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Purpose: Outcomes for children with relapsed and refractory high-risk neuroblastoma (RR-HRNB) remain dismal. The BEACON Neuroblastoma trial (EudraCT 2012-000072-42) evaluated three backbone chemotherapy regimens and the addition of the antiangiogenic agent bevacizumab (B)., Materials and Methods: Patients age 1-21 years with RR-HRNB with adequate organ function and performance status were randomly assigned in a 3 × 2 factorial design to temozolomide (T), irinotecan-temozolomide (IT), or topotecan-temozolomide (TTo) with or without B. The primary end point was best overall response (complete or partial) rate (ORR) during the first six courses, by RECIST or International Neuroblastoma Response Criteria for patients with measurable or evaluable disease, respectively. Safety, progression-free survival (PFS), and overall survival (OS) time were secondary end points., Results: One hundred sixty patients with RR-HRNB were included. For B random assignment (n = 160), the ORR was 26% (95% CI, 17 to 37) with B and 18% (95% CI, 10 to 28) without B (risk ratio [RR], 1.52 [95% CI, 0.83 to 2.77]; P = .17). Adjusted hazard ratio for PFS and OS were 0.89 (95% CI, 0.63 to 1.27) and 1.01 (95% CI, 0.70 to 1.45), respectively. For irinotecan ([I]; n = 121) and topotecan (n = 60) random assignments, RRs for ORR were 0.94 and 1.22, respectively. A potential interaction between I and B was identified. For patients in the bevacizumab-irinotecan-temozolomide (BIT) arm, the ORR was 23% (95% CI, 10 to 42), and the 1-year PFS estimate was 0.67 (95% CI, 0.47 to 0.80)., Conclusion: The addition of B met protocol-defined success criteria for ORR and appeared to improve PFS. Within this phase II trial, BIT showed signals of antitumor activity with acceptable tolerability. Future trials will confirm these results in the chemoimmunotherapy era.

Purpose: AcSé-ESMART is a proof-of-concept, phase I or II, platform trial, designed to explore targeted agents in a molecularly enriched cancer population. Arms A and B aimed to define the recommended phase II dose and activity of the CDK4/6 inhibitor ribociclib with topotecan and temozolomide (TOTEM) or everolimus, respectively, in children with recurrent or refractory malignancies., Patients and Methods: Ribociclib was administered orally once daily for 16 days after TOTEM for 5 days (arm A) or for 21 days with everolimus orally once daily continuously in a 28-day cycle (arm B). Dose escalation followed the continuous reassessment method, and activity assessment the Ensign design. Arms were enriched on the basis of molecular alterations in the cell cycle or PI3K/AKT/mTOR pathways., Results: Thirty-two patients were included, 14 in arm A and 18 in arm B, and 31 were treated. Fourteen patients had sarcomas (43.8%), and 13 brain tumors (40.6%). Main toxicities were leukopenia, neutropenia, and lymphopenia. The recommended phase II dose was ribociclib 260 mg/m 2 once a day, temozolomide 100 mg/m 2 once a day, and topotecan 0.5 mg/m 2 once a day (arm A) and ribociclib 175 mg/m 2 once a day and everolimus 2.5 mg/m 2 once a day (arm B). Pharmacokinetic analyses confirmed the drug-drug interaction of ribociclib on everolimus exposure. Two patients (14.3%) had stable disease as best response in arm A, and seven (41.2%) in arm B, including one patient with T-acute lymphoblastic leukemia with significant blast count reduction. Alterations considered for enrichment were present in 25 patients (81%) and in eight of nine patients with stable disease; the leukemia exhibited CDKN2A/B and PTEN deficiency., Conclusion: Ribociclib in combination with TOTEM or everolimus was well-tolerated. The observed activity signals initiated a follow-up study of the ribociclib-everolimus combination in a population enriched with molecular alterations within both pathways., Competing Interests: Xavier PaolettiConsulting or Advisory Role: MSD Oncology, Daiichii Sankyo Jonathan RubinoResearch Funding: Roche/Genentech (Inst), Novartis (Inst), Bristol Myers Squibb/Celgene (Inst), Cyclacel (Inst), AstraZeneca (Inst), Taiho Oncology (Inst) Nicolas AndreResearch Funding: BMS (Inst)Travel, Accommodations, Expenses: BMS Isabelle AertsConsulting or Advisory Role: AstraZenecaTravel, Accommodations, Expenses: Jazz Pharmaceuticals Gilles VassalConsulting or Advisory Role: Bayer, Roche/Genentech, AstraZeneca, Bristol Myers Squibb, Lilly, Ipsen, NovartisTravel, Accommodations, Expenses: Bristol Myers Squibb, Roche Birgit GeoergerConsulting or Advisory Role: Roche/Genentech, Boehringer Ingelheim, Bayer, AZD, NovartisNo other potential conflicts of interest were reported.

Purpose: The objective of this prospective study was to assess overall survival and event-free survival in patients with intraocular unilateral retinoblastoma (Reese-Ellsworth group V) treated by primary enucleation with or without adjuvant therapy depending on histopathologic risk factors., Patients and Methods: Patients (n = 123) were divided into three groups on the basis of risk factors for extraocular relapse and metastasis assessed on centralized histologic examination of enucleated eyes. Group 1 (n = 70) had minimal or no choroidal involvement and/or prelaminar or no optic nerve involvement and received no adjuvant therapy. Group 2 (n = 52) had massive choroidal involvement and/or intra- or retrolaminar optic nerve involvement and/or anterior segment involvement and received four courses of adjuvant chemotherapy. Group 3 (n = 1) had invasion of the surgical margin of the optic nerve and/or microscopic extrascleral involvement and received six courses of adjuvant chemotherapy with intrathecal thiotepa, consolidation chemotherapy, and autologous stem-cell rescue. Genetic testing was also performed., Results: Median follow-up for the 123 patients was 71 months. No disease progression, relapse, or distant metastasis occurred during follow-up. No second malignancies occurred. This requires confirmation with longer follow-up. Secondary bilateralization occurred in two patients with identified RB1 germline mutation. Adjuvant chemotherapy was well tolerated, with limited toxicity. Molecular testing found constitutional RB1 gene mutations in only nine of 100 evaluated patients., Conclusion: The survival rate of 100% was excellent, including 57% of patients who received no adjuvant therapy, suggesting that chemotherapy could be de-escalated in some patients, especially those with massive choroidal involvement.

Purpose: To retrospectively analyze the clinical features and results of treatment in 56 infants with fibrosarcoma enrolled onto cooperative European protocols between 1979 and 2005 and treated with a combination of surgery and chemotherapy., Patients and Methods: We performed a retrospective case review of infants under the age of 2 years with fibrosarcoma treated between 1979 and 2005 in six European studies. Patients were staged according to the Intergroup Rhabdomyosarcoma Staging System international classification as a function of the type of initial surgery and the extent of disease and were treated with surgery and chemotherapy. Survival was calculated using the Kaplan-Meier method., Results: Primary tumor site was the limbs in 66% of patients; median tumor diameter was more than 5 cm in 63% of patients; and postoperative staging was as follows: group I, 22%; group II, 27%; group III, 47%; and group IV, 4%. Response rate to chemotherapy was 75%, and the specific response rate to vincristine-dactinomycin was 71%. Local control was obtained in 84% of patients. At the end of follow-up, 45% of survivors had been treated by surgery alone, 6% by chemotherapy alone, 46% by surgery and chemotherapy, and 2% by surgery, chemotherapy, and radiotherapy. The 5-year overall survival (OS) rate was 89%. The 5-year OS and event-free survival rates for localized patients were 89% and 81%, respectively., Conclusion: Although complete resection is rarely feasible at diagnosis, conservative surgery remains the mainstay treatment for infantile fibrosarcoma. An alkylating agent-free and anthracycline-free regimen is usually effective and should be chosen as first-line chemotherapy for inoperable tumors. Overall prognosis is good, but progression or relapse, mainly local, remains possible.