Citations

The NCCN Guidelines for Kidney Cancer focus on the screening, diagnosis, staging, treatment, and management of renal cell carcinoma (RCC). Patients with relapsed or stage IV RCC typically undergo surgery and/or receive systemic therapy. Tumor histology and risk stratification of patients is important in therapy selection. The NCCN Guidelines for Kidney Cancer stratify treatment recommendations by histology; recommendations for first-line treatment of ccRCC are also stratified by risk group. To further guide management of advanced RCC, the NCCN Kidney Cancer Panel has categorized all systemic kidney cancer therapy regimens as “Preferred,” “Other Recommended Regimens,” or “Useful in Certain Circumstances.” This categorization provides guidance on treatment selection by considering the efficacy, safety, evidence, and other factors that play a role in treatment selection. These factors include pre-existing comorbidities, nature of the disease, and in some cases consideration of access to agents. This article summarizes surgical and systemic therapy recommendations for patients with relapsed or stage IV RCC.

Abstract Introduction: Selinexor is a first-in-class, central nervous system (CNS) penetrant, oral inhibitor of exportin 1 (XPO1), the sole nuclear exporter of many key tumor suppressors. Selinexor is FDA-approved for refractory multiple myeloma and DLBCL and has been evaluated in a phase 1 trial in children with leukemia. We report a phase 1 trial of selinexor in children and adolescents with recurrent CNS and solid tumors, including lymphoma (NCT02323880). Methods: A rolling-six design was used to evaluate selinexor (10 or 25 mg tablets) administered twice or once weekly during a 28-day cycle. Dose determination was based on protocol-defined dose limiting toxicity (DLT) using CTCAEv4 during cycle 1. First dose pharmacokinetics (PK) were performed. Results: 43 subjects were enrolled (17 males); median (range) age was 15 (6-20) years. 27 (63%) had CNS tumors, most commonly high-grade glioma (n=12); 16 (37%) had extracranial solid tumors. 42 were evaluable for DLT. At the starting dose (35 mg/m2/dose, twice weekly), no DLTs were observed in 6 subjects, however, 2 subjects had unexpected late myelosuppression delaying initiation of cycle 2. The dosing schedule was amended to twice weekly for 3 weeks followed by a 1 week break. 12 subjects received 35 mg/m2/dose; 4 experienced DLTs [grade 3 fatigue (n=2), grade 3 thrombocytopenia (n=1), or grade 3 ALT increase (n=1)]. The dose was de-escalated to 20 mg/m2/dose, 3 weeks on, 1 week off. 12 subjects enrolled; 3 experienced a DLT [grade 3 increased AST/ALT, acute reversible neurologic changes, or neutropenia (each n=1)]. At the 20 mg/m2 (n=12) and 35 mg/m2 (n=19) dose levels, respectively, the mean ± SD Cmax (ng/ml) was 324±116 and 535±174, and AUC (hr•ng/ml) was 3092 ± 842 and 5156 ± 1227. This was comparable to PK in adults receiving 35 and 50 mg/m2. Based on a desire to achieve a higher Cmax and avoid breaks in schedule, and emerging evidence for similar effectiveness with decreased toxicity in adults receiving continuous once weekly dosing, we evaluated a dosing schedule with once weekly dosing for all 4 weeks of each cycle. At the initial dose level (45 mg/m2 weekly), 2 of 6 subjects had DLTs [prolonged grade 2 thrombocytopenia or grade 3 seizure in a primary CNS tumor patient]. Six subjects received 35 mg/m2/dose once weekly; 1 DLT [grade 3 thrombocytopenia] was observed. Non-dose-limiting toxicity (Grade ≥2 occurring in >10% of subjects during cycle 1) included lymphopenia, leukopenia, neutropenia, thrombocytopenia, anorexia, fatigue, hypophosphatemia, nausea, and vomiting. Subjects received a median (range) of 1 (1-9) cycle; 13 received 2-3 cycles, and 6 received 5-9 cycles. Conclusions: Selinexor-related toxicities were primarily hematological and gastrointestinal. The maximum tolerated dose (MTD) of selinexor in children and adolescents with recurrent solid and CNS tumors is 20 mg/m2/dose twice weekly for 3 weeks followed by one week off. On a continuous once weekly schedule, the MTD and recommended phase 2 starting dose of selinexor is 35 mg/m2/dose. Citation Format: Adam L. Green, Charles G. Minard, Xiaowei Liu, Joel M. Reid, Kerice Pinkney, Stephan Voss, Marvin D. Nelson, Elizabeth Fox, Brenda J. Weigel, Julia Glade Bender. Phase 1 trial of selinexor in children and adolescents with recurrent/refractory solid and CNS tumors (ADVL1414): A Children’s Oncology Group Phase 1 Consortium trial [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P162.

10019 Background: Pevonedistat (PEV), a first in class inhibitor of NEDD8 activating enzyme (NAE), prevents the activation of Cullin-RING ligases (CRL) necessary for proteasome mediated degradation of key regulatory proteins important in cell survival. In adults with solid tumors, the maximum tolerated dose (MTD) in combination with chemotherapy is 20-25 mg/m2. Antitumor activity of PEV has been demonstrated in preclinical models of childhood cancer. In vivo additive activity has been demonstrated for PEV in combination with IRN and alkylating agents. The objectives of this study are to determine the MTD and recommended Phase 2 dose of PEV in combination with IRN and TMZ and describe the toxicities, pharmacokinetic (PK), and pharmacodynamics (PD) properties of this combination. Methods: We conducted a phase 1 trial of PEV in combination with IRN and TMZ in pediatric patients (pts) with recurrent or refractory solid tumors and brain tumors. During cycle 1, PEV was administered intravenously on days 1, 8, 10, and 12, with IRN (IV, 50mg/m2) and TMZ (orally, 100mg/m2), on days 8-12 of a 28 day cycle. In subsequent cycles, PEV was administered on days 1, 3, and 5, with IRN and TMZ on days 1-5 of a 21 day cycle. Dose escalation was determined using the Rolling 6 Design. Results: 30 pts enrolled. All pts were eligible and evaluable for cycle 1 dose limiting toxicity (DLT) assessment. Median (range) age was 13 (1-21) years; 19 (63%) were male. Eleven pts had brain tumors, and 19 pts had solid tumors. Six pts each enrolled on PEV dose levels (DL) 1 (15mg/m2), 2 (20mg/m2), 3 (25mg/m2) and 4 (35mg/m2) as well as an expanded PK cohort at DL4. Cycle 1 grade 3/4 toxicities include lymphopenia (n = 5), leukopenia (n = 4), neutropenia (n = 2), elevated ALT (n = 2), elevated AST (n = 1), diarrhea (n = 1), flu-like symptoms (n = 1). The most frequent non-dose limiting AEs in cycle 1 were anemia (87%), WBC decreased (77%), nausea (57%), diarrhea (53%), ALT increased (50%), AST increased (50%), and vomiting (50%). PK analyses showed the mean area under the curve at the 25 mg/m2 dose level on day 8 (in combination with irinotecan and temozolomide) was 1300 hr•ng/mL, half-life (T ½) was 5-6 hours, time to maximum concentration (Tmax) was 1 hour, and mean clearance was 20 L/hr/m2. There were 3 DLTs, 2 of which were related to protocol therapy (diarrhea and thrombocytopenia), among 12 patients on DL4. Thus the MTD was not exceeded at any dose level. PK at the 25 mg/m2 dose level are comparable to those in adult patients. PK from the 12 patients on DL4 (35mg/m2) as well as responses of all patients are pending. Conclusions: PEV in combination with IRN and TMZ is well tolerated in children with solid or brain tumors. PEV PK was not altered by the addition of irinotecan and temozolomide. Further PK and PD analyses are ongoing to establish the recommended phase 2 dose. Clinical trial information: NCT03323034.

10018 Background: Outcomes for children with relapsed/refractory (R/R) AML and MDS are poor and new therapies are needed. Pevonedistat is an inhibitor of the NEDD-8 activating enzyme, a key regulator of the ubiquitin proteasome system that is responsible for protein turnover, cell growth and survival. In preclinical models, pevonedistat was synergistic with cytarabine (AraC) and azacitidine (aza). The combination of pevonedistat + aza in adults with AML demonstrated improved responses compared to either single agent. We evaluated the feasibility, toxicity and pharmacokinetics (PK) of pevonedistat in combination with aza, fludarabine, AraC (Aza-FLA) in children with R/R AML and MDS. Methods: Pevonedistat 20 mg/m2, IV days 1, 3, 5, the recommended adult dose, was administered in combination with aza (75 mg/m2, days 1-5), fludarabine (30 mg/m2, days 6-10), and AraC (2000 mg/m2, days 6-10). Intrathecal AraC was administered at the start of therapy and additional doses given to patients with CNS leukemia. If < 33% of the initial 6 enrolled patients experienced dose limiting toxicity (DLT) during cycle 1 the regimen would be considered tolerable and 6 additional patients could enroll to further assess tolerability and PK. Pevonedistat PK was determined during cycle 1 following doses 1 and 5. Response was evaluated after cycle 1. Results: A total of 12 patients were enrolled, median age was 13 years (range 1-21). All patients received prior chemotherapy, median number of prior regimens was 2 (range 1-5) and 3 (25%) patients had prior hematopoietic stem cell transplant. Diagnoses were AML NOS (n = 10, 83%), acute monocytic leukemia (n = 1), and therapy related AML (n = 1). One of the initial 6 patients had DLTs (hypertension, GGT elevation, and proteinuria); pevonedistat 20 mg/m2 + Aza-FLA was considered tolerable. Six additional patients were enrolled, two had DLTs (weight loss, hypoxia). Overall, 3/12 (25%) of patients experienced DLTs. As expected, using the intensive Aza-FLA backbone, myelosuppression, electrolyte abnormalities, and hepatic transaminase elevation were common. Day 1 PK parameters (n = 12, mean±SD) were: Cmax= 223±91 ng/mL, AUC0-24h= 892±216 ng/hr/mL, T1/2=4.3±1.2 hours, CL = 23.2±6.9 L/hr/m2. PK parameters were similar following doses 1 and 5, for patients < 12 (n = 6) and ≥ 12 (n = 6) years, and to adult PK profiles. Ten patients were evaluable for response. The overall response rate was 30% (95% CI: 7,75) with 3 patients achieving a CR with incomplete hematologic recovery (CRi). Conclusions: Pevonedistat 20 mg/m2 combinedwith Aza-FLA was tolerable in children with R/R AML. The toxicity of the regimen was similar to other intensive AML regimens. PK parameters were similar among the two age groups and were comparable to adults. Within the confines of a phase I study, there was limited anti-leukemic activity of the combination of pevonedistat +Aza-FLA in R/R AML. Clinical trial information: NCT03813147.

10010 Background: Cabozantinib is an inhibitor of multiple receptor tyrosine kinases (RTKs) including MET, VEGFR2, RET, and AXL. Preclinical and clinical data support these RTKs as potential therapeutic targets; Safety, tolerability, and responses were demonstrated in a COG phase 1 trial. We conducted a multi-center open label phase 2 trial to determine the activity of cabozantinib in select pediatric solid tumors (NCT02867592). Methods: Patients age 2-30 years old with selected relapsed or refractory cancer that was measurable (RECISTv.1.1) were eligible. Using a Simon minimax design, patients were enrolled to six strata: Osteosarcoma (OS), Ewing sarcoma (EWS), rhabdomyosarcoma (RMS), non-rhabdomyosarcoma soft tissue sarcoma (NRSTS), Wilms tumor (WT), and rare tumor (a non-statistical stratum including tumors of specific histologies or molecular features). Cabozantinib (40 mg/m2/day) was administered on a continuous schedule (1 cycle = 28 days). For the OS stratum, activity was determined based on objective response rate (ORR, complete response (CR) + Partial response (PR)) or disease control success defined as at least stable disease (SD) for ≥ 4 months. For all other strata, the primary endpoint was ORR. Pharmacokinetics were performed in patients < 19 years. Results: Between May 2017- Oct 2020, 109 patients enrolled (105 eligible, 104 evaluable for response and toxicity). Median age was 15.8 (range 5.6-27.1) years; 55 were male. In the OS stratum, 10/29 (34%) patients had central review confirmed disease control ≥ 4 months (2 PR, 8 SD), exceeding the protocol-defined criteria for activity of cabozantinib in OS. Median duration of therapy was 3 cycles (range 1-28+). In EWS, RMS, NRSTS, and WT strata (n = 13 evaluable patients each) no PR or CR were observed. In the rare tumor stratum (n = 23), 1/4 patients with renal cell carcinoma, 1/1 patients with RET fusion positive papillary thyroid cancer had a PR, and 1 patient with medullary thyroid cancer had a delayed PR. SD ≥ 6 cycles was seen in patients with EWS (n = 2), NRSTS (n = 5), WT (n = 3), and hepatocellular carcinoma (n = 1). At data cutoff (12/31/2020), 430 treatment cycles were administered; two patients remain on therapy. Cycle 1 and later cycle dose limiting toxicities (DLT) were seen in 20 (19%) and 39 (38%) patients, respectively. Common DLT were elevated liver enzymes, bilirubin, and lipase, hyponatremia, weight loss, anorexia, nausea, vomiting, wound dehiscence, palmar-plantar erythrodysesthesia, and pneumothorax. Day 1 pharmacokinetics (mean ± SD, n = 16) demonstrated a maximum plasma concentration of 556 ± 376 ng/ml, half-life 106 ± 102 hours, and area under the curve (AUC0-24h) 8093 ± 4368 ng•h/mL. Conclusions: Cabozantinib is active in patients with relapsed refractory OS and deserves further study in this disease. PRs were also seen in select carcinomas. Activity is limited in other sarcomas and WT. Clinical trial information: NCT02867592.

10008 Background: The NCI-Children’s Oncology Group (COG) Pediatric Molecular Analysis for Therapy Choice (MATCH) trial assigns patients age 1 to 21 years with relapsed or refractory solid tumors, lymphomas, and histiocytic disorders to phase 2 treatment arms of molecularly-targeted therapies based on genetic alterations detected in their tumor. Arm E evaluated the MEK inhibitor selumetinib (ARRY-142886) in patients whose tumors harbored activating alterations in the MAPK pathway ( ARAF, BRAF, HRAS, KRAS, NRAS, MAP2K1, GNA11, GNAQ hotspot mutations; NF1 inactivating mutations; BRAF fusions). Methods: Patients received selumetinib 25 mg/m2/dose (max 75 mg/dose) PO BID for 28-day cycles until disease progression or intolerable toxicity with response assessments obtained every 2-3 cycles. The primary endpoint was objective response rate (ORR); secondary endpoints included progression-free survival (PFS). Patients with low grade glioma were excluded. Results: A total of 21 patients (median age 14 years; range 5-21) were enrolled between 10/2017 and 8/2019, with 20 patients evaluable for response. Diagnoses were high grade glioma (HGG; n = 8), rhabdomyosarcoma (n = 7), adenocarcinoma (n = 2), and one each of MPNST, endodermal sinus/yolk sac tumor, plexiform neurofibroma (PN), and neuroblastoma. MAPK pathway alterations detected consisted of inactivating NF1 mutations (n = 8), hotspot mutations in KRAS (n = 8), NRAS (n = 3), and HRAS (n = 1), and BRAF V600E (n = 2). No objective responses were observed. Three patients had a best response of stable disease (HGG with NF1 mutation, 6 cycles; HGG with KRAS mutation, 12 cycles; PN with NF1 mutation, 13 cycles prior to removal for dose-limiting toxicity). Six-month PFS was 15% (95% CI: 4%, 34%). Adverse events that were deemed possibly, probably, or definitely attributable to study drug included one case each of grade 3 uveitis, lymphopenia, and thromboembolic event; one grade 4 CPK elevation; and one grade 5 thromboembolic event. Conclusions: Selumetinib did not result in tumor regression in this cohort of children and young adults with treatment-refractory tumors with activating MAPK pathway alterations. Of note, two patients with HGG initially had stable disease, but ultimately progressed after 6 and 12 cycles, respectively. Selumetinib has previously demonstrated activity in low grade glioma and PN and is now FDA-approved for PN. The results of our study indicate that MAPK pathway mutation status alone is insufficient to predict response to selumetinib monotherapy. It is likely that selumetinib and other MEK inhibitors will require combination with targeted or cytotoxic agents for optimal efficacy in children with persistent or progressive cancers after front-line chemotherapy. Clinical trial information: NCT03213691. Clinical trial information: NCT03155620.

PURPOSE The combination of gemcitabine and cisplatin (GC) is a standard therapy for metastatic urothelial carcinoma. Based on data that angiogenesis plays a role in urothelial carcinoma growth and progression, a randomized placebo-controlled trial was performed with the primary objective of testing whether patients treated with GC and bevacizumab (GCB) have superior overall survival (OS) than patients treated with GC and placebo (GCP). PATIENTS AND METHODS Between July 2009 and December 2014, 506 patients with metastatic urothelial carcinoma without prior chemotherapy for metastatic disease and no neoadjuvant or adjuvant chemotherapy within 12 months were randomly assigned to receive either GCB or GCP. The primary end point was OS, with secondary end points of progression-free survival, objective response, and toxicity. RESULTS With a median follow-up of 76.3 months among alive patients, the median OS was 14.5 months for patients treated with GCB and 14.3 months for patients treated with GCP (hazard ratio for death = 0.87; 95% CI, 0.72 to 1.05; two-sided stratified log-rank P = .14). The median progression-free survival was 8.0 months for GCB and 6.7 months for GCP (hazard ratio = 0.77; 95% CI, 0.63 to 0.95; P = .016). The proportion of patients with grade 3 or greater adverse events did not differ significantly between both arms, although increased bevacizumab-related toxicities such as hypertension and proteinuria occurred in the bevacizumab-treated arm. CONCLUSION The addition of bevacizumab to GC did not result in improved OS. The observed median OS of about 14 months is consistent with prior phase III trials of cisplatin-based chemotherapy.

AbstractBackgroundPrexasertib (LY2606368) is a novel, second‐generation, selective dual inhibitor of checkpoint kinase proteins 1 (CHK1) and 2 (CHK2). We conducted a phase 1 trial of prexasertib to estimate the maximum‐tolerated dose (MTD) and/or recommended phase 2 dose (RP2D), to define and describe the toxicities, and to characterize the pharmacokinetics (PK) of prexasertib in pediatric patients with recurrent or refractory solid and central nervous system (CNS) tumors.MethodsPrexasertib was administered intravenously (i.v.) on days 1 and 15 of a 28‐day cycle. Four dose levels, 80, 100, 125, and 150 mg/m2, were evaluated using a rolling‐six design. PK analysis was performed during cycle 1. Tumor tissue was examined for biomarkers (CHK1 and TP53) of prexasertib activity.ResultsThirty patients were enrolled; 25 were evaluable. The median age was 9.5 years (range: 2‐20) and 21 (70%) were male. Twelve patients (40%) had solid tumors and 18 patients (60%) had CNS tumors. There were no cycle 1 or later dose‐limiting toxicities. Common cycle 1, drug‐related grade 3/4 toxicities (> 10% of patients) included neutropenia (100%), leukopenia (68%), thrombocytopenia (24%), lymphopenia (24%), and anemia (12%). There were no objective responses; best overall response was stable disease in three patients for five cycles (hepatocellular carcinoma), three cycles (ependymoma), and five cycles (undifferentiated sarcoma). The PK appeared dose proportional across the 80‐150 mg/m2 dose range.ConclusionsAlthough the MTD of prexasertib was not defined by this study, 150 mg/m2 administered i.v. on days 1 and 15 of a 28‐day cycle was determined to be the RP2D.

AbstractBackgroundEntinostat is an oral small molecule inhibitor of class I histone deacetylases (HDAC), which has not previously been evaluated in pediatrics. We conducted a phase I trial to determine the maximum tolerated dose/recommended phase 2 dose (MTD/RP2D), toxicity profile, pharmacokinetics (PK), and pharmacodynamics (PD) of entinostat in children with relapsed or refractory solid tumors including central nervous system (CNS) malignancies.MethodsA rolling six dose escalation design evaluated two dose levels. Entinostat oral tablet formulation was administered once per week, four doses per 28‐day cycle. PK and PD studies were performed.ResultsTwenty‐one eligible patients’ median (range) age was 14 years (6‐20). Six subjects were treated at 3 mg/m2dose level and 15 were treated in 4 mg/m2dose level. The study included patients with CNS tumors (n = 12), sarcomas (n = 6), or other solid tumors (n = 3). Eight patients were not fully evaluable for toxicity due to progression of disease prior to receiving the required percentage of protocol therapy. No cycle one dose‐limiting toxicity (DLT) was observed at either dose level. A three‐fold higher area under the curve (AUC) was achieved in our cohort compared to adults using a similar dosing schedule. The PD studies showed increase in acetylated lysine in peripheral blood leukocytes at both doses.ConclusionsEntinostat was well tolerated with no DLT observed. All patients experienced progression within the first two cycles, except one patient with ependymoma with stable disease. Based on PK and PD, the R2PD in pediatric patients with solid tumors is 4 mg/m2orally administered once weekly.