Dataset Information

Phase I study of the anti-IGF1R antibody cixutumumab with everolimus and octreotide in advanced well-differentiated neuroendocrine tumors.

ABSTRACT: Preclinical data suggest multiple roles for the IGF1 receptor (IGF1R) in neuroendocrine tumors (NETs), including mediating resistance to mammalian target of rapamycin (mTOR) inhibitors. Everolimus, an oral mTOR inhibitor, and octreotide long-acting repeatable (LAR) are approved for subgroups of well-differentiated NET. The primary objective of the present study was to establish the safety and recommended phase II dose (RP2D) of cixutumumab, a monoclonal antibody (MAB) against IGF1R, with everolimus and octreotide LAR. Patients with well-differentiated NET were treated with 10? mg everolimus p.o. daily, 20? mg octreotide LAR i.m. every 21 days, and escalating doses of cixutumumab. An expansion cohort was enrolled at RP2D. Correlative studies included the evaluation of mTOR pathway inhibition in paired tumor biopsies and the effects of this combination on metabolism via indirect calorimetry. Nineteen patients with progressive disease were enrolled, including nine to the expansion portion. Two patients had dose-limiting toxicities of grade 3 mucositis at 15? mg/kg cixutumumab. Long-term tolerance at RP2D was problematic, and the most common ?grade 3 adverse event was fatigue. One patient with metastatic insulinoma had a confirmed partial response, whereas 17 had stable disease. The median progression-free survival was 43.6 weeks, and the median overall survival was 25.5 months. The RP2D of this combination per the predefined study protocol of 10? mg/kg cixutumumab i.v., 20? mg octreotide LAR i.m. every 21 days plus 10 ?mg everolimus p.o. daily is associated with non-dose-limiting toxicities that limit long-term tolerance. Although a signal of activity was noted in the present study, this will need to be reconciled with limited tolerance of the combination and data from larger studies of anti-IGF1R MABs in NET that have been disappointing.

SUBMITTER: Dasari A

PROVIDER: S-EPMC4566955 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

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Phase I study of the anti-IGF1R antibody cixutumumab with everolimus and octreotide in advanced well-differentiated neuroendocrine tumors.

Dasari Arvind A Phan Alexandria A Gupta Sanjay S Rashid Asif A Yeung Sai-Ching Jim SC Hess Kenneth K Chen Helen H Tarco Emily E Chen Huiqin H Wei Caimiao C Anh-Do Kim K Halperin Daniel D Meric-Bernstam Funda F Yao James J

Endocrine-related cancer 20150421 3

Preclinical data suggest multiple roles for the IGF1 receptor (IGF1R) in neuroendocrine tumors (NETs), including mediating resistance to mammalian target of rapamycin (mTOR) inhibitors. Everolimus, an oral mTOR inhibitor, and octreotide long-acting repeatable (LAR) are approved for subgroups of well-differentiated NET. The primary objective of the present study was to establish the safety and recommended phase II dose (RP2D) of cixutumumab, a monoclonal antibody (MAB) against IGF1R, with everoli ...[more]

PMID: 25900182

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Project description:BackgroundEverolimus, an oral inhibitor of mammalian target of rapamycin (mTOR), has shown antitumor activity in patients with advanced pancreatic neuroendocrine tumors, in two phase 2 studies. We evaluated the agent in a prospective, randomized, phase 3 study.MethodsWe randomly assigned 410 patients who had advanced, low-grade or intermediate-grade pancreatic neuroendocrine tumors with radiologic progression within the previous 12 months to receive everolimus, at a dose of 10 mg once daily (207 patients), or placebo (203 patients), both in conjunction with best supportive care. The primary end point was progression-free survival in an intention-to-treat analysis. In the case of patients in whom radiologic progression occurred during the study, the treatment assignments could be revealed, and patients who had been randomly assigned to placebo were offered open-label everolimus.ResultsThe median progression-free survival was 11.0 months with everolimus as compared with 4.6 months with placebo (hazard ratio for disease progression or death from any cause with everolimus, 0.35; 95% confidence interval [CI], 0.27 to 0.45; P<0.001), representing a 65% reduction in the estimated risk of progression or death. Estimates of the proportion of patients who were alive and progression-free at 18 months were 34% (95% CI, 26 to 43) with everolimus as compared with 9% (95% CI, 4 to 16) with placebo. Drug-related adverse events were mostly grade 1 or 2 and included stomatitis (in 64% of patients in the everolimus group vs. 17% in the placebo group), rash (49% vs. 10%), diarrhea (34% vs. 10%), fatigue (31% vs. 14%), and infections (23% vs. 6%), which were primarily upper respiratory. Grade 3 or 4 events that were more frequent with everolimus than with placebo included anemia (6% vs. 0%) and hyperglycemia (5% vs. 2%). The median exposure to everolimus was longer than exposure to placebo by a factor of 2.3 (38 weeks vs. 16 weeks).ConclusionsEverolimus, as compared with placebo, significantly prolonged progression-free survival among patients with progressive advanced pancreatic neuroendocrine tumors and was associated with a low rate of severe adverse events. (Funded by Novartis Oncology; RADIANT-3 ClinicalTrials.gov number, NCT00510068.).

Project description:BackgroundSeveral studies have demonstrated the antitumor activity of first-generation somatostatin analogs (SSAs), primarily targeting somatostatin receptor (sstr) subtypes 2 and 5, in neuroendocrine tumors (NET). Pasireotide, a second-generation SSA, targets multiple sstr subtypes. We compared the efficacy and safety of pasireotide plus everolimus to everolimus alone in patients with advanced, well-differentiated, progressive pancreatic NET.Patients and methodsPatients were randomized 1 : 1 to receive a combination of everolimus (10 mg/day, orally) and pasireotide long-acting release (60 mg/28 days, intramuscularly) or everolimus alone (10 mg/day, orally); stratified by prior SSA use, and baseline serum chromogranin A and neuron-specific enolase. The primary end point was progression-free survival (PFS). Secondary end points included overall survival, objective response rate, disease control rate, and safety. Biomarker response was evaluated in an exploratory analysis.ResultsOf 160 patients enrolled, 79 were randomized to the combination arm and 81 to the everolimus arm. Baseline demographics and disease characteristics were similar between the treatment arms. No significant difference was observed in PFS: 16.8 months in combination arm versus 16.6 months in everolimus arm (hazard ratio, 0.99; 95% confidence interval, 0.64-1.54). Partial responses were observed in 20.3% versus 6.2% of patients in combination arm versus everolimus arm; however, overall disease control rate was similar (77.2% versus 82.7%, respectively). No significant improvement was observed in median overall survival. Adverse events were consistent with the known safety profile of both the drugs; grade 3 or 4 fasting hyperglycemia was seen in 37% versus 11% of patients, respectively.ConclusionsThe addition of pasireotide to everolimus was not associated with the improvement in PFS compared with everolimus alone in this study. Further studies to delineate mechanisms by which SSAs slow tumor growth in NET are warranted.

Project description:Objective: To report the rate of candidate actionable somatic mutations in patients with locally advanced and metastatic gastro-enteropancreatic (GEP) neuroendocrine tumors (NET) and of other genetic alterations that may be associated with tumorigenesis. Methods: A phase II mutation targeted therapy trial was conducted in patients with advanced well-differentiated G1/G2 GEP-NET. Mutations found in the mTOR pathway-associated genes led to treatment with the mTOR inhibitor everolimus, and were defined as actionable. Tumor deoxyribonucleic acid (DNA) from GEP-NET were sequenced and compared with germline DNA, using the OncoVAR-NET assay, designed for hybrid capture sequencing of 500 tumor suppressor genes and oncogenes. Somatic variants were called and copy-number (CN) variant analysis was performed. Results: Thirty patients (14 small-intestine, 8 pancreatic, 3 unknown primary NET, and 5 of other primary sites) harbored 37 lesions (4 patients had DNA of multiple lesions sequenced). Only 2 patients with sporadic NET (n = 26) had an actionable mutation leading to treatment with everolimus. Driver somatic mutations were detected in 18 of 30 patients (21/37 lesions sequenced). In the remaining samples without a driver mutation, CN alterations were found in 11/16 tumors (10/12 patients), including CN loss of chromosome (Chr) 18 (P<.05), CN gain of Chr 5, and loss of Chr 13. CN losses in Chr 18 were more common in patients without driver mutations detected. Pronounced genetic heterogeneity was detected in patients with multiple lesions sequenced. Conclusion: Genome-wide DNA sequencing may identify candidate actionable genes and lead to the identification of novel target genes for advanced well-differentiated GEP-NET. Abbreviations: Chr = chromosome; CN = copy number; DNA = deoxyribonucleic acid; FDA = Food and Drug Administration; GEP = gastro-enteropancreatic; MEN-1 = multiple endocrine neoplasia syndrome type 1; mTOR = mammalian target of rapamycin; NET = neuroendocrine tumor; PFS = progression-free survival; PNET = pancreatic neuroendocrine tumors; SINET = small-intestine neuroendocrine tumor.

Project description:IntroductionRecent classification of neuroendocrine neoplasms has defined well-differentiated high-grade neuroendocrine tumors (NET G3) as a distinct entity from poorly differentiated neuroendocrine carcinoma. The optimal treatment for NET G3 has not been well-described. This study aimed to evaluate metastatic NET G3 response to different treatment regimens.Materials and methodsThis was a retrospective study of patients with NET G3 within the Mayo Clinic database. Patients' demographics along with treatment characteristics, responses, and survival were assessed. Primary endpoints were progression-free survival (PFS) and overall survival. Secondary endpoints were objective response rate (ORR) and disease control rate (DCR).ResultsTreatment data was available in 30 patients with median age of 59.5 years at diagnosis. The primary tumor was mostly pancreatic (73.3%). Ki-67 index was ≥55% in 26.7% of cases. Treatments included capecitabine + temozolomide (CAPTEM) (n = 20), lutetium 177 DOTATATE (PRRT; n = 10), Platinum-etoposide (EP; n = 8), FOLFOX (n = 7), and everolimus (n = 2). CAPTEM exhibited ORR 35%, DCR 65%, and median PFS 9.4 months (95% confidence interval, 2.96-16.07). Both EP and FOLFOX showed similar radiographic response rates with ORR 25.0% and 28.6%; however, median PFS durations were quite distinct at 2.94 and 13.04 months, respectively. PRRT had ORR of 20%, DCR of 70%, and median PFS of 9.13 months.ConclusionAmong patients with NET G3, CAPTEM was the most commonly used treatment with clinically meaningful efficacy and disease control. FOLFOX or PRRT are other potentially active treatment options. EP has some activity in NET G3, but responses appear to be short-lived. Prospective studies evaluating different treatments effects in patients with NET G3 are needed to determine an optimal treatment strategy.Implications for practiceHigh-grade well-differentiated neuroendocrine tumors (NET G3) are considered a different entity from low-grade NET and neuroendocrine carcinoma in terms of prognosis and management. The oral combination of capecitabine and temozolomide is considered a good option in the management of metastatic NET G3 and may be preferred. FOLFOX is another systemic option with reasonable efficacy. Similar to other well-differentiated neuroendocrine tumors, peptide receptor radionuclide therapy seems to have some efficacy in these tumors.

Dataset Information

Phase I study of the anti-IGF1R antibody cixutumumab with everolimus and octreotide in advanced well-differentiated neuroendocrine tumors.

Publications

Phase I study of the anti-IGF1R antibody cixutumumab with everolimus and octreotide in advanced well-differentiated neuroendocrine tumors.

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