A phase II clinical trial of MK-0646, an insulin-like growth factor-1 receptor inhibitor (IGF-1R), in patients with metastatic well-differentiated neuroendocrine tumors (NETs).

e16201 Background: Limited systemic treatment options are available for progressive well-differentiated neuroendocrine tumors (NET), also called carcinoid tumors. Given emerging evidence for immunotherapy response in high grade NET including small cell lung cancer, we sought to determine the efficacy of combination immunotherapy with ipilimumab and nivolumab in patients with advanced, progressive, well-differentiated NET in an open label phase II clinical trial. Methods: Eligible patients had well-differentiated, nonfunctional NET of lung, pancreas, or GI origin that had progressed within the past 12 months after at least one line of prior therapy. Patients received nivolumab 240 mg every 2 weeks and ipilimumab 1mg/kg every 6 weeks for up to 2 years. Primary endpoint was objective response rate (ORR) by RECIST v1.1. Using a Simon’s 2-stage design, the study planned to accrue up to 56 patients. Based on published response rates to everolimus of 5%, we hypothesized that this regimen would be considered promising if the true ORR is > 15%. Results: Nine patients were enrolled prior to study closure due to funding, including 6 patients with NET of lung origin, 2 pancreatic, and 1 small bowel (Table). Median age was 71 years. All patients had distant metastatic disease at enrollment, with an average of 2 prior lines of therapy. Four of 9 patients achieved the primary endpoint of confirmed objective response, all of whom have ongoing response with a median duration of 15.4 months. Five of 9 patients, including all 4 responders, experienced immune-related toxicity requiring treatment modification or discontinuation. The trial did not accrue the target of 56 patients, however, objective response in 4 of 9 patients (ORR 44.4%, 90% CI: 16.9-74.9%) excluded the response rate target (15%). Conclusions: The impressive ORR of 44% with a median duration of response exceeding 15 months in this small clinical trial warrants further study of combination CTLA-4 and PD-1 inhibition in previously treated well-differentiated NET. Our ongoing immunologic and genomic correlative analysis in responders and non-responders will help inform future study of immunotherapy in this patient population in need of new systemic therapy approaches. Clinical trial information: NCT03420521. [Table: see text]

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A phase 2 study of the insulin-like growth factor-1 receptor inhibitor MK-0646 in patients with metastatic, well-differentiated neuroendocrine tumors

Cancer ◽

10.1002/cncr.27459 ◽

2012 ◽

Vol 118 (19) ◽

pp. 4795-4800 ◽

Cited By ~ 44

Author(s):

Diane L. Reidy-Lagunes ◽

Efsevia Vakiani ◽

Michal F. Segal ◽

Ellen M. Hollywood ◽

Laura H. Tang ◽

...

Keyword(s):

Growth Factor ◽

Neuroendocrine Tumors ◽

Insulin Like Growth Factor ◽

Phase 2 ◽

Phase 2 Study ◽

Well Differentiated ◽

Receptor Inhibitor

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A phase II study of the insulin-like growth factor type I receptor inhibitor IMC-A12 in patients with metastatic uveal melanoma

Melanoma Research ◽

10.1097/cmr.0000000000000694 ◽

2020 ◽

Vol 30 (6) ◽

pp. 574-579

Author(s):

Jane Mattei ◽

Alexej Ballhausen ◽

Roland Bassett ◽

Michael Shephard ◽

Chandrani Chattopadhyay ◽

...

Keyword(s):

Growth Factor ◽

Uveal Melanoma ◽

Phase Ii ◽

Phase Ii Study ◽

Type I ◽

Insulin Like Growth Factor ◽

Factor Type ◽

Receptor Inhibitor

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A phase II trial of LEE011 in combination with everolimus in the treatment of advanced well differentiated neuroendocrine tumors of foregut origin.

Journal of Clinical Oncology ◽

10.1200/jco.2018.36.4_suppl.tps546 ◽

2018 ◽

Vol 36 (4_suppl) ◽

pp. TPS546-TPS546 ◽

Cited By ~ 1

Author(s):

Nitya Prabhakar Raj ◽

Virginia Kelly ◽

Jennifer A. Chan ◽

A. Dasari ◽

Marinela Capanu ◽

...

Keyword(s):

Clinical Trial ◽

Overall Survival ◽

Disease Progression ◽

Neuroendocrine Tumors ◽

Phase Ii ◽

Drug Combination ◽

Objective Response ◽

Metastatic Breast ◽

Open Label ◽

Well Differentiated

TPS546 Background: Changes in the retinoblastoma (Rb) tumor suppressor pathway are believed to contribute to the development of well differentiated neuroendocrine tumors (WDNETs). In the pre-clinical setting, loss or downregulation of proteins that normally inhibit the cyclin dependent kinases Cdk4 and Cdk6 have contributed to NET development. Separately, rigorous investigation of everolimus in WDNETs has demonstrated a survival benefit in this patient (pt) population. Pre-clinical data suggests that the Cdk4/Cdk6 inhibitor LEE011 is synergistically active with everolimus. The aim of this study is to evaluate the efficacy and safety of LEE011 in combination with everolimus in pts with advanced WDNETs of foregut origin (thymic, bronchopulmonary, gastric, duodenal, pancreatic). Methods: This study is a multicenter, non-randomized, open-label phase II clinical trial using a Simon two stage optimal design. Main inclusion criteria include: adult patients with WDNET of foregut origin, low to intermediate grade, unresectable and/or metastatic, disease progression ≤ 12 months prior to enrollment, ECOG 0-1. Between 15 and 43 patients will be enrolled from three sites across the US. LEE011 300mg daily, 3 weeks on and 1 week off, in combination with everolimus 2.5mg daily (final dosing based on phase 1b clinical trial performed in metastatic breast cancer; LEE011X2106) will be administered orally until disease progression, unacceptable toxicity, investigator decision, or pt withdrawal. All enrolled pts will be followed by telephone contact for overall survival until death or consent withdrawal. The primary endpoint, progression free survival, will be assessed based on radiographic review by RECISTv1.1. Main secondary endpoints include establishing the safety of this drug combination in this patient population, objective response rate, clinical benefit rate, and overall survival. Correlative objectives include exploring the effect of this drug combination on biomarkers related to the Rb pathway and/or WDNET pathogenesis. This trial began enrollment in 2/27/2017, with 10 patients enrolled to date. Clinical trial information: NCT03070301.

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A phase II clinical trial of sunitinib following hepatic transarterial embolization for metastatic neuroendocrine tumors

Annals of Oncology ◽

10.1093/annonc/mdr614 ◽

2012 ◽

Vol 23 (9) ◽

pp. 2335-2341 ◽

Cited By ~ 31

Author(s):

J.R. Strosberg ◽

J.M. Weber ◽

J. Choi ◽

T.L. Campos ◽

T.L. Valone ◽

...

Keyword(s):

Clinical Trial ◽

Neuroendocrine Tumors ◽

Phase Ii ◽

Transarterial Embolization ◽

Phase Ii Clinical Trial

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Phase II clinical trial of parenteral hydroxyurea in combination with fluorouracil, interferon and filgrastim in the treatment of advanced pancreatic, gastric and neuroendocrine tumors

Cancer Chemotherapy and Pharmacology ◽

10.1007/s00280-003-0727-4 ◽

2004 ◽

Vol 53 (4) ◽

pp. 337-340 ◽

Cited By ~ 10

Author(s):

Andreas Kaubisch ◽

Ron Kaleya ◽

Hilda Haynes ◽

Alla Rozenblit ◽

Scott Wadler

Keyword(s):

Clinical Trial ◽

Neuroendocrine Tumors ◽

Phase Ii ◽

Phase Ii Clinical Trial

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Protein Signature Predicts Response to Neoadjuvant Treatment With Chemotherapy and Bevacizumab in HER2-Negative Breast Cancers

JCO Precision Oncology ◽

10.1200/po.20.00086 ◽

2021 ◽

pp. 286-306

Author(s):

Mads H. Haugen ◽

Ole Christian Lingjærde ◽

Ingrid Hedenfalk ◽

Øystein Garred ◽

Elin Borgen ◽

...

Keyword(s):

Clinical Trial ◽

Growth Factor ◽

Phase Ii ◽

Antiangiogenic Therapy ◽

Pathologic Complete Response ◽

Neoadjuvant Treatment ◽

Unmet Need ◽

Phase Ii Clinical Trial ◽

Primary Tumors ◽

Protein Signature

PURPOSE Antiangiogenic therapy using bevacizumab has proven effective for a number of cancers; however, in breast cancer (BC), there is an unmet need to identify patients who benefit from such treatment. PATIENTS AND METHODS In the NeoAva phase II clinical trial, patients (N = 132) with large (≥ 25 mm) human epidermal growth factor receptor 2 (HER2)-negative primary tumors were randomly assigned 1:1 to treatment with neoadjuvant chemotherapy (CTx) alone or in combination with bevacizumab (Bev plus CTx). The ratio of the tumor size after relative to before treatment was calculated into a continuous response scale. Tumor biopsies taken prior to neoadjuvant treatment were analyzed by reverse-phase protein arrays (RPPA) for expression levels of 210 BC-relevant (phospho-) proteins. Lasso regression was used to derive a predictor of tumor shrinkage from the expression of selected proteins prior to treatment. RESULTS We identified a nine-protein signature score named vascular endothelial growth factor inhibition response predictor (ViRP) for use in the Bev plus CTx treatment arm able to predict with accuracy pathologic complete response (pCR) (area under the curve [AUC] = 0.85; 95% CI, 0.74 to 0.97) and low residual cancer burden (RCB 0/I) (AUC = 0.80; 95% CI, 0.68 to 0.93). The ViRP score was significantly lower in patients with pCR ( P < .001) and in patients with low RCB ( P < .001). The ViRP score was internally validated on mRNA data and the resultant surrogate mRNA ViRP score significantly separated the pCR patients ( P = .016). Similarly, the mRNA ViRP score was validated ( P < .001) in an independent phase II clinical trial (PROMIX). CONCLUSION Our ViRP score, integrating the expression of nine proteins and validated on mRNA data both internally and in an independent clinical trial, may be used to increase the likelihood of benefit from treatment with bevacizumab combined with chemotherapy in patients with HER2-negative BC.

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