An Open Label, Single-Centre, Phase II Study of Everolimus With EBRT for the Treatment of mNET Liver Metastasis
Conditions
Carcinoma, Neuroendocrine
Conditions: official terms
Carcinoma, Neuroendocrine
Study Type
Interventional
Study Phase
Phase 1/Phase 2
Study Design
Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Intervention
Name: Everolimus
Type: Drug
Overall Status
Not yet recruiting
Summary
Approximately 50% of patients with neuroendocrine cancers present with metastasis, a vast majority to the liver. In such patients, one treatment option for liver-directed therapy is surgical resection. However, a significant proportion of patients are not eligible for resection because of patient factors (age, comorbidities) or tumor-related factors.

There have been scant data on the utility of EBRT (external-beam radiotherapy) and SABR (stereotactic ablative radiotherapy) for metastatic neuroendocrine tumors of the liver. This study will measure the effects of concurrent everolimus with external-beam radiotherapy to the liver for metastatic neuroendocrine New methods of tumor assessment are needed in NETs. Three new techniques are being developed at the Sunnybrook Research Institute to assess tumour response to treatment: (1) contrast enhanced ultrasound; (2) perfusion CT; and (3) perfusion MRI. These methods are devised to measure tumour perfusion and blood flow as response indicators and can measure cell death non-invasively.

1. Concurrent everolimus given with external-beam radiotherapy to the liver for metastatic neuroendocrine tumors of the liver will enhance the efficacy of radiotherapy and add little, if any, toxicity

2. New radiological measures of CEUS and DCE-CT are effective measure to delineate tumor response in NETs.
Detailed Description
This is a single-centre, single-arm, open-label proof-of-concept study to analyze the imaging effects (CT, DCE-CT, DCE-MRI, CEUS) of neoadjuvant and concurrent everolimus with radiotherapy of neuroendocrine metastases to the liver. Total number of study enrolment is 10.

Patients will receive a dose of everolimus of 7.5mg to be started 30 days prior to radiation. Everolimus is to continue for 14 days post radiation.

Patients will receive external-beam radiotherapy (up to 30Gy[Grays] in 10 fractions) or SBRT [stereotactic ablative radiotherapy] (up to 60Gy in 3-5 fractions given on alternating weekdays over 1 -2 weeks). The decision to treat with either external-beam radiotherapy or SBRT will be based on whether the lesions are amenable to SBRT (preferred treatment), which is determined by the size of the target lesion, liver sparing and organs-at-risk dose constraints. The prescription dose of external-beam radiotherapy and SBRT will similarly be determined by these factors.

Patients will undergo CT (chest, abdomen, pelvis), dynamic contrast-enhanced (DCE) MRI, DCE-CT and CEUS at baseline, prior to starting radiation, and within 7 days of finishing radiotherapy. Biomarkers (Urinary 5-HIAA [hydroxyindoleacetic acid] if functional, and Chromogranin A) will be done baseline, 7 days after finishing radiotherapy, and 60 days after finishing radiotherapy.
Criteria for eligibility
Healthy Volunteers: No
Maximum Age: N/A
Minimum Age: 18 Years
Gender: Both
Criteria: Inclusion Criteria:

1. Histological and/or cytological diagnosis of unresectable neuroendocrine tumor with liver metastases confirmed on imaging scans

2. Ki-67<55%

3. No prior everolimus within 3 months prior to registration

4. No prior radiotherapy to the liver

5. 1-3 liver metastatic lesions confirmed on imaging scans

6. Maximum size of target metastatic lesion is 6 cm or less

7. At least 700 cc of liver uninvolved by tumour

8. Previous liver resection, systemic therapy or local ablation therapy is allowed.

9. Extrahepatic disease is allowed if maximum involved organs (including the liver) is 3 or less.

10. Child-Pugh's A liver function

11. Male or female: Age ≥ 18 years

12. Life expectancy > 6 months

13. ECOG [Eastern Cooperative Oncology Group] PS [Performance Status] ≤1

14. Laboratory Requirements - within 14 days prior to registration:

Hematology

- neutrophils ≥ 1.5 x 109/L

- platelets ≥ 100 x 109/L

- hemoglobin ≥ 90 g/L Biochemistry

- bilirubin ≤ 1.5 x upper limit of normal

- serum creatinine ≤ 1.5 x upper limit of normal

- AST [aspartate aminotransferase] ≤ 3 x upper limit of normal (≤ 5 x if liver metastases present)

- ALT [Alanine Amino Transferase] ≤ 3 x upper limit of normal (≤ 5 x if liver metastases present)

- INR [international normalized ratio] ≤ 1.3 Urinalysis

- Proteinuria ≤ grade 1 (by dipstick)

15. Before patient registration/randomization, written informed consent must be given according to local Institutional and/or University Human Experimentation Committee requirements.

16. Patients must be accessible for treatment and follow up.

Exclusion Criteria:

1. Major surgical procedure, open biopsy or significant traumatic injury within 28 days prior to registration (i.e. patients must have recovered to less than or equal to grade 1 from any major surgery), or anticipation of need for major surgical procedure during or within 7 weeks after chemo-radiotherapy

2. Known to have clinical or radiological evidence of CNS (central nervous system) metastases

3. Patients with a past or current history (within last 2 years) of other malignancies, except for the indication under this study and curatively treated basal and squamous skin cancer or in-situ cancer of the cervix. Prior treatment of localized prostate cancer is permitted if treatment was greater than 5 years ago and the patient currently has no biochemical evidence of recurrence.

4. Active hepatitis (infectious or non-infectious)

5. Uncontrolled diabetes mellitus

6. Patients with known history or present encephalopathy

7. Gross clinically detectable ascites

8. Women of childbearing potential with a positive pregnancy test at baseline or lactating. Postmenopausal women must have been amenorrheic for at least 12 months to be considered of non childbearing potential. Females patients must not be pregnant or become pregnant during this study and for 6 months after the last dose of everolimus

9. Sexually active males and females (of childbearing potential) unwilling to practice contraception during the study. Patients of childbearing potential must be willing to use a reliable method of birth control. i.e.: double barrier method, oral contraceptive, implant, dermal contraception, long-term injectable contraceptive, intrauterine device or tubal ligation during the study.

10. Prior radiotherapy to the right upper quadrant of the liver

11. Contraindication to CT & CEUS dye injection and MRI

12. Body habitus and or tumor location not allowing for CEUS

13. Any other serious intercurrent illness such as cardiovascular disease, HIV or any neurological disease

14. Patients taking other approved or investigational drug/anticancer treatment (other than ongoing androgen ablation and oral prednisone which are permitted) during the study period, including chemotherapy, biological response modifiers, immunotherapy, surgery or radiotherapy.

15. Patients concurrently participating in another clinical trial
Location
Odette Cancer Centre, Sunnybrook Health Science Centre
Toronto, Ontario, Canada
Status: Not yet recruiting
Start Date
May 2015
Completion Date
September 2019
Sponsors
Sunnybrook Health Sciences Centre
Source
Sunnybrook Health Sciences Centre
Record processing date
ClinicalTrials.gov processed this data on July 28, 2015
ClinicalTrials.gov page