bluuebunny/crossref_metadata_2025 huggingface dataset:
Molecular risk stratification in pediatric medulloblastoma
Authors: Pfister S. M. , Mendrzyk F. , Korshunov A. , Wittmann A. , Toedt G. , Benner A. , Werft W. , Kulozik A. , Scheurlen W. , Radlwimmer B. , Lichter P.
Published: March 2020

9506

Background: Medulloblastoma is the most common malignant brain tumor and a significant cause of cancer mortality in children. Despite considerable therapeutic advances, prognosis remains poor, with a five-year-survival rate of about 60% emphasizing the urgent need for markers to allow for a more accurate tailoring of treatment intensity. Methods: We performed genome-wide analysis of DNA-copy number in 112 medulloblastomas using array-CGH. All patients had received craniospinal irradiation after surgery. Standard adjuvant chemotherapy with lomustine, cisplatin and vincristine or a regimen with equal potency had been administered to 73 patients. To identify novel prognostic markers, DNA copy number information was correlated with survival data using log rank and chi-square tests. For selected candidate genes identified by array-CGH, mRNA and protein expression were analyzed by real-time quantitative PCR, and immunohistochemically on tissue microarrays consisting of medulloblastomas from 189 patients. Results: Copy-number gains of chromosomes 6 and 17q, high-level amplifications of MYC and MYCN, and loss of 9p21.3 (CDKN2A locus) were identified as significant adverse prognostic markers; monosomy 6 was associated with good prognosis. Monosomy 6 and gain of 17q were mutually exclusive, whereas trisomy 6 almost always occurred in conjunction with 17q gain. Tumors with trisomy 6 and 17q gains exhibit strong up-regulation of MAP3K7 (chr. 6) and NLK (17q) mRNA, two key-enzymes of the non-canonical calcium-dependent Wnt-signaling pathway. Furthermore, this subgroup exclusively shows high mRNA-expression of several cancer-retina antigens (e.g. GNGT1, GNGT2, PDE6, RCV1, RDS and NRL). Tumors with monosomy 6, in contrast, display highly activated canonical Wnt signaling as indicated by nuclear protein expression of beta-catenin. Conclusions: We propose a model for the molecular risk stratification of medulloblastoma comprising five risk groups with significantly different survival using copy-number status of MYC, MYCN, and chromosomes 6 and 17q. Furthermore, we give evidence for a role of noncanonical calcium-dependent Wnt-signalling in medulloblastoma metastasis in a subset of tumors. Cancer-retina antigens could be used to facilitate the diagnosis and follow-up of this molecular subgroup.

No significant financial relationships to disclose.
Successful treatment of childhood astrocytomas with cisplatin and irinotecan
Authors: Mora J. , Cruz O. , Parareda A. , de Torres C. , Guillen A. , Navarro R. , Garcia G. , Costa J.
Published: March 2020

9508

Background: Childhood astrocytomas are a heterogeneous group of neoplasms for which non-surgical management is controversial. After a pilot study suggesting that irinotecan/cisplatin (I/C) may be effective for spinal cord astrocytomas in children (Mora et al, Neuro-Oncol 2007), we initiated a phase II trial for progressing astrocytomas with the aim of avoiding radiation therapy for low grade's and improve outcome for high grade's. Methods: The indication for adjuvant therapy was based upon histology, the extent of surgical resection, and the presence of clinical or neuroradiological signs of progression. Weekly Irinotecan (50 mg/m2 and 65 mg/m2 the last 2 cycles) and Cisplatin (30 mg/m2) for four consecutive weeks (1 cycle), and a total of 4 cycles was used. Results: Since 2004, 17 children aged 7m-17y were treated including 5 WHO grade I, 6 grade II, 3 grade III, and 3 non biopsied tumors: 2 intrinsic brain-stem tumors (BST) and 1 optic-pathway (OP) tumor. No patient had clinical signs of neurofibromatosis. Primary sites included 4 supratentorial, 3 BST, 3 OP, 1 cerebellar, and 6 spinal tumors. Gross total resection was performed in 1 case, subtotal in 4 and only biopsy in 9. Six patients received chemotherapy and one radiotherapy prior to the I/C regimen. Vomiting was easily controlled except for patients with BST. All but 2 patients, because of C allergy, completed the protocol with no documented ototoxic, renal, or GI side effects. Eleven (65%) pts had a complete clinical response, including 1 BST and all the spinal cord cases. Remarkably all the clinical responses were rapid, within the first 1–2 weeks of treatment. Twelve (70%) pts had a <25 [O1] % reduction of the tumor size at the end of therapy including 2 spinal cord cases that achieved complete radiological responses 10 months after the end of therapy. One BST patient progressed on therapy. Thus far, none of the low grade cases have received radiotherapy, although median f/u is only 1 year. All pts are alive and well. Conclusions: Remarkable clinicoradiological responses and avoidance of radiotherapy was obtained using the I/C regimen for childhood astrocytoma.

No significant financial relationships to disclose.
Augmented Berlin-Frankfurt-Muenster (ABFM) regimen for children with standard-risk acute lymphoblastic leukemia (SR-ALL) and slow early response (SER)
Authors: Matloub Y. H. , Angiolillo A. , Bostrom B. , Stork L. , Hunger S. P. , Nachman J. , Sather H. , La M. , Carroll W. L. , Gaynon P. S.
Published: March 2020

9511

Background: Numerous studies have shown that SER in ALL has a negative impact on outcome. Children's Cancer Group CCG-1882 demonstrated that post-induction intensification greatly improved the outcome of children with high-risk ALL and SER. Five year event-free-survival (EFS), and overall survival (OS) for the augmented regimen was 75 ± 4% vs 55 ± 4.5%, and 78 ± 4% vs 67 ± 5% for the standard regimen, p <0.001 and 02 respectively (N Engl J Med 1998; 338:1663–71). Methods: Therefore, COG-1952 and COG- 1991, studies for patients with SR-ALL, assigned the slow early responders to augmented therapy, while others were randomized according to the study design. Study eligibility criteria were similar for both, and included newly diagnosed children with National Cancer Institute SR criteria. COG-1952 accrued a total of 2,027 patients and COG-1991 accrued 3,054. In COG-1952 patients were deemed SER if their day-7 marrow had >5% blasts, and their day-14 marrow >25%. COG-1991 used the same criteria for SER, but also added patients whose day-7 marrow had >25% blasts and their day-14 marrow had >5% blasts to the SER group. This was based on the unfavorable outcome of this subgroup in COG-1952. The augmented therapy in COG-1991 like the CCG-1882 and COG-1952, was based on a COG-modified ABFM, but differed in using dexamethasone as the sole steroid and pegylated asparaginase as the asparaginase preparation, as compared to prednisone in induction and maintenance, and native E coli asparaginase. Results: Comparative groups with days 7 and 14 M3 marrows and unfavorable cytogenetics included 126 patients from COG-1991 and 81 from the COG-1952 were assigned to their corresponding ABFM regimens. Four year EFS and OS were 85% ± 5% and 90 ± 4% for CCG-1991 vs 61 ± 5.6% and 75 ± 5% for CCG-1952, p = 0.003 and 0.04 respectively. Conclusion: We conclude that the use of dexamethasone, and pegylated asparaginase greatly improves the outcome of children with NCI-SR with SER treated on a modified augmented BFM therapy, thus supporting the use of these agents in ALL therapy.

No significant financial relationships to disclose.
Overall and cause specific long term mortality following childhood cancer: The role of cancer treatment
Authors: de Vathaire F. , Tukenova M. , Oberlin O. , Doyon F. , Guibout C.
Published: March 2020

9520

Background: A multi-centre French cohort study was performed to evaluate the role of treatment in the long-term overall and cause-specific mortality among childhood cancer survivors. Methods: This study cohort included 3,057 patients treated for a solid tumours before the age of 17 between 1942–1986, in 5 French centres and who survived at least 5 years from diagnosis. Detailed clinical and therapeutic data were extracted for each patients from medical records. For 2,081of the 2,178 patients who received radiotherapy, radiation doses were estimated at 188 anatomical sites, including heart (7 sites) and lungs (10 sites). 98% of patients were identified in French National Registry of Physical Persons (RNIPP) and we obtained the death causes of 95% of dead patients. Overall and cause-specific mortality standardized ratios (SMR), absolute excess risk (AER) of death were studied using Poisson regression. Results: 50% of patients were treated by chemotherapy (CT) plus radiotherapy (RT), 22% by CT alone and 21% by RT alone. During an average follow-up of 25 years, 465 patients dead. The overall SMR was 7.3 (95% CI: 6.7–8.0) and AER was 6 deaths per 1,000 person-years. SMR for death due to cancer other than the 1st cancer (SC) was 16.1 (95%, CI 13.5–18.9). SMRs were significantly elevated for non-cancer overall mortality, infectious and parasitic diseases, diseases of the circulatory, nervous and respiratory system, congenital anomalies, symptoms, signs and ill- defined conditions’ (SMRs of 2.6, 15.7, 6.4, 8.5, 4.6, 3.2, respectively). RT was associated an increase in the risk for overall and SC related deaths (RR = 2.0; 95% CI: 1.5–2.7; RR = 1.8; 95% CI: 1.1–2.9; respectively). CT was associated with an increased risk for overall, SC and non- cancer related deaths (RR = 1.6; 95% CI: 1.3–2.0; RR = 1.9; 95% CI: 1.2–3.0; RR = 1.8; 95% CI: 1.1–2.9 respectively). We were not able to find any evidence for an interaction between CT and RT, whatever the end point considered. Among the 26 circulatory deaths, 24 received RT, the mean radiation dose of the heart (P=0.0006) and treatment with spindle inhibitors (P=0.009) were significantly associated to death by cardiac disease. Conclusions: In the future, death due to cardiac pathologies could be an important issue for long term survivors of childhood cancer.

No significant financial relationships to disclose.
Conduct of an international collaborative osteosarcoma trial at centers located in a developed and developing country
Authors: Rivera G. K.
Published: March 2020

9527

Background: We conducted a collaborative protocol (twinning program) for newly diagnosed patients with localized osteosarcoma (OS 99) at SJCRH (sponsor) and CMH (partner site), a public tertiary-care pediatric hospital and bone tumor center in Santiago, Chile. Methods: CMH was selected as the partner site because Chile has a well developed public health system including free treatment for children with cancer. SJCRH trained and financially supported specialized personnel and provided oversight of study conduct and monitoring. The study was approved by the respective Human Subjects Protection Committees and a Data Safety Monitoring Board. Treatment comprised 12 cycles of chemotherapy (with growth factor support) given every 3 weeks for a total of 35 weeks and definitive surgery after 4 cycles of chemotherapy. Pathology studies and selected imaging studies were centrally reviewed at SJCRH. Patient costs were covered by the Chilean Ministry of Health and SJCRH except for sargramostim which was donated by Berlex Oncology. Patient care and study conduct were discussed in a multidisciplinary forum on a monthly basis. The two study teams maintained close communication through videoconferencing, and site visits. Results: Of the 72 eligible patients enrolled on study, 22 were treated in Santiago (2003–2006). Rare discrepancies in interpretation of diagnostic imaging and pathology studies were addressed in a timely manner. Preliminary results demonstrated similar patient outcomes and treatment tolerance at the two sites. Limb-salvage surgery was performed in 12 Chilean patients. Median per-patient costs were lower in Chile (US $80,000) than at SJCRH ($400,000). Conclusions: It is feasible, safe, and cost-effective to simultaneously treat pediatric patients with osteosarcoma on modern protocols, through well designed and rigorously monitored twinning programs that include countries with different level of resources.

No significant financial relationships to disclose.
Cancer in adolescents and young adults (AYA) in North Netherlands (1989–2003): Increased incidence, stable survival and high incidence of secondary tumors
Authors: van Gaal J. C. , de Bont E. S. , Bastiaannet E. , Schaapveld M. , Kluin-Nelemans J. C. , van der Graaf W. T.
Published: March 2020

9538

Background: Lack of improvement in survival in AYA cancer patients as compared to children has led to increased awareness of this young population. We performed a population-based study of the incidence and survival of primary tumors and incidence of second tumors in patients 12–24 years, diagnosed in North Netherlands. Methods: Patients, diagnosed 1989–2003, classified according to Birch, were retrieved from the regional cancer registry and were divided into age groups (12–15, 16–19, 20–24). Age-specific incidence rates per 100,000 were calculated using population data from Statistics Netherlands. Three-year moving means of incidence were calculated for the three age groups. 5-years survival over time for males (M) and females (F) was calculated; difference in survival was assessed with log-rank test. Results: From 1989–2003 1,118 patients were diagnosed: lymphoma 22.9%, germ-cell malignancies 14.5%, melanoma 13.7%, carcinoma 12.7%, sarcoma 11.7%, CNS tumors 11.5%, leukaemia 10%. The total age-specific incidence rates per 100,000 were: M:13.4 (12–15 yrs), 26.9 (16–19 yrs), and 27.5 (20–24 yrs) and F:13.9, 20.7, 20.7. M/F ratio was 1.32. Between 1999–2003 a remarkable high incidence of Hodgkin's lymphoma in 16–19 yrs (M 9.4, F 7.6), germ cell malignancies 14.1 (M, 20–24), and melanoma 7.0 (F, 20–24) was found. The estimated annual percent change in incidence was 2.15% (p=0.001) overall. Multivariate analysis of the incidence showed a significant increase by age and year of diagnosis. The 5 years-survival was 0.80, 0.80 and 0.82 for the three age groups. Survival did not change significantly during the study period, except for a better survival for leukemias (p=0.04). With a follow-up of 8.7 years the relative risk of secondary tumors was 34.98 (23.06- 50.89; p<0.05). Conclusions: Between 1989 and 2003 the total incidence of cancer in AYA increased. Except for leukaemia survival was stable over time. No difference in survival between the age groups (12–15;16–19; 20–24) was found. From 1999–2003 a remarkable high incidence of Hodgkin's lymphomas (M, 16–19), germ cell malignancies (M, 20–24) and melanomas (F, 20–24) was observed. The relative risk of a secondary tumor in this young cohort was 35-fold increased.

No significant financial relationships to disclose.
Research, policy and practice related to survivors of childhood, adolescent and young adult cancers in British Columbia (BC), Canada: A population-based approach
Authors: Rogers P. C. , Broemeling A. , Pritchard S. L. , Goddard K. , Xie L. , Poole B. , Sheps S. , McBride M. L.
Published: March 2020

9539

Background and Purpose: Prevalence of long term survivors of pediatric, adolescent and young adult cancers is increasing. In BC we are using a multidimensional population approach to address research and care for these survivors. Information on trends in prevalence of survivors and use of physician services are presented. Methods: We have identified a cohort of patients under 25, diagnosed from population registries since 1970, and linked their records with person-based longitudinal records of health utilization. Results: Prevalence rate of cancer survivors aged 0–59 years, originally diagnosed under age 25, increased 5 fold between 1975 and 2005, from 26 per 100,000 to 147 per 100,000; 78% were aged 20 or older. A total subgroup of 3,787 individuals surviving five years or more, diagnosed between 1970 and 1995, were identified; 2,590 (68%) of these were linked to physician visit records (excluding visits within BC's Children's Hospital) from 1986 to 2000. In year 2000, 77% of survivors had at least one physician visit; 75% of survivors saw a family physician (FP), and 44% of survivors visited a specialist physician with a specialty that could be related to a late effect. Between 1986 and 2000 survivor prevalence increased 3.3% per year; total visits by survivors to FPs increased by 11.6% per year and by 10.6% per year to specialists. In 1986, 66% of physician visits were for patients older than 20 which increased to 79% by 2000. A provincial pediatric oncology network consisting of oncologists and community care representatives has been established to implement changes to long-term follow up policy. Conclusion: The prevalence rate and utilization of health services among survivors of childhood, adolescent and young adult cancers continues to escalate. Research results, along with other published literature, will inform the development of policy and practice within the BC Network.

No significant financial relationships to disclose.
Prognostic factors in metastatic rhabdomyosarcoma (RMS): The results of a pooled analyze from U.S. and European cooperative groups
Authors: Oberlin O. , Rey A. , Lyden E. , Bisogno G. , Stevens M. C. , Meyer W. H. , Bergeron C. , Ellershaw C. , McDowell H. , Carli M.
Published: March 2020

9542

Background: Prognosis factors on outcome for metastatic RMS are still matter of discussion. The analysis of a large cohort of patients can give arguments for development of risk-based therapy. Methods: We studied data from SIOP 84, SIOP 98, European Intergroup MMT89–91, Italian RMS4.99, IRS-III, -IV Pilot, -IV, -V, -D9501 to look at the influence of age, histology, sites of primary and metastatic disease, and number of sites of metastatic disease at the 3 year event-free survival. Results: 788 patients were included in the analyze and 776 in the multivariate analyse. The 3 year overall survival and EFS were 34% (se 1.7) and 27 % (se 1.6) respectively. By univariate analysis, 3-year EFS was significantly influenced by age 10 years or more (15% vs 36%), alveolar histology (28% vs 40%), location of primary tumor in unfavorable site -parameningeal, extremity and “other” sites- (31% vs 48%) the presence of three or more metastatic (17% vs 38%), the presence of bone or bone marrow involvement (24% vs 45%). By multivariate analysis, histology had no more impact on EFS. The EFS was strongly correlated to the number of the 4 other unfavorable prognostic factors: age, site of the primary, number of metastis sites, bone/bone marrow involvement relative risks were 1.6 for age (p<0.0001), 1.4 for site of primary tumor (p=0.002), 1.3 for bone/bone marrow involvement (p=0.005), 1.4 for number of metastatic sites (p=0.002). EFS was 58% for the 46 patients without any factors and was respectively 40%, 22%, 14% and 4% in patients with 1 factor (250 patients), 2 factors (233 patients), 3 factors (177 patients) or 4 factors (70 patients) (p<0.01). Conclusions: This analysis identified subsets of patients with very different outcomes. Patients with EFS less than 50% might be appropriate candidates for experimental approaches.

No significant financial relationships to disclose.
A phase Ib study of oxaliplatin in combination with fluorouracil (5FU) and leucovorin (LV) in pediatric patients (pts) with advanced solid tumors
Authors: Gore L. , Kuttesch J. , Hunger S. P. , Herzog C. , Narendaren A. , Boklan J. , Foreman N. K. , Ivy S. P. , Boucher N. , Trippett T. M.
Published: March 2020

9548

Background: Platinums have significant activity in a wide variety of pediatric tumors, and oxaliplatin exhibits synergy with 5FU and LV in adults with colorectal cancer in FOLFOX regimens. The primary objectives of this study are to determine the maximum tolerated dose (MTD) of the modified FOLFOX6 regimen in pediatric tumors. Secondary objectives include safety, PK pharmacokinetic (PK) and PET scan efficacy analyses. Methods: Pts age <21 years with advanced cancers and adequate organ function are eligible. Patients are stratified by tumor type (CNS or non-CNS) to better delineate the potential neurotoxicity in patients with altered neurologic function. Pts received oxaliplatin starting at 85 mg/m2 and LV 400 mg/m2 over 2 hours on day 1 followed by a 5FU bolus of 400 mg/m2 then 2,400 mg/m2 continuous infusion over 46 hours, every 2 weeks (3 courses = 1 cycle), with integrated PK sampling in a limited dose escalation design. Standard 3+3 dose escalation, definitions of dose limiting toxicity (DLT), and dose modification for toxicity are implemented. The MTD is expanded to 15 patients to confirm and further characterize tolerability and toxicity. Results: To date, 15 very heavily pre-treated patients (7 M, 8 F) have received 25 cycles (range 1–4, median 2) of treatment at 2 dose levels. One of 8 pts at dose level 2 (oxaliplatin 100 mg/m2) developed DLT (delay in repeat treatment > 14 days due to grade 3 platelets). Treatment has been well tolerated. The most frequently reported related grade 3–4 adverse events (AEs) are reversible leukocytes (29%), neutropenia (43%), platelets (35%) and lymphopenia (21%). 31 of 90 courses (34%) have been delayed for neutropenia and thrombocytopenia. Anti-tumor activity to date includes a confirmed partial response lasting 15 weeks in a patient with osteosarcoma, and prolonged stable disease in 5 other pts with brain tumors (2), hepatoblastoma (2) and sarcoma (1). Conclusions: The modified FOLFOX6 regimen has significant but reversible myelosuppression in heavily pre-treated pediatric patients, but is tolerable and has promising activity in several tumor types. Cohort expansion continues at 100 mg/m2 of oxaliplatin. PET scan and pharmacokinetic analyses will be presented.

No significant financial relationships to disclose.
Pre-clinical studies and phase I clinical trial of the anti-CD22 immunotoxin CAT-3888 (BL22) for pediatric acute lymphoblastic leukemia (ALL)
Authors: Wayne A. , Findley H. W. , Lew G. , Ahuja Y. , Gu L. , Stetler-Stevenson M. , Kreitman R. J. , Pastan I.
Published: March 2020

9560

Background: ALL is the most common childhood malignancy. Although highly curable, therapy is associated with multiple toxicities and ALL remains the most frequent cause of pediatric cancer mortality. Most ALL is CD22+ and we evaluated the anti-CD22 immunotoxin RFB4(dsFv)-PE38 (BL22 or CAT-3888) in the treatment of pediatric ALL. Methods: In vitro cytotoxicity was assessed on blasts from 42 children with CD22+ ALL. In vivo studies were performed using a xenograft model (SCID mouse - EU1 human ALL cell line). A pediatric phase I trial of CAT-3888 was initiated. Results: CAT-3888 induced in vitro cytotoxicity against most ALL samples (median IC50 9.8 ng/ml). A dose response was observed in murine xenografts with significant prolongation of leukemia free survival (p<0.05). 18 subjects (15 ALL, 3 lymphoma; 3 - 22 years of age) were treated on a Phase I trial at doses of 10 - 40 mcg/kg QOD for 3 - 6 doses with cycles repeated every 21 - 28 days. Treatment was well tolerated and no dose limiting toxicity was seen. Pharmacokinetics were influenced by disease burden and T1/2 showed an inverse relationship to marrow blasts (r2=0.5) consistent with rapid drug binding by CD22+ cells. All subjects were heavily pre-treated and had progressive high burden disease at the time of treatment. Transient clinical activity was observed in 16 of 18 subjects as evidenced by decreased peripheral blast count (8), decreased marrow infiltration (3), decreased extramedullary disease (2), increased platelet count (2), increased neutrophil count (1), increased reticulocyte count (1), improved PET scan (1), decreased tumor-associated pain (2), and/or peripheral blast count stabilization (3). A dose response was apparent with 4 of 9 (44%) achieving stable disease at or above doses of 30 mcg/kg. Conclusions: The majority of pediatric ALL blasts are highly sensitive in vitro to CAT-3888 at concentrations far below clinically achievable levels. CAT-3888 is well tolerated in pediatric patients and activity has been seen in most subjects treated on the phase I trial. CD22 represents a relevant target for pediatric ALL. A new higher affinity anti-CD22 immunotoxin (HA22 or CAT-8015) is in development.

No significant financial relationships to disclose.
Phase I study of oral irinotecan, temozolomide, and vincristine for children with refractory solid tumors: A Children's Oncology Group study
Authors: Perentesis J. P. , Wagner L. M. , Ames M. M. , Reid J. M. , Stewart C. F. , Ingle A. M. , Blaney S. M. , Adamson P. C.
Published: March 2020

9563

Background: Both temozolomide (TEM) and vincristine (VCR) can increase the preclinical activity of low-dose protracted irinotecan (IRN) against pediatric solid tumors. Because these drugs have different dose-limiting toxicities (DLTs) and mechanisms of action, we combined these three agents and sought to determine the maximum tolerated dose (MTD) of orally administered IRN when given with fixed- dose TEM and VCR in children with relapsed or refractory solid tumors, using the antibiotic cefixime to reduce IRN-associated diarrhea. Methods: We studied two dose levels of oral IRN (35 or 50 mg/m2) administered on days 1–5 and 8–12, combined with oral TEM 100 mg/m2 on days 1–5 and intravenous VCR 1.5 mg/m2 on days 1 and 8. Courses were repeated every 21 days. Oral cefixime was started 5 days before chemotherapy and continued daily. Results: Of 21 patients enrolled, 17 (ages 3–21, median 14 yrs) were evaluable for toxicity and have to date received 46 courses (range 1–8, median 2). At the IRN dose of 50 mg/m2/d, 4 of 12 patients had DLT, including elevated ALT/AST (1), abdominal pain (1), hypokalemia (1), anorexia (1), thrombocytopenia (1), and fatal liver failure in a patient with metastatic disease in the liver and porta hepatis (1). In contrast, none of 5 patients treated at the dose of 35 mg/m2/d experienced first-course DLT, defining this dose as the MTD. UGT1A1 genotype did not correlate with DLT in this small trial. The median SN-38 lactone area under the curve (0–6h) at the IRN dose of 50 mg/m2/day was 13.5 ng/ml*h (range 3.8 to 30.9); pharmacokinetic analysis of patients treated at 35 mg/m2/day is ongoing. Six patients with the following tumors received more than 2 courses: neuroblastoma, ependymoma, hepatoblastoma, fibrillary astrocytoma, osteosarcoma, and Ewing sarcoma. Central review of response data is underway. Three patients continue on therapy at the MTD. Conclusions: Oral administration of IRN together with TEM and VCR was feasible and well tolerated at the MTD of 35 mg/m2 given dx5x2. Further study using a shorter 5-day course of oral IRN is planned.

No significant financial relationships to disclose.
A phase I study of zoledronic acid and low dose cyclophosphamide in children with recurrent/refractory neuroblastoma: A New Approaches to Neuroblastoma Therapy (NANT) study
Authors: Russell H. V. , Groshen S. , Ara T. , DeClerck Y. , Malkovsky M. , Reynolds C. P. , Matthay K. , Blaney S. M.
Published: March 2020

9572

Background: Zoledronic acid (ZA), is a new generation, highly potent bisphosphonate that delays progression of bone metastases in adult malignancies. Bone metastases occur in 60% of children with advanced neuroblastoma. Pre-clinical studies demonstrated ZA with low dose chemotherapy delayed progression of osteolytic neuroblastoma lesions in a xenograft mouse model, prompting a phase I trial of ZA in neuroblastoma. Methods: Three dose levels of intravenous ZA (2, 3 or 4 mg/m2) administered every 28 days were evaluated in combination with continuous daily oral cyclophosphamide (CTX) (25 mg/m2/day) in patients with recurrent/refractory neuroblastoma and cortical bone lesions. The primary objective was to determine a recommended dose of ZA for future trials. Serial blood and urine samples were collected for pharmacokinetics, markers of osteoclast activity, and immunologic assays. Results: 14 patients (9 male), median age 7.9 years (0.8 - 26.6 years), were enrolled at ZA dose levels 2 mg/m2 (n=4), 3 mg/m2 (n=3), and 4 mg/m2 (n=7). To date, 13 patients are evaluable for toxicity. Thirty-nine cycles were administered with a median of 1 cycle per patient (range 1 - 12). Treatment was well tolerated; one DLT (Grade 3 hypophosphatemia) occurred at 4 mg/m2 ZA. Other grade 3 or 4 toxicities attributable to the combination included hypocalcemia (n=2), elevated transaminases (n=2), neutropenia (n=2), anemia (n=1), lymphopenia (n=1), and hypokalemia (n=1). Hypocalcemia occurred in 69% of first cycles and 8% of subsequent cycles. There were no renal toxicities or dental complications. There have been 2 partial responses by MIBG (central review pending), 4 stable disease, and 7 progressive disease; one patient is too early for response. Pharmacokinetic and correlative biology study results are pending. Conclusions: ZA is well tolerated and had evidence of responses when given with low dose CTX to children with recurrent/refractory neuroblastoma. The recommended dose of ZA for subsequent study is 4 mg/m2. Future studies incorporating ZA into the regimen for children with NB and cortical bone lesions are planned.

No significant financial relationships to disclose.
Randomized phase III trial of sorafenib versus placebo in patients with advanced hepatocellular carcinoma (HCC)
Authors: Llovet J. , Ricci S. , Mazzaferro V. , Hilgard P. , Raoul J. , Zeuzem S. , Poulin-Costello M. , Moscovici M. , Voliotis D. , Bruix J.
Published: March 2020

LBA1

Background: HCC is the 3rd cause of cancer death globally with most deaths occurring within 1 year of diagnosis. No standard therapy exists for advanced HCC. Sorafenib (Sor) is a multikinase inhibitor with anti-angiogenic, pro-apoptotic and Raf kinase inhibitory activity, with clinical activity in a phase II HCC trial. This large, multicenter, randomized, placebo-controlled phase III trial evaluated the efficacy and safety of Sor vs placebo (P) in pts with HCC. Methods: Patients with advanced measurable HCC, no prior systemic treatment, ECOG PS 0–2 and Child-Pugh status A received Sor 400 mg bid or P. Primary efficacy endpoints were overall survival (OS) and time to symptomatic progression (TTSP). Time to progression (TTP) and disease control rate (DCR; CR+PR+SD for at least 2 cycles) were secondary endpoints.Treatment arms were compared for OS and TTSP using a 1-sided log-rank test [overall a of 0.02 (OS) and 0.005 (TTSP)] stratified by region, ECOG PS and tumor burden. An O’Brien-Fleming-type error spending function determined criteria for early stopping for efficacy. Results: 602 pts (Sor n=299; P n=303) were randomized. Baseline characteristics were similar for Sor vs P: median age (67 vs 68 y), male (87% vs 87%), ECOG PS 0 (54% vs 54%), Child-Pugh A (95% vs 98%), and BCLC stage C (82% vs 83%). Based on 321 deaths (Sor n=143; P n=178), the hazard ratio (HR) for OS (Sor/P) was 0.69 (95% CI: 0.55, 0.87; p=0.0006), representing a 44% improvement in OS vs P which met early stopping criteria. Median OS was 10.7 vs 7.9 mos (Sor vs P). Primary TTSP analysis demonstrated no statistically significant difference for Sor vs P. HR for TTP (independent assessment) was 0.58 (95% CI: 0.45, 0.74; p=0.000007). Median TTP was longer (5.5 vs 2.8 mos) and DCR was higher (43% vs 32%) with Sor vs P. Incidence of serious adverse events was similar for Sor vs P (52% vs 54%). The most frequent grade 3/4 events were diarrhea (11% vs 2%), hand-foot skin reaction (8% vs 1%), fatigue (10% vs 15%), and bleeding (6% vs 9%) for Sor vs P. Conclusions: Sorafenib was well tolerated and is the first agent to demonstrate a statistically significant improvement in OS for pts with advanced HCC. This effect is clinically meaningful and establishes sorafenib as first-line treatment for these pts.

[Table: see text]
Phase III trial of lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone in newly diagnosed multiple myeloma (E4A03): A trial coordinated by the Eastern Cooperative Oncology Group
Authors: Rajkumar S. V. , Jacobus S. , Callander N. , Fonseca R. , Vesole D. , Williams M. , Abonour R. , Siegel D. , Greipp P.
Published: March 2020

LBA8025

Background: We compared lenalidomide plus high (standard) dose Dex (R+HighD) versus lenalidomide plus low dose Dex (R+LowD) in newly diagnosed MM. Methods: Pts with untreated, symptomatic MM were eligible. Pts in both arms received lenalidomide 25 mg/day PO days 1–21 every 28 days. In addition, pts in the R+HighD arm received Dex 40 mg days 1–4, 9–12, and 17–20 PO every 28 days; pts in the R+LowD arm received Dex 40 mg days 1, 8, 15, and 22 PO every 28 days. The primary null hypothesis was that response rates at 4 months on the 2 arms are equivalent. Planned sample size was 196 eligible pts per arm with one-sided 0.10 Type I and 0.05 Type II error rate. Pre-planned interim analysis is performed by an independent DMC when full information is available on 25%, 50% and 75% of accrual. All analysis were intent to treat. Results: 445 pts (median age, 65 yrs) were accrued; 223 randomized to R+HighD, 222 to R+LowD. Arms were well balanced for age, gender, stage, bone lesions, hemoglobin, beta-2 microglobulin, performance status, bone marrow plasma cells, and M protein levels at baseline. Major grade 3 or higher toxicities included thromboembolism (22.1% with R+HighD vs 6.1% in R+LowD), infection/pneumonia (15.7% vs 7.5%) and hyperglycemia (9.7% vs 6.6%). Grade 3 or higher non-hematologic toxicities occurred in 65.9% (R+HighD) versus 54.9% (R+LowD) respectively; corresponding grade 4 or higher rates were 20.3% vs 13.1% respectively. Overall survival (OS) at first interim analysis was significantly superior with R+LowD, P<0.001; one year survival 96.5% (R+LowD) versus 86% (Rev+HighD). OS differences in favor of R+LowD were seen in pts <65 (P=0.015; one year rate 98% vs 90%) and pts 65 and older (P=0.004; one year rate 95% vs 83%), respectively. DMC recommended release of survival results, and recommended switching all pts to R+LowD. DMC also recommended closure of an expansion phase trial of R+HighD investigating optimal thromboprophylaxis. Conclusions: Lenalidomide plus low-dose dexamethasone is associated with superior OS compared to lenalidomide plus high-dose dexamethasone. This study has major implications for future use of high-dose dexamethasone in the treatment of MM.

No significant financial relationships to disclose.
A translational study to investigate the association between smoking-induced lung inflammation and lung metastases (LM) from breast cancer (BC).
Authors: Morris Patrick Glyn , Zhou Xi Kathy , Milne Ginger L , Goldstein Daniel A. , Hawks Laura , Uzunaslan Didem , Dang Chau T. , Keenan Kathleen , Modi Shanu , Fornier Monica Nancy , Sklarin Nancy T. , D'Andrea Gabriella , Lake Diana , Theodoulou Maria , Traina Tiffany A. , Dickler Maura N. , Goldfarb Shari Beth , Hudis Clifford , Dannenberg Andrew J
Published: March 2020

10514

Background: Retrospective and preclinical studies suggest that smokers are at increased risk for LM from BC, possibly mediated by lung inflammation and the bioactive lipid, PGE2. To investigate this link in pts, we examined urinary PGE-M, a stable end metabolite of PGE2. Methods: A translational study was conducted, consisting of pts with LM (n=100), pts with mets but no known lung mets (NKL, n=100) and controls (CTRLS) with a history of BC (n=200). Pts receiving steroids and radiotherapy were excluded. Pts gave urine (PGE-M), blood (biomarkers), had BMI measured, and completed a validated questionnaire (smoking, NSAIDs, confounders). PGE-M was measured by mass spectrometry, normalized to urinary creatinine and compared between grps in both univariate and multivariate models, correcting for covariates. Results: From 09/2010 to 06/2011, 400 pts, med age 58 yrs (range 24-88) enrolled. There were no significant differences between grps in smoking and NSAID exposure (table). PGE-M (med; range) was highest among pts with LM (6.7; 0.7 - 43.4) compared to pts with NKL (4.6; 0.7 - 26.8) and CTRLS (4.2; 0.9 – 62.6, P<0.001). In univariate analysis, smoking pack year was associated with PGE-M (ρ=0.13, P=0.01), and ever smokers with LM had the highest PGE-M (med 7.4; range 0.8-28.9). In a multivariable model ever smokers with LM had higher PGE-M than never smoking CTRLS (P=0.03). Pts with >24 pack year smoking history and LM had the highest co-variate-adjusted log PGE-M (P=0.03). In this model, age (P<0.001), pack year smoking hx (P=0.02), receipt of chemoRx ≤1 mth (P=0.003) and BMI (P=0.002) were all associated with higher PGE-M. Conversely, receipt of NSAIDs ≤7 days was associated with lower PGE-M (P<0.001). Conclusions: Increased lung inflammation, as characterized by PGE-M, occurs in ever smokers with LM from BC, supporting the hypothesis that changes in the lung microenvironment (“soil”) predispose to metastasis. [Table: see text]
Clinical activity of avapritinib in ≥ fourth-line (4L+) and PDGFRA Exon 18 gastrointestinal stromal tumors (GIST).
Authors: Heinrich Michael C. , Jones Robin Lewis , von Mehren Margaret , Bauer Sebastian , Kang Yoon-Koo , Schoffski Patrick , Eskens Ferry , Mir Olivier , Cassier Philippe Alexandre , Serrano Cesar , Tap William D. , Trent Jonathan C. , Rutkowski Piotr , Patel Shreyaskumar , Chawla Sant P. , Meiri Eyal , Zhou Teresa , Mamlouk Khalid Kevin , Roche Maria , George Suzanne
Published: March 2020

11022

Background: Targeting oncogenic KIT and PDGFRA mutations revolutionized treatment of patients (pts) with advanced GIST; however, nearly all pts succumb to resistant disease. Avapritinib is a potent and selective kinase inhibitor with broad activity against oncogenic KIT/PDGFRA mutants, including PDGFRA D842V and other primary or secondary resistance mutations. Updated results from the phase 1 NAVIGATOR (NCT02508532) study of avapritinib in pts with advanced GIST are presented. Methods: Adult pts with unresectable PDGFRA D842V or other mutant GIST who progressed on imatinib and ≥ 1 other tyrosine kinase inhibitor (TKI) were treated with oral, daily, continuous avapritinib. Adverse events (AE) and response by mRECIST 1.1 per central radiology were assessed. Safety from the overall population (30-600 mg doses) and efficacy in the response evaluable 4L+ and PDGFRA Exon 18 (Ex 18) populations treated at the MTD (400 mg)/RP2D (300 mg) were analyzed. Results: As of 16 Nov 2018, 237 pts [172 KIT, 62 PDGFRA Ex 18 (56 D842V, 6 non-D842V), 2 PDGFRA N659K, 1 missing] were enrolled including 111 in the 4L+ population (primarily KIT, median 4 prior TKI) and 43 in the Ex 18 population (median 1 prior TKI). The 4L+ ORR was 22% [1 CR, 23 PR (1 pending)], and 52 SD with median duration of response (mDOR) of 10.2 months (95% CI: 7.2-NE). The Ex 18 ORR was 86% [3 CR, 34 PR (1 pending)] and 5 SD; mDOR was not reached (95% CI: 11.3-NE). Most AE were grade 1-2, most commonly nausea (63%), fatigue (58%), anemia (49%), periorbital edema (42%), diarrhea (40%), vomiting (40%), decreased appetite (38%), increased lacrimation (33%), peripheral edema (33%) and memory impairment (most common cognitive AE, 29%). 10% of pts discontinued due to a related AE. Grade 3-4 related AE ≥ 2% were anemia, fatigue, hypophosphatemia, hyperbilirubinemia, neutropenia, and diarrhea. Conclusions: Avapritinib has important clinical activity in pts with advanced GIST who have no effective therapies. The ORR and DOR of avapritinib in 4L+ exceeds that of approved 2nd and 3rd line therapies and shows unprecedented activity in D842V and other Ex 18 mutant PDGFRA GIST. Results suggest avapritinib has the potential to change the treatment paradigm of pts with advanced GIST. Clinical trial information: NCT02508532.
Lisocabtagene maraleucel (liso-cel) treatment of patients (pts) with relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma (NHL) and secondary CNS lymphoma: Initial results from TRANSCEND NHL 001.
Authors: Abramson Jeremy S. , Palomba Maria Lia , Arnason Jon E. , Lunning Matthew Alexander , Solomon Scott R. , Farazi Thalia , Garcia Jacob , Xie Benhuai , Newhall Kathryn J. , Dehner Christine , Siddiqi Tanya
Published: March 2020

7515

Background: No clinical studies have yet evaluated CAR T cell therapies in pts with R/R B-cell NHL who have secondary CNS lymphoma. We report data from this pt subgroup receiving liso-cel (JCAR017), an investigational, anti-CD19 CAR T cell product administered as a defined composition of CD4+/CD8+ CAR T cells, in the phase 1 TRANSCEND NHL 001 study. Methods: Eligible pts had confirmed B-cell NHL with R/R disease after ≥2 prior lines of therapy. Pts with secondary CNS lymphoma could enroll or, if it developed on study, could continue to receive liso-cel. After lymphodepleting chemotherapy, liso-cel was administered at 1 of 2 dose levels (DL): DL1 = 50 × 106 or DL2 = 100 × 106 total CAR+ T cells. Efficacy was evaluated per the Lugano criteria. Pts achieving a complete response could be retreated with liso-cel upon progressive disease. Results: At data cutoff, 9 pts with secondary CNS lymphoma at initial treatment (n = 6), retreatment (n = 2), or cycle 2 (n = 1) received liso-cel. 4 pts were treated at DL1 and 5 at DL2. The median (range) age was 60 (47‒73) years and number of prior lines of therapy was 3 (2‒7). Median time to peak CAR+ T cell expansion was 12.5 (7–112) days. 1 of 9 pts had grade (G)2 cytokine release syndrome (CRS) and 1 of 9 pts had a neurological event (NE; G3 decreased level of consciousness). No retreatment pts had CRS or NE; however, 1 retreatment pt had an NE of G2 temporal edema with initial treatment with liso-cel. 5 pts received prophylactic levetiracetam. 1 pt received corticosteroids and tocilizumab. Other toxicities were predominantly cytopenias. There were no treatment-related deaths. 4 pts responded to liso-cel; all had a best response of complete response, of which 2 are ongoing at 270 and 545 days post-liso-cel. All 4 responses occurred after initial liso-cel treatment; no retreated pts responded. Conclusions: In the ongoing TRANSCEND NHL 001 study, liso-cel continues to demonstrate the ability to be safely delivered to pts with R/R B-cell NHL, including those with secondary CNS lymphoma, a population of pts with a highly unmet medical need. No excess NE was noted in this population. This cohort continues to be evaluated. Clinical trial information: NCT02631044.
Managing cytokine release syndrome (CRS) and neurotoxicity with step-fractionated dosing of mosunetuzumab in relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma (NHL).
Authors: Bartlett Nancy L. , Sehn Laurie Helen , Assouline Sarit E. , Bosch Francesc , Magid Diefenbach Catherine S. , Flinn Ian , Hong Jungyong , Kim Wonseog S , Matasar Matthew J. , Nastoupil Loretta J. , Schuster Stephen J , Shadman Mazyar , Yoon Sung-Soo , Bender Brendan , Kwan Antonia , Cunlin Wang , Wei Michael C. , Yin Shen , Yousefi Kasra , Budde L. Elizabeth
Published: March 2020

7518

Background: T-cell directed therapies (e.g., CAR-T, blinatumomab) are associated with significant risk of Grade (Gr) ≥3 neurotoxicity and CRS/infusion-related reaction (IRR). Mosunetuzumab is a CD20/CD3 bispecific antibody that directs T-cells to engage and eliminate malignant B-cells. We report safety results from an ongoing phase 1/1b study of mosunetuzumab in patients (pts) with R/R B-cell NHL. Methods: Pts received ascending doses on Day 1, Day 8, and Day 15 of Cycle 1 (step-fractionation), then a fixed dose on Day 1 of every 21-day cycle thereafter, up to a maximum of 17 cycles. Primary outcome measures included safety and efficacy. Results: As of October 23, 2018, 114 pts who received step-fractionated dosing of mosunetuzumab were evaluable for safety (Table). The majority of adverse events (AE) occurred during Cycle 1 and 2. Neurologic AEs (NAE), defined from Nervous System or Psychiatric System Organ Classes, were mostly low grade, transient (median duration 4 days) and reversible; most common ones were headache (14%) and dizziness (8%). Gr ≥3 NAEs occurred in 4 pts (4%) with only 1 treatment-related event (hepatic encephalopathy). CRS/IRR was reported in 25% of pts, with only 1 Gr 3 event. Most common CRS symptoms were pyrexia (86%), chills (38%), and tachycardia and headache (14% each). There were no Gr 5 events related to CRS or NAEs. No apparent dose toxicity relationship was observed with step-fractionation in these pts, despite escalation of the Cycle 1 Day 15 dose to 20 mg, consistent with observed peak IL-6 levels after a low Cycle 1 Day 1 dose. In these pts, objective responses were observed in 24/73 (33%; complete response [CR], 13 [18%]) aggressive NHL and 17/32 (53%; CR, 10 [31%]) indolent NHL pts. Conclusions: Step-fractionation has enabled continued dose escalation of mosunetuzumab with no apparent increases in toxicity, exhibiting a promising risk-benefit profile. Clinical trial information: NCT02500407; GO29781. [Table: see text]
MET inhibitor resistance in patients with MET exon 14-altered lung cancers.
Authors: Guo Robin , Offin Michael , Brannon A. Rose , Chow Andrew , Delasos Lukas , Somwar Romel , Wilkins Olivia , Scott Kerry , Tian Yuan , Cecchi Fabiola , Hembrough Todd A. , Li Bob T. , Rudin Charles M. , Kris Mark G. , Arcila Maria E. , Rekhtman Natasha , Paik Paul K. , Ladanyi Marc , Zehir Ahmet , Drilon Alexander E.
Published: March 2020

9006

Background: MET exon 14 alterations comprise a novel class of lung cancer drivers. MET tyrosine kinase inhibitors (TKIs) are active in patients with these cancers, but objective response rates (ORRs) are modest (~30%-40%). A subset of these cancers may harbor intrinsic resistance. Moreover, patients with initial benefit invariably develop acquired resistance. We set out to identify potential resistance mechanisms. Methods: We studied patients with stage IV MET exon 14-altered lung cancers who received a MET TKI. When feasible, tumor and/or plasma samples were collected, prioritizing paired pre- and post-TKI collection. Tumor samples underwent targeted mass spectrometry analysis (Nantomics) and DNA- (including MSK-IMPACT)/RNA-based (MSK-Fusion) next-generation sequencing (NGS). Plasma cfDNA underwent targeted NGS. ORR and progression-free survival (PFS) were assessed (RECIST v1.1). Results: 74 patients received a MET TKI (1 TKI n = 55; ≥2 TKIs n = 19). 91% received crizotinib as their 1st TKI. Pre-TKI MET levels in tumor tissue (range 0-2120 amol/µg) were associated with outcomes: ORR 63% (n = 7/11) and median PFS 6.9 mos with detectable MET vs ORR 0% (n = 0/5) and median PFS 4.6 mos with undetectable MET (HR for PFS 0.3). Pre-TKI RAS pathway activation was associated with response: ORR 0% (n = 0/6) with KRAS/NF1/RASA1 mutation vs ORR 29% (n = 25/87) in others. Similar outcomes were observed with pre-TKI KRAS expression (n = 16, all with detectable KRAS levels): ORR 0% (n = 0/2) in KRAS ≥700 amol/µg vs ORR 50% (n = 7/14) < 700 amol/µg. Acquired resistance (Jackman criteria) was seen in 29 patients, 9 with paired pre-/post-treatment samples. On-target acquired resistance was found in 2/9 patients (22%): MET D1228N (n = 1), HGF amplification (n = 1). Potential off-target acquired resistance mechanisms were found in 5/9 pts (44%): KRAS G13V (n = 1), RASA1 S742* (n = 1), MDM2 amplification (n = 2), EGFR amplification (n = 1). Conclusions: Lack of MET expression or RAS pathway activation is associated with poor MET TKI outcomes in MET exon14-altered lung cancers. On-target acquired resistance is found in < 25% of patients; HGF amplification is a novel mechanism. Off-target intrinsic/acquired resistance may be mediated by RAS/MDM2/EGFR pathway activation.