26 research outputs found
Lorlatinib with or without chemotherapy in ALK-driven refractory/relapsed neuroblastoma: phase 1 trial results.
Neuroblastomas harbor ALK aberrations clinically resistant to crizotinib yet sensitive pre-clinically to the third-generation ALK inhibitor lorlatinib. We conducted a first-in-child study evaluating lorlatinib with and without chemotherapy in children and adults with relapsed or refractory ALK-driven neuroblastoma. The trial is ongoing, and we report here on three cohorts that have met pre-specified primary endpoints: lorlatinib as a single agent in children (12 months to <18 years); lorlatinib as a single agent in adults (≥18 years); and lorlatinib in combination with topotecan/cyclophosphamide in children (<18 years). Primary endpoints were safety, pharmacokinetics and recommended phase 2 dose (RP2D). Secondary endpoints were response rate and 123I-metaiodobenzylguanidine (MIBG) response. Lorlatinib was evaluated at 45-115 mg/m2/dose in children and 100-150 mg in adults. Common adverse events (AEs) were hypertriglyceridemia (90%), hypercholesterolemia (79%) and weight gain (87%). Neurobehavioral AEs occurred mainly in adults and resolved with dose hold/reduction. The RP2D of lorlatinib with and without chemotherapy in children was 115 mg/m2. The single-agent adult RP2D was 150 mg. The single-agent response rate (complete/partial/minor) for <18 years was 30%; for ≥18 years, 67%; and for chemotherapy combination in <18 years, 63%; and 13 of 27 (48%) responders achieved MIBG complete responses, supporting lorlatinib's rapid translation into active phase 3 trials for patients with newly diagnosed high-risk, ALK-driven neuroblastoma. ClinicalTrials.gov registration: NCT03107988
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Impact of Whole‐Body Radiation Dose on Response and Toxicity in Patients With Neuroblastoma After Therapy With 131I‐Metaiodobenzylguanidine (MIBG)
BACKGROUND:(131) I-metaiodobenzylguanidine ((131) I-MIBG) is a targeted radiopharmaceutical for patients with neuroblastoma. Despite its tumor-specific uptake, the treatment with (131) I-MIBG results in whole-body radiation exposure. Our aim was to correlate whole-body radiation dose (WBD) from (131) I-MIBG with tumor response, toxicities, and other clinical factors. METHODS:This retrospective cohort analysis included 213 patients with high-risk neuroblastoma treated with (131) I-MIBG at UCSF Benioff Children's Hospital between 1996 and 2015. WBD was determined from radiation exposure rate measurements. The relationship between WBD ordered tertiles and variables were analyzed using Cochran-Mantel-Haenszel test of trend, Kruskal-Wallis test, and one-way analysis of variance. Correlation between WBD and continuous variables was analyzed using Pearson correlation and Spearman rank correlation. RESULTS:WBD correlated with (131) I-MIBG administered activity, particularly with (131) I-MIBG per kilogram (P < 0.001). Overall response rate did not differ significantly among the three tertiles of WBD. Correlation between response by relative Curie score and WBD was of borderline significance, with patients receiving a lower WBD showing greater reduction in osteomedullary metastases by Curie score (rs = 0.16, P = 0.049). There were no significant ordered trends among tertiles in any toxicity measures (grade 4 neutropenia, thrombocytopenia < 20,000/μl, and grade > 1 hypothyroidism). CONCLUSIONS:This study showed that (131) I-MIBG activity per kilogram correlates with WBD and suggests that activity per kilogram will predict WBD in most patients. Within the range of activities prescribed, there was no correlation between WBD and either response or toxicity. Future studies should evaluate tumor dosimetry, rather than just WBD, as a tool for predicting response following therapy with (131) I-MIBG
Peripheral Blood Transcript Signatures after Internal 131I-mIBG Therapy in Relapsed and Refractory Neuroblastoma Patients Identifies Early and Late Biomarkers of Internal 131I Exposures
131I-metaiodobenzylguanidine (131I-mIBG) is a targeted radiation therapy developed for the treatment of advanced neuroblastoma. We have previously shown that this patient cohort can be used to predict absorbed dose associated with early 131I exposure, 72 h after treatment. We now expand these studies to identify gene expression differences associated with 131I-mIBG exposure 15 days after treatment. Total RNA from peripheral blood lymphocytes was isolated from 288 whole blood samples representing 59 relapsed or refractory neuroblastoma patients before and after 131I-mIBG treatment. We found that several transcripts predictive of early exposure returned to baseline levels by day 15, however, selected transcripts did not return to baseline. At 72 h, all 17 selected pathway-specific transcripts were differentially expressed. Transcripts CDKN1A (P < 0.000001), FDXR (P < 0.000001), DDB2 (P < 0.000001), and BBC3 (P < 0.000001) showed the highest up-regulation at 72 h after 131I-mIBG exposure, with mean log2 fold changes of 2.55, 2.93, 1.86 and 1.85, respectively. At day 15 after 131I-mIBG, 11 of the 17 selected transcripts were differentially expressed, with XPC, STAT5B, PRKDC, MDM2, POLH, IGF1R, and SGK1 displaying significant up-regulation at 72 h and significant down-regulation at day 15. Interestingly, transcripts FDXR (P = 0.01), DDB2 (P = 0.03), BCL2 (P = 0.003), and SESN1 (P < 0.0003) maintained differential expression 15 days after 131I-mIBG treatment. These results suggest that transcript levels for DNA repair, apoptosis, and ionizing radiation-induced cellular stress are still changing by 15 days after 131I-mIBG treatment. Our studies showcase the use of biodosimetry gene expression panels as predictive biomarkers following early (72 h) and late (15 days) internal 131I exposure. Our findings also demonstrate the utility of our transcript panel to differentiate exposed from non-exposed individuals up to 15 days after exposure from internal 131I
Incidence and risk factors for secondary malignancy in patients with neuroblastoma after treatment with 131I-metaiodobenzylguanidine
Several reports of second malignant neoplasm (SMN) in patients with relapsed neuroblastoma after treatment with (131)I-MIBG suggest the possibility of increased risk. Incidence of and risk factors for SMN after (131)I-MIBG have not been defined. This is a multi-institutional retrospective review of patients with neuroblastoma treated with (131)I-MIBG therapy. A competing risk approach was used to calculate the cumulative incidence of SMN from time of first exposure to (131)I-MIBG. A competing risk regression was used to identify potential risk factors for SMN. The analytical cohort included 644 patients treated with (131)I-MIBG. The cumulative incidence of SMN was 7.6% (95% confidence interval [CI], 4.4-13.0%) and 14.3% (95% CI, 8.3-23.9%) at 5 and 10 years from first (131)I-MIBG, respectively. No increase in SMN risk was found with increased number of (131)I-MIBG treatments or higher cumulative activity per kilogram of (131)I-MIBG received (p = 0.72 and p = 0.84, respectively). Thirteen of the 19 reported SMN were haematologic. In a multivariate analysis controlling for variables with p < 0.1 (stage, age at first (131)I-MIBG, bone disease, disease status at time of first (131)I-MIBG), patients with relapsed/progressive disease had significantly lower risk of SMN (subdistribution hazard ratio 0.3, 95% CI, 0.1-0.8, p = 0.023) compared to patients with persistent/refractory neuroblastoma. The cumulative risk of SMN after (131)I-MIBG therapy for patients with relapsed or refractory neuroblastoma is similar to the greatest published incidence for high-risk neuroblastoma after myeloablative therapy, with no dose-dependent increase. As the number of patients treated and length of follow-up time increase, it will be important to reassess this risk