Irinotecan-temozolomide with temsirolimus or dinutuximab in children with refractory or relapsed neuroblastoma (COG ANBL1221): an open-label, randomised, phase 2 trial.
Ontology highlight
ABSTRACT:
SUBMITTER: Mody R
PROVIDER: S-EPMC5527694 | biostudies-literature | 2017 Jul
REPOSITORIES: biostudies-literature
Publications
Irinotecan-temozolomide with temsirolimus or dinutuximab in children with refractory or relapsed neuroblastoma (COG ANBL1221): an open-label, randomised, phase 2 trial.
Mody Rajen R Naranjo Arlene A Van Ryn Collin C Yu Alice L AL London Wendy B WB Shulkin Barry L BL Parisi Marguerite T MT Servaes Sabah-E-Noor SE Diccianni Mitchell B MB Sondel Paul M PM Bender Julia G JG Maris John M JM Park Julie R JR Bagatell Rochelle R
The Lancet. Oncology 20170523 7
<h4>Background</h4>Outcomes for children with relapsed and refractory neuroblastoma are dismal. The combination of irinotecan and temozolomide has activity in these patients, and its acceptable toxicity profile makes it an excellent backbone for study of new agents. We aimed to test the addition of temsirolimus or dinutuximab to irinotecan-temozolomide in patients with relapsed or refractory neuroblastoma.<h4>Methods</h4>For this open-label, randomised, phase 2 selection design trial of the Chil ...[more]
Similar Datasets
Project description:PurposeThe combination of irinotecan, temozolomide, dintuximab, and granulocyte-macrophage colony-stimulating factor (I/T/DIN/GM-CSF) demonstrated activity in patients with relapsed/refractory neuroblastoma in the randomized Children's Oncology Group ANBL1221 trial. To more accurately assess response rate and toxicity, an expanded cohort was nonrandomly assigned to I/T/DIN/GM-CSF.Patients and methodsPatients were eligible at first relapse or first designation of refractory disease. Oral T and intravenous (IV) irinotecan were administered on days 1 to 5 of 21-day cycles. DIN was administered IV (days 2-5), and GM-CSF was administered subcutaneously (days 6-12). The primary end point was objective response, analyzed on an intent-to-treat basis per the International Neuroblastoma Response Criteria.ResultsSeventeen eligible patients were randomly assigned to I/T/DIN/GM-CSF (February 2013 to March 2015); 36 additional patients were nonrandomly assigned to I/T/DIN/GM-CSF (August 2016 to May 2017). Objective (complete or partial) responses were observed in nine (52.9%) of 17 randomly assigned patients (95% CI, 29.2% to 76.7%) and 13 (36.1%) of 36 expansion patients (95% CI, 20.4% to 51.8%). Objective responses were seen in 22 (41.5%) of 53 patients overall (95% CI, 28.2% to 54.8%); stable disease was also observed in 22 of 53. One-year progression-free and overall survival for all patients receiving I/T/DIN/GM-CSF were 67.9% ± 6.4% (95% CI, 55.4% to 80.5%) and 84.9% ± 4.9% (95% CI, 75.3% to 94.6%), respectively. Two patients did not receive protocol therapy and were evaluable for response but not toxicity. Common grade ≥ 3 toxicities were fever/infection (18 [35.3%] of 51), neutropenia (17 [33.3%] of 51), pain (15 [29.4%] of 51), and diarrhea (10 [19.6%] of 51). One patient met protocol-defined criteria for unacceptable toxicity (grade 4 hypoxia). Higher DIN trough levels were associated with response.ConclusionI/T/DIN/GM-CSF has significant antitumor activity in patients with relapsed/refractory neuroblastoma. Study of chemoimmunotherapy in the frontline setting is indicated, as is further evaluation of predictive biomarkers.
| S-EPMC7325366 | biostudies-literature
Project description:BackgroundShort-term infusions of dinutuximab beta plus isotretinoin and cytokines administered in previous immunotherapy studies in neuroblastoma were associated with severe pain. Here, long-term, continuous infusion of single-agent dinutuximab beta was evaluated in patients with relapsed/refractory neuroblastoma.MethodsIn this open-label, single-arm, Phase 2 study, patients with either refractory or relapsed high-risk neuroblastoma received dinutuximab beta by continuous infusion over 10 days of each cycle, for up to five cycles. The primary endpoint was objective response rate 24 weeks after the end of cycle 5. Secondary endpoints included adverse events, intravenous morphine use, best response, duration of response, and three-year progression-free and overall survival.ResultsOf the 40 patients included, 38 had evaluable response. Objective response rate was 26% and best response rate 37%. Median duration of response was 238 days (IQR 108-290). Three-year progression-free and overall survival rates were 31% (95% CI 17-47) and 66% (95% CI 47-79), respectively. Prophylactic intravenous morphine use and duration of use decreased with increasing cycles. The most common grade 3 treatment-related adverse events were pain, diarrhea, and hypokalemia.ConclusionLong-term continuous infusion of single-agent dinutuximab beta is tolerable and associated with clinically meaningful responses in patients with relapsed/refractory high-risk neuroblastoma.Clinical trial registrationThe study is registered with ClinicalTrials.gov (NCT02743429) and EudraCT (2014-000588-42).
| S-EPMC10667538 | biostudies-literature
Project description:The rationale for studying the combination of bevacizumab, irinotecan, and temozolomide (BIT) in neuroblastoma (NB) is based on the following: (i) vascular endothelial growth factor (VEGF) expression is associated with an aggressive phenotype, (ii) anti-VEGF antibody bevacizumab enhances irinotecan-mediated suppression of NB xenografts, (iii) bevacizumab safety has been established in pediatric phase I studies, and (iv) irinotecan + temozolomide (IT) is a standard salvage chemotherapy. We conducted a phase II study of BIT in patients with measurable/evaluable refractory or relapsed high-risk NB (www.clinicaltrials.gov, NCT01114555). Each cycle consisted of bevacizumab (15 mg/kg intravenously [IV]) on days 1 and 15 plus irinotecan (50 mg/m2 /day IV) and temozolomide (150 mg/m2 /day orally) on days 4-8. Patients could have previously received, but not relapsed on, IT. An early stopping rule mandated continuing therapy only if more than five patients of 27 evaluable patients achieved partial response (PR) or complete response (CR) after four cycles. Thirty-three heavily pretreated patients (nine primary refractory; 24 relapsed) received one to eight cycles of BIT. Toxicities were expected and transient. Grade 4 toxicities were neutropenia (30%) and thrombocytopenia (24%). Grade 3 toxicities included hepatic transaminitis (15%), proteinuria (9%), and diarrhea (3%). Overall responses were as follows: three CR (all in prior IT-treated patients), 18 no response, and 12 progressive disease. Only one of 23 patients assessable for the early stopping rule regarding efficacy achieved PR/CR, so patient accrual was discontinued. Median progression-free survival and overall survival was 7.7 ± 1.7 and 31.5 ± 5.6 months, respectively; all patients continued anti-NB therapy post-BIT. BIT was well tolerated, but the addition of bevacizumab did not improve response rates in resistant NB compared to historical data for IT.
| S-EPMC5555116 | biostudies-literature
Project description:Prognosis in children with refractory and relapsed high-risk neuroblastoma is poor. Only a minority of patients obtain remission when treated with second-line chemotherapy regimens. Chemotherapy combined with anti-GD2 antibodies has previously been shown to increase response and survival rates. We retrospectively analyzed a cohort of 25 patients with relapsed or refractory high-risk neuroblastoma who were treated with irinotecan/temozolomide chemotherapy in combination with the anti-GD2 antibody dinutuximab beta. The therapy resulted in an objective response rate of 64%, with 32% of patients achieving a complete response. Response to treatment was observed in patients with refractory disease (n=5) and those with first (n=12) or consecutive (n=8) relapses, including patients with progressing disease. In four patients, best response was achieved after more than 5 cycles, suggesting that some patients may benefit from prolonged chemotherapy and dinutuximab beta treatment. Fourteen of our 25 patients had previously received dinutuximab beta, four of whom achieved complete response and six partial response (objective response rate 71%). The therapy was well tolerated, even in heavily pre-treated patients and those who had previously received dinutuximab beta treatment. Toxicities were comparable to those previously reported for the individual therapies, and no discontinuations due to toxicities occurred. Combination of chemotherapy with dinutuximab beta is a promising treatment option for patients with relapsed or refractory high-risk neuroblastoma and should be further explored in clinical studies.
| S-EPMC9936065 | biostudies-literature
Project description:PurposeIn phase I testing, alisertib tablets with irinotecan and temozolomide showed significant antitumor activity in patients with neuroblastoma. This study sought to confirm activity of this regimen; evaluate an alisertib oral solution; and evaluate biomarkers of clinical outcomes.Patients and methodsWe conducted a two-stage phase II trial of alisertib tablets (60 mg/m2/dose × 7 days), irinotecan (50 mg/m2/dose i.v. × 5 days), and temozolomide (100 mg/m2/dose orally × 5 days) in patients with relapsed or refractory neuroblastoma. The primary endpoint was best objective response. A separate cohort was treated with alisertib at 45 mg/m2 using oral solution instead of tablets. Exploratory analyses sought to identify predictors of toxicity, response, and progression-free survival (PFS) using pooled data from phase I, phase II, and oral solution cohorts.ResultsTwenty and 12 eligible patients were treated in the phase II and oral solution cohorts, respectively. Hematologic toxicities were the most common adverse events. In phase II, partial responses were observed in 19 evaluable patients (21%). The estimated PFS at 1 year was 34%. In the oral solution cohort, 3 patients (25%) had first cycle dose-limiting toxicity (DLT). Alisertib oral solution at 45 mg/m2 had significantly higher median C max and exposure compared with tablets at 60 mg/m2. Higher alisertib trough concentration was associated with first cycle DLT, whereas MYCN amplification was associated with inferior PFS.ConclusionsThis combination shows antitumor activity, particularly in patients with MYCN nonamplified tumors. Data on an alisertib oral solution expand the population able to be treated with this agent.
| S-EPMC6295246 | biostudies-literature
Project description:BackgroundPatients with primary refractory and relapsed neuroblastoma have a poor prognosis since safe and effective chemotherapies for these patients are currently limited. The development of new chemotherapy regimens for these patients is imperative to improve survival outcomes.MethodsWe retrospectively analyzed 40 patients with refractory (n = 36) or relapsed (n = 4) neuroblastoma who received irinotecan, etoposide, and carboplatin (IREC) as a second-line treatment. We evaluated their therapeutic response and the toxicity of IREC. We also assessed the impact of UGT1A1 gene polymorphisms, which are involved in irinotecan metabolism, on outcomes and toxicity.ResultsA total of 112 cycles of IREC were administered to 40 patients with a median of 2 cycles per patient (range, 1-9). Six (15%) patients (UGT1A1 wild-type [n = 2] and heterozygous [n = 4]) showed objective responses, including partial response (n = 1), tumor shrinkage (n = 4), and improved findings on their MIBG scan (n = 1). Grade 4 neutropenia, grade 4 leukopenia, and grades 3-4 gastrointestinal toxicity were observed in 110 (98%), 88 (79%), and 3 (3%) cycles, respectively. There was no IREC-related mortality. Patients with UGT1A1 polymorphisms showed a higher frequency of grade 4 leukopenia, but these patients did not have increased treatment-related mortality or non-hematologic toxicity.ConclusionsIREC showed an objective response rate of 15% including 1 case with partial response. IREC was well tolerated regardless of UGT1A1 genotype. This study suggests that IREC is a promising second-line chemotherapy for refractory or relapsed neuroblastoma.
| S-EPMC9089216 | biostudies-literature
Project description:PurposeAlisertib is an oral Aurora A kinase inhibitor with preclinical activity in neuroblastoma. Irinotecan and temozolomide have activity in patients with advanced neuroblastoma. The goal of this phase I study was to determine the maximum tolerated dose (MTD) of alisertib with irinotecan and temozolomide in this population.Patients and methodsPatients age 1 to 30 years with relapsed or refractory neuroblastoma were eligible. Patients received alisertib tablets at dose levels of 45, 60, and 80 mg/m(2) per day on days 1 to 7 along with irinotecan 50 mg/m(2) intravenously and temozolomide 100 mg/m(2) orally on days 1 to 5. Dose escalation of alisertib followed the rolling six design. Samples for pharmacokinetic and pharmacogenomic testing were obtained.ResultsTwenty-three patients enrolled, and 22 were eligible and evaluable for dose escalation. A total of 244 courses were administered. The MTD for alisertib was 60 mg/m(2), with mandatory myeloid growth factor support and cephalosporin prophylaxis for diarrhea. Thrombocytopenia and neutropenia of any grade were seen in the majority of courses (84% and 69%, respectively). Diarrhea in 55% of courses and nausea in 54% of courses were the most common nonhematologic toxicities. The overall response rate was 31.8%, with a 50% response rate observed at the MTD. The median number of courses per patient was eight (range, two to 32). Progression-free survival rate at 2 years was 52.4%. Pharmacokinetic testing did not show evidence of drug-drug interaction between irinotecan and alisertib.ConclusionAlisertib 60 mg/m(2) per dose for 7 days is tolerable with a standard irinotecan and temozolomide backbone and has promising response and progression-free survival rates. A phase II trial of this regimen is ongoing.
| S-EPMC4872349 | biostudies-literature
Project description:Dinutuximab beta is approved for the maintenance treatment of patients with high-risk neuroblastoma (HR-NB), including patients with relapsed/refractory (R/R) disease. However, the data on its use in real-world clinical practice is limited. We retrospectively reviewed the clinical records of 54 patients with HR-NB who received maintenance therapy with dinutuximab beta in first-line (37 patients) or R/R settings (17 patients) at three centers in Poland. Of the 37 patients who received first-line treatment, twenty-eight had a complete response, two had a partial response, three had progressive disease, and four relapsed at the end of treatment. The median overall survival (OS) was 24.37 months, and the three-year progression-free survival (PFS) and OS were 0.63 and 0.80, respectively. Of the 17 patients in the R/R group, 11 had a complete response, two had a partial response, one had stable disease, and three had progressive disease or relapsed at the end of treatment. The median OS was 33.1 months and the three-year PFS and OS were 0.75 and 0.86, respectively. Treatment was generally well tolerated, including in patients with co-morbidities and those who had experienced toxicities with previous therapies. These findings demonstrate that the use of dinutuximab beta is feasible and beneficial as a first-line or R/R treatment in routine clinical practice in Poland.
| S-EPMC10455178 | biostudies-literature
Project description:PurposeIrinotecan and temozolomide have single-agent activity and schedule-dependent synergy against neuroblastoma. Because protracted administration of intravenous irinotecan is costly and inconvenient, we sought to determine the maximum-tolerated dose (MTD) of oral irinotecan combined with temozolomide in children with recurrent/resistant high-risk neuroblastoma.Patients and methodsPatients received oral temozolomide on days 1 through 5 combined with oral irinotecan on days 1 through 5 and 8 through 12 in 3-week courses. Daily oral cefixime was used to reduce irinotecan-associated diarrhea.ResultsFourteen assessable patients received 75 courses. Because neutropenia and thrombocytopenia were initially dose-limiting, temozolomide was reduced from 100 to 75 mg/m(2)/d for subsequent patients. Irinotecan was then escalated from 30 to 60 mg/m2/d. First-course grade 3 diarrhea was dose-limiting in one of six patients treated at the irinotecan MTD of 60 mg/m2/d. Other toxicities were mild and reversible. The median SN-38 lactone area under the plasma concentration versus time curve at this dose was 72 ng . hr/mL. One patient with bulky soft tissue disease had a complete response through six courses. Six additional patients received a median of seven courses (range, three to 22 courses) before progression.ConclusionThis all-oral regimen was feasible and well tolerated in heavily pretreated children with resistant neuroblastoma, and seven (50%) of 14 assessable patients had response or disease stabilization for three or more courses in this phase I trial. SN-38 lactone exposures were similar to those reported with protracted intravenous irinotecan. The dosages recommended for further study in this patient population are temozolomide 75 mg/m2/d plus irinotecan 60 mg/m2/d when given with cefixime.
| S-EPMC2667827 | biostudies-literature
Project description:PurposeThe hu14.18-IL2 fusion protein consists of interleukin-2 molecularly linked to a humanized monoclonal antibody that recognizes the GD2 disialoganglioside expressed on neuroblastoma cells. This phase II study assessed the antitumor activity of hu14.18-IL2 in two strata of patients with recurrent or refractory neuroblastoma.Patients and methodsHu14.18-IL2 was given intravenously (12 mg/m(2)/daily) for 3 days every 4 weeks for patients with disease measurable by standard radiographic criteria (stratum 1) and for patients with disease evaluable only by [(123)I]metaiodobenzylguanidine (MIBG) scintigraphy and/or bone marrow (BM) histology (stratum 2). Response was established by independent radiology review as well as BM histology and immunocytology, and durability was assessed by repeat evaluation after more than 3 weeks.ResultsThirty-nine patients were enrolled (36 evaluable). No responses were seen in stratum 1 (n = 13). Of 23 evaluable patients in stratum 2, five patients (21.7%) responded; all had a complete response (CR) of 9, 13, 20, 30, and 35+ months duration. Grade 3 and 4 nonhematologic toxicities included capillary leak, hypoxia, pain, rash, allergic reaction, elevated transaminases, and hyperbilirubinemia. Two patients required dopamine for hypotension, and one patient required ventilatory support for hypoxia. Most toxicities were reversible within a few days of completing a treatment course and were expected based on phase I results.ConclusionPatients with disease evaluable only by MIBG and/or BM histology had a 21.7% CR rate to hu14.8-IL2, whereas patients with bulky disease did not respond. Hu14.18-IL2 warrants further testing in children with nonbulky high-risk neuroblastoma.
| S-EPMC3020698 | biostudies-literature