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Background/rationale: Diffuse intrinsic pontine glioma (DIPG) in children remains essentially incurable with a median survival of 12 months. Radiation therapy is currently the standard treatment modality. To date chemotherapy or biologic agents have had no meaningful increase in survival, making it imperative to profile novel therapeutic combinations. Data from biopsied DIPG showed the PI3K/AKT/mTOR pathway as a major oncogenic player. At the gene level high PDGFR amplification (most commonly seen) and overexpression of the PI3K-Akt-mTOR pathway were noted in these tumors. Focal amplifications of genes within the receptor tyrosine kinase-Ras-phosphoinositol 3-kinase signaling pathway were found in 47% of DIPG. Thus targeting this pathways with mTOR inhibitors could hold therapeutic promise. Elevated expression of DNA repair proteins in the NHEJ and HRR pathway are known to induce resistance to radiation. Preclinical data shows inhibition of these pathways potentiates the sensitivity of these tumors to radiation. SAHA a pan HDAC inhibitor, has been associated with decreased expression of key DNA repair proteins in both the NHEJ and HRR pathways. Both temsirolimus (an mTOR inhibitor) and SAHA are well described in pediatric clinical trials with an established maximum tolerated dose (MTD). The efficacy of the combination of temsirolimus and SAHA has been well-established in other malignancies including prostate cancer, mantle lymphoma, and renal carcinoma. This is the first multi-targeted therapeutic trial in pediatric DIPG, using SAHA and temsirolimus in a combinatorial approach, targeting the key oncogenic pathway and molecules along with enhancing the radiation sensitivity. Correlative study: Stratum I (chemoradiotherapy phase): Histone acetylation will be quantified from peripheral blood mononuclear cell (PBMC) collected prior to the first dose of vorinostat and radiation and at the end of radiation. Stratum I and II (maintenance phase): Evaluation of histone acetylation, phosphorylated 70S6K and Akt on day 1 and 8 (prior to chemotherapy with temsirolimus) during cycle 1 and cycle 2. Methods Patients with a performance score of 50 or greater with newly diagnosed (Stratum 1) or progressive DIPG (stratum II) as confirmed by gadolinium enhanced MRI are eligible. Biopsy is not mandatory. Stratum I: Patients will receive radiation therapy concurrently with vorinostat on the days of radiation at a dose of 230mg/m2/dose, followed by adjuvant therapy with vorinostat and temsirolimus for 10 cycles if patients do not have progressive disease. Stratum II: Patients will receive vorinostat and temsirolimus for 12 cycles (28 day cycle), if patient does not have progressive disease. SAHA will be given once daily at 230 mg/m2 orally from day 1 to day 8, along with temsirolimus at 25mg/m2 intravenously on day 1 and day 8. This will be the dose level 1 and 2 dose escalations and 1 dose de-escalation will be allowed. A standard 3+3 design will be used and a minimum of 9 patients and a maximum of 18 patients will be enrolled. Trial is ongoing (30% of planned patients enrolled), with patients now in the second dose level (enrollment of this cohort started on September 2018). No dose limiting toxicity (DLT) were noted at the first dose level. Trial: NCT02420613 (currently recruiting). Note: This abstract was not presented at the meeting. Citation Format: Soumen Khatua, Joya Chandra, Miriam M. Morrell, Heather B. Meador, David I. Sandberg, Jeffrey Weinberg, Greg Fuller, Leena Ketonen, Jason M. Johnson, Kenneth R. Hess, Wafik Zaky. A Phase I study of Suberoylanilide Hydroxamic Acid (SAHA) with Temsirolimus in children with newly diagnosed or progressive diffuse intrinsic pontine glioma (DIPG) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT113.

Scientific background/rationale: The prognosis of recurrent/refractory medulloblastoma (MB), ependymoma (EP) and atypical teratoid/rhabdoid neoplasms (AT/RT) which constitutes the majority of malignant posterior fossa tumors (MPFT) in children, remains dismal with no defined effective therapy. Current treatment strategies have significant toxicities, thus profiling newer trials with clinical efficacy and minimal side-effects are imperative. Advantages of direct infusion of Natural Killer (NK) cells into the ventricles could enhance therapeutic efficacy by maximally concentrating them in the brain in close proximity to the tumor area, bypassing the blood brain barrier and alleviating toxicity often seen with systemic chemotherapy. We have shown efficacy of activated and propagated NK cells to lyse and kill the MPFT in vitro and tumor explants in mice models. We demonstrated in a pilot study for the first time in humans, the feasibility of infusions of biologic agents into the fourth ventricle. Infusing biologic agents into the lateral ventricles are well established in neurooncology. The current ongoing study is the first-in-human, loco-regional infusion of NK cells directly into the brain evaluating safety and efficacy in the context of a phase I trial with an intent to avoid the significant side-effects of systemic therapy. This novel trial, will hopefully be able to provide therapeutic efficacy and a meaningful increase in the survival of these children. Correlative studies: Cerebrospinal fluid (CSF) withdrawn during infusions of NK cells will be evaluated for the immunophenotype, function, persistence of NK cells and influx or presence of any other immune cells. Methods: NK cells are directly infused into the lateral or fourth ventricles, after placement of a catheter at that location. Recurrent or refractory MB, AT/RT and EP involving the brain and/or spine at original diagnosis or relapse with histological verification are eligible. Three to six evaluable patients, are entered at a dose level in this study for determination of maximum tolerated dose (MTD). A minimum of 9 patients and a maximum of 24 patients are planned to be enrolled. After autologous expanded NK cell product have been manufactured as per good manufacturing guidelines (GMP) and released, patients receive 3 cycles of NK cell infusions over 12 weeks. Each cycle consists of 1 infusion per week for 3 weeks followed by a rest week (week 4). Dosing is based on recipient body surface area (BSA) and 3 dose levels will be evaluated. Currently the trial is at the final cohort (third dose level), with no dose limiting toxicity (DLT) noted with the previous dose levels. 80% of the initial minimal accrual have been met. Also as a secondary aim we will evaluate the anti-tumor activity of the NK cell infusions within the confines of a phase I study. Trial (NCT02271711-recruiting) Citation Format: Soumen Khatua, Dean Lee, Laurence Cooper, Judy Moyes, David Sandberg, Zsila Sadighi, Heather Meador, Leena Ketonen, Michael E. Rytting, Jason M. Johnson, Dristhi Raagonanan, Diane D. Liu, Vidya Gopalakrishnan, Wafik Zaky. Phase I study of intraventricular infusions of autologous ex vivo expanded NK cells in children with recurrent/refractory malignant posterior fossa tumors of the central nervous system [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT216.

The clinical utility of blood analysis such as circulating tumor cells (CTCs) has garnered increasing interest in recent years. However very few studies were conducted in pediatric cancer patients especially in brain tumor, osteosarcoma, and leukemia patients due to the lack of an effective tool to isolate/capture CTC from these patients. For example, only three independent studies were published to investigate CTC capture from adult brain tumor patients but zero studies were conducted with pediatric brain cancer patients. Our previous studies showed the high specificity of using cell surface vimentin (CSV) to identify and capture CTCs from various types of adult tumor patients using a manual isolation method. Here we present the first automated system for capturing CTCs across different types of pediatric tumors. This automated system utilizes the Abnova CytoQuest system loaded with the CSV antibody 84-1-coated microfluidic cassette for capturing CTCs from peripheral blood samples. This automated assay was very sensitive because as few as one tumor cell can be captured out from one million normal cells. Based on our preliminary study, our success rate for non-DIPG brain tumor, ALL, and AML patients is 100%. This success provides a potential opportunity for analyzing brain tumor genetic properties using blood samples instead of the invasive tumor biopsy; likewise, this high sensitivity assay opens up clinical opportunities to use this assay for transplant and treatment decision making. Note: This abstract was not presented at the meeting. Citation Format: Izhar S. Batth, Wafik Zaky, Soumen Khatua, Najat C. Daw, Kris M. Mahadeo, Sajad Khazal, Aisha Albert, Wilber Huang, Diva Chen, Jonathan B. Gill, Eugenie Kleinerman, Richard Gorlick, Shulin Li. Automated capture and analysis of circulating tumor cells across different types of tumors in pediatric cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1345.

Background/rationale: Diffuse intrinsic pontine glioma (DIPG) in children remains essentially incurable with a median survival of 12 months. Radiation therapy is currently the standard treatment modality. To date chemotherapy or biologic agents have had no meaningful increase in survival, making it imperative to profile novel therapeutic combinations. Data from biopsied DIPG showed the PI3K/AKT/mTOR pathway as a major oncogenic player. At the gene level high PDGFR amplification and overexpression of the PI3K-Akt-mTOR pathway were noted in these tumors. Focal amplifications of genes within the PI3K-Akt-mTOR signaling pathway were found in 47% of DIPG. Thus targeting these pathways with mTOR inhibitors could hold promise. Elevated expression of DNA repair proteins in the NHEJ and HRR pathway are known to induce resistance to radiation. Preclinical data shows inhibition of these pathways potentiates the sensitivity of these tumors to radiation. Recent genomic and epigenetic insights demonstrates the role of histone deacetylase (HDAC) in these tumors. Vorinostat a pan HDAC inhibitor has been associated with decreased expression of key DNA repair proteins in both the NHEJ and HRR pathways and have been tested in clinical trial for children with DIPG. Both temsirolimus (an mTOR inhibitor) and vorinostat are well described in pediatric clinical trials with a determined maximum tolerated dose (MTD). The efficacy of the combination of temsirolimus and vorinostat has been well-established in other malignancies including prostate cancer, mantle lymphoma, and renal carcinoma. This is the first multi-targeted therapeutic trial in pediatric DIPG, using vorinostat and temsirolimus in a combinatorial approach, targeting the key oncogenic pathway and molecules along with enhancing the radiation sensitivity. Correlative study: Stratum I (chemoradiotherapy phase): Histone acetylation will be quantified from peripheral blood mononuclear cell (PBMC) collected prior to the first dose of vorinostat and radiation and at the end of radiation. Stratum I and II (maintenance phase): Evaluation of histone acetylation, phosphorylated 70S6K and Akt on day 1 and 8 (prior to chemotherapy with temsirolimus) during cycle 1 and cycle 2 will be performed. Methods: Patients with a performance score of 50 or greater with newly diagnosed (Stratum 1) or progressive DIPG (stratum II) as confirmed by gadolinium enhanced MRI, will be eligible. Biopsy is not mandatory. Stratum I: Patients will receive radiation therapy concurrently with vorinostat on the days of radiation at a dose of 230 mg/m2/dose orally, followed by maintenance phase with vorinostat and temsirolimus for 12 cycles if patients do not have progressive disease. Stratum I and Stratum II (maintenance phase): Patients will receive vorinostat and temsirolimus for 12 cycles (28 day cycle), if patient do not have progressive disease. Vorinostat will be given once daily orally at 230 mg/m2/dose orally from day 1 to day 8, along with temsirolimus at 25mg/m2 intravenously on day 1 and day 8. This will be dose level 1 with provisions for 2 higher dose levels and 1 lower dose level if needed. A standard 3+3 design will be used and a minimum of 9 patients and a maximum of 18 patients will be enrolled. Trial is continuing as planned and patient are on dose level 1. Trial: NCT02420613 (currently recruiting). Citation Format: Soumen Khatua, Vidya Gopalakrishnan, Joya Chandra, Leena Ketonen, David I. Sandberg, Jeffrey Weinberg, Fuller Gregory, Kenneth R. Hess, Natalie Slone, Heather Meador, Mirriam Morrell, Wafik Zaky. A phase I study of vorinostat and temsirolimus in children with newly diagnosed or progressive diffuse intrinsic pontine glioma (DIPG) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT029. doi:10.1158/1538-7445.AM2017-CT029

Scientific background/rationale: The prognosis of recurrent/refractory medulloblastoma (MB), ependymoma (EP) and atypical teratoid/rhabdoid neoplasms (AT/RT), which constitutes the majority of malignant posterior fossa tumors (MPFT) in children, remain dismal with no defined effective therapy. Current treatment strategies have significant toxicities and thus profiling newer trials with clinical efficacy and minimal side-effects are imperative. Advantages of direct infusion of natural killer (NK) cells into the ventricles could enhance therapeutic efficacy by maximally concentrating them in the central nervous system (CNS) near the tumor area, bypassing the blood brain barrier and alleviating toxicity as seen with systemic chemotherapy. We have shown the efficacy of activated and propagated NK cells to lyse and kill the MPFT in vitro and tumor explants in mice models. Also, in a first-time human in vivo pilot study, we demonstrated the feasibility of infusions of biologic agents into the fourth ventricle. Infusing biologic agents through catheters placed in the lateral ventricles are well established in neurooncology. The current ongoing study is the first-in-human, loco-regional infusion of NK cells directly into the brain evaluating safety with intent to avoid the significant side-effects of systemic therapy. This novel trial will hopefully be able to provide therapeutic efficacy and a significant increase in the survival of these children. The current format of this trial incorporates changes including different dose, schedule, routes of intraventricular infusions of NK cells from the previously presented version of the trial, and thus submitted. Correlative studies: Cerebrospinal fluid (CSF) drawn during infusions of NK cells will be evaluated for the immunophenotype, function, persistence of NK cells and influx or presence of any other immune cells and correlating with tumor response. Methods: This trial (NCT02271711-recruiting) will proceed with infusions of NK cells directly into the lateral or fourth ventricles, after placement of a catheter at that location. Recurrent or refractory MB, AT/RT and EP involving the brain and/or spine at original diagnosis or relapse with histological verification will be eligible. Three to six evaluable patients may be entered at a dose level in this study for determination of maximum tolerated dose (MTD). A minimum of nine patients and a maximum of twenty-four patients will be enrolled. After autologous expanded NK cell product have been manufactured as per good manufacturing practice (GMP) guidelines and released, patients will receive three cycles of NK cell infusions over 12 weeks. Each cycle consists of one infusion per week for three weeks followed by a rest week (week 4). Dosing is based on recipient body surface area (BSA), and three dose levels will be evaluated. Currently, the trial is in the second cohort, with no dose limiting toxicity (DLT) noted with the previous dose level. 35% of the minimal accrual has been met. Also as a secondary aim, we will evaluate the antitumor activity of the NK cell infusions within the confines of a phase I study Citation Format: Soumen Khatua, Vidya Gopalakrishnan, Laurence Cooper, Dean Lee, David I. Sandberg, Michael Rytting, Jason J. Johnson, Leena Ketonen, Diane Liu, Judy Moyes, Wafik Zaky. Phase I study of intraventricular infusions of autologous exvivo expanded NK cells in children with recurrent/refractory malignant posterior fossa tumors of the central nervous system [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT033. doi:10.1158/1538-7445.AM2017-CT033

Background: Vemurafenib (Vem) is approved by the US Food and Drug Administration for the treatment of BRAF V600-mutant melanoma. Vem also has demonstrated activity in BRAF V600-mutant non-melanoma cancers. However, with monotherapy, all patients eventually experience disease progression, and more effective treatments are needed. On the basis of preclinical studies showing that combined inhibition of the BRAF and PI3K/mTOR pathways may overcome the primary or innate resistance mechanisms in BRAF-mutant malignancies, we conducted a phase I trial combining Vem with the mTOR inhibitor everolimus (Eve). Objectives: Primary objectives of this open-label phase I trial were to evaluate safety and tolerability, and to determine the maximum tolerated dose (MTD) of the Vem and Eve combination in patients with BRAF-mutant advanced cancers; the secondary objective was to assess efficacy. Methods: Escalating doses of Vem twice daily (BID) and Eve once daily (QD) were combined using the standard 3 + 3 design, and then an expansion cohort was enrolled and treated at the MTD. Treatment was administered in 28-day cycles. MTD was defined as the highest dose studied in which incidence of dose-limiting toxicity (DLT) was less than 33%. Younger patients were enrolled at the accruing dose level, with body surface area-based dose adjustments for smaller children. Results: Twenty patients (14 male, 6 female) with BRAF-mutant (18 V600E, 1 V600K, 1 G469A) melanoma (n = 7) or central nervous system (n = 5), thyroid (n = 4), non-small cell lung (n = 1), colorectal (n = 1), appendiceal (n = 1), or unknown primary (n = 1) cancer were enrolled. The median age of the 18 adult patients was 64 years (range 16-85 years); the 2 pediatric patients were aged 10 and 13 years. Prior therapies included surgery (n = 18, 90%), radiation (n = 11, 55%), cytotoxic chemotherapy (n = 14, 70%), and a prior phase I trial (n = 10, 50%). Ten patients (50%) had prior treatment with BRAF/MEK inhibitor(s). Ten patients had received 2 or more lines of systemic therapies. No dose-limiting toxicity was observed at dose level 1 (Vem 720 mg BID, Eve 5 mg QD). Two DLTs (rash, fatigue) were observed at dose level 2 (Vem 720 mg BID, Eve 10 mg QD). Dose level 1 was determined to be the MTD. Grade >3 toxic effects included rash (n = 4), fatigue (n = 4), photosensitivity (n = 1), anemia (n = 1), hyperglycemia (n = 1), and hypertriglyceridemia (n = 1). After excluding 1 patient who withdrew consent before restaging, we found that 5 patients (26%) had a partial response (melanoma = 1, non-melanoma = 4), 9 (47%) had stable disease, and 5 (26%) had progression as the best response. Among 9 evaluable patients with a history of prior treatment with BRAF/MEK inhibitors, 2 had a partial response and 5 had stable disease. Two patients are continuing the treatment after 5 and 16 cycles. Conclusion: The combination of Vem (720 mg BID) and Eve (5 mg QD) is safe, well-tolerated, and has activity in patients with BRAF-mutant advanced cancers, including those previously treated with a BRAF/MEK inhibitor. Citation Format: Muhammad Rizwan Khawaja, Soumen Khatua, Daniel Karp, Filip Janku, David Hong, Javier Munoz, Apostolia Tsimberidou, Wafik Zaky, Steven I. Sherman, Patrick Hwu, Funda Meric-Bernstam, Vivek Subbiah. A phase I dose escalation trial of vemurafenib in combination with the mTOR inhibitor everolimus for melanoma and non-melanoma cancers with a BRAF aberration. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT052.