Phase II study of vemurafenib in children and young adults with tumors harboring BRAF V600 mutations: NCI-COG pediatric MATCH trial (APEC1621) Arm G.

BACKGROUND: This is a phase II subprotocol of the NCI-COG Pediatric MATCH study evaluating vemurafenib, a selective oral inhibitor of BRAF V600 mutated kinase, in patients with relapsed or refractory solid tumors harboring BRAF V600 mutations. METHODS: Patients received vemurafenib at 550 mg/m2 (maximum 960 mg/dose) orally twice daily for 28-day cycles until progression or intolerable toxicity. The primary aim was to determine the objective response rate and secondary objectives included estimating progression-free survival and assessing the tolerability of vemurafenib. RESULTS: Twenty-two patients matched to the subprotocol and 4 patients (18%) enrolled. Primary reasons for non-enrollment were ineligibility due to exclusions of low-grade glioma (nâ=â7) and prior BRAF inhibitor therapy (nâ=â7). Enrolled diagnoses were one each of histiocytosis, ameloblastoma, Ewing sarcoma, and high-grade glioma, all with BRAF V600E mutations. Treatment was overall tolerable with mostly expected grade 1/2 adverse events (AE). Grade 3 or 4 AE on treatment were acute kidney injury, hyperglycemia, and maculopapular rash. One patient came off therapy due to AE. One patient (glioma) had an objective partial response and remained on protocol therapy for 15 cycles. CONCLUSION: There was a low accrual rate on this MATCH subprotocol, with only 18% of those who matched with BRAFV600 mutations enrolling, resulting in early termination, and limiting study results (ClinicalTrials.gov Identifier: NCT03220035).

Olaparib for childhood tumors harboring defects in DNA damage repair genes: arm H of the NCI-COG Pediatric MATCH trial.

BACKGROUND: The National Cancer Institute-Children's Oncology Group Pediatric Molecular Analysis for Therapy Choice (MATCH) precision oncology platform trial enrolled children aged 1-21 years with treatment-refractory solid tumors and predefined actionable genetic alterations. Patients with tumors harboring alterations in DNA damage repair (DDR) genes were assigned to receive olaparib. METHODS: Tumor and blood samples were submitted for centralized molecular testing. Tumor and germline sequencing were conducted in parallel. Olaparib was given twice daily for 28-day cycles starting at a dose 30% lower than the adult recommended phase 2 dose (RP2D). The primary endpoint was the objective response. RESULTS: Eighteen patients matched (1.5% of those screened) based on the presence of a deleterious gene alteration in BRCA1/2, RAD51C/D, or ATM detected by tumor sequencing without germline subtraction or analysis of loss of heterozygosity (LOH). Eleven (61%) harbored a germline mutation, with only one exhibiting LOH. Six patients enrolled and received the olaparib starting dose of 135 mg/m2/dose. Two participants were fully evaluable; 4 were inevaluable because <85% of the prescribed dose was administered during cycle 1. There were no dose-limiting toxicities or responses. Minimal hematologic toxicity was observed. CONCLUSION: Most DDR gene alterations detected in Pediatric MATCH were germline, monoallelic, and unlikely to confer homologous recombination deficiency predicting sensitivity to olaparib monotherapy. The study closed due to poor accrual. CLINICALTRIALS.GOV IDENTIFIER: NCT03233204. IRB approved: initial July 24, 2017.

Phase II Study of Ulixertinib in Children and Young Adults With Tumors Harboring Activating Mitogen-Activated Protein Kinase Pathway Alterations: APEC1621J of the National Cancer Institute-Children's Oncology Group Pediatric MATCH Trial.

PURPOSE: The National Cancer Institute-Children's Oncology Group (NCI-COG) Pediatric MATCH trial assigns patients age 1-21 years with refractory malignancies to phase II treatment arms of molecularly targeted therapies on the basis of genetic alterations detected in their tumor. Patients with activating alterations in the mitogen-activated protein kinase pathway were treated with ulixertinib, an extracellular signal-regulated kinase (ERK)1/2 inhibitor. METHODS: As there were no previous pediatric data, ulixertinib was initially tested in a dose escalation cohort to establish the recommended phase II dose (RP2D) before proceeding to the phase II cohort. Ulixertinib was administered at 260 mg/m2/dose orally twice a day (dose level 1 [DL1], n = 15) or 350 mg/m2/dose orally twice a day (DL2, n = 5). The primary end point was objective response rate; secondary end points included safety/tolerability and progression-free survival (PFS). RESULTS: Twenty patients (median 12 years; range, 5-20) were treated, all evaluable for response. CNS tumors comprised 55% (11/20) of diagnoses, with high-grade glioma and low-grade glioma most common (n = 5 each). All CNS tumors except one harbored BRAF fusions or V600E mutations. Rhabdomyosarcoma (n = 5) was the most frequent non-CNS diagnosis. DL1 was declared the RP2D in the dose escalation cohort after dose-limiting toxicities in Cycle 1 occurred in 1/6 patients at DL1 and 2/5 patients at DL2, including fatigue, anorexia, rash, nausea, vomiting, diarrhea, dehydration, hypoalbuminemia, and hypernatremia. No objective responses were observed. Six-month PFS was 37% (95% CI, 17 to 58). Three patients with BRAF-altered CNS tumors achieved stable disease >6 months. CONCLUSION: Ulixertinib, a novel targeted agent with no previous pediatric data, was successfully evaluated in a national precision medicine basket trial. The pediatric RP2D of ulixertinib is 260 mg/m2/dose orally twice a day. Limited single-agent efficacy was observed in a biomarker-selected cohort of refractory pediatric tumors.

Tazemetostat for tumors harboring SMARCB1/SMARCA4 or EZH2 alterations: results from NCI-COG pediatric MATCH APEC1621C.

BACKGROUND: National Cancer Institute-Children's Oncology Group Pediatric Molecular Analysis for Therapy Choice assigns patients aged 1-21 years with refractory solid tumors, brain tumors, lymphomas, and histiocytic disorders to phase II trials of molecularly targeted therapies based on detection of predefined genetic alterations. Patients whose tumors harbored EZH2 mutations or loss of SMARCB1 or SMARCA4 by immunohistochemistry were treated with EZH2 inhibitor tazemetostat. METHODS: Patients received tazemetostat for 28-day cycles until disease progression or intolerable toxicity (max 26 cycles). The primary endpoint was objective response rate; secondary endpoints included progression-free survival and tolerability of tazemetostat. RESULTS: Twenty patients (median age = 5 years) enrolled, all evaluable for response and toxicities. The most frequent diagnoses were atypical teratoid rhabdoid tumor (n = 8) and malignant rhabdoid tumor (n = 4). Actionable alterations consisted of SMARCB1 loss (n = 16), EZH2 mutation (n = 3), and SMARCA4 loss (n = 1). One objective response was observed in a patient with non-Langerhans cell histiocytosis with SMARCA4 loss (26 cycles, 1200 mg/m2/dose twice daily). Four patients with SMARCB1 loss had a best response of stable disease: epithelioid sarcoma (n = 2), atypical teratoid rhabdoid tumor (n = 1), and renal medullary carcinoma (n = 1). Six-month progression-free survival was 35% (95% confidence interval [CI] = 15.7% to 55.2%) and 6-month overall survival was 45% (95% CI = 23.1% to 64.7%). Treatment-related adverse events were consistent with prior tazemetostat reports. CONCLUSIONS: Although tazemetostat did not meet its primary efficacy endpoint in this population of refractory pediatric tumors (objective response rate = 5%, 90% CI = 1% to 20%), 25% of patients with multiple histologic diagnoses experienced prolonged stable disease of 6 months and over (range = 9-26 cycles), suggesting a potential effect of tazemetostat on disease stabilization.

Implementing Modernized Eligibility Criteria in US National Cancer Institute Clinical Trials.

In 2018, the Cancer Therapy Evaluation Program (CTEP) at the US National Cancer Institute published new protocol template language that focused on organ function and prior and concurrent cancers in an effort to modernize eligibility criteria for cancer treatment trials. We conducted an analysis of CTEP-supported trials to evaluate the uptake and incorporation of the new language. The analysis included evaluation of 122 protocols approved in the years 2018-2020 for inclusion of the modernized eligibility criteria and consistency with new protocol template language related to 7 major eligibility criteria. These were cardiac function, liver function, kidney function, HIV status, prior and/or concurrent malignancies, treated and/or stable brain metastasis, and new and/or progressive brain metastases. Overall, CTEP trials evaluated in this period demonstrated that eligibility criteria were implemented to a relatively high degree ranging from a low of 54.1% for prior and/or concurrent malignancies to a high of 93.4% for eligibility criteria related to HIV infection. The findings demonstrate that modernized eligibility criteria can be successfully implemented but that consistent implementation requires sustained focused effort. As a result of these findings, CTEP began a new initiative in January 2022 that incorporates a specific review of eligibility criteria for new protocols to promote and improve consistency with the modernization effort.

Phase II Study of Selumetinib in Children and Young Adults With Tumors Harboring Activating Mitogen-Activated Protein Kinase Pathway Genetic Alterations: Arm E of the NCI-COG Pediatric MATCH Trial.

PURPOSE: The NCI-COG Pediatric MATCH trial assigns patients age 1-21 years with relapsed or refractory solid tumors, lymphomas, and histiocytic disorders to phase II studies of molecularly targeted therapies on the basis of detection of predefined genetic alterations. Patients with tumors harboring mutations or fusions driving activation of the mitogen-activated protein kinase (MAPK) pathway were treated with the MEK inhibitor selumetinib. METHODS: Patients received selumetinib twice daily for 28-day cycles until disease progression or intolerable toxicity. The primary end point was objective response rate; secondary end points included progression-free survival and tolerability of selumetinib. RESULTS: Twenty patients (median age: 14 years) were treated. All were evaluable for response and toxicities. The most frequent diagnoses were high-grade glioma (HGG; n = 7) and rhabdomyosarcoma (n = 7). Twenty-one actionable mutations were detected: hotspot mutations in KRAS (n = 8), NRAS (n = 3), and HRAS (n = 1), inactivating mutations in NF1 (n = 7), and BRAF V600E (n = 2). No objective responses were observed. Three patients had a best response of stable disease including two patients with HGG (NF1 mutation, six cycles; KRAS mutation, 12 cycles). Six-month progression-free survival was 15% (95% CI, 4 to 34). Five patients (25%) experienced a grade 3 or higher adverse event that was possibly or probably attributable to study drug. CONCLUSION: A national histology-agnostic molecular screening strategy was effective at identifying children and young adults eligible for treatment with selumetinib in the first Pediatric MATCH treatment arm to be completed. MEK inhibitors have demonstrated promising responses in some pediatric tumors (eg, low-grade glioma and plexiform neurofibroma). However, selumetinib in this cohort with treatment-refractory tumors harboring MAPK alterations demonstrated limited efficacy, indicating that pathway mutation status alone is insufficient to predict response to selumetinib monotherapy for pediatric cancers.

Biostatistical and Logistical Considerations in the Development of Basket and Umbrella Clinical Trials.

Oncology clinical trials are undergoing transformation to evaluate targeted therapies addressing a wider variety of biologically defined cancer subgroups. Multiarm basket and umbrella trials conducted under master protocols have become more prominent mechanisms for the clinical evaluation of promising new biologically driven anticancer therapies that are integral to precision oncology medicine. These new trial designs permit efficient clinical evaluation of multiple therapies in a variety of histologically and biologically defined cancers. These complex trials require extensive planning and attention to many factors, including choice of biomarker assay platform, mechanism for processing clinicopathologic and biomarker data to assign patients to substudies, and statistical design, monitoring, and analysis of substudies. Trial teams have expanded to include expertise in the interface between biology, clinical oncology, bioinformatics, and statistics. Strategies for the design, conduct, and analysis of these complex trials will continue to evolve to meet new challenges and opportunities in precision oncology medicine.

Treatment and survival in a population-based sample of patients diagnosed with gastroesophageal adenocarcinoma.

AIM: To examine the extent of use of specific therapies in clinical practice, and their relationship to therapies validated in clinical trials. METHODS: The US National Cancer Institutes' Patterns of Care study was used to examine therapies and survival of patients diagnosed in 2001 with histologically-confirmed gastroesophageal adenocarcinoma (n = 1356). The study re-abstracted data and verified therapy with treating physicians for a population-based stratified random sample. RESULTS: Approximately 62% of patients had stomach adenocarcinoma (SAC), while 22% had gastric-cardia adenocarcinoma (GCA), and 16% lower esophageal adenocarcinoma (EAC). Stage IV/unstaged esophageal cancer patients were most likely and stage I-III stomach cancer patients least likely to receive chemotherapy as all or part of their therapy; gastric-cardia patients received chemotherapy at a rate between these two. In multivariable analysis by anatomic site, patients 70 years and older were significantly less likely than younger patients to receive chemotherapy alone or chemoradiation for all three anatomic sites. Among esophageal and stomach cancer patients, receipt of chemotherapy was associated with lower mortality; but no association was found among gastric-cardia patients. CONCLUSION: This study highlights the relatively low use of clinical trials-validated anti-cancer therapies in community practice. Use of chemotherapy-based treatment was associated with lower mortality, dependent on anatomic site. Findings suggest that physicians treat lower esophageal and SAC as two distinct entities, while gastric-cardia patients receive a mix of the treatment strategies employed for the two other sites.

Implementation of timeline reforms speeds initiation of National Cancer Institute-sponsored trials.

BACKGROUND: The National Cancer Institute (NCI) organized the Operational Efficiency Working Group in 2008 to develop recommendations for improving the speed with which NCI-sponsored clinical trials move from the idea stage to a protocol open to patient enrollment. METHODS: Given the many stakeholders involved, the Operational Efficiency Working Group advised a multifaceted approach to mobilize the entire research community to improve their business processes. New staff positions to monitor progress, protocol-tracking Web sites, and strategically planned conference calls were implemented. NCI staff and clinical teams at Cooperative Groups and Cancer Centers strived to achieve new target timelines but, most important, agreed to abide by absolute deadlines. For phase I-II studies and phase III studies, the target timelines are 7 months and 10 months, whereas the absolute deadlines were set at 18 and 24 months, respectively. Trials not activated by the absolute deadline are automatically disapproved. RESULTS: The initial experience is encouraging and indicates a reduction in development times for phase I-II studies from the historical median of 541 days to a median of 442 days, an 18.3% decrease. The experience with phase III studies to date, although more limited (n = 25), demonstrates a 45.7% decrease in median days. CONCLUSIONS: Based upon this progress, the NCI and the investigator community have agreed to reduce the absolute deadlines to 15 and 18 months for phase I-II and III trials, respectively. Emphasis on initiating trials rapidly is likely to help reduce the time it takes for clinical trial results to reach patients in need of new treatments.

Blinded independent central review of progression-free survival in phase III clinical trials: important design element or unnecessary expense?

Progression-free survival is an important end point in advanced disease settings. Blinded independent central review (BICR) of progression in randomized clinical trials has been advocated to control bias that might result from errors in progression assessments. However, although BICR lessens some potential biases, it does not remove all biases from evaluations of treatment effectiveness. In fact, as typically conducted, BICRs may introduce bias because of informative censoring, which results from having to censor unconfirmed locally determined progressions. In this article, we discuss the rationale for BICR and different ways of implementing independent review. We discuss the limitations of these approaches and review published trials that report implementing BICR. We demonstrate the existence of informative censoring using data from a randomized phase II trial. We conclude that double-blinded trials with consistent application of measurement criteria are the best means of ensuring unbiased trial results. When such designs are not practical, BICR is not recommended as a general strategy for reducing bias. However, BICR may be useful as an auditing tool to assess the reliability of marginally positive results.

Patterns of care for adjuvant therapy in a random population-based sample of patients diagnosed with colorectal cancer.

OBJECTIVES: Over the past decade, clinical trials have proved the efficacy of treatments for colorectal cancer (CRC). This study tracks dissemination of these treatments for patients diagnosed with stage II and III disease and compares risk of death for those who received guideline therapy to those who did not. METHODS: We conducted a stratified randomly sampled, population-based study of CRC treatment trends in the United States. Multivariate models were used to explore patient characteristics associated with receipt of treatments. We pooled data with a previous study-patients diagnosed in 1987-1991 and 1995. Cox proportional hazards models were used to assess observed cause-specific and all-cause mortality. RESULTS: In 2000, guideline therapy receipt decreased among stage III rectal cancer patients, but increased for stage III colon and stage II rectal cancer patients. As age increased, likelihood of receiving guideline treatment decreased (p < 0.0001). Overall, race/ethnicity was significantly associated with guideline therapy (p = 0.04). Rectal patients were less likely to have received guideline treatment. Consistent with randomized clinical trial findings, all-cause mortality was lower in patients who received guideline therapy, regardless of Charlson comorbidity score. CONCLUSIONS: Mortality was decreased in patients receiving guideline therapy. Although, rates of guideline-concordant therapy are low in community clinical practice, they are apparently increasing. Newer treatment (oxaliplatin, capecitabine) started to disseminate in 2000. Racial disparities, present in 1995, were not detected in 2000. Age disparities remain despite no evidence of greater chemotherapy-induced toxicity in the elderly. More equitable receipt of cancer treatment to all segments of the community will help to reduce mortality.