Among adverse events that were at least possibly related to the treatment, there were no grade 4 or 5 events, and only 4 reversible grade 3 events in 4 patients (2 hemiparesis, 1 skin infection and 1 anxiety). Estimations of distribution volumes based on T2-weighted imaging were dose dependent and ranged from 1.5 to 20.8 cm3, and for dose level 7, 10.5 - 19.0 cm3. The mean volume of distribution/volume of infusion ratio (Vd/Vi) was 3.4 ±1.1, and for dose level 7, 3.5 ± 1.0. The mean lesion absorbed dose was 33.3 ± 25.9 Gy, and for dose level 7, 50.1 ± 22.9 Gy. The mean ratio of lesion-to-whole body absorbed dose was 910. The mean volume of distribution/tumor volume ratio on dose level 7 was 82.5%, but the mean tumor overlap was 40.5%. No death occurred as a result of the treatment. Median survival was 15.3 months (n = 29, 95% CI 12.7 - 17.4). Median follow-up time of the 5 surviving patients is 27.2 months (range 11.5 - 72.4). Overall survival rate at 12 months was 64.7% (22/34, 4 alive), and overall survival rate at 24 months 14.7% (5/34, 3 alive). Conclusions: CED in the brain stem of children with DIPG who were previously irradiated is a safe therapeutic strategy. An infusion volume of 4,000 mcl appears to be a reasonable single dose for a target distribution volume but enhanced tumor coverage is likely needed. There seems to be a survival benefit using this therapeutic strategy and outcomes might be dependent on dosimetry and distribution patterns. Clinical trial information: NCT01502917.

e13592 Background: Tumors metastasizing to the central nervous system (CNS) are associated with significant mortality. We tested the toxicity and dosimetry of intraventricular 131I-labeled monoclonal antibody 8H9 targeting surface glycoprotein B7-H3 in patients with primary or metastatic CNS tumors. Methods: Tumor B7-H3 expression was assessed by immunohistochemistry. CSF flow was determined by 111Indium-DTPA cisternography. 131 patients received 2 mCi tracer of intra-Ommaya 124I- or 131I-8H9 for nuclear imaging followed by a therapeutic injection (10-80 mCi, dose levels 1-8 in 10 mCi increments for phase I patients; expanded cohort 50 mCi/injection) 131I-8H9. Pharmacokinetics were studied by serial CSF and blood samplings over 48 hours. Dosimetry was based on pharmacokinetics and region of interest analyses on serial PET. Toxicity was defined by the CTCAE v.3.0. 8H9 dosimetry and therapy injections were repeated after 1 month if no serious adverse events or progressive disease ensued. Tumor response was determined by clinical, radiographic, cytologic criteria; overall survival was noted. Results: 57 patients (ages 2 – 54 years, median age 11.7 years) received 158 injections Primary CNS diagnoses included medulloblastoma (n = 23), ependymoma (N = 8), chordoma (n = 1), rhabdoid tumor (n = 1), choroid plexus carcinoma (n = 3), ETMR (n = 3), glioblastoma multiforme (n = 1) , PXA (n = 1); metastatic tumors included sarcoma (n = 9), melanoma (n = 4), retinoblastoma (n = 2), and ovarian carcinoma (n = 1). Injections were well tolerated and routinely administered in the outpatient setting. Rare self-limited adverse events included grade 1 or 2 fever, headache, vomiting; 3 injections were associated with grade 3 toxicities requiring discontinuation of therapy including chemical meningitis (n = 2),and increasing communicating hydrocephalus (n = 1), Although not a dose limiting toxicity, myelosuppression occurred in patients who had received craniospinal radiation and at dose levels 6 and higher (≥60 mCi). 16 patients remain alive including patients with high-risk malignancies including choroid plexus carcinoma, ETMR, recurrent ependymoma and recurrent medulloblastoma. Conclusions: We conclude that intraventricular 131I-8H9 is safe, has favorable dosimetry to CSF, and may have clinical utility in the treatment of primary and metastatic CNS tumors. Clinical trial information: NCT00089245.

6084 Background: R/M ACC is a malignant neoplasm most commonly of salivary gland origin with no standard treatment. The impact of combined PD-1/CTLA-4 checkpoint blockade in R/M ACC is unknown. Methods: In a two-stage minimax phase II trial, pts with progressive R/M ACC (non-salivary primaries allowed) were enrolled and treated with nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks (1 cycle = 6 weeks). Imaging, using RECIST v1.1 response assessment, was scheduled to be performed approximately every 12 weeks. The primary endpoint was overall response rate (ORR = complete response [CR]+partial response [PR]) per RECIST v1.1. To detect a difference between an unacceptable ORR of 5% and a desirable ORR of 20% (one-sided type I error of 10%, power of 90%), at least 1 in the first 18 pts required an observed response. At least 4 responses of 32 total pts were needed to meet the primary endpoint. Treatment beyond progression of disease (PD) was allowed at the discretion of the investigator. A second cohort of pts with non-ACC salivary cancer is still accruing for separate analysis. Results: From 6/12/2017-6/20/2018, 32 pts were enrolled and evaluable for the primary endpoint. There was 1 confirmed PR in the first 18 pts, therefore enrollment of the second stage continued. ORR was 6% (2/32). One additional pt had an unconfirmed PR (-31% regression before CNS PD). For best overall response, there were 2 PRs, 15 SD, and 11 PD. Four pts never reached a first disease assessment: 3 due to death from clinical PD and 1 was removed for toxicity. Six pts discontinued the trial for toxicities (Grade 4 (G4) neutropenia/sepsis and G3 adrenal insufficiency (1), G2 hypophysitis (2), G3 arthritis > 7 days (1), G3 colitis (1), and G3 hepatitis/G4 creatinine kinase (CK) elevation (1)). The 2 confirmed PRs consisted of -73.1% and -58.4% regressions, with a duration of therapy of 18.4 and 7.8 months, respectively (treatment ongoing for both). Conclusions: The study did not meet its primary endpoint, though the responses observed were dramatic. Paired biopsy and peripheral blood samples will be analyzed to elucidate insights into mechanisms of response and resistance to dual checkpoint blockade. Clinical trial information: NCT03172624.

BACKGROUND: While immunotherapy has revolutionized the treatment for several solid tumors, pseudoprogression, radiographically defined as the initial increase in tumor volume followed by tumor shrinkage, is less clearly defined. This is particularly noteworthy for patients with central nervous system metastases, commonly seen in patients with advanced melanoma or non-small cell lung cancer treated with PD-1 or CTLA-4 inhibitors. B7-H3 (CD276) is a transmembrane protein belonging to the B7 family of costimulatory molecules. (1) Several solid tumors overexpress B7-H3, and expression appears to be closely associated with immune escape, tumor cell invasion and metastases. The incidence of pseudoprogression after B7-H3 therapy is unknown. METHOD: A 4 year old girl with central nervous system metastases of neuroblastoma underwent resection of 2 left parietal lobe lesions, the largest 1.4 cm with edema, enhancement and restricted diffusion, followed by craniospinal radiation therapy, irinotecan, temozolomide, inducing a second remission with expected MR appearance in the operative cavity. She was then registered to clinicaltrials.gov (NCT00089245) with intraventricular 131-I-anti B7-H3. One month after therapy, routine MR revealed increased nodular enhancement around both operative cavities with adjacent leptomeningeal enhancement, concerning for progressive neuroblastoma. The patient remained asymptomatic. RESULTS: A repeat brain performed 2 weeks later showed interval resolution of both the operative cavity and leptomeningeal enhancement and edema. Repeat brain and spine MR performed 6 months later shows continued remission with complete resolution of all enhancement and edema. RESULTS: Anti- B7-H3 therapy caused an immediate inflammatory reaction with spontaneous radiographic resolution and return to baseline 2 weeks later, all in the absence of concurrent steroid administration. CONCLUSION: Though the precise frequency and timeline is unclear, B7-H3 directed therapy may be added to the list of immunotherapeutic agents recognized to cause pseudoprogression. Key efforts are now being made to correlate the appearance of CNS neuroblastoma pseudoprogression with overall survival.

Historically, systemic therapy for radioactive iodine (RAI)-refractory thyroid cancer has been understudied. Available drugs have modest efficacy. Romidepsin is a histone deacetylase inhibitor with potent antitumor effects both in vitro and in vivo. In thyroid cancer cell lines, romidepsin increases expression of both thyroglobulin and the sodium iodide symporter messenger RNAs, suggesting the possibility of improved iodine concentrating ability of RAI-resistant tumors.This was a single-institution Simon 2-stage phase II clinical study. Eligible patients had progressive, RAI-refractory, recurrent/metastatic, nonmedullary, nonanaplastic thyroid cancer. Response Evaluation Criteria in Solid Tumors (RECIST) 1.0 measurable disease and adequate organ/marrow function were required. Romidepsin 13 mg/m² was administered intravenously on days 1, 8, and 15, in cycles of 28 days. The primary endpoint was the response rate by RECIST; change in RAI avidity was a secondary endpoint. The study closed after the first stage due to the lack of response.Twenty patients were enrolled: female, 50%; median age, 64 years; histology, 8 papillary/1 follicular/11 Hürthle. Grade 4-5 adverse events (AEs) possibly related to the drug: grade 5, 1 sudden death; grade 4, 1 pulmonary embolus. Twelve of 20 subjects had a reported adverse event. No RECIST major responses have been seen. Response per protocol: stable disease, 13; disease progression, 7. Restoration of RAI avidity was documented in two patients. Median overall survival and time on study was 33.2 (1-71+) and 1.7 (0.46-12) months, respectively.We observed preliminary signs of in vivo reversal of RAI resistance after treatment with romidepsin. However, no major responses were observed and accrual was poor after the grade 5 AE.

The PI3K/AKT/mTOR pathway is aberrantly activated in many pediatric solid tumors including gliomas and medulloblastomas. Preclinical data in a pediatric glioma model demonstrated that the combination of perifosine (AKT inhibitor) and temsirolimus (mTOR inhibitor) is more potent at inhibiting the axis than either agent alone. We conducted this study to assess pharmacokinetics and identify the maximum tolerated dose for the combination.We performed a standard 3+3 phase I, open-label, dose-escalation study in patients with recurrent/refractory pediatric solid tumors. Four dose levels of perifosine (25-75 mg/mTwenty-three patients (median age 8.5 years) with brain tumors (diffuse intrinsic pontine glioma [DIPG] n = 8, high-grade glioma n = 6, medulloblastoma n = 2, ependymoma n = 1), neuroblastoma (n = 4), or rhabdomyosarcoma (n = 2) were treated. The combination was generally well tolerated and no dose-limiting toxicity was encountered. The most common grade 3 or 4 toxicities (at least possibly related) were thrombocytopenia (38.1%), neutropenia (23.8%), lymphopenia (23.8%), and hypercholesterolemia (19.0%). Pharmacokinetic findings for temsirolimus were similar to those observed in the temsirolimus single-agent phase II pediatric study and pharmacokinetic findings for perifosine were similar to those in adults. Stable disease was seen in 9 of 11 subjects with DIPG or high-grade glioma; no partial or complete responses were achieved.The combination of these AKT and mTOR inhibitors was safe and feasible in patients with recurrent/refractory pediatric solid tumors.

The mammalian target of rapamycin complex 1 (mTORC1) is aberrantly activated in many head and neck squamous cell carcinomas (HNSCCs). This phase I study combines the mTORC1 inhibitor temsirolimus with carboplatin and paclitaxel.This was a single institution phase I study for patients with R/M HNSCC with a standard 3 + 3 design. Three doses of temsirolimus were planned: 15, 20, and 25 mg. Due to excessive toxicity with the original study regimen, the protocol was amended to carboplatin AUC 1.5, paclitaxel 80 mg/m(2), and temsirolimus (according to dose escalation plan), all on days 1 and 8 of a 21-day cycle.18 patients (14 male, 4 female) enrolled, with median age 56 years (range 33-78). The most common toxicities were anemia, leukopenia, thrombocytopenia, and hyperglycemia. Among all patients treated, the confirmed objective partial response (cPR) rate was 22 %. DLT was not exceeded among 6 patients treated at dose level 3 of the revised protocol, and 4 of 6 subjects treated at this dose level had cPRs.The phase II recommended regimen is temsirolimus 25 mg, carboplatin AUC 1.5, and paclitaxel 80 mg/m(2), all on days 1 and 8 of a 21-day cycle. A phase II study of this regimen in R/M HNSCC is ongoing.

Aim Neurocutaneous melanocytosis is a rare neurocutaneous syndrome defined by the presence of large and/or multiple congenital cutaneous nevi and melanocytic deposits in the central nervous system. We sought to define the spectrum of central nervous system abnormalities in children with neurocutaneous melanocytosis. Method We retrospectively reviewed cases of neurocutaneous melanocytosis referred to the pediatric neuro-oncology service at our center from 2003 to 2010. Results Of 14 patients (11 males, 3 females) identified, eight were living. Median age of survivors was 31 months (range 12mo–6y 10mo) while median age of death was 81 months (19mo–28y). Of the six patients who died, all had diffuse leptomeningeal melanocytic deposits and four had leptomeningeal melanoma. All patients had neuroimaging: six had findings suggestive of diffuse leptomeningeal melanocytosis; seven had multifocal melanocytic deposits; and one patient had normal neuroimaging but focal seizures. Spinal abnormalities were common: three patients had extensive dorsal spinal arachnoid cysts and one had a benign cervical spindle cell tumor. Seven patients had epilepsy. Three patients had profound developmental delay; the other 11 patients had no or mild delay. Interpretation Children with neurocutaneous melanocytosis exhibit a wide range of intracranial and intraspinal abnormalities and variable clinical outcomes.

BACKGROUND: For patients with stage III through IVB head and neck squamous cell carcinoma (HNSCC), concurrent high-dose cisplatin plus radiation therapy is a widely accepted standard of care. HNSCC tumors that express high levels of vascular endothelial growth factor have been associated with a worse prognosis, and bevacizumab may sensitize tumors to cisplatin and radiation. METHODS: Planned treatment consisted of definitive intensity-modulated radiation therapy (IMRT) (total, 70 grays) with concurrent cisplatin (50 mg/m2 on days 1, 2, 22, 23, 43, and 44) and bevacizumab (15 mg/kg on days 1, 22, and 43). The primary endpoint was 2-year progression-free survival (PFS), and overall survival (OS) was a secondary endpoint. RESULTS: Forty-two previously untreated patients (34 men and 8 women; median age, 55 years; range, 27-75 years) with stage III through IV HNSCC without distant metastasis (oropharyngeal carcinoma, 39 patients; laryngeal carcinoma, 3 patients) were treated. Human papillomavirus (HPV) status by was determined by in situ hybridization (HPV positive, 16 patients; HPV negative, 14 patients, unknown HPV status, 12 patients). The toxicities (determined according to version 3.0 of Common Terminology Criteria for Adverse Events Common) that were experienced by all patients (any grade) were mucositis, lymphopenia, leukopenia, throat pain, fatigue, and anemia. There were 2 treatment-related deaths, including 1 sudden death and 1 death from aspiration pneumonia. The median follow-up was approximately 31.8 months (range

A greater understanding of the Ras-MAP kinase-signaling pathway in pediatric low-grade glioma (LGG) has led to the ability to target this pathway with therapeutic intent. The PBTC conducted a multi-institutional phase II study (NCT01089101) evaluating selumetinib (AZD6244, ARRY-142886), a MEK I/II inhibitor, in children with recurrent/refractory LGG assigned to 6 strata and treated at 25 mg/m2/dose PO BID for up to two years. Here we present the data from three of these strata. Stratum I included children with non-NF-1 and non-optic pathway recurrent/refractory pilocytic astrocytoma (PA) harboring BRAF aberrations (BRAF V600e mutation or the BRAF-KIAA 1549 fusion). Eight of 25 (32%) patients achieved a partial response (PR) with 2-year PFS of 66+11%. Two of 7 (29%) patient tumors with a BRAF V600e mutation and 6/18 (33%) with a BRAF KIAA-1549 fusion had a PR. Stratum 3 enrolled NF-1-associated LGG. Tissue for tumor BRAF evaluation was not required for eligibility. Ten of 25 (40%) achieved PR with a 2-year PFS of 96+4%. Only one patient progressed while on treatment. Stratum 4 included children with non-NF-1 optic pathway/hypothalamic LGG. Tissue for tumor BRAF evaluation was not required for eligibility. Two of 16 (12.5%) had a PR with a 2-year PFS of 65+13%. The BRAF aberration status of the responders in strata 3 and 4 is mostly unknown. All responses were confirmed centrally and seven patients remain on treatment. The most common toxicities were grade 1/2 CPK elevation, diarrhea, hypoalbuminemia, elevated AST and rash. Rare grade 3/4 toxicities included elevated CPK, rash, neutropenia, emesis and paronychia. Selumetinib was effective in treating children with recurrent/refractory LGG, including those with NF-1 associated LGG and PA harboring BRAF V600e mutation or BRAF-KIAA 1549 fusion. Larger prospective studies are necessary to determine the future, specific role of this agent in treating children with various LGG molecular subtypes.

Background: Heat shock protein 90 (Hsp90) is a molecular chaperone that maintains the stability of a number of key cellular oncoproteins (client proteins). When Hsp90 is inhibited, its client proteins undergo ubiquitination and degradation. HER2 is one of the most sensitive client proteins of Hsp90 and we have previously shown that tanespimycin, a geldanamycin-based Hsp90 inhibitor, is active in trastuzumab-refractory HER2+ MBC, with a RR of 22% and clinical benefit rate of 59%. Ganetespib is a synthetic, small molecule, IV administered, non-geldanamycin Hsp90 inhibitor which has broader inhibitory effects on oncoproteins with pre-clinical antitumor activity in more breast cancer (BC) subtypes, including triple negative breast cancer (TNBC). We therefore tested ganetespib in an unselected cohort of patients with advanced BC. Methods: Pts with locally advanced or MBC were treated with single agent ganetespib at 200mg/m2 once weekly for 3 weeks, on a 28 day cycle. The primary endpoint of the trial was overall response rate using RECIST 1.1. Pts with HER2+ BC were required to have received prior therapy with trastuzumab. No more than 3 lines of chemotherapy in the metastatic setting were permitted and there was no limit on prior lines of hormone therapy. Pts were evaluated for response after 2 cycles. The trial used a Simon two-stage design requiring at least 3 responses among the first 22 pts, to allow expansion to a total of 40 pts. Results: A total of 14 pts have been treated thus far with a median age of 45.3 years (36.6 to 59.1) and the following subtypes: 8 ER+/HER2+, 3 ER-/HER2+, 1 ER+/HER2− and 2 TNBC. Pts received a median of 1.84 cycles (0.33 to 4). The most common treatment-related AEs were Grade 1/2 and included the following: diarrhea (64%), fatigue (50%), nausea (35%), vomiting (14%), insomnia (14%) and hypersensitivity reactions (35%). The diarrhea had an early onset (< 24 hrs) and lasted up to 48 hrs post-infusion and was managed with either Imodium or similar anti-diarrheal medication. Pts who developed a hypersensitivity reaction were successfully re-challenged following pre-medication using dexamethasone plus H1/H2 antagonists. Grade 3 AEs were limited to 2 pts: 1 with an asymptomatic and reversible elevation in serum amylase, and the other with abdominal pain and diarrhea requiring a dose reduction to 175mg/m2. Of the 10 pts evaluable for efficacy, there is 1 confirmed partial response (PR), 1 minor response (MR) and 2 pts with stable disease (14%). The pt with MR had TNBC and was taken off-study due to a complicated pneumonia requiring hospitalization (unrelated). The remaining 3 pts had HER2+ BC; 2 of these 3 pts (1 PR, 1 SD) are continuing on study and have completed 4 cycles thus far. Updated toxicity and efficacy data will be presented. Conclusions: These data show activity for single agent ganetespib in different subtypes of breast cancer. Ganetespib was well tolerated, with expected gastrointestinal toxicity that was mild in nature and manageable in all patients. Accrual continues and we will present updated data at the meeting. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-17-08.

Preclinical studies demonstrate synergistic anti-tumor activity with the combination of everolimus and cisplatin. We conducted a phase I study to establish the recommended phase II of oral everolimus to be given with low-dose weekly intravenous cisplatin.Part A used a standard 3 + 3 dose escalation scheme. There were 4 planned dose levels of everolimus: 2.5, 5, 7.5, and 10 mg/day. Subjects received oral everolimus during days 1-21 and cisplatin 20 mg/m(2) intravenously (fixed dose) on days 1, 8, and 15 of a 28-day cycle. Pharmacokinetic (PK) blood samples were collected on day 1 and day 8 of cycle 1 in Part A. After the phase II recommended dose was established (Part A), 6 additional subjects were enrolled in an expansion cohort (Part B). Response was assessed by RECIST q 2 cycles for all subjects.Thirty patients were enrolled (18 male, 12 female) and 29 were treated. Median age was 61 years (31-79) and the median number of prior cytotoxic chemotherapy regimens was 2 (0-3). Eighty-three percent of subjects had received prior RT. DLTs occurred at dose level 1 (sudden death of unclear cause in a patient with melanoma metastatic to liver) and dose level 2 (bowel obstruction). No DLTs occurred at dose levels 3 and 4. The most common adverse events (≥grade 3) among 28 patients evaluable for toxicity were lymphopenia (36%), hyperglycemia (11%), fatigue (11%), and venous thrombosis (11%). PK analysis of everolimus demonstrated dose-proportional increases in C (max) (mean 91.9 ng/ml) and AUC(0-INF) (mean 680.5 h*ng/ml) at dose level 4. Three partial responses were seen (metastatic pulmonary carcinoid, n = 2; metastatic sinus carcinoma, n = 1). Prolonged stable disease ≥6 cycles occurred in subjects with pulmonary carcinoid, oropharyngeal squamous cell carcinoma, basal cell carcinoma, papillary thyroid carcinoma, and esthesioneuroblastoma (n = 1 each).The phase II recommended dose is everolimus 10 mg/day (days 1-21) + cisplatin 20 mg/m(2) (days 1, 8, and 15) of a 28-day cycle. PK data demonstrate dose-proportional increases in exposure, as previously described for everolimus monotherapy. Anti-tumor activity was observed in several tumor types.

BACKGROUND: Cerebral cavernomas are encountered in pediatric patients with central nervous system (CNS) tumors and may cause neurological compromise. The incidence of cavernomatous lesions on brain MR of pediatric patients treated with intraventricular radioimmunotherapy is unknown. METHODS: 217 patients were treated on institutional clinical trials with 2- 5 serial intraventricular injections 124I- or 131I- (2- 100 mCi) labeled monoclonal antibodies (cRIT) targeting tumor associated antigens. Pre-treatment brain MR at baseline and periodically for follow up over several years were obtained. Brain MR with Gradient echo T2*-weighted imaging and susceptibility-weighted imaging was used to identify cavernomatous lesions. RESULTS: Of 217 patients, 175/ (80.645%) identified as Caucasian, 18 (8.29%) African American, 9 (4.15%) Asian and 15 (6.91%) wished not to identify. Median age at the time of cRIT was 7.6 years (9 months-34.5 years). Median time for MR follow-up examinations was 38.4 months from the time of first cRIT. Cavernomatous lesions were detected in 22/217 (10 %) patients, and in 17/80 patients (21%) who survived > 2 years since cRIT. All in patients with prior external beam radiotherapy 22 (99%) Caucasian, 1 (1%) African American. Diagnoses were, metastatic neuroblastoma (N=12), medulloblastoma (N=8), ependymoma (n=1), pineoblastoma(n=1), and rhabdomyosarcoma (n=1). 12 patients had unifocal cavernomas frontal lobes (N=9), temporal lobe (N=2) or parietal (N=1). Multiple supratentorial and infratentorial lesions were detected in 9 patients; Only 1 patient had lesions involving the brainstem. One patient with cavernomas and concurrent vasculitis had neurologic symptoms; remaining patients were asymptomatic. CONCLUSIONS: Cavernomatous lesions are found in 10% of all patients and 21% of long term survivors treated with cRIT and external beam radiotherapy. The majority of lesions are multifocal and supratentorial. Despite numerous lesions, patients remain without neurologic compromise.

BACKGROUND: Preclinical studies suggest that additive or synergistic effects are achieved with the combination of pemetrexed plus gemcitabine. A phase 1 study of pemetrexed plus gemcitabine given every 2 weeks demonstrated encouraging preliminary efficacy against head and neck squamous cell cancer (HNSCC). METHODS: This was an open-label, single-institution, single-arm, phase 2 study for patients who had received no more than 2 cytotoxic regimens for recurrent and/or metastatic HNSCC. All patients received pemetrexed 500 mg/m2 intravenously plus gemcitabine 1250 mg/m2 intravenously every 2 weeks with vitamin B12 and folate support. The primary endpoint was the objective response rate according to Response Evaluation Criteria in Solid Tumors (RECIST); secondary endpoints were to estimate overall survival and to evaluate safety and tolerability. RESULTS: Twenty-five patients received therapy. All patients had received prior radiotherapy, and half had received prior cytotoxic chemotherapy for recurrent and/or metastatic disease. Neutropenia (grade ≥3) occurred in 24% of patients. Four patients (16%) had a partial response (PR) according to RECIST, and 5 additional patients (20%) had objective tumor reductions of >20 but

BRAF V600E hyperactivates ERK and signals as an RAF inhibitor-sensitive monomer. While RAF inhibitors can produce impressive clinical responses in patients with mutant BRAF tumors, the mechanisms of resistance to these drugs are incompletely characterized. Here, we report a complete response followed by clinical progression in a patient with a BRAF V600E-mutant brain tumor treated with dabrafenib. Whole-exome sequencing revealed a secondary BRAF L514V mutation at progression that was not present in the pretreatment tumor. Expressing BRAF V600E L514V induces ERK signaling, promotes RAF dimer formation, and is sufficient to confer resistance to dabrafenib. A novel class of RAF dimer inhibitors and an ERK inhibitor are effective against BRAF L514V-mediated resistance. Collectively, our results validate a novel biochemical mechanism of RAF inhibitor resistance mediated by a secondary mutation, emphasizing that like driver mutations in cancer, the spectrum of mutations that drive resistance to targeted therapy are heterogeneous and perhaps emerge with a lineage-specific prevalence. Citation Format: Jiawan Wang, Zhan Yao, Philip Jonsson, Amy Allen, Alice Can Ran Qin, Sharmeen Uddin, Ira J. Dunkel, Mary Petriccione, Katia Manova, Sofia Haque, Marc Rosenblum, David J. Pisapia, Neal Rosen, Barry S. Taylor, Christine A. Pratilas. A secondary mutation in BRAF confers resistance to RAF inhibition in a BRAF V600E-mutant brain tumor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3184.

BACKGROUND: Tumors metastasizing to the CNS are associated with significant mortality. We tested the toxicity and dosimetry of intraventricular (131)I-labeled monoclonal antibody 8H9 targeting B7-H3 in patients with CNS tumors. METHODS: Tumor B7-H3 expression was assessed by immunohistochemistry. Patients received 2 mCi tracer of intra-Ommaya (124)I- or (131)I-8H9 followed by a therapeutic injection (10-80 mCi, dose levels 1-8 in 10 mCi increments -phase I patients; expanded cohort 50 mCi/injection) (131)I-8H9. Dosimetry was based on serial CSF, blood samplings and ROI analyses on nuclear imaging. . Toxicity was defined by the CTCAE v.3.0. Repeat injections were permitted if no serious adverse events or progressive disease ensued. Tumor response was determined by clinical, radiographic, cytologic criteria; overall survival was noted. RESULTS: 131 patients received 383 injections [median age 5.4 years (1.2- 53.6)] Injections were well tolerated. Rare self-limited adverse events included grade 1 or 2 fever, headache, vomiting, biochemical elevations in AST/ALT and 1 injection with grade 3 ALT elevation (dose level 3)., Myelosuppression occurred in patients with prior craniospinal radiation and at dose levels 6 and higher (>60 mCi). Of 93 patients treated for CNS neuroblastoma, an improved overall survival was noted compared to survival reported with conventional therapies. Interpatient variability for total absorbed dose to the CSF and blood was observed; mean absorbed CSF dose was 104.9 cGy/mCi by CSF sampling, and 2.6 cGy/mCi to the blood. CONCLUSIONS: Intraventricular (131)I-8H9 is safe, has favorable dosimetry to CSF, and has clinical utility for high risk primary and metastatic CNS tumors.

6087Background: mutations (BRAFm) are the most common mutations in thyroid cancer. BRAF inhibitors (DAB) are active in BRAFm melanoma, but there is less activity noted in BRAFm thyroid cancer. Prec...

Meningiomas are among the most common brain tumors in adults. They are most commonly located over the cerebral convexities and are infrequently found in an intraventricular location. Ionizing cranial radiation is a risk factor for late occurrence of meningiomas within the radiation field. While pathologic grading of meningiomas is straightforward, significant variability often exists between pathologists in applying standard grading criteria. This has implications for prognosis. Radiation-induced meningiomas may also have predilection to recur. The authors describe a case of an intraventricular meningioma occurring 23 years after cranial irradiation for childhood acute lymphoblastic leukemia.

Lymphomas of the central nervous system, spine, and orbit consist of both systemic lymphomas and primary central nervous system lymphomas. This article addresses the typical imaging findings of lymphoma in both immunocompetent and immunocompromised patients, discusses the differential possibilities, and reviews the response criteria being used in clinical trials. Also described are metabolic imaging techniques with nuclear medicine and advanced MR imaging and how they can help improve the understanding of tumor biology.

BACKGROUND AND PURPOSE: Diffuse intrinsic pontine gliomas are inoperable high-grade gliomas with a median survival of less than 1 year. Convection-enhanced delivery is a promising local drug-delivery technique that can bypass the BBB in diffuse intrinsic pontine glioma treatment. Evaluating tumor response is critical in the assessment of convection-enhanced delivery of treatment. We proposed to determine the potential of 3D multivoxel 1 H-MR spectroscopy to evaluate convection-enhanced delivery treatment effect in these tumors. MATERIALS AND METHODS: We prospectively analyzed 3D multivoxel 1 H-MR spectroscopy data for 6 patients with nonprogressive diffuse intrinsic pontine gliomas who received convection-enhanced delivery treatment of a therapeutic antibody (Phase I clinical trial NCT01502917). To compare changes in the metabolite ratios with time, we tracked the metabolite ratios Cho/Cr and Cho/NAA at several ROIs: normal white matter, tumor within the convection-enhanced delivery infusion site, tumor outside of the infused area, and the tumor average. RESULTS: There was a comparative decrease in both Cho/Cr and Cho/NAA metabolite ratios at the tumor convection-enhanced delivery site versus tumor outside the infused area. We used MR spectroscopy voxels with dominant white matter as a reference. The difference between changes in metabolite ratios became more prominent with increasing time after convection-enhanced delivery treatment. CONCLUSIONS: The comparative change in metabolite ratios between the convection-enhanced delivery site and the tumor site outside the infused area suggests that multivoxel 1 H-MR spectroscopy, in combination with other imaging modalities, may provide a clinical tool to accurately evaluate local tumor response after convection-enhanced delivery treatment.

The purpose of this study was to evaluate the efficacy and tolerability of the addition of 2 monoclonal antibodies, bevacizumab and cetuximab, to 2 cycles of high-dose cisplatin administered concurrently with intensity-modulated radiation therapy (IMRT) for head and neck squamous cell carcinoma (HNSCC).Patients with newly diagnosed stage III/IVB (M0) HNSCC received cetuximab (400 mg/m(2) loading dose, followed by 250 mg/m(2) weekly), bevacizumab (15 mg/kg, days 1 and 22), and cisplatin (50 mg/m(2) , days 1, 2, 22, and 23) concurrently with IMRT (70 Gy). The primary endpoint was progression-free survival (PFS). Secondary endpoints were overall survival (OS) and safety and tolerability.Among 30 patients enrolled in this study, the primary tumor site was the oropharynx in 24 patients (p16 immunohistochemistry was positive in 17, negative in 1, and not done in 6 of the oropharyngeal tumors). Median age was 57 years (range, 38-77 years) and 27 patients had clinical stage IVA disease. All patients completed the full planned dose of radiation therapy. The most common ≥ grade 3 adverse events were lymphopenia, mucositis (functional), and dysphagia. With a median follow-up of 33.8 months, 2-year PFS was 88.5% (95% confidence interval [CI] = 68.1-96.1) and 2-year OS was 92.8% (95% CI = 74.2-98.1).The addition of bevacizumab and cetuximab to 2 cycles of cisplatin, given concurrently with IMRT, was well-tolerated and was associated with favorable efficacy outcomes in this patient population. © 2015 Wiley Periodicals, Inc. Head Neck 38: E566-E570, 2016.

Extraneural metastases of ependymoma are rare, and have been reported in the lungs, lymph nodes, pleura, mediastinum, liver, diaphragmatic muscle, and bone. We report a case of anaplastic ependymoma with distant metastases to the vertebral bones, lungs, liver, and lymph nodes following treatment with bevacizumab. Recent research has hypothesized that angiogenic tumors may develop means of resistance to antiangiogenic therapies, and some evidence suggests potential for antiangiogenic therapies to promote additional means for cancer spread. Nevertheless, antiangiogenic therapies continue to demonstrate potential as potent therapies for the treatment of many cancers, and should continue to be researched for future uses.

Abnormal expression and constitutive activation of TrkA, TrkB and TrkC due to gene fusions are oncogenic drivers in many cancer types. Entrectinib, a potent, brain-penetrant Trk inhibitor, has demonstrated rapid, deep, and sustained clinical responses in patients with advanced or metastatic Trk-fusion-positive solid tumors across multiple histologies. For tyrosine kinase inhibitors, point mutations that disrupt the binding between the inhibitor and kinase domain of the target are a common mechanism of resistance. By design, entrectinib retains its potency against gatekeeper mutations in Trk, ROS1 and ALK. On the other hand, solvent front mutations, G595R in TrkA or G623R in TrkC (analogous to ROS1 G2032R and ALK G1202R), have been identified as resistance mutations in a clinical setting. Preclinically, upregulation of the MAPK pathway was observed following the introduction of such mutation in Trk-fusion-positive cancer cell lines. In vitro combination screening and in vivo efficacy study further demonstrated the potential for entrectinib-trametinib (a MEK inhibitor) combination to overcome the drug resistance mediated by solvent front mutations. In the clinic, a 34-year-old female patient with ETV6-NTRK3 positive mammary analog secretory carcinoma (MASC) who progressed despite multiple courses of prior multi-modal therapy, including crizotinib, experienced a rapid confirmed partial response (PR: 89% reduction at nadir) with entrectinib treatment. Seven months later, asymptomatic progressive disease (PD) was detected at a solitary tumor site, a biopsy of which showed a G623R solvent front mutation. After three more months on entrectinib, the patient experienced generalized progression and was in need of additional therapy. She was then treated with another Trk inhibitor with no clinical benefit. She then received palliative radiation therapy to symptomatic pleural/chest wall metastases. Supported by the preclinical data on combination therapy, a single patient protocol was subsequently developed to allow co-administration of entrectinib and trametinib. Significant tumor regression was achieved within the first eight weeks, including sustained resolution of tumor-associated pain and hypertrophic osteoarthropathy. In conclusion, we have identified a mitigation strategy, utilizing an approved agent combined with a well-characterized clinical stage agent, to overcome acquired Trk-inhibitor resistance, presumably by overcoming solvent front mutation-driven MAPK activation. The successful translation of a preclinical observation made at the bench to clinical practice at the bedside has greatly extended the duration of tumor regression and provided continued care to a Trk-fusion positive patient even after the emergence of resistance. This clinical observation will be further explored in a dedicated Phase 1/1b combination study. Citation Format: Ge Wei, Edna Chow Maneval, Vanessa Esquibel, Michael F. Berger, Sofia Haque, Roopal Patel, Colin Walsh, Zachary Hornby, Pratik Multani, Gary Li. Overcoming drug resistance to Trk inhibition by rational combination of entrectinib and trametinib: from bench to bedside [abstract]. In: Proceedings of the AACR Precision Medicine Series: Opportunities and Challenges of Exploiting Synthetic Lethality in Cancer; Jan 4-7, 2017; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2017;16(10 Suppl):Abstract nr B28.

BACKGROUND: High-risk and recurrent medulloblastoma (MB) is associated with significant mortality. The murine monoclonal antibody 3F8 targets the cell-surface disialoganglioside GD2 on MB. We tested the efficacy, toxicity, and dosimetry of compartmental radioimmunotherapy (cRIT) with intraventricular(131)I-labeled 3F8 in patients with MB on a phase II clinical trial. METHODS: Patients with histopathologically confirmed high-risk or recurrent MB were eligible for cRIT. After determining adequate cerebrospinal fluid (CSF) flow, patients received 2 mCi (where Ci is Curie) (124)I-3F8 or (131)I-3F8 with nuclear imaging for dosimetry, followed by up to four therapeutic (10 mCi/dose) (131)I-3F8 injections. Dosimetry estimates were based on serial CSF and blood samplings over 48 hr plus region-of-interest analyses on serial imaging scans. Disease evaluation included pre- and posttherapy brain/spine magnetic resonance imaging approximately every 3 months for the first year after treatment, and every 6–12 months thereafter. RESULTS: Forty-three patients received a total of 167 injections; 42 patients were evaluable for outcome. No treatment-related deaths occurred. Toxicities related to drug administration included acute bradycardia with somnolence, headache, fatigue, and CSF pleocytosis consistent with chemical meningitis and dystonic reaction. Total CSF absorbed dose was 1,453 cGy (where Gy is Gray; 350.0–2,784). Median overall survival from first dose of cRIT was 24.9 months (95% confidence interval [CI]:16.3–55.8). Patients treated in radiographic and cytologic remission were at a lower risk of death compared to patients with radiographically measurable disease (hazard ratio: 0.40, 95% CI: 0.18–0.88, P = 0.024). CONCLUSIONS: cRIT with (131)I-3F8 is safe, has favorable dosimetry to CSF, and when added to salvage therapy using conventional modalities, may have clinical utility in maintaining remission in high-risk or recurrent MB.

The PI3K/Akt/mTOR signaling pathway is aberrantly activated in various pediatric tumors. We conducted a phase I study of the Akt inhibitor perifosine in patients with recurrent/refractory pediatric CNS and solid tumors. This was a standard 3+3 open-label dose-escalation study to assess pharmacokinetics, describe toxicities, and identify the MTD for single-agent perifosine. Five dose levels were investigated, ranging from 25 to 125 mg/m2/day for 28 days per cycle. Twenty-three patients (median age 10 years, range 4–18 years) with CNS tumors (DIPG [n = 3], high-grade glioma [n = 5], medulloblastoma [n = 2], ependymoma [n = 3]), neuroblastoma (n = 8), Wilms tumor (n = 1), and Ewing sarcoma (n = 1) were treated. Only one DLT occurred (grade 4 hyperuricemia at dose level 4). The most common grade 3 or 4 toxicity at least possibly related to perifosine was neutropenia (8.7%), with the remaining grade 3 or 4 toxicities (fatigue, hyperglycemia, fever, hyperuricemia, and catheter-related infection) occurring in one patient each. Pharmacokinetics was dose-saturable at doses above 50 mg/m2/day with significant inter-patient variability, consistent with findings reported in adult studies. One patient with DIPG (dose level 5) and 4 of 5 patients with high-grade glioma (dose levels 2 and 3) experienced stable disease for two months. Five subjects with neuroblastoma (dose levels 1 through 4) achieved stable disease which was prolonged (≥11 months) in three. No objective responses were noted. In conclusion, the use of perifosine was safe and feasible in patients with recurrent/refractory pediatric CNS and solid tumors. An MTD was not defined by the 5 dose levels investigated. Our RP2D is 50 mg/m2/day.

6081 Background: Activation of the PI3K/mTOR signaling pathway is common in HNSCC. PI3K inhibitors have been shown to enhance radiosensitivity. BYL719 is an α-specific PI3K inhibitor that is synergistic and efficacious when combined with cetuximab, an FDA-approved radiosensitizing agent in HNSCC. This study evaluates the addition of BYL719 to cetuximab and radiation in the treatment of locally advanced HNSCC. Methods: This is a single-institution, phase I study. Patients with Stage III-IVB HNSCC received cetuximab 400 mg/m2 IV loading dose prior to intensity modulated radiation therapy (IMRT), followed by 250 mg/m2 weekly infusions during IMRT. BYL719 was given orally during IMRT in 3 dose levels (DLs): 1) 200 mg, 2) 250 mg, and 3) 300 mg per day in a standard 3 + 3 dose escalation design. Results: 11 patients are evaluable; median age-60 years (36-73); Stage III-1, IVA-9, IVB-1; oropharynx primary-9, unknown primary-2; HPV-positive -10. 8 patients completed treatment. 3 patients were treated on DL 1 and 2 without a dose limiting toxicity (DLT). Both patients on DL 3 experienced a DLT of grade 3 mucositis. Related adverse events (AEs) of any grade experienced by all 8 patients include: mucositis, weight loss, and hyperglycemia. Related grade 3 and 4 AEs in at least 2 patients include: mucositis (4), dysphagia (4), and decreased lymphocyte count (2). An additional 3 patients have been enrolled onto DL 2 and are undergoing treatment. All other patients had a complete response (CR) on post-treatment PET (from 6/2015 - 9/2016) and remain free of disease. Of 6 patients with mutational analysis, 1 had an activating PIK3CA mutation associated with a rapid response on serial intra-treatment MRIs. Conclusions: BYL719 administered at DLs 200 mg or 250 mg oral daily with cetuximab and IMRT resulted in expected AEs of radiation-based treatment with cetuximab and tolerable class-related AEs of PI3K inhibitors. BYL719 300 mg oral daily exceeds the maximum tolerated dose; the phase II recommended dose is pending completion of expansion of DL 2. All patients who completed treatment had a CR. Further evaluation of the addition of BYL719 to the platinum-sparing regimen of cetuximab + IMRT in the treatment of locally advanced HNSCC is warranted. Clinical trial information: NCT02282371.

6085 Background: BRAFV600E mutations (BRAFm) are the most common mutations in thyroid cancer. BRAF inhibitors are active in BRAFm melanoma, but there is less activity noted in BRAFm thyroid cancer. Preclinically, BRAF inhibitors inhibit BRAFm thyroid cancers only transiently due to activation of HER2/HER3, driven by a neuregulin-dependent autocrine loop. The addition of LAP, a HER2/HER3 kinase inhibitor, sensitizes the cell to growth suppression by BRAF inhibitors (Cancer Discov 5(3):520, 2013). A phase I study evaluating the combination of DAB, a BRAF inhibitor, and LAP was initiated to evaluate the safety and pharmacodynamic changes the combination. Methods: Eligibility included thyroid cancers with the presence of a BRAFV600E mutation. Any prior treatment was allowed. All patients received DAB 150 mg bid starting 2 weeks prior to LAP. Doses of daily lapatinib were escalated in a standard 3+3 design at (1) 750 mg; (2) 1250 mg; (3) 1500 mg. Toxicities, including Dose Limiting Toxicities (DLT), were noted only after both drugs were started. Patients (pts) removed before the start of LAP were not included in the analysis. Biopsies were done at baseline, after the start of DAB, and after the start of both DAB and LAP. Responses were defined using RECIST 1.1. Results: 15 evaluable pts were enrolled on the phase I portion of the study. Gender – 10/15 (67%) male; median age – 63 years; histology – differentiated thyroid cancer (DTC) 13 (87%), anaplastic thyroid cancer (ATC) 2 (13%); brain metastases – 4/15 (27%); prior tyrosine kinase inhibitor – 9/15 (54%). There was one DLT - Grade 5 event unlikely related to drugs in a pt with ATC. Grade 4 toxicities – 0. Grade 3 toxicities –lymphocytes (1). The partial response rate is 60%. The response rate in the DTC group is 69% (0% in ATC). One other pt came off treatment due to withdrawal of consent. Median progression-free survival is 15 months (range, 2-34+ months). Median follow up is 15 months. Translational studies are pending. Conclusions: The combination of DAB 150 mg bid and LAP 1500 mg daily was safe and well-tolerated. Furthermore, significant activity was noted, especially at the top dose level. Further investigation with this regimen is warranted. Clinical trial information: NCT01947023. [Table: see text]

10545 Background: Neuroblastoma metastatic to the central nervous system (CNS NB) is associated with significant mortality (median survival < 6 months, < 10% survival at 36 months). Intraventricular compartmental radioimmunotherapy (cRIT) with radio-iodinated murine IgG1 monoclonal antibody 131I-8H9 targeting tumor cell-surface glycoprotein B7-H3 offers a therapeutic strategy. We analyzed overall survival of patients with CNS NB treated with intraventricular 131I-8H9 cRIT at Memorial Sloan Kettering Cancer Center (MSK) since 2003. Methods: After radiographic and/or pathologic confirmation of CNS NB, and assessment of adequate CSF flow, cRIT eligible patients underwent treatment on an IRB-approved protocol with either temozolomide/irinotecan-based CNS salvage regimen incorporating craniospinal radiation therapy, 131I-8H9 cRIT plus systemic immunotherapy (group 1), or non-regimen therapies with 131I-8H9 cRIT (group 2). cRIT administration involved a 2mCi tracer of 124I- or 131I-8H9 with nuclear imaging and CSF sampling for dosimetry followed by 1 or 2 therapeutic injections up to 70 mCi 131I-8H9. Disease surveillance included serial MR brain/spine, MIBG, CT, and bone marrow evaluation. Data are presented as overall survival after detection of CNS metastasis. Results: 105 patients with CNS NB were evaluated;80 patients (76%) were treated (57 group 1, 23 group 2). Of the 25 patients who were not eligible for cRIT, survival averaged 8.6 months. Of 19 patients with radiographic evidence of disease at the time of cRIT, 7 (36%) demonstrated post cRIT radiographic improvement. At analysis, 45/80 (56%) patients were alive 4.8–152 months (median 58 months) after CNS metastasis, including 36 (45%) at 36 months and 23 (29%) > 60 months. Subgroup analyses of 131I-8H9–treated patients identified age at NB diagnosis (≤18 months), relapse restricted to CNS and group 1 status as factors positively correlated with survival. Conclusions: 76% of patients with CNS NB treated at MSK received 131I-8H9 cRIT, and approximately half completed multimodality CNS salvage regimen with 131I-8H9 cRIT. Despite advanced CNS involvement, over 50% of patients treated with 131I-8H9 cRIT are still alive and nearly 50% have survived at least 36 months. Clinical trial information: NCT00089245.

2010 Background: Diffuse intrinsic pontine glioma (DIPG) represents one of the most deadly central nervous system tumors of childhood with a median survival of less than 12 months. Convection-enhanced delivery (CED) has been recently hypothesized as a means for augmenting distribution of therapeutic agents within the brain stem. We conducted this study to evaluate CED in children with DIPG. Methods: We performed a standard 3+3 phase I, open-label, dose escalation study in patients with non-progressive DIPG 4 to 14 weeks post-completion or radiation therapy. Seven dose levels of a single injection of 124I-8H9 (range 0.25 to 4.0 mCi, 250 to 4000 mcl) were studied. Results: 25 children were treated. The average age at enrollment 8 years old (range 3-17). There was no dose limiting toxicity (DLT) and adverse events were limited to grade 1 or 2 (CTCAE v4.0). Estimations of distribution volumes were dose dependent and ranged from 1.5 to 20.1 cm3. The mean volume of distribution/volume of infusion (Vd/Vi) was 3.4 (SD 1.2). The mean lesion absorbed dose was 1527 rad/mCi. The mean tumor coverage on dose level 7 was 107%. Conclusions: CED in the brain stem of children with DIPG who were previously irradiated is a safe therapeutic strategy. Up to 4 mCi of 124I-8H9 was well tolerated. An infusion volume of 4000 mcl appears to be a reasonable single dose for good tumor coverage. PET-based dosimetry validates the conceptual basis for direct drug delivery. Based on our finding CED merits further exploration in early phase clinical trials for children with DIPG. Clinical trial information: NCT01502917.

BackgroundThere is a clinical need to improve the efficacy of standard cetuximab + concurrent intensity-modulated radiation therapy (IMRT) for patients with locally and/or regionally advanced HNSCC. Taxanes have radiosensitizing activity against HNSCC, and nab-paclitaxel may offer therapeutic advantage in comparison with other taxanes.Patients and methodsThis was a single-institution phase I study with a modified 3 + 3 design. Four dose levels (DLs) of weekly nab-paclitaxel were explored (30, 45, 60, and 80 mg/m(2)), given with standard weekly cetuximab (450 mg/m(2) loading dose followed by 250 mg/m(2) weekly) and concurrent IMRT (total dose, 70 Gy).ResultsTwenty-five eligible patients (20 M, 5 F) enrolled, with median age 58 years (range, 46-84 years). Primary tumor sites were oropharynx, 19 (10 human papillomavirus [HPV] pos, 8 HPV neg, 1 not done); neck node with unknown primary, 2; larynx 2; and oral cavity and maxillary sinus, 1 each. Seven patients had received prior induction chemotherapy. Maximum tolerated dose (MTD) was exceeded at DL4 (nab-paclitaxel, 80 mg/m(2)) with three dose-limiting toxicities (DLTs) (grade 3 neuropathy, grade 3 dehydration, with grade 3 mucositis grade 3 anemia) among five assessable patients. There was only one DLT (grade 3 supraventricular tachycardia) among six patients at DL3 (nab-paclitaxel, 60 mg/m(2)), and this was deemed the MTD. Among 23 assessable patients, the most common ≥ g3 AEs were lymphopenia 100%, functional mucositis 65%, and pain in throat/oral cavity 52%. At a median follow-up of 33 months, 2-year failure-free survival (FFS) is 65% [95% confidence interval (CI) 42% to 81%] and 2-year overall survival (OS) is 91% (95% CI 69-97).ConclusionThe recommended phase II dose for nab-paclitaxel is 60 mg/m(2) weekly when given standard weekly cetuximab and concurrent IMRT. This regimen merits further study as a nonplatinum alternative to IMRT + cetuximab alone.Clinicaltrialsgov idNCT00736619.

Background The PI3K/AKT/mTOR pathway is aberrantly activated in many pediatric solid tumors including gliomas and medulloblastomas. Preclinical data in a pediatric glioma model demonstrated that the combination of perifosine (AKT inhibitor) and temsirolimus (mTOR inhibitor) is more potent at inhibiting the axis than either agent alone. We conducted this study to assess pharmacokinetics and identify the maximum tolerated dose for the combination. Procedure We performed a standard 3+3 phase I, open-label, dose-escalation study in patients with recurrent/refractory pediatric solid tumors. Four dose levels of perifosine (25–75 mg/m2/day) and temsirolimus (25–75 mg/m2 IV weekly) were investigated. Results Twenty-three patients (median age 8.5 years) with brain tumors (diffuse intrinsic pontine glioma [DIPG] n = 8, high-grade glioma n = 6, medulloblastoma n = 2, ependymoma n = 1), neuroblastoma (n = 4), or rhabdomyosarcoma (n = 2) were treated. The combination was generally well tolerated and no dose-limiting toxicity was encountered. The most common grade 3 or 4 toxicities (at least possibly related) were thrombocytopenia (38.1%), neutropenia (23.8%), lymphopenia (23.8%), and hypercholesterolemia (19.0%). Pharmacokinetic findings for temsirolimus were similar to those observed in the temsirolimus single-agent phase II pediatric study and pharmacokinetic findings for perifosine were similar to those in adults. Stable disease was seen in 9 of 11 subjects with DIPG or high-grade glioma; no partial or complete responses were achieved. Conclusions The combination of these AKT and mTOR inhibitors was safe and feasible in patients with recurrent/refractory pediatric solid tumors.

Background Pralatrexate (FotolynTM; Allos Therapeutics Inc.) is an antifolate dihydrofolate reductase (DHFR) inhibitor. We conducted a phase II study of pralatrexate with folic acid and B12 supplementation in patients with recurrent and/or metastatic head and neck squamous cell cancer (R/M HNSCC). Patients and methods This was a single-arm, Simon optimal two stage phase II study. Patients with R/M HNSCC previously treated with chemotherapy were eligible. The study was initiated with a dosing schedule of pralatrexate 190 mg/m2 biweekly on a 4-week cycle with vitamin supplementation. Due to toxicity concerns, the dosing was modified to 30 mg/m2 weekly for 3 weeks in a 4-week cycle with vitamin supplementation. Radiologic imaging was to be obtained about every 2 cycles. Results Thirteen subjects were enrolled; 12 were treated. Seven of the twelve patients had previously received ≥2 lines of chemotherapy. The most common grade 3 toxicity was mucositis (3 patients). Seven patients did not complete two cycles of therapy due to progression of disease (4), toxicity (1), death (1), and withdrawal of consent (1). Two deaths occurred: one due to disease progression and the other was an unwitnessed event that was possibly related to pralatrexate. No clinical activity was observed. The median overall survival was 3.1 months. The study was closed early due to lack of efficacy. Conclusions Pralatrexate does not possess clinical activity against previously treated R/M HNSCC. Evaluation of pralatrexate in other clinical settings of HNSCC management with special considerations for drug toxicity may be warranted.