CapTem Plus Radioembolization for NET Liver Metastases

  • STATUS
    Recruiting
  • End date
    Dec 7, 2025
  • participants needed
    55
  • sponsor
    Abramson Cancer Center of the University of Pennsylvania
Updated on 10 October 2021

Summary

Grade 2 neuroendocrine tumors have an intermediate rate of progression following embolotherapy of liver metastases. The combination of capecitabine and temozolomide has been shown to be an active regimen in this disease. Both drugs are radiosensitizers, and in a safety and feasibility study were combined with yttrium-90 radioembolization with acceptable additive toxicities and better than expected response and duration of disease control. This study expands use of this regimen in a Phase 2 investigation to confirm efficacy of the integrated chemoradiation technique.

Description

Embolotherapy of Neuroendocrine Hepatic Metastases Embolization of symptomatic or progressive hepatic neuroendocrine metastases has been performed for decades with a response rate on the order of 60%. NCCN, NANETs, and ENETs guidelines all endorse embolotherapy in this setting. Practice in the U.S. is roughly evenly divided among the four methods of embolotherapy: bland embolization with microspheres alone, conventional chemoembolization with Lipiodol-drug emulsions, embolization with drug-eluting microspheres, and radioembolization with yttrium-90 microspheres. In the absence of prospective clinical trials, outcomes with each of the four methods appear similar.

Y90 Radioembolization From the patient perspective, radioembolization is appealing because of its low toxicity profile relative to the other forms of embolotherapy. Since the technique involves instillation of 25-35 micron microspheres into the tumor interstitium via the hepatic artery, rather than occlusion of tumor feeding vessels as in the other methods of embolization, the post-embolization syndrome is minimized and most patients can be treated on an outpatient basis with minimal toxicity.

A multi-center retrospective analysis of 148 patients reported an objective response rate of 63%, 95% disease control rate, and 70 months median overall survival. A series of 48 patients from Australia had 55% objective response, 77% disease control, and a median survival of 35 months for the entire cohort, but median survival time was not reached among the responders. A similar US single-center series of 40 patients found an objective response rate of 64%, 96% disease control, and a median overall survival of 34 months.

Use of Capecitabine-Temozolomide (CapTem) for NETs In 2005, Fine described a regimen of capecitabine for 14 days with twice-daily temozolomide on days 10-14 of the two-week cycle. This combination was shown in the laboratory to have far greater activity against NET cells than either agent alone or given in other combinations. This was followed by two clinical reports of 30 and 18 patients from the same center showing 60%-70% objective response rates, 22% stable disease, and median TTP of 18 and 14 months in heavily pre-treated patients who had failed somatostatin analog therapy, many also progressing after other systemic therapy and/or embolotherapies. There were no grade 4 toxicities, and only thrombocytopenia at grade 3. This was confirmed in a recent update on 143 patients who had 54% PR and 35% SD by RECIST 1.1. 61% had >50% reduction in an initally elevated CgA level. Median PFS was 17 months [95% CI, 15-24 mo] for G1 and 14.5 mo [10-14.5] for G2. The ECOG 2211 trial compared CapTem to temozolomide alone in metastatic pancreatic NETS and reported a significant improvement in PFS with the combination, from 14.4 mo for temozolomide alone to 22.7 months with CapTem, HR 0.58[0.36-0.93], p = 0.023 without a statistical difference between Grade 1 and 2 tumors.

Fluoropyrimidines are radiosensitizers, often used with radiation therapy in the treatment of gastrointestinal malignancies. Temozolomide is used synergistically with radiation for glioblastoma. Capecitabine has been used in combination with Y-90 radioembolization to treat advanced hepatic malignancies at standard doses with acceptable additive toxicities.

Clinical Data to Date The safety and feasibility of combining of CapTem and Y90 radioembolization was evaluated at the University of Pennsylvania. The Penn Neuroendocrine Tumor Board identified patients with progressive grade 2 tumors with liver-dominant metastases and extrahepatic disease. A multidisciplinary treatment plan was created with CapTem given according to the Fine protocol, and lobar radioembolizations on day 7 of the 2nd and 4th cycles. 21 patients were treated. 19 completed the planned therapy; one patient who had received a prior cycle of radioembolization developed grade 2 bilirubin elevation after the first lobar treatment and did not have the other lobe treated, the other decline a 2nd embolization because of post-embolization pain. There were no unexpected toxicities. There were six grade 3/4 thrombocytopenias, one each of grade 3 fatigue, nausea, and hand-foot skin reaction, and one case of REILD. Among patients evaluable for response at median 22 months (range, 10-52 mo), ORR was 74% with three complete responses. Median chromogranin A reduction was 87%. Median PFS was not reached, with mean PFS of 38.5 months.

This preliminary experience suggests that CapTemY90 can be employed as a safe and active combination regimen integrating systemic and liver-directed therapies in grade 2 NETs. Toxicities were similar to those reported for CapTem or radioembolization alone. The next step is a prospective Phase 2 evaluation of the efficacy of therapy to confirm safety and to assess if disease control is improved relative to expectation from either therapy alone.

Details
Condition Liver Metastasis, Secondary Malignant Neoplasm of Liver, Hepatic Metastases, Neuroendocrine Tumor Grade 2, Liver Metastases
Treatment Capecitabine tablets + temozolomide tablets + SIR-Spheres
Clinical Study IdentifierNCT04789109
SponsorAbramson Cancer Center of the University of Pennsylvania
Last Modified on10 October 2021

Eligibility

Yes No Not Sure

Inclusion Criteria

Patients with confirmed diagnosis of histologic grade 2 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 <
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 serum HCG for women of child-bearing age)

Exclusion Criteria

Contraindications to capecitabine 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 trial
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, - Pregnant and lactating women are ineligible
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