CapTemY90 for Grade 2/3 NET Liver Metastases

Official title

UPCC 04219 Phase 2 Study of Capecitabine-Temozolomide(CapTem) With Yttrium-90 Radioembolization in the Treatment of Patients With Unresectable Metastatic Grade 2/3 Neuroendocrine Tumors

Overview

This is a Phase 2 evaluation of hepatic-progression free survival among patients with Grade 2 liver-dominant NET metastases undergoing combination therapy with CapTem and Y90 radioembolization.The hypothesis is to confirm safety and to assess if disease control is improved relative to expectation from either therapy alone. A Grade 3 arm was added in 2025.

Detailed description

Patients with liver-dominant Grade 2/3 NET metastases from any primary will start CapTem and undergo simulation angiography for radioembolization planning during the first cycle. If they tolerate CapTem and are not excluded from radioembolization, then TARE will be performed on Day 7 of Cycle 2, with additional TARE of Day 7 of cycle 3 or 4 as needed to treat the entire tumor burden. Patients will remain on CapTem until progression or intolerance.

Primary outcome measure is hepatic progression-free survival.

Interventions

• Drug Capecitabine Oral Product
  Capecitabine 750 mg/m2 twice daily orally for 14 days
• Drug Temozolomide Oral Product
  temozolomide 200 mg/m2 orally on Days 10-14, with 14 days between cycles
• Combination product transarterial radioembolization
  Trans-arterial radioembolization (TARE) on Day 7 of cycle 2 and, if needed for the other lobe, Day 7 of either cycle 3 or 4.

Primary outcome measures

• Intra-hepatic progression-free survival [Time frame: 2 years. Time from initiation of study therapy until first documented intra-hepatic disease progression, death due to any cause or last scan date that documented intra-hepatic progression-free status.]

Secondary outcome measures (8)

• Overall Progression free survival [Time frame: 2 years. time from initiation of study therapy until first documented intra- or extra-hepatic disease progression, death due to any cause or last scan date that documented progression-free status]
• Intra-hepatic tumor responses by RECIST [Time frame: 2 years. from time of initiation of study therapy until subject comes off of study, or study closes]
• Intra-hepatic tumor responses by EASL [Time frame: 2 years. from time of initiation of study therapy until subject comes off of study, or study closes]
• extra-hepatic tumor responses [Time frame: 2 years. from time of initiation of study therapy until subject comes off of study, or study closes]
• Number of participants with systemic toxicities [Time frame: From period of enrollment to 24 months after last treatment]
• Number of participants with hepatic toxicities [Time frame: From period of enrollment to 24 months after last treatment]
• Change in CgA over time [Time frame: Tumor markers will be assessed at baseline and then every 3 months for 24 months.]
• Quality of Life by European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire for Neuroendocrine tumor [Time frame: Quality of life will be measured at baseline and then every 3 months for 24 months .]

Eligibility criteria

Inclusion criteria

• Patients with confirmed diagnosis of histologic grade 2 or 3 well differentiated neuroendocrine tumor with unresectable liver metastases (primary tumor or other extrahepatic disease may be present)
• Patients with at least one measurable liver metastases, with size > 1cm (RECIST criteria)
• Patients with liver dominant disease defined as ≥50% tumor body burden confined to the liver
• Liver tumor burden does not exceed 50% of the liver volume
• Patent main portal vein
• At least 4 weeks since last administration of last chemotherapy and /or radiotherapy
• Age >18 years.
• Life expectancy of greater than 6 months.
• ECOG performance status 0-2.
• Adequate liver function as measured by: Total bilirubin ≤ 2.0mg/dl, ALT, AST ≤5 times ULN, albumin ≥2.5g/dl.
• Patients must have adequate organ and marrow function as defined below:
• platelets >100,000/mcL (may be corrected by transfusion)
• serum creatinine < 2.0 mg/dl
• INR <1.6, (may be corrected by transfusion)
• Ability to understand and the willingness to sign a written informed consent document.
• Women of child bearing potential and fertile men are required to use effective contraception (negative urine or serum βHCG for women of child-bearing age)

Exclusion criteria

• Contraindications to capecitibine or temozolomide
• Contraindicated for both contrast-enhanced MRI and CT
• Patients previously treated with transarterial embolization (with or without chemotherapy) or with radioembolization (Y-90 microspheres)
• Contraindication for radioembolization procedures:
• excessive hepatopulmonary shunt as determined by the investigator
• inability to deliver Y90 microspheres without risk of non-target embolization of extra-hepatic structures
• Subjects consenting to the trial who fail their simulation angiography will be removed from the study and replaced.
• Patients may not be receiving any other investigational agents.
• Absolute contraindication to intravenous iodinated contrast (Hx of significant previous contrast reaction, not mitigated by appropriate pre-medication).
• Choledochoenteric anastomosis, transpapillary stent or sphincterotomy of duodenal papilla;
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
• Pregnant and lactating women are ineligible

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 4 centers

• UC San Diego — La Jolla
• University of Miami Miller School of Medicine-Sylvester Cancer Center — Miami
• Roswell Park Comprehensive Cancer Center — Buffalo
• University of Pennsylvania — Philadelphia

Publications

• Modlin IM, Moss SF, Chung DC, Jensen RT, Snyderwine E. Priorities for improving the management of gastroenteropancreatic neuroendocrine tumors. J Natl Cancer Inst. 2008 Sep 17;100(18):1282-9. doi: 10.1093/jnci/djn275. Epub 2008 Sep 9. PMID 18780869
• Norheim I, Oberg K, Theodorsson-Norheim E, Lindgren PG, Lundqvist G, Magnusson A, Wide L, Wilander E. Malignant carcinoid tumors. An analysis of 103 patients with regard to tumor localization, hormone production, and survival. Ann Surg. 1987 Aug;206(2):115-25. doi: 10.1097/00000658-198708000-00001. PMID 2440390
• Talamonti MS, Stuart K, Yao JC. Neuroendocrine tumors of the gastrointestinal tract: how aggressive should we be? In: Perry M, ed. American Society of Clinical Oncology 2004 Education Book. Alexandria: American Society of Clinical Oncology, 2004;206-215.
• Arnold R, Trautmann ME, Creutzfeldt W, Benning R, Benning M, Neuhaus C, Jurgensen R, Stein K, Schafer H, Bruns C, Dennler HJ. Somatostatin analogue octreotide and inhibition of tumour growth in metastatic endocrine gastroenteropancreatic tumours. Gut. 1996 Mar;38(3):430-8. doi: 10.1136/gut.38.3.430. PMID 8675099
• Saltz L, Trochanowski B, Buckley M, Heffernan B, Niedzwiecki D, Tao Y, Kelsen D. Octreotide as an antineoplastic agent in the treatment of functional and nonfunctional neuroendocrine tumors. Cancer. 1993 Jul 1;72(1):244-8. doi: 10.1002/1097-0142(19930701)72:13.0.co;2-q. PMID 8389666
• Rinke A, Muller HH, Schade-Brittinger C, Klose KJ, Barth P, Wied M, Mayer C, Aminossadati B, Pape UF, Blaker M, Harder J, Arnold C, Gress T, Arnold R; PROMID Study Group. Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: a report from the PROMID Study Group. J Clin PMID 19704057
• Caplin ME, Pavel M, Cwikla JB, Phan AT, Raderer M, Sedlackova E, Cadiot G, Wolin EM, Capdevila J, Wall L, Rindi G, Langley A, Martinez S, Blumberg J, Ruszniewski P; CLARINET Investigators. Lanreotide in metastatic enteropancreatic neuroendocrine tumors. N Engl J Med. 2014 Jul 17;371(3):224-33. doi: 10.1056/NEJMoa1316158. PMID 25014687
• Yao JC, Shah MH, Ito T, Bohas CL, Wolin EM, Van Cutsem E, Hobday TJ, Okusaka T, Capdevila J, de Vries EG, Tomassetti P, Pavel ME, Hoosen S, Haas T, Lincy J, Lebwohl D, Oberg K; RAD001 in Advanced Neuroendocrine Tumors, Third Trial (RADIANT-3) Study Group. Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med. 2011 Feb 10;364(6):514-23. doi: 10.1056/NEJMoa1009290. PMID 21306238

Identifiers

NCT: NCT04339036 · UPCC 04219 · 04219

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗