Recurrent Pediatric Solid Tumors Research Articles

OTHR-05. ROLES OF GEMCITABINE-OXALIPLATIN (GEMOX) ADD-ON THERAPY IN INFANT-TYPE BRAIN TUMORS: A SINGLE CENTER EXPERIENCE

Abstract BACKGROUND Combined gemcitabine and oxaliplatin (GemOx) was evaluated in recurrent pediatric solid tumors, showing safety but limited activity. In neuro-oncological infant patients, chemotherapy intensified to high doses (HDC) represents the cornerstone, avoiding radiotherapy toxicities. We describe the roles of GemOx towards autologous transplantation in infant-type brain tumors. METHODS From May 2017 to January 2024, at the Meyer Children’s Hospital IRCCS in Florence, six children (median age 19 months, sex equally distributed, three high-grade gliomas, a metastatic medulloblastoma MM, a pineoblastoma, a choroid plexus carcinoma CPC) completed GemOx after induction chemotherapy delivered according to Italian program for malignant brain tumors under 3 years. GemOx was administered to achieve clinical and neuroradiological permissiveness to HDC and to raise the possibility of second look neurosurgery. RESULTS Gemcitabine 1000 mg/m2 and Oxaliplatin 100 mg/m2 were given every 14-28 days for 1-6 cycles. At re-assessment, maximum every four cycles, disease control was optimal (five stable diseases and one partial response according to RECIST criteria). After GemOx, one patient was also subjected to further neurosurgery. The treatment was overall well tolerated, except for Common Terminology Criteria for Adverse Events (CTCAE) grade 4 platelet toxicity in two patients (one of whom also developed hydrocephalus CTCAE 3 and hyponatremia CTCAE 4 during treatment). All patients were safely exposed to HDC (1-2 courses). MM and CPC patients progressed respectively 4 ad 19 months after the end of GemOx. The latter underwent second look neurosurgery, and a radiotherapy course was delivered to both, considering the achievement of permissive age. To date all patients are alive. CONCLUSIONS In brain infant-type malignant tumors strategies are limited due to the extremely vulnerable age. GemOx treatment should be considered a reasonable and safe option waiting for intensified treatment, especially in radiotherapy delaying programs, and it should result incisive in the therapeutic or palliative choice.

Abstract CT058: A multicenter phase 1-2a clinical study of Orotecan (oral irinotecan HCl, VAL-413) in patients with recurrent pediatric solid tumors

Abstract Background: Intravenous irinotecan hydrochloride (IRN-IV) is approved for the treatment of adult colorectal cancer. An off-label regimen of IRN-IV administered as a 60-min i.v. infusion daily for 5-10 days, bi-weekly in combination with other agents such as temozolomide has been recommended for use in treating children with solid tumors (Blaney. ClinCanRes, 2001; Slotkin. PedBloodCan, 2023). While this regimen has shown promise in published clinical trials across a range of pediatric cancers including Ewing sarcoma, neuroblastoma, rhabdomyosarcoma, hepatoblastoma and medulloblastoma, the protracted administration schedule of IRN-IV is costly and inconvenient thereby negatively impacting patients’ quality of life. Oral regimens utilizing IRN-IV have been developed and implemented with favorable tumor responses (Wagner. ClinSarcRes, 2015). Unfortunately, the palatability of the IRN-IV is poor, leading to reduced compliance. Development of an advanced oral formulation to improve tolerability and patient compliance is an important unmet need. VAL-413 is a novel formulation developed to improve the palatability of oral irinotecan. This Phase 1-2a multi-center clinical trial seeks to examine the safety and tolerability of this novel formulation and assess pharmacokinetics compared to the already established oral regimen. This trial is ongoing (CT.gov: NCT04337177) and currently enrolling the 110mg/m2/day cohort, with no dose limiting toxicity observed to date. Initial pharmacokinetic observations demonstrate similarity for the VAL-413 formulation and i.v. irinotecan given orally for both the parent compound and SN38 active metabolite. TABLE 1. NAND Methods Eligibility: Up to 20 patients ≥ 1 year of age or ≤ 30 years of age with recurrent pediatric solid tumors and adequate bone marrow, renal and liver function, for whom irinotecan therapy is a treatment option will be enrolled. Trial Design: Two different dose levels of VAL-413, 90mg/m2/day or 110mg/m2/day are being studied in combination with fixed-dose temozolomide (100mg/m2/day) using a standard 3 + 3 phase I design. In the event a dose of 90 mg/m2/day is not tolerable due to toxicity, a lower dose of 75 mg/m2/day may be implemented. Treatment: During the first cycle of treatment, each patient will receive 4 daily doses of VAL-413 and one daily dose of the intravenous preparation of irinotecan taken orally (IRN-IVPO). During all subsequent cycles, only VAL-413 will be given with temozolomide in 5-day courses administered every 21 days, as tolerated. Outcome Measures: Toxicity is assessed by NCI CCTCAEv5; tumor response is assessed by RECIST 1.1. A taste survey instrument will assess palatability of VAL-413 vs. IRN-IVPO; comparative intrapatient pharmacokinetics of irinotecan and its metabolites is assessed. Citation Format: James Geller, Patrick Thompson, Javier Oesterheld, Aerang Kim, Meghann McManus, Jeffrey Bacha, Dennis M. Brown, Markos Leggas, Sarath Kanekal, Neil Sankar, Lorena Lopez, Noymi Yam, Lars M. Wagner. A multicenter phase 1-2a clinical study of Orotecan (oral irinotecan HCl, VAL-413) in patients with recurrent pediatric solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT058.

A pilot clinical study of oral irinotecan HCl (VAL-413) in patients with recurrent pediatric solid tumors.

TPS10073 Background: Intravenous irinotecan hydrochloride (IRN-IV) is approved for the treatment of adult colorectal cancer and also used off-label to treat a range of adult and pediatric tumors including recurrent Ewing sarcoma, rhabdomyosarcoma, neuroblastoma, hepatoblastoma, Wilms tumor, gynecologic cancers, lung cancer and medulloblastoma. Previously, a regimen of IRN-IV administered as a 60-min i.v. infusion daily for 5 days, bi-weekly in combination with other agents such as temozolomide has been recommended use in treating children with solid tumors (Blaney. ClinCanRes, 2001). Protracted administration schedule of IRN-IV is inconvenient for patients, so oral regimens utilizing IRN-IV have been developed and implemented with favorable tumor response (Wagner. ClinSarcRes, 2015). Unfortunately, the palatability of the IRN-IV is poor, leading to reduced compliance especially in younger pediatric patients. Development of an advanced formulation to improve tolerability and patient compliance is an important unmet need. VAL-413 is a novel formulation developed to improve palatability of oral irinotecan. This pilot trial will examine the safety and tolerability of this novel formulation and assess pharmacokinetics compared to current oral regimen. Methods: Eligibility: Up to 20 patients ≥ 1 year of age or ≤ 30 years of age with recurrent pediatric solid tumors and adequate bone marrow, renal and liver function, for whom irinotecan therapy is a treatment option will be enrolled. Trial Design: Two different dose levels of VAL-413, 90mg/m2/day or 110mg/m2/day will be studied in combination with fixed-dose temozolomide using a standard 3 + 3 phase I design. In the event the starting dose of 90 mg/m2/day is not tolerable due to toxicity, a lower dose of 75 mg/m2/day may be implemented. Treatment: During the first cycle of treatment, each patient will receive 4 daily doses of VAL-413 and one daily dose of the intravenous preparation of irinotecan taken orally (IRN-IVPO). During all subsequent cycles, only VAL-413 will be given with temozolomide in 5-day courses administered every 21 days, as tolerated. Outcome Measures:Toxicity is assessed by NCI CCTCAEv5; tumor response is assessed by RECIST 1.1. A palatability survey instrument will assess palatability of VAL-413 vs. IRN-IVPO; comparative intra-patient pharmacokinetics of irinotecan and its metabolites will be assessed. This trial is ongoing (CT.gov: NCT04337177), with no DLT observed to date. Clinical trial information: NCT04337177 .

Abstract CT135: A pilot clinical study of orotecan (oral irinotecan HCl, VAL-413) in patients with recurrent pediatric solid tumors

Abstract Background: Intravenous irinotecan hydrochloride (IRN-IV) is approved for the treatment of adult colorectal cancer. IRN-IV is also used off-label to treat a range of adult and pediatric tumors including recurrent Ewing sarcoma, rhabdomyosarcoma, neuroblastoma, hepatoblastoma, Wilms tumor, gynecologic cancers, lung cancer and medulloblastoma. Previously, a regimen of IRN-IV administered as a 60-min i.v. infusion daily for 5 days in combination with other agents such as temozolomide has been recommended use in treating children with solid tumors (Blaney. ClinCanRes, 2001). Protracted administration schedule of intravenous irinotecan is inconvenient for patients, so oral regimens utilizing IRN-IV have been developed (Wagner. ClinSarcRes, 2015). Unfortunately, the palatability of the intravenous preparation is poor, leading to reduced compliance especially in younger pediatric patients. Development of an advanced formulation to improve tolerability and patient compliance is an important unmet need. VAL-413 is a novel formulation developed to improve palatability of oral irinotecan. Methods: Eligibility: Up to 20 patients ≥ 1 year of age or ≤ 30 years of age with recurrent pediatric solid tumors and adequate bone marrow, renal and liver function, for whom irinotecan therapy is a treatment option will be enrolled. Trial Design: Two different dose levels of VAL-413, 90mg/m2/day or 110mg/m2/day will be studied in combination with fixed-dose temozolomide using a standard 3 + 3 phase I design. In the event the starting dose of 90 mg/m2/day is not tolerable due to toxicity, a lower dose of 75 mg/m2/day may be implemented. Treatment: During the first cycle of treatment, each patient will receive 4 daily doses of VAL-413 and one daily dose of the intravenous preparation of irinotecan taken orally (IRN-IVPO). During all subsequent cycles, only VAL-413 will be given with temozolomide in 5-day courses administered every 21 days, as tolerated. Outcome Measures: Toxicity is assessed by NCI CCTCAEv5; tumor response is assessed by RECIST 1.1. A palatability survey instrument will assess palatability of VAL-413 vs. IRN-IVPO; comparative intrapatient pharmacokinetics of irinotecan and its metabolites will be assessed. This trial is ongoing (CT.gov: NCT04337177), with no DLT observed to date. Citation Format: Jeffrey Bacha, Dennis Brown, Sarath Kanekal, Neil Sankar, Lorena Lopez, Noymi Yam, Lars Wagner, James Geller, Markos Leggas, Patrick Thompson, Javier Osterheld. A pilot clinical study of orotecan (oral irinotecan HCl, VAL-413) in patients with recurrent pediatric solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT135.

Abstract CT256: A pilot clinical study of VAL-413 (Orotecan®, oral irinotecan HCl) in patients with recurrent pediatric solid tumors

Abstract Intravenous irinotecan hydrochloride (IRN-IV) is approved for the treatment of adult colorectal cancer. IRN-IV is also widely used off-label for a range of adult and pediatric solid tumors including recurrent Ewing sarcoma, rhabdomyosarcoma, neuroblastoma, hepatoblastoma, Wilms tumor, gynecologic cancers, lung cancer and medulloblastoma. Recently, commercially available intravenous irinotecan has been administered orally (IRN-IVPO) in pediatric patients to improve convenience, reduce in-clinic time and overall cost of treatment. Unfortunately, the palatability of the intravenous preparation is poor, leading to reduced compliance especially in younger pediatric patients. Development of an advanced formulation to improve tolerability and patient compliance is an important unmet need. VAL-413 is a novel formulation developed to improve palatability of oral irinotecan. We will report on an ongoing Phase 1-2 first-in-human clinical trial of VAL-413, designed to test the hypothesis that VAL-413 improves palatability without significant pharmacokinetic differences from IRN-IVPO using intra-patient comparison of pharmacokinetic profiles. The evaluation of two dose levels will help to formally define a recommended dose for advanced clinical studies. Trial Design: Patients ≥ 1 year of age or ≤ 30 years of age with recurrent pediatric solid tumors and adequate bone marrow, renal and liver function, for whom irinotecan therapy is a treatment option, are eligible. Up to 20 eligible patients will receive VAL-413 90mg/m2/day or 110mg/m2/day using a standard 3 + 3 design. During the first cycle of treatment, each patient will receive four daily doses of VAL-413 and one daily dose of IRN-IVPO, together with five (5) days of concurrent temozolomide. Pharmacokinetic assessments will follow both VAL-413 and IRN-IVPO administration using a limited sampling strategy. During all subsequent cycles, only VAL-413 will be given with temozolomide in 5-day courses administered every 21 days. Up to 17 cycles of treatment may be administered on this study. Outcome Measures: Toxicity is assessed by NCI CCTCAEv5; tumor response is assessed by RECIST 1.1. A palatability survey instrument will assess palatability of VAL-413 vs. IRN-IVPO; and comparative intrapatient pharmacokinetics of irinotecan and its metabolites will be assessed in all patients. Citation Format: James Geller, Patrick Thompson, Javier Oesterheld, Dennis M. Brown, Jeffrey Bacha, Sarath Kanekal, Lorena Lopez, Markos Leggas, Neil Sankar, Noymi Yam, Lars M. Wagner. A pilot clinical study of VAL-413 (Orotecan®, oral irinotecan HCl) in patients with recurrent pediatric solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT256.

A pilot clinical study of VAL-413 (oral irinotecan HCl) in patients with recurrent pediatric solid tumors.

TPS10063 Background: Intravenous irinotecan hydrochloride (IRN-IV) is approved for the treatment of adult colorectal cancer. IRN-IV is also widely used off-label for a range of adult and pediatric solid tumors including recurrent Ewing sarcoma, rhabdomyosarcoma, neuroblastoma, hepatoblastoma, Wilms tumor, gynecologic cancers, lung cancer and medulloblastoma. Previously, a regimen of IRN-IV administered as a 60-min i.v. infusion daily for 5 days, every 21 days has been recommended use in treating children with solid tumors (Blaney. ClinCanRes, 2001 ). Protracted administration schedule of intravenous irinotecan is inconvenient for patients, so oral regimens utilizing IRN-IV have been developed (Wagner. ClinSarcRes, 2015 ). Unfortunately, the palatability of the intravenous preparation is poor, leading to reduced compliance especially in younger pediatric patients. Development of an advanced formulation to improve tolerability and patient compliance is an important unmet clinical need. VAL-413 is a novel formulation developed to improve palatability of oral irinotecan. Methods: Eligibility: Up to 20 patients ≥ 1 year and ≤ 30 years of age with recurrent pediatric solid tumors and adequate bone marrow, renal and liver function, for whom irinotecan therapy is a treatment option will be enrolled. Trial Design: Two different dose levels of VAL-413, 90mg/m2/day or 100mg/m2/day will be studied in combination with a fixed-dose of temozolomide using a standard 3 + 3 phase I design. In the event that the starting dose of 90 mg/m2/day is not tolerable due to toxicity, a lower dose of 75 mg/m2/day may be implemented. Treatment: During the first cycle of treatment, each patient will receive 4 daily doses of VAL-413 and one daily dose of the intravenous preparation of irinotecan taken orally (IRN-IVPO). During all subsequent cycles, only VAL-413 will be given with temozolomide in 5-day courses administered every 21 days, as tolerated. Outcome Measures: Toxicity is assessed by NCI CCTCAEv5; tumor response is assessed by RECIST 1.1. A palatability survey instrument will assess palatability of VAL-413 vs. IRN-IVPO; and comparative intrapatient pharmacokinetics of irinotecan and its metabolites will be assessed in all patients. This trial is ongoing (CT.gov: NCT04337177). Enrolment of the first dose level is ongoing, with no DLT observed to date. Clinical trial information: NCT04337177.

First phase 1 clinical study of olaparib in pediatric patients with refractory solid tumors

The survival of patients with high-risk, refractory, relapsed, or metastatic solid tumors remains dismal. A poly(ADP-ribose) polymerase (PARP) inhibitor could be effective for the treatment of pediatric solid tumors with defective homologous recombination. This open-label, multicenter phase 1 clinical trial evaluated the safety, tolerability, and efficacy of olaparib, a PARP inhibitor, in pediatric patients with refractory solid tumors to recommend a dose for Phase 2 trials. Olaparib (62.5, 125, and 187.5 mg/m2 twice daily) was administered orally every day (1 cycle=28 days) using a standard 3 + 3 dose-escalation design. Patients aged 3-18 years with recurrent pediatric solid tumors were eligible. Pharmacokinetic and pharmacodynamic analyses were performed. Fifteen patients were enrolled and received olaparib monotherapy, which was well tolerated. The recommended phase 2 dose for daily administration was 187.5 mg/m2 twice daily. Pharmacokinetics were dose proportional. The area under the concentration-time curve from 0 to 12 h and the peak plasma concentration for 187.5 mg/m2 twice daily in children were comparable to previous data obtained in a 200-mg, twice-daily cohort and lower than those in the 300-mg twice-daily cohort in adults. Pharmacodynamic studies demonstrated substantial inhibition of PARP activity. Two partial responses were observed in patients with Wilms tumor and neuroblastoma. This report is the first clinical trial to describe the use of a PARP inhibitor as monotherapy in children. Olaparib was well tolerated, with preliminary antitumor responses observed in DNA damage response-defective pediatric tumors. This Phase 1 trial evaluated the efficacy and safety of olaparib in patients with refractory childhood solid tumors. Olaparib was well tolerated, achieving objective response in 2/15 patients. The DNA damage response was attenuated in nearly one-half of advanced neuroblastoma patients, demonstrating the utility of the PARP inhibitor. The results support further investigation of olaparib as a new treatment for DNA damage-response or repair-defective pediatric cancers.

The Efficacy and Safety of Anlotinib in Pediatric Patients With Refractory or Recurrent Solid Tumors

Objective: Refractory or recurrent pediatric solid tumors lack effective treatments, and are associated with dismal outcomes. Hence, there is an urgent need for a novel therapeutic strategy. This study aimed to evaluate the efficacy and safety of anlotinib, a novel oral multi-kinase angiogenesis inhibitor, in pediatric patients with refractory or recurrent solid tumors. Methods: This single-institutional, observational retrospective study was conducted in Sun Yat-sen University Cancer Center, China. Refractory or recurrent pediatric solid tumor patients treated with anlotinib between 2018 and 2020 were evaluated. Results: Forty-one and 30 patients were enrolled to evaluate the efficacy and safety of anlotinib, respectively. There was partial response in five patients, stable disease in 22 patients, no patient with complete response, with an objective response ratio of 12.2% (5/41; 95% CI 1.7-22.7). The disease control rate was 65.9% (27/41; 95% CI 50.7-81) and the median progression-free survival was 2.87 months (95% CI 0.86-4.88). The incidence rates of any grade and grade 3–4 adverse events were 80% (24/30) and 23.3% (7/30), respectively. Bleeding (20%, 6/30), hand-foot syndrome (16.7%, 5/30), and diarrhea (13.3%, 4/30) were the most common adverse events. Grade 3–4 adverse events included hypertension, hand-foot syndrome, diarrhea, anemia, and thrombocytopenia. There were no adverse events-related deaths. Conclusion: For heavily pretreated pediatric solid tumors, anlotinib monotherapy and its combination with chemotherapy may be an effective treatment option with tolerable adverse events. It is necessary to monitor blood pressure when using anlotinib in children.

The efficacy and safety of anlotinib in refractory/recurrent/advanced pediatric solid tumors: A retrospective study.

11556 Background: Refractory and recurrent advanced pediatric solid tumors are short of effective treatment and with a dismal outcome, thus an urgent need for novel and effective treatment. The aim of the study is to evaluate the efficacy and safety of anlotinib, a novel and oral multi-target receptor tyrosine kinase inhibitor, in refractory or recurrent advanced pediatric solid tumors. Methods: The retrospective, single-institutional, observed study was conducted in Sun Yat-sen University cancer center in China. Refractory, recurrent, or advanced pediatric solid tumors patients treated with anlotinib between 2018 to 2020 were evaluated. Results: Forty-one patients and thirty patients were enrolled in the study to evaluated efficacy and safety, respectively. The objective response ratio (ORR) was 12.2% (95%CI 1.7-22.7): complete response (n = 0) and partial response (n = 5) (Table). The disease control rate (DCR) was 65.9% (95%CI 50.7-81). The median progression-free survival (PFS) was 2.87 months (95%CI 0.86-4.88). According to anlotinib treatment schedule, all patients were divided into three groups: anlotinib monotherapy (A, n = 16), anlotinib combined with immune checkpoint inhibitor treatment (A + ICI, n = 6), anlotinib combined with salvage chemotherapy (A + SC, n = 19). The ORR, DCR and median PFS for three groups were 6.3% (95%CI 7.1-19.6), 56.3% (95%CI 28.9-83.6), 2.43months, 16.7% (95%CI 26.2-59.5), 66.7% (95%CI 12.5-120.9), 1.13months, 15.8% (95%CI 2.3-33.8), 73.7% (95%CI 51.9-95.5), 2.87months, respectively. There was no significantly difference between three groups in aforementioned response index. The incidence rates of any grade and grade 3-4 adverse events were 80% and 20%, respectively. Bleeding (20%), hand-foot syndrome (13.3%), and diarrhea (13.3%) were the most common adverse events. Grade 3-4 adverse events include hypertension, hand-foot syndrome, diarrhea, anemia, and thrombocytopenia. There was no adverse events-related death. Conclusions: For heavily pretreated pediatric solid tumors, anlotinib may be an effective treatment with tolerable adverse events. Further prospective randomized controlled clinical study is warranted.[Table: see text]

CTNI-75. A PILOT CLINICAL TRIAL OF OROTECAN (VAL-413), A NOVEL ORAL DOSAGE FORMULATION OF IRINOTECAN: IMPLICATIONS FOR PEDIATRIC BRAIN TUMORS

Abstract Tumors of the brain and of the central nervous system (CNS) are the most common solid tumors in children. Intravenous irinotecan hydrochloride (IRN-IV) is approved for the treatment of adult colorectal cancer. IRN-IV is also used off-label in a wide range of treatment regimens for recurrent adult and pediatric tumors including glioblastoma, pediatric glioma and medulloblastoma. Recently, commercially available IRN-IV has been administered orally (IRN-IVPO) in pediatric patients to reduce intravenous administration-related side effects, improve convenience and reduce clinic time and costs. Unfortunately, the poor palatability of this preparation leads to poor compliance, especially in pediatric patients. VAL-413 is novel formulation developed to improve tolerability of oral irinotecan. The current study (NCT04337177) evaluates the safety and pharmacokinetics of VAL-413 administered with temozolomide for treatment of recurrent pediatric solid tumors. METHODS: Up to 20 patients ≥ 1 to ≤ 30 years of age with recurrent pediatric solid tumors will be enrolled. The primary objective is to establish the recommended phase II dose of VAL-413 when given in combination with temozolomide. Secondary objectives include characterization of the pharmacokinetics of VAL-413 vs. IRN-IVPO, evaluating palatability of VAL-413, assessing the toxicity profile of VAL-413 in combination with temozolomide, and assessment of tumor response. Toxicity is evaluated based on CTCAEv5 and tumor response based on RECISTv1.1. An update on the progress of this trial will be presented.

Abstract CT137: A pilot pharmacokinetic study of VAL413 in patients with recurrent pediatric solid tumors

Abstract Background: Ewing's sarcoma (EWS) is the second most common malignant bone tumor affecting children, adolescents and young adults. Intravenous irinotecan hydrochloride (IRN-IV) is approved for the treatment of adult colorectal cancer. IRN-IV is also widely used off-label as salvage therapy for patients with recurrent EWS, rhabdomyosarcoma, neuroblastoma, hepatoblastoma, and medulloblastoma. Prior adult and pediatric trials demonstrate that the combination of intravenous irinotecan and temozolomide has significant antitumor activity in advanced EWS. Recently, commercially available intravenous irinotecan has been administered orally (IRN-IVPO) in pediatric patients to reduce intravenous administration-related side effects, improve convenience and reduce clinic time and costs. Unfortunately, the taste of the iv preparation can be limiting, leading to poor compliance especially in pediatric patients. Development of an advanced formulation to improve tolerability and patient compliance is an important unmet need. Methods: VAL-413 is novel formulation developed to improve tolerability of oral irinotecan for the treatment of cancer. This study (USIND#135675) aims to establish the recommended phase II dose of VAL-413 when given in combination with temozolomide. Secondary objectives include characterization of the pharmacokinetics of VAL-413 vs. conventional irinotecan given orally (IRN-IVPO), evaluating palatability of VAL-413, assessing the toxicity profile of VAL-413 in combination with temozolomide, and assessment of tumor response. Up to 20 patients &gt= 1 to &lt= 30 years of age with recurrent pediatric solid tumors will be enrolled at two different dose levels of VAL-413 in combination with fixed-dose temozolomide using a standard 3 + 3 design. During the first cycle of treatment, each patient will receive 4 daily doses of VAL-413 and one daily dose of IRN-IVPO, together with 5 days of concurrent temozolomide. During all subsequent cycles, only VAL-413 will be given with temozolomide in 5-day courses administered every 21 days. Up to 17 cycles of treatment may be administered on this study. This study design will test the hypothesis that VAL-413 will not have significant pharmacokinetic differences from IRN-IVPO using intra-patient comparison of pharmacokinetic profiles. The evaluation of two dose levels will help to formally define a recommended Phase II dose for further studies. Toxicity will be evaluated based on CTCAEv5 and tumor response based on RECISTv1.1. Citation Format: James I. Geller, Dennis Brown, Jeffrey Bacha, Neil Sankar, Sarath Kanekal, Mark Leggas, Lars Wagner. A pilot pharmacokinetic study of VAL413 in patients with recurrent pediatric solid tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT137.

A phase I/II study of lenvatinib (LEN) plus everolimus (EVE) in recurrent and refractory pediatric solid tumors, including CNS tumors.

10527 Background: Proangiogenic signaling pathways cooperate with mTOR-mediated regulation of cell growth and maintenance to drive development of many pediatric cancers. We report results of the phase 1 dose escalation for LEN + EVE in pediatric patients (pts) with recurrent solid and CNS tumors conducted by Children’s Oncology Group. Methods: Dose escalation was conducted using a rolling-6 design. Pts received LEN + EVE orally once daily in continuous 28-day cycles. Dose determination was based on toxicity (CTCAE v4.03) during cycle 1. Pharmacokinetics (PK) of plasma LEN and EVE were monitored. Results: 17 pts were enrolled (9 male; 8 female). Median (range) age was 10 (3–21) years; 8 pts had CNS tumors. 17 were evaluable for dose-limiting toxicity (DLT). Enrollment started at dose level 1 (DL 1; LEN 11 mg/m2 + EVE 3 mg/m2) and, after treatment of 3 pts, was initially de-escalated to DL –1 (LEN 8 mg/m2 + EVE 3 mg/m2) due to DLT of proteinuria in 1 pt and self-resolving headache in another who, on review, did not meet the definition of DLT. No pts enrolled at DL –1 (n = 5) experienced DLT. Overall, DLTs were observed in 2 of the first 6 patients enrolled at DL 1: the initial pt with proteinuria and 1 more pt with hypertriglyceridemia and hypercholesteremia. Because 2 pts had reversible DLT of different categories not related to Cmax or AUC, the DL 1 cohort was expanded to enroll an additional 6 pts, none of whom had DLT. Thus, 2/12 pts experienced DLT at DL 1. Overall, most common treatment-emergent adverse events (TEAEs; ≥ 50% of pts) were diarrhea, hypertension, hypertriglyceridemia, vomiting, abdominal pain, headache, and hypothyroidism. 47% of pts had ≥ 1 treatment-related TEAE grade ≥ 3; the most frequent was proteinuria (n = 2). On cycle 1 day 15, mean (SD) Cmax (ng/mL) for LEN at DL –1 and DL 1, respectively, was 314 (150) and 359 (270), and mean (SD) AUC0-8h (hr•ng/mL) for LEN was 1570 (935) and 1780 (1100). Taking all toxicities and PK into account, no further dose escalation was recommended. Best overall response in pts with measurable disease was 2/11 stable disease, 7/11 progressive disease, and 2/11 not evaluable. Conclusions: The recommended phase 2 dose of LEN + EVE in children with solid and CNS tumors was LEN 11 mg/m2 + EVE 3 mg/m2, with maximum daily doses capped at 18 mg and 5 mg, respectively. The toxicity profile was no more than additive to single-agent therapy. PK exposure was comparable with children on single-agent LEN and to adults receiving LEN + EVE. Enrollment to the phase 2 portion (Ewing sarcoma, high-grade glioma, and rhabdomyosarcoma strata) is ongoing. Clinical trial information: NCT03245151.

Phase I clinical study of oral olaparib in pediatric patients with refractory solid tumors: study protocol

BackgroundThere is no established standard chemotherapy for recurrent pediatric solid tumors such as neuroblastoma and sarcoma. Since some of these tumor cells show dysfunctions in homologous recombination repair, the goal is to conduct a phase I study of olaparib, a poly(ADP-ribose) polymerase inhibitor. In this clinical trial, the aims are to evaluate the safety, tolerability, and efficacy of olaparib in pediatric patients with refractory solid tumors and to recommend a dose for phase II trials.MethodsIn this open-label, multicenter study, olaparib tablets (62.5, 125, and 187.5 mg/m2 b.i.d.) will be administered orally in a standard 3 + 3 dose escalation design. Patients aged 3 to 18 years with recurrent pediatric solid tumors are eligible. Pharmacokinetic and pharmacodynamic analyses will also be performed.DiscussionThis study aims to extend the indications for olaparib by assessing its safety and efficacy in pediatric refractory solid tumor patients.Trial registrationUMIN-CTR (UMIN000025521); Registered on January 4, 2017.

Clinical Relevance of Genomic Changes in Recurrent Pediatric Solid Tumors

PURPOSE: Relapsed/refractory pediatric cancers show poor prognosis; however, their genomic patterns remain unknown. To investigate the genetic mechanisms of tumor relapse and therapy resistance, we characterized genomic alterations in diagnostic and relapsed lesions in patients with relapsed/refractory pediatric solid tumors using targeted deep sequencing. PATIENTS AND METHODS: A targeted sequencing panel covering the exons of 381 cancer genes was used to characterize 19 paired diagnostic and relapsed samples from patients with relapsed/refractory pediatric solid tumors. RESULTS: The mean coverage for all samples was 930.6× (SD = 213.8). Among the 381 genes, 173 single nucleotide variations (SNVs)/insertion-deletions (InDels), 100 copy number alterations, and 1 structural variation were detected. A total of 72.6% of SNVs in primary tumors were also found in recurrent lesions, and 27.2% of SNVs in recurrent tumors had newly occurred. Among SNVs/InDels detected only in recurrent lesions, 71% had a low variant allele fraction (<10%). Patients were classified into three categories based on the mutation patterns after cancer treatment. A significant association between the major mutation patterns and clinical outcome was observed. Patients whose relapsed tumor had fewer mutations than the diagnostic sample tended to be older, had longer progression-free survival, and achieved complete remission after relapse. Contrastingly, patients whose genetic profile only had concordant mutations without any change had the worst outcome. CONCLUSIONS: We characterized genomic changes in recurrent pediatric solid tumors. These findings could help to understand the biology of relapsed childhood cancer and to develop personalized treatment based on their genetic profile.

Abstract 2352: Defining a pediatric cancer dependency map

Abstract Many children with metastatic or recurrent pediatric solid tumors continue to have poor survival, and there is an immense need to identify novel therapeutic approaches. Moreover, these cancers typically have simple genomes with limited known druggable molecular events. In order to discover new vulnerabilities in pediatric solid tumors, we have performed genome-scale CRISPR-Cas9 loss-of-function screening and deep “omic” characterization in over 60 pediatric cancer cell lines to date, including neuroblastoma, medulloblastoma, Ewing sarcoma, malignant rhabdoid tumor and rhabdomyosarcoma lines, to begin defining a pediatric cancer dependency map. Global analyses of the pediatric dependency landscape have identified emerging classes of pediatric cancers, including epigenetic-driven, aberrant transcription factor-driven and receptor tyrosine kinase-driven malignancies. For example, the preferential dependencies identified in a subset of neuroblastoma, which has aberrantly high expression of the transcription factor MYCN, are highly enriched for an interconnected network of genes annotated to have transcription factor activity. In addition to the global evaluation, we have developed methods and tools for prioritizing targets for further validation within a cancer type. These tools computationally integrate the pediatric dependency data across multiple datasets to identify categories of genetic dependencies that are especially strong hits or enriched hits in a specific pediatric malignancy. As an example, the intersection of MYCN-amplified neuroblastoma specific dependencies and H3-lysine 27 acetylation (H3K27ac) profiling across MYCN-amplified neuroblastoma allowed us to identify a transcriptional core regulatory circuit (CRC) that may drive the malignant state. Furthermore, targeting transcription with the BRD4 inhibitor JQ1 and CDK7 inhibitor THZ1 caused synergistic killing of neuroblastoma cells suggesting a novel therapeutic approach to treating this disease. Thus, defining a comprehensive pediatric cancer dependency map and developing the methods and tools to prioritize vulnerabilities in different cancer types will allow us to discover both novel biology and new therapeutic opportunities in childhood malignancies. Citation Format: Neekesh V. Dharia, Clare Malone, Amanda Balboni Iniguez, Lillian Guenther, Liying Chen, Gabriela Alexe, Adam D. Durbin, Mark W. Zimmerman, Andrew Hong, Pratiti Bandopadhayay, Mariella G. Filbin, Thomas Howard, Brenton Paolella, Iris Fung, Josephine Lee, Phil Montgomery, John M. Krill-Burger, Brian J. Abraham, Jennifer Roth, David E. Root, Richard A. Young, A. Thomas Look, Rameen Beroukhim, Jesse S. Boehm, William C. Hahn, Todd R. Golub, Aviad Tsherniak, Francisca Vazquez, Kimberly Stegmaier. Defining a pediatric cancer dependency map [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2352.

Abstract B36: Enhancement of histone deacetylase inhibitor's efficacy with hydroxychloroquine via autophagy inhibition in pediatric tumor cell lines

Abstract Background: Histone deacetylase (HDAC) inhibitors, such as vorinostat, have been of interest in adult and pediatric cancers. Preclinical in vitro data has shown an effect in many different cancer cell types, but response has not correlated well in xenograft models. A concern is the effect of the HDAC inhibitors being compensated by autophagy. Autophagy is induced by multiple anticancer agents, as a tumor survival-promoting mechanism. Hydroxychloroquine, an autophagy inhibitor, treatment leads to the accumulation of autophagosomes, and accelerates tumor cell death. The hypothesis of this study is that by combining a HDAC inhibitor with hydroxychloroquine, there will be an improved anti-tumor response compared to HDAC inhibitor alone in pediatric cancer cell lines. Objectives: To determine if there is an improved efficacy of vorinostat when combined with hydroxychloroquine in pediatric solid tumor cell lines. Methods: Three pediatric cancer cell lines: Hepatoblastoma (Hep293TT), Ewing's Sarcoma (SKES1), and Medulloblastoma (D283) were treated with different concentrations of vorinostat or hydroxychloroquine, and cell viability was measured by CellTiter Glo assay. Dose-response curves were plotted to determine IC50 (inhibitory concentration 50%). The expression of proliferation and autophagy markers was determined by Western blot analysis. Results: The IC50 of vorinostat and hydroxychloroquine was in the rage of 0.5-1.25μM and 25-50μM, respectively. To evaluate the functional consequences, cells were treated with vorinostat and hydroxychloroquine alone and in combination for 72 hours. The combination treatment resulted in a dramatic decrease in cell viability, with these two drugs cooperating in a dose-dependent manner. Overall, in all three cell lines there was an improved response when vorinostat was combined with hydroxychloroquine. LC3, a mammalian homolog of yeast Atg8, is a reliable marker of autophagosomes, and tracking the conversion of LC3-I to LC3-II is indicative of autophagy blockade. Hydroxychloroquine treatment resulted in profound conversion of LC3-I to LC3-II, and this effect was greater in cells treated with both vorinostat and hydroxychloroquine alone. Therefore, hydroxychloroquine blocked autophagic flux, which was more pronounced in the setting of autophagy induction by vorinostat. Finally, exposure to the combination of vorinostat and hydroxychloroquine resulted in decreased levels of phospho-ERK compared to single-agent treatment, indicating reduced cell proliferation. Taken together, our data demonstrate that when autophagy was inhibited by hydroxychloroquine in the presence of vorinostat, autophagosomes accumulated and cell viability/proliferation reduced. Conclusion: Preclinical studies in the different pediatric cancer cell lines show a clear and improved response when vorinostat is combined with hydroxychloroquine compared to vorinostat alone. The increased LC3-II/I ratio indicative of efficient autophagy inhibition while the decrease in the phospho-ERK signifies a decrease in proliferation. Furthermore the IC50 concentration of vorinostat, about 200ng/ml, necessary for effect is well within the achievable clinical range of 150-500ng/ml. The next step would be to validate these results in a xenograft model with one of the pediatric cancer tumors, and then hopefully continue forward to build a phase 1 clinical trial in recurrent pediatric solid tumors. This combination of drugs has yet to be explored in pediatrics but has the potential to enhance the effect of an established chemotherapy agent with a well-known and easily accessible non-cancer drug. Citation Format: Abigail Joy Cruz, Hima Bansal, Gail Tomlinson, Sanjay Bansal, Steven Weitman. Enhancement of histone deacetylase inhibitor's efficacy with hydroxychloroquine via autophagy inhibition in pediatric tumor cell lines. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Pediatric Cancer Research: From Mechanisms and Models to Treatment and Survivorship; 2015 Nov 9-12; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(5 Suppl):Abstract nr B36.

Phase I study of single-agent perifosine for recurrent pediatric solid tumors.

9540 Background: Perifosine is a synthetic alkylphospholipid which inhibits Akt activity and also has been reported to affect the JNK and MAPK signaling pathways. Single agent trials of perifosine in adults have demonstrated responses in patients with renal cell carcinoma, advanced brain tumors, soft-tissue sarcomas, hepatocellular carcinoma, as well as in hematologic malignancies including multiple myeloma and Waldenstrom's macroglobulinemia. We sought to determine the safety of perifosine in children with recurrent solid tumors Methods: Pediatric patients with recurrent solid tumors were enrolled in a phase I, open-label, dose-escalating study to assess pharmacokinetics (PK), and to identify the maximally tolerated dose (MTD). Cohorts of 3 pts were treated at three dose levels: 25mg/m2/day, 50mg/m2/day and 75mg/m2/day using 50mg tablets of perifosine after a loading dose on D#1 Results: 9 pts (4 male, 5 female) with high-grade glioma (n=5), medulloblastoma (n=2) or neuroblastoma (n=2) have been treated to date. Their median age was 13 years (range 5-18), most were heavily pretreated, with a median of 3 prior treatment regimens (range 1-10). No DLTs were observed. No ≥ grade 3 toxicities or adverse events have been encountered. Grade 2 toxicities that were possibly related to perifosine include asthenia (22%), asymptomatic transaminase elevation (22%), neutropenia (33%), leukopenia (11%), hyperglycemia (22%), hypomagnesemia (22%), hypophosphatemia (11%), and colitis which resolved despite drug continuation (11%). Preliminary PK data resulted in the following steady state serum levels: 14.1±4μ M for dose level 1, 32.8±8.1 μ M for dose level 2, and 31.6 ±7.8μ M for dose level 3. Conclusions: Perifosine is well tolerated in children with advanced solid tumors. No significant financial relationships to disclose.

A phase 1/pilot study of radiofrequency ablation for the treatment of recurrent pediatric solid tumors

This prospective study was designed to be the first to evaluate the toxicity of radiofrequency ablation (RFA) in patients with recurrent pediatric solid tumors. From 2003 through 2008, a phase 1/pilot study of RFA for recurrent pediatric solid tumors was conducted. A multidisciplinary cancer management team selected appropriate candidates for the study. Imaging-guided RFA was performed percutaneously. Repeat RFA was performed for recurrences when appropriate. Toxicity and imaging response was assessed at 1 month and 3 months prospectively. Accrual stopped in 2006, and data collection stopped in 2008. Sixteen patients (ages 4 years-33 years; median age, 15 years) and 56 tumor sites were treated in 37 RFA sessions including 38 pulmonary, 11 musculoskeletal, and 7 hepatic lesions (82 lesion-treatments). Postprocedural pain was moderate (median 5 on a scale from 1 to 10) and lasted a median of 9 days. Prolonged hospitalization (beyond 1 day) occurred 17 times (range, 2 days-25 days; median, 3 days). Hypoxia supported by supplemental oxygen occurred in 8 of 16 patients and resolved within 1 month after each RFA. No patient had tumor lysis syndrome but myoglobinuria/hemoglobinuria occurred in 6 of 16 patients, all without renal damage. Serious complications from pulmonary RFA included 2 diaphragmatic hernias. Of 82 lesions imaged, 24 (29%) remained ablated at the end of the study. The toxicity from RFA of recurrent pediatric solid tumors was real but limited, and RFA may offer a local tumor control alternative in carefully selected cases.

Pediatric Phase I and Pharmacokinetic Study of Erlotinib Followed by the Combination of Erlotinib and Temozolomide: A Children's Oncology Group Phase I Consortium Study

We conducted a phase I and pharmacokinetic study of the epidermal growth factor receptor (EGFR) inhibitor erlotinib as a single agent and in combination with temozolomide in children with refractory solid tumors. Erlotinib was administered orally once daily to cohorts of three to six children for a single 28-day course. Patients then received the combination of daily erlotinib and temozolomide daily for 5 days for all subsequent 28-day courses. An oral erlotinib solution was administered during the dose-finding phase and a tablet formulation was subsequently studied at the maximum-tolerated dose (MTD). Pharmacokinetic studies and ERBB-receptor expression and signaling studies were performed. Forty-six patients, median age 11.5 years, received erlotinib at doses of 35, 50, 65, 85, or 110 mg/m(2)/d. At 110 mg/m(2)/d, two of four patients had dose-limiting toxicity (DLT) consisting of rash and hyperbilirubinemia, whereas one of six patients developed dose-limiting rash at 85 mg/m(2)/d. The most frequent non-DLTs included diarrhea, rash, and hyperbilirubinemia. The combination of erlotinib and temozolomide was well tolerated. The median apparent erlotinib clearance was 3.1 L/h/m(2) and the median terminal half-life was 8.7 hours. One patient with a neurocytoma had stable disease for 19 months, two patients with neuroblastoma remained on study for 23 and 24 months, and one patient with myoepithelioma had a mixed response. The recommended phase II dose of erlotinib in recurrent pediatric solid tumors is 85 mg/m(2)/d, either alone or in combination with temozolomide.

Phase II study of 21 day continuous intravenous infusion (CIVI) topotecan for recurrent pediatric solid tumors: A Children’s Oncology Group Study (COG A09713)

8523 Background: The anti-tumor activity of topotecan is schedule-dependent, with protracted administration having the greatest pre-clinical efficacy. We determined the response rate of selected recurrent pediatric solid tumors to a 21-day CIVI of topotecan. Methods: Patients with Ewing’s sarcoma family of tumors (ESFT), osteosarcoma (OS), soft tissue sarcomas (STS), medulloblastoma (MB)/PNET, astrocytoma, or neuroblastoma (NB) recurrent or refractory to conventional therapy, measurable disease, and adequate organ function were treated with topotecan 0.3 mg/m2/day CIVI for 21 consecutive days, followed by 7 days without therapy prior to response assessment. Courses could be repeated every 28 days. Results: 55 patients were enrolled; two were ineligible, two were removed from protocol therapy prior to evaluation for response, and one was inevaluable for response, leaving 53 and 50 patients evaluable for toxicity and response, respectively. Objective responses were seen in 2/20 patients with ESFT (both partial responses, 3 and 19 courses), 0/10 OS patients, and 0/12 STS patients. There were insufficient patients enrolled to determine the response rate for the MB/PNET, astrocytoma, and NB strata. The most common grade 3 or 4 toxicities during the first course of therapy were thrombocytopenia (12/53), neutropenia (8/53), and fatigue (7/53). Conclusion: Although responses were observed in ESFT, no activity was seen in other sarcoma strata. Further development of prolonged topotecan CIVI for pediatric sarcomas is not warranted. No significant financial relationships to disclose.