e16703 Background: ONC201 is an imipridone with specificity for the dopamine-like DRD2 receptor. Anti-cancer effects involve up-regulation of TRAIL/DR5, dual AKT/ERK pathway inhibition, and integrated stress response. Because TCGA analysis showed very high DRD2 expression in neuroendocrine tumors, especially pheochromocytoma-paragangliomas (PC-PG), an investigator initiated IND study of ONC201 in neuroendocrine tumors (CCF IRB17-808; CASE2716; IND132665; NCT03034200) was done. Methods: ONC201 dose was 625 mg po/wk. Metastatic PG-PG were enrolled in cohort A. Other neuroendocrine patients were entered in cohort B. Two additional patients had single patient IND. Because hypertension is an issue from catecholamine producing PC-PG, all PC-PG patients had combined alpha + beta blockade and bp was monitored in the clinical research unit after dose #1 ONC201. Additional data was obtained with daily home bp monitoring, often with a wireless cuff which connects into EPIC via MyChart. Labs, scans, and clinic visits were done at week 6, then every 3 months from initial ONC201 dose. Patients with clinical benefit remained on study and could get radiation for bone metastases. Results: Neuroendocrine tumors were treated with ONC201 included 10 PC-PG, 3 with MTC 13 with other varieties including sarcomas, adrenal cortical carcinoma (ACC), neuroblastoma, and GI neuroendocrine tumor (NET). ONC201 was exceptionally well tolerated. All patients were able to maintain or improve KPS while on study. No adverse effects on bp were seen. The only ONC201-related AE was temporary grade 1 neurocognitive dysfunction for ~36 hours after weekly ONC201 dosing in 2/10 PC-PG patients. 4/10 PC-PG patients remain on study at 28, 22, 22, and 4 month. 1 DSRCT patient achieved a PR at 3 months and has been treated 28 months. An ACC patient was initially responsive (PR), but rapidly progressed in liver; 1 GI NET patient had -10% reduction by RECIST at 3 months and remains on treatment. MTC may be responsive (1 no response, 2 stable and improving by RECIST at 3 months). Conclusions: ONC201 is very well tolerated with excellent quality of life and extended clinical benefit against neuroendocrine tumors. Although ONC201 has activity against neuroendocrine tumors, especially PC-PG, increased efficacy will likely require combination therapy. Clinical trial information: NCT03034200 . [Table: see text]
Abstract Medulloblastoma (MB), Neuroblastoma (NB), and Ewing Sarcoma (ES) are malignant pediatric neuroectodermal solid tumors. Current treatments are highly intensive but toxic and subsets of patients such as metastatic and/or relapsed patients have a dismal outcome (Esiashvili N et al, 2008; Leavey PJ et al, 2008; Bernstein ML et al, 2006). Targeted treatments with reduced side effects are urgently needed. Immunotherapy is a promising approach to inducing tumor control. Among various strategies of immunotherapy, dendritic cell-based vaccines have shown promising preliminary activity in the setting of minimal residual disease (Lasky JL et al, 2013; Westers TM et al, 2011; Shumway NM et al, 2009). To evaluate the feasibility of dendritic cell based vaccine in pediatric solid tumors, we incubated HLA A02+ human peripheral blood mononuclear cells (PBMC) with monocyte-derived autologous dendritic cells (DCs) pulsed with or without whole tumor cell lysates in interferon-ã (INFã) ELISPOT assays. We demonstrated that the number of spots detected in test wells (Daoy: 141.6±3, SKPNDW: 233.3±33.5, EWS502: 157.6±22.3, TC71: 249.6±24.5) is significantly (p<0.05) greater than control wells (PBS: 42±2), suggesting successful tumor antigen presenting of DCs and specific immune response from PBMC. To test T-cell responses, we isolated CD8+ T cells from PBMC and incubated them with tumor cell lysate pulsed mature DCs. Interestingly, we observed a similar trend in activation but fewer number of spots (PBS: 27±9, Daoy: 52.6±14.5, SKPNDW: 76.6±30.1, EWS502: 44.6±8.3, TC71: 68.6±19) in ELISPOT assays. Further analysis using HLA-DR blocking antibody (L243) showed that CD4+ T cell function is required for the responsive activity of PBMC because the number of spots was significantly (p = 0.03) reduced in test wells with the antibody (45.5±4.9) compared to that in control wells (352.5±17.6). These data indicate that both CD4+ and CD8+ T cells are required for the T-cell immune response to tumor antigens in whole tumor cell lysate presented by DCs. We next tested in vitro cytotoxic activity of DC-activated PBMCs to MB, NB, and ES cells by DELFIA cytotoxicity assay. PBMCs incubated with tumor lysate pulsed DCs induced significantly increased cell lysis compared to control PBMCs in Daoy (78±4.8% vs. 46.5±3.5% at E:T = 10:1, p = 0.019), SKPNDW (80±14.1% vs. 15±2.3% at E:T = 10:1, p = 0.016), and TC71 (82.5±3.5% vs. 39.5±13.4% at E:T = 20:1, p = 0.036). Taken together, our proof-of-principle studies demonstrated the efficacy of DC-based vaccines using whole tumor cell lysate as antigens in pediatric neuroectodermal solid tumors. Further investigation in the preclinical setting in a xenograft NSG model is warranted. Citation Format: Stacey Zahler, Wen Luo, Janet Ayello, Mitchell S. Cairo. Engineering dendritic cell-based vaccines as targeted immunotherapy against medulloblastoma, neuroblastoma, and Ewing sarcoma. [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 4913.
6622 Background: Children, adolescents, and young adults have rare cancers and standard-of-care treatment is commonly very aggressive. Virtual visits provide include many of the nuances of face-to face communication. These are much friendlier than phone calls or email and can be scheduled and structured to provide a large amount of information efficiently. Methods: Cleveland Clinic uses HIPPA-compliant software from American Well (Boston, MA) that allows the health care provider and patient to use a phone, tablet, or desktop computer for video visits. Our intake process involves obtaining a Medical Record Number (MRN), sending a brief summary, uploading or sending a CD with images in DICOM, and having an administrative assistant schedule the virtual visit. Telemedicine sessions typically last <60 minutes. During the visit a summary is updated, images are reviewed, and this and other information shared via email after the visit. Results: In 2017+ 2018 we conducted 223 virtual visits; 85% were <30 years old (table). The summary has been a key to efficient and effective organization and includes not only contact information and past medical history, but also an “Opportunities to Improve Health" section (problem list /action plan). Topics discussed in solid tumor patients include: 1) local control, 2) medical therapy (chemotherapy), 3) imaging and tumor markers, 4) control of side effects and nutrition, 5) social issues and goals of care (which can include palliative care and hospice), and 6) follow-up. A power point with key images and the updated summary and articles are emailed at the end of the visit to the patient & caregivers and often referring physician, NP, or PA . Visit diagnoses have included osteosarcoma and Ewing sarcoma (73%), but also other rare cancers such as rhabdomyosarcoma, DSRCT, paraganglioma, and adrenal cortical carcinoma. Survivorship and cGVHD have also been discussed. Conclusions: A structured virtual visit to help young people and their caregivers understand complex multi-disciplinary cancer care is now possible for all regions of North America. A major source of satisfaction has been two-way sharing of information to improve not only cancer control, but also improved nutrition, communication, and proactive toxicity reduction. [Table: see text]
Abstract Purpose: Tumor dopamine-like DRD2 receptor expression is higher in pheochromocytoma-paraganglioma (PC-PG) compared with other cancers. ONC201 is a bitopic DRD2 antagonist with preclinical ONC201 activity in desmoplastic small round cell tumor (DSRCT). Patients and Methods: Patients (N = 30) with neuroendocrine tumors were treated on this investigator-initiated trial (NCT03034200). ONC201 dose and schedule were 625 mg orally weekly in cohorts A (PC-PG) + B (other neuroendocrine tumors) and 625 mg orally on 2 consecutive days each week in cohort C, which included 5 responding patients. The primary endpoint was radiographic response measured using RECIST. Secondary endpoints included progression-free survival, overall survival, and safety. Results: In arm A (n = 10; all PC-PG), 50% (5/10) exhibited a partial response (PR) and 2 additional patients had stable disease (SD) >3 months. Median duration of therapy for arm A patients was 9 months (range: 1.5–33 months) with 5 patients treated >1 year. In arm B (n = 12), there were 1 PR (DSRCT) and 2 SD (DSRCT; neuroblastoma) >3 months. Median duration of therapy in arm A was 18 months (range: 1–33 months) and arm B was 3 months (range: 1.5–33 months). Arm C PC-PG (N = 8) showed 1 PR and 7 SD at 3 months, with median duration of therapy >10 months. There was no decline in Karnofsky performance status at week 12 for 28 of 30 patients and no dose modification due to treatment-related adverse events. Conclusions: Oral ONC201 was well tolerated in patients with metastatic neuroendocrine tumors and associated with clinical benefit, including tumor responses, particularly in some patients with DSRCT and the majority of patients with PC-PG. See related commentary by Owen and Trikalinos, p. 1748
Myeloablative conditioning and allogeneic hematopoietic stem cell transplant (alloHSCT) in children with acute myeloid leukemia (AML) in first complete remission (CR1) may be associated with significant acute toxicity and late effects. Reduced-intensity conditioning (RIC) and alloHSCT in children is safe, feasible, and may be associated with less adverse effects. Gemtuzumab ozogamicin (GO) induces a response in 30% of patients with CD33+ relapsed/refractory AML. The dose of GO is significantly lower when combined with chemotherapy. We examined the feasibility and toxicity of RIC alloHSCT followed by GO targeted immunotherapy in children with CD33+ AML in CR1/CR2. Conditioning consisted of fludarabine 30 mg/m2 × 6 days, busulfan 3.2 to 4 mg/kg × 2 days ± rabbit antithymocyte globulin 2 mg/kg × 4 days followed by alloHSCT from matched related/unrelated donors. GO was administered ≥60 days after alloHSCT in 2 doses (8 weeks apart), following a dose-escalation design (4.5, 6, 7.5, and 9 mg/m2). Fourteen patients with average risk AML received RIC alloHSCT and post-GO consolidation: median age 13.5 years at transplant (range, 1 to 21), male-to-female 8:6, and disease status at alloHSCT 11 CR1 and 3 CR2. Eleven patients received alloHSCT from 5-6/6 HLA-matched family donors: 8 received peripheral blood stem cells, 2 received bone marrow, and 1 received related cord blood transplantation. Three patients received an unrelated allograft (two 4-5/6 and one 9/10) from unrelated cord blood unit and bone marrow, respectively. Neutrophil and platelet engraftment was observed in all assessable patients (100%), achieved at median 15.5 days (range, 7 to 31) and 21 days (range, 10 to 52), respectively. Three patients received GO at dose level 1 (4.5 mg/m2 per dose), 5 at dose level 2 (6 mg/m2 per dose), 3 at dose level 3 (7.5 mg/m2 per dose), and 3 at dose level 4 (9 mg/m2 per dose). Three of 14 patients received only 1 dose of GO after alloHSCT. One patient experienced grade III transaminitis, which resolved; no grade IV transaminitis, no grade III/IV hyperbilirubinemia, or sinusoidal obstructive syndrome were observed. The second dose of GO was given at median of 143 days (range, 120 to 209) after alloHSCT. Probability of grades II to IV acute and chronic graft-versus-host disease were 21% and 33.5%, respectively. Probability of overall survival after RIC alloHSCT and GO consolidation at 1 and 5 years was 78% and 61%, respectively. Probability of 5-year event-free survival after RIC alloHSCT and GO consolidation in patients in CR1 was 78%. No dose-limiting toxicities probably or directly related to GO were observed in this cohort. This preliminary data demonstrate that RIC followed by alloHSCT and consolidation with GO appears to be safe in children and adolescents with CD33+ AML in CR1/CR2. A phase II trial is currently underway investigating this approach with a GO dose of 9 mg/m2 per dose.
There are limited data on spine stereotactic radiosurgery (SRS) in treating adolescent and young adult (AYA) patients. SRS has the advantages of highly conformal radiation dose delivery in the upfront and retreatment settings, means for dose intensification, and administration over a limited number of sessions leading to a decreased treatment burden. In this study, the authors report the oncological and toxicity outcomes for AYA patients with metastatic sarcoma treated with spine radiosurgery and provide clinicians a guide for considerations in dose, volume, and fractionation.
'%3e%3ccircle r='20' fill='%23008'/%3e%3ccircle r='17.5' fill='%23fff'/%3e%3ccircle r='3.5' fill='%23008'/%3e%3cg id='d'%3e%3cg id='c'%3e%3cg id='b'%3e%3cg id='a' fill='%23008'%3e%3ccircle r='.875' transform='rotate(7.5 -8.75 133.5)'/%3e%3cpath d='M0 17.5.6 7 0 2l-.6 5L0 17.5z'/%3e%3c/g%3e%3cuse xlink:href='%23a' transform='rotate(15)'/%3e%3c/g%3e%3cuse xlink:href='%23b' transform='rotate(30)'/%3e%3c/g%3e%3cuse xlink:href='%23c' transform='rotate(60)'/%3e%3c/g%3e%3cuse xlink:href='%23d' transform='rotate(120)'/%3e%3cuse xlink:href='%23d' transform='rotate(-120)'/%3e%3c/g%3e%3c/svg%3e)