An Open Label, Single-Centre, Pilot Study of Everolimus With EBRT for the Treatment of mNET Liver Metastasis

NCT02205515 | Completed Phase 1 DMC

• 1 other identifier: File#13-907/OZM-057
• Study Type: interventional
• Target: 17
• Locations: 1 country
• Sites: 1

Brief 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. 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. 2.New radiological measures of CEUS and DCE-CT are effective measure to delineate tumor response in NETs.

Conditions

Carcinoma, Neuroendocrine

Outcome Measures

Primary Outcomes (1)

• The tolerability and efficacy of Everolimus concurrent with external-beam radiotherapy will be examined

  Through study completion an average of 1 year

Secondary Outcomes (4)

• The response rate (as measured by RECIST version 1.1 criteria) of combined treatment with Everolimus and radiation to metastatic liver lesions in neuroendocrine cancers will be examined

  Screening, every 12weeks during the study until off-treatment due to progression

• The association between tumor perfusion and blood flow in vivo as measured by dynamic contrast-enhanced (DCE)-CT, CEUS, with clinical safety and efficacy outcomes will be preliminary explored

  During the duration of the study

• The effects of tumor perfusion and blood flow (on liver metastasis) as measured by DCE-MRI, DCE-CT and CEUS at baseline, during Everolimus but prior to SBRT, and post-SBRT in patients with neuroendocrine cancer metastatic to liver will be explored

  Screening, Day 26-28, and 7 days follow-up after last RT

• The biochemical response (Urinary 5HIAA and Chromogranin A) of combined treatment with Everolimus and radiation to metastatic liver lesions in neuroendocrine cancers will be examined

  Screening, Day 26-28, and 7 days follow-up after last RT, 30 & 90 days after completing radiotherapy and at progression. 5HIAA to be also done as clinically indicated

Study Arms (1)

Radiotherapy

OTHER

SBRT or EBRT

Drug: Everolimus

Interventions

Everolimus DRUG

Everolimus is a novel derivative of rapamycin.

Also known as: Afinitor

Radiotherapy

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Histological and/or cytological diagnosis of unresectable neuroendocrine tumor with liver metastases confirmed on imaging scans
• Ki-67\<55%
• No prior Everolimus within 3 months prior to registration
• No prior radiotherapy to the liver
• liver metastatic lesions confirmed on imaging scans
• Size of target metastatic lesion is 6 cm or less
• At least 700 cc of liver uninvolved by tumor
• Previous liver resection, systemic therapy or local ablation therapy (radiofrequency ablation, transarterial chemoemolization, radioemolization) is allowed.
• Extrahepatic disease is allowed if maximum involved organs (including the liver) is 3 or less (i.e. oligometastases).
• Child-Pugh's A liver function
• Male or female: Age ≥ 18 years
• Life expectancy \> 6 months
• ECOG PS ≤1
• Laboratory Requirements - within 14 days prior to registration:
• Hematology Absolute Neutrophils Count ≥ 1.5 x 109/L Platelets ≥ 100 x 109/L Hemoglobin ≥ 90 g/L Biochemistry Serum Bilirubin ≤ 1.5 x upper limit of normal Serum Creatinine ≤ 1.5 x upper limit of normal AST ≤ 3 x upper limit of normal ALT ≤ 3 x upper limit of normal INR ≤ 1.5 Fasting Serum Cholesterol ≤ 300 mg/dl or 7.75 mmol/L Fasting Triglycerides ≤ 2.5 x ULN Adequate Glucose Control Urinalysis Proteinuria ≤ grade 1 (by dipstick)

You may not qualify if:

• 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
• Known to have clinical or radiological evidence of CNS metastases
• Patients with hepatitis
• Patients with neuroendocrine tumor of a pancreatic origin
• 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.
• Uncontrolled diabetes mellitus
• Active bleeding diathesis, or an oral anti-vitamin K medication (except low dose warfarin, LMWH, or acetylsalicylic acid or equivalent) as long as the INR is \<1.5.
• Patients with known history or present encephalopathy
• Gross clinically detectable ascites
• Any comorbidity or concomitant medication that would contraindicate treatment with Everolimus
• 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
• 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.
• Prior radiotherapy to the right upper quadrant of the liver
• Contraindication to CT dye injection
• Contraindication to MRI

Sponsors & Collaborators

• Sunnybrook Health Sciences Centre: lead

Study Sites (1)

Odette Cancer Centre, Sunnybrook Health Science Centre

Toronto, Ontario, M4N 3M5, Canada

Location

MeSH Terms

Conditions

Carcinoma, Neuroendocrine

Interventions

Everolimus

Condition Hierarchy (Ancestors)

Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue

Intervention Hierarchy (Ancestors)

Sirolimus; Macrolides; Lactones; Organic Chemicals

Study Officials

• Simron Singh, MD

  Odette Cancer Centre, Sunnybrook HSC

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 25, 2014
• First Posted: July 31, 2014
• Study Start: March 1, 2016
• Primary Completion: September 1, 2021
• Study Completion: October 1, 2021
• Last Updated: August 19, 2022

Record last verified: 2022-08

Locations

CA (1)