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Efficacy and Safety of High-Specific-Activity ¹³¹I-MIBG Therapy in Patients with Advanced Pheochromocytoma or Paraganglioma.

ABSTRACT: Patients with metastatic or unresectable (advanced) pheochromocytoma and paraganglioma (PPGL) have poor prognoses and few treatment options. This multicenter, phase 2 trial evaluated the efficacy and safety of high-specific-activity ¹³¹I-meta-iodobenzylguanidine (HSA ¹³¹I-MIBG) in patients with advanced PPGL. Methods: In this open-label, single-arm study, 81 PPGL patients were screened for enrollment, and 74 received a treatment-planning dose of HSA ¹³¹I-MIBG. Of these patients, 68 received at least 1 therapeutic dose (∼18.5 GBq) of HSA ¹³¹I-MIBG intravenously. The primary endpoint was the proportion of patients with at least a 50% reduction in baseline antihypertensive medication use lasting at least 6 mo. Secondary endpoints included objective tumor response as assessed by Response Evaluation Criteria in Solid Tumors version 1.0, biochemical tumor marker response, overall survival, and safety. Results: Of the 68 patients who received at least 1 therapeutic dose of HSA ¹³¹I-MIBG, 17 (25%; 95% confidence interval, 16%-37%) had a durable reduction in baseline antihypertensive medication use. Among 64 patients with evaluable disease, 59 (92%) had a partial response or stable disease as the best objective response within 12 mo. Decreases in elevated (≥1.5 times the upper limit of normal at baseline) serum chromogranin levels were observed, with confirmed complete and partial responses 12 mo after treatment in 19 of 28 patients (68%). The median overall survival was 36.7 mo (95% confidence interval, 29.9-49.1 mo). The most common treatment-emergent adverse events were nausea, myelosuppression, and fatigue. No patients had drug-related acute hypertensive events during or after the administration of HSA ¹³¹I-MIBG. Conclusion: HSA ¹³¹I-MIBG offers multiple benefits, including sustained blood pressure control and tumor response in PPGL patients.

SUBMITTER: Pryma DA

PROVIDER: S-EPMC6495236 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Abstract Introduction: Iobenguane scan positive cancers including pheochromocytoma/paraganglioma (PPGL), neuroblastoma, and gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are heterogeneous tumors that arise from neuroendocrine cells. Recently, high-specific-activity I-131 meta-iodobenzylguanidine (HSA I-131 MIBG, AZEDRA®) was approved in the US for treatment of adult and pediatric patients 12 years and older with iobenguane scan positive, unresectable, locally advanced or metastatic PPGL. We present a pooled analysis of all available clinical trials to further assess the safety profile of HSA I-131 MIBG. Methods: 118 patients from four HSA I-131 MIBG clinical trials (NCT00339131; NCT00458952; NCT00874614; NCT00659984) were included in a pooled analysis for safety assessments. Adverse events (AEs), laboratory tests, number and quantity of HSA I-131 MIBG doses, hypertensive events, blood pressure (BP), heart rate, ECG, and AEs of special interest (AESI) were analyzed using descriptive statistics. Results: Gastrointestinal (GI) toxicities, especially nausea and vomiting, were the most common AEs associated with HSA I-131 MIBG. GI toxicities were not reported after dosimetry doses. GI, blood and lymphatic system, and vascular disorders were higher in PPGL than in neuroblastoma after therapeutic dose 1 when compared to therapeutic dose 2. The incidence of potentially clinically significant changes in BP was similar following dosimetric and therapeutic doses and are consistent with the underlying hypertension associated with PPGL. No spike in systolic and diastolic BP was observed within the first 4 hours of HSA I-131 MIBG administration, and there were no acute hypertensive crises following dosing. A possibly drug-related mild increase in BP within 48 hours of therapeutic dosing was observed in 1 subject with PPGL. Variations in heart rate (>20 beats/min) were higher after therapeutic dose 1 than after other doses. No clinically significant trends were seen in mean ECG results or mean changes from baseline. All patients received at least one concomitant medication. About 40% of patients received β-blockers, 39% α-blockers, and about 27% other peripheral vasodilators. 87.3% of patients reported an AESI, defined as AEs that are related to the acute and/or chronic effects of radiation toxicity seen any time post dosing. The most common AESIs were nausea (66.1%), thrombocytopenia (50.0%), fatigue (50.0%), neutropenia (42.4%), and diarrhea (22.9%). The incidence of most AESIs were similar after each therapeutic dose. Conclusions: HSA I-131 MIBG demonstrated a favorable safety profile in iobenguane scan positive cancers. AEs followed an expected pattern comparable to other radioactive therapeutic agents. Most cardiovascular events, including hypertensive events mostly commonly observed in PPGL, were not considered related to HSA I-131 MIBG.

Project description:BackgroundPheochromocytomas (PCCs) and paragangliomas (PGLs) are neuroendocrine tumors that are mostly benign. Metastatic disease does occur in about 10% of cases of PCC and up to 25% of PGL, and for these patients no effective therapies are available. Patients with mutations in the succinate dehydrogenase subunit B (SDHB) gene tend to have metastatic disease. We hypothesized that a down-regulation in the active succinate dehydrogenase B subunit should result in notable changes in cellular metabolic profile and could present a vulnerability point for successful pharmacological targeting.MethodsMetabolomic analysis was performed on human hPheo1 cells and shRNA SDHB knockdown hPheo1 (hPheo1 SDHB KD) cells. Additional analysis of 115 human fresh frozen samples was conducted. In vitro studies using N1,N11-diethylnorspermine (DENSPM) and N1,N12- diethylspermine (DESPM) treatments were carried out. DENSPM efficacy was assessed in human cell line derived mouse xenografts.ResultsComponents of the polyamine pathway were elevated in hPheo1 SDHB KD cells compared to wild-type cells. A similar observation was noted in SDHx PCC/PGLs tissues compared to their non-mutated counterparts. Specifically, spermidine, and spermine were significantly elevated in SDHx-mutated PCC/PGLs, with a similar trend in hPheo1 SDHB KD cells. Polyamine pathway inhibitors DENSPM and DESPM effectively inhibited growth of hPheo1 cells in vitro as well in mouse xenografts.ConclusionsThis study demonstrates overactive polyamine pathway in PCC/PGL with SDHB mutations. Treatment with polyamine pathway inhibitors significantly inhibited hPheo1 cell growth and led to growth suppression in xenograft mice treated with DENSPM. These studies strongly implicate the polyamine pathway in PCC/PGL pathophysiology and provide new foundation for exploring the role for polyamine analogue inhibitors in treating metastatic PCC/PGL. PRéCIS: Cell line metabolomics on hPheo1 cells and PCC/PGL tumor tissue indicate that the polyamine pathway is activated. Polyamine inhibitors in vitro and in vivo demonstrate that polyamine inhibitors are promising for malignant PCC/PGL treatment. However, further research is warranted.

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Efficacy and Safety of High-Specific-Activity 131I-MIBG Therapy in Patients with Advanced Pheochromocytoma or Paraganglioma.

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Efficacy and Safety of High-Specific-Activity ¹³¹I-MIBG Therapy in Patients with Advanced Pheochromocytoma or Paraganglioma.