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Supplementary Table 1, Figures 1-3 from Targeting the p53 Pathway in Retinoblastoma with Subconjunctival Nutlin-3a

BACKGROUND: Dual inhibition of CDK4/6 and mTOR in DIPG and pediatric HGG has strong biologic rationale, given prevalent genetic alterations resulting in upregulated cell cycle and PI3K/mTOR pathways in these diseases, as well as non-overlapping agent toxicities. This study sought to evaluate safety/tolerability and determine the recommended phase 2 dose (RP2D) of ribociclib and everolimus among children with newly diagnosed DIPG and HGG post-radiotherapy. METHODS: Patients were enrolled according to a Rolling-6 design and received oral ribociclib and everolimus once daily for 21 and 28 days, respectively, starting 2-4 weeks post-completion of radiotherapy. All HGG and biopsied DIPG patients were screened for RB protein presence by immunohistochemistry. Pharmacokinetics and survival data were analyzed. RESULTS: Nineteen patients enrolled (median age: 8 years [range: 2-18]). Three patients enrolled at each of dose levels 1 and 2 without dose-limiting toxicities (DLTs). Thirteen patients enrolled at dose level 3, with one patient experiencing a DLT (grade 3 infection). One patient came off therapy prior to cycle 9 due to cardiac toxicity. The most common grade 3/4 toxicities were neutropenia (33%), leucopenia (17%), and lymphopenia (11%). Steady-state everolimus exposures in combination were 1.9±0.9-fold higher than single-agent administration. Median overall survival (OS) for 15 patients with DIPG was 13.9 months, with 12-, 24-, and 36-month OS of 53.3%, 38.9%, and 38.9%. Median event-free survival for four patients with HGG was 10.5 months. Among patients with tumor molecular profiling, two longer survivors (OS: 20, >37 months) had evidence of cell cycle upregulation with CDKN2A/B deletion and CDK4 overexpression identified. CONCLUSIONS: The combination of ribociclib and everolimus was well-tolerated post-radiotherapy in children with newly diagnosed DIPG and HGG, with a RP2D of ribociclib 170 mg/m2 days 1-21 and everolimus 1.5 mg/m2 days 1-28. Results will inform a molecularly-guided phase II study currently underway to evaluate efficacy.

Nearly one-third of children with medulloblastoma, a malignant embryonal tumor of the cerebellum, succumb to their disease. Conventional response monitoring by imaging and cerebrospinal fluid (CSF) cytology remains challenging and a marker for measurable residual disease (MRD) is lacking. Here, we show the clinical utility of CSF-derived cell-free DNA (cfDNA) as a biomarker of MRD in serial samples collected from children with medulloblastoma (123 patients, 476 samples) enrolled on a prospective trial. Using low-coverage whole-genome sequencing, tumor-associated copy-number variations (CNVs) in CSF-derived cfDNA are investigated as an MRD surrogate. MRD is detected at baseline in 85% and 54% of patients with metastatic and localized disease, respectively. The number of MRD-positive patients decline with therapy, yet those with persistent MRD have significantly higher risk of progression. Importantly, MRD detection precedes radiographic progression in half who relapse. Our findings advocate for the prospective assessment of CSF-derived liquid biopsies in future trials for medulloblastoma.

We performed a phase-1 pharmacokinetic optimal dosing study of intraventricular topotecan (IT), administered daily 5×, to determine whether, the maximum tolerated dose of IT topotecan was also the pharmacokinetic optimal dose.Patients received topotecan administered through an intraventricular access device (0.1 or 0.2 mg/dose), daily × 5 every other week 2× (Induction); every 3 weeks × 2 (Consolidation); then every 4 weeks for up to 11 courses (Maintenance). Ventricular CSF pharmacokinetic studies were performed on day 1, week 1 of induction, and in a subset of patients after a single intralumbar topotecan dose on day 1, week 3.Nineteen patients were enrolled. All were evaluable for toxicity and 18 were assessable for pharmacokinetics. Arachnoiditis requiring corticosteroid therapy occurred in or one of three patients at the 0.1 mg dose level and two of the initial three patients enrolled at the 0.2 mg dose level. All subsequent patients were therefore treated with concomitant dexamethasone. Pharmacokinetic evaluation after accrual of the first seven patients revealed that a topotecan lactone concentration1 ng/ml for 8 hours was attained in all patients and thus, further dose escalation was not pursued. Results of simulation studies showed that at the dose levels evaluated,99.9% of patients are expected to achieve CSF topotecan lactone concentrations1 ng/ml for at least 8 hours.Intraventricular topotecan, 0.2 mg, administered daily for 5 days with concomitant dexamethasone is well tolerated and was defined to be the pharmacokinetic optimal dose in this trial.

(131)I-metaiodobenzylguanidine (MIBG) is a targeted radiopharmaceutical with activity in patients with relapsed or refractory neuroblastoma. Irinotecan is a known radiosensitizer with activity in neuroblastoma. This phase I study aimed to determine the recommended phase 2 dose of MIBG together with fixed doses of vincristine and irinotecan.Patients 1 to 30 years old with relapsed or refractory neuroblastoma and MIBG-avid tumors were eligible. All patients had autologous hematopoietic stem cells (PBSC) available and met standard phase I organ function requirements. Irinotecan (20 mg/m(2)/dose IV) was given on days 0 to 4 and 7 to 11, with vincristine (1.5 mg/m(2) IV) on days 0 and 7. MIBG was given on day 1 following a 3 + 3 phase I dose escalation design starting at 8 mCi/kg MIBG. PBSCs were administered at dose level 8 mCi/kg for prolonged myelosuppression and for all patients at 12 mCi/kg or more.Twenty-four patients evaluable for dose escalation (median age, 6.7 years; range, 1.9-26.8 years) received 1 (n = 17), 2 (n = 5), or 3 (n = 2) cycles of therapy. Myelosuppression and diarrhea were the most common toxicities. Two of 6 patients at the 18 mCi/kg dose level had dose-limiting toxicity (DLT), including one with protocol-defined DLT with prolonged mild aspartate aminotransferase elevation. Eighteen mCi/kg was the recommended phase 2 dose. Six additional patients were treated at 18 mCi/kg, with one additional DLT. Responses (2 complete and 4 partial responses) occurred in 6 of 24 (25%) evaluable patients.MIBG is tolerable and active at 18 mCi/kg with standard doses of vincristine and irinotecan.

Lapatinib is a small molecule reversible tyrosine kinase inhibitor of EGFR and ErbB2 that shows in vitro and in vivo activity against a range of EGFR and ErbB2-dependent adult cancer cell lines and that has clinical efficacy against ErbB2-overexpressing breast cancer.Lapatinib was tested against the cell lines of the PPTP in vitro panel at concentrations ranging from 1.0 nM to 10.0 microM. Lapatinib was tested against the xenografts of the PPTP in vivo panels using a twice-daily oral administration schedule for 6 weeks (5 days on, 2 days off) at a dose of 160 mg/kg (320 mg/kg/day). Lapatinib pharmacokinetic parameters were determined in scid(-/-) mice.The median IC(50) value for lapatinib against the entire PPTP cell line panel was 6.84 microM (range, 2.08 to10.0 microM). Lapatinib was well tolerated in vivo, with toxicity in only 1.5% of the treated animals. Lapatinib induced significant differences in EFS distribution compared to controls in 1 of 41 xenografts tested. No objective responses were observed in any of the solid tumor panels or in the ALL panel. Lapatinib systemic exposure was consistent with previously observed values.Lapatinib has little activity against the xenografts of the PPTP's in vivo panel, and its in vitro activity occurs at concentrations above those associated with specific EGFR/ErbB2 inhibition. These results likely reflect lack of ErbB2 overexpression in the models studied and suggest that adult and pediatric cancers may fundamentally differ in the applicability of EGFR family members as therapeutic targets.

The objective of this phase I study was to investigate the safety of an all-oral combination chemotherapy regimen: topotecan and capecitabine. Topotecan was administered once a day for 5 consecutive days followed by 2 days of rest and was administered again for 5 consecutive days. The starting dose of topotecan was 0.5 mg/m2/d(-1). Capecitabine was administered concurrently at an oral dose of 1800 mg/m2/d(-1) divided twice daily for 14 concurrent consecutive days. Each cycle of treatment was 21 days. Topotecan pharmacokinetic studies were performed on day 1 of cycles 1 and 2. Nineteen patients with refractory cancer were treated. Dose-limiting toxicity (thrombocytopenia, diarrhea) was observed in 2 of 3 patients at a topotecan dose of 2.0 mg/m2/d(-1). A total of 10 patients were treated at the maximum-tolerated dose of topotecan (1.5 mg/m2/d(-1)) and only 1 treatment-related grade 3 nonhematologic toxic event was demonstrated; however, grade 3 hematologic toxicity was observed in 8 of 10 patients at the maximum-tolerated dose, although no correlated clinical sequela resulted. One patient achieved a partial response and 7 achieved stable disease for 4 months or longer. Measurement of plasma topotecan showed pharmacokinetics consistent with no alteration by capecitabine. In conclusion, we recommend further investigation of oral topotecan (1.5 mg/m2/d(-1)) on days 1 to 5 of each week for 2 weeks in combination with capecitabine (180 mg/m2 twice daily) on days 1 to 14 within a 21-day cycle.

Potentiation of 5-fluorouracil/leucovorin (FUra/LV) cytotoxicity by IFN-gamma in colon carcinoma cells is dependent on FUra-induced DNA damage, the Fas death receptor, and independent of p53 and RNA-mediated FUra toxicity, which occurs in normal gastrointestinal tissues. This provides a rationale for enhancing the selective action of FUra/LV by IFN-gamma in the treatment of colorectal carcinoma. Based on results from our preclinical studies we designed a Phase I trial combining FUra (370 mg/m2) and LV (200 mg/m2), i.v. bolus daily x 5 days, with escalating doses of IFN-gamma (10-100 micro g/m2) s.c. on days 1, 3, and 5, every 28 days. Twenty-five patients with carcinomas were enrolled; 6 patients received IFN-gamma on days 1 and 3 only. The dose-limiting toxicity, stomatitis, occurred most frequently at 100 micro g/m2 IFN-gamma. Minor response or SD was observed in 2 of 9 patients and in 4 of 12 patients at dose levels ofor =50 micro g/m2 andor =75 micro g/m2 IFN-gamma, respectively. Three evaluable chemonaive patients demonstrated partial response (2) or complete response (1). Serial plasma samples revealed peak FUra concentrations of100 micro M; at 100 micro g/m2 IFN-gamma plasma concentrations5 units/ml persisted for 6.5 h and1 unit/ml for 28.5 h. The pharmacokinetic parameters of IFN-gamma correlated with a 2-3-fold up-regulation of Fas expression at 24 h in CD15+ cells in peripheral blood samples. Furthermore, clinically relevant IFN-gamma concentrations up-regulated Fas expression and sensitized HT29 colon carcinoma cells in vitro to FUra/LV cytotoxicity. On the basis of the modulation of Fas signaling, FUra/LV combined with IFN-gamma has shown activity in a Phase I trial in colorectal carcinoma and warrants additional evaluation in Phase II.

A case of Pseudomonas aeruginosa septicemia complicated by ecthyma gangrenosum is presented. The usefulness of monitoring aminoglycoside concentrations in the treatment of septicemia is stressed. The pathophysiology and treatment of ecthyma gangrenosum and the pharmacokinetics of tobramycin are reviewed.

Fluctuations in the atmospheric ozone column may significantly increase mean transmitted ultraviolet radiation at biologically sensitive wavelengths, and increase mean photodissociation rates in the lower stratosphere.