None listed
Conditions
Brief summary
No effective standard treatment of advanced progressive neuroendocrine tumours (NETs) exists, but over the past decade at Fremantle Hospital, we have developed new radiopeptide therapies with encouraging results using Lutetium-177 octreotate. Recently, we have combined this radioisotope with radiosensitizing chemotherapy to achieve stabilization of disease in over 90% of patients and tumour shrinkage in over half the NETs. We now seek to combine Lutetium-177 octreotate with a new targeted agent, Everolimus which has proven, although minor suppressive effect on NET progression. We propose to combine a standard activity of 177Lu-octreotate with escalating doses of Everolimus to define the maximum safe dose achievable. We will then design a study to define the efficacy of this novel radiopeptide Everolimus combination in NET patients with progressive disease.
Interventions
Phase I/II study of Everolimus in combination with Lutetium-177 octreotate radiopeptide therapy for the treatment of advanced gastroenteropancreatic neuroendocrine tumours (GEP NETs).
Lutetium-177 octreotate administered by intravenous infusion of 8 GBq for 4 cycles at intervals of 8 weeks in conjunction with amino acid solution (Synthamin Baxter Australia) as an outpatient. Everolimus (Afintor Novartis Australia) to be adminstered orally in escalating dose 5 mg for 3 patients, 7.5 mg for 3 pa
Phase I/II study of Everolimus in combination with Lutetium-177 octreotate radiopeptide therapy for the treatment of advanced gastroenteropancreatic neuroendocrine tumours (GEP NETs). Lutetium-177 octreotate administered by intravenous infusion of 8 GBq for 4 cycles at intervals of 8 weeks in conjunction with amino acid solution (Synthamin Baxter Australia) as an outpatient. Everolimus (Afintor Novartis Australia) to be adminstered orally in escalating dose 5 mg for 3 patients, 7.5 mg for 3 patients and 10 mg in all subsequent patients (given manageable toxicity) each day for 6 months commencing in the week prior to start of Lutetium-177 octreotate radiopeptide therapy.
Sponsors
Fremantle Hospital
Study design
Allocation
Non-randomised trial
Intervention model
Single group
Primary purpose
Treatment
Masking
Open (masking not used)
Eligibility
Sex/Gender
All
Age
18 Years to 90 Years
Healthy volunteers
No
Inclusion criteria
1 Presence of advanced, unresectable GEP-NET, which have progressed on standard therapy, or those with uncontrolled symptoms, or massive disease requiring urgent treatment. Tumour has been biopsy - proven and avid on 68Ga-octreotate PET CT or on tracer 177Lu-octreotate or 111In-octreotide gamma scanning 2 Age > 18 years 3 WHO performance status < 2 4 Neutrophils >1.5 x 109/L, platelets > 100 x 109/L, Hb > 90 g/L 5 Bilirubin < 1.5 x ULN, ALT/AST < 2.5 x ULN ( < 5 x ULN in patients with liver metastases) 6 Fasting serum cholesterol < 7.75 mmol/L AND triglycerides < 2.5 x ULN 7 INR < 1.5 (Anticoagulation is allowed if target INR < 1.5 on a stable dose of warfarin or on a stable dose of LMW heparin for > 2 weeks at time of enrolment 8 Serum creatinine < 1.5 x ULN 9 Signed informed consent 10 Accessible for follow-up
Exclusion criteria
1 Patients who have received anti-cancer therapies within 4 weeks of start of study drug (including chemotherapy, radiation, antibody based therapy, etc) 2 Patients who had major surgery or significant traumatic injury within 4 weeks of start of study drug, or may require major surgery during the course of the study 3 Prior treatment with an investigational drug within preceding 4 weeks 4 Patients receiving chronic systemic corticosteroids or another immunosuppressive agent. Topical or inhaled corticosteroids allowed. 5 Patients should not receive immunization with attenuated live vaccines within 1 week of study entry or during study period and should not be in close contact with people who have received attenuated live vaccines. Live vaccines include intranasal influenza, MMR, oral polio, BCG, yellow fever, varicella and TY21a typhoid vaccines. 6 Uncontrolled brain or leptomeningeal metastases, including patients who continue to require glucocorticoids for brain or leptomeningeal metastases. 7 Other malignancies within the past 3 years except for neuroendocrine tumour or adequately treated cancer of the cervix or basal/squamous cell carcinomata of the skin. 8 Patients who have any severe and/or uncontrolled medical conditions or other conditions that could affect their participation such as: NYHA Class 111 or IV, unstable angina, symptomatic congestive cardiac failure, myocardial infarction within 6 months of start of study, serious uncontrolled cardiac arrhythmia or any other clinically significant cardiac disease. 9 Severely impaired lung function defined by spirometry and DLCO that is 50% of normal predicted value and/or O2 sat that is < 88% at rest on room air 10 Uncontrolled diabetes as defined by fasting serum glucose > 1.5 x ULN 11 Active liver infections or disease such as cirrhosis, or severe hepatic impairment (Child-Pugh class C) 12 HBV, HCV or HIV positive 13 Impairment of gastrointestinal function or GI disease that may significantly alter the absorption of everolimus (e.g ulcerative disease, uncontrolled nausea, vomiting, diarrhoea, malabsorption syndrome or substantial small bowel resection) 14 Patients with an active bleeding diathesis 15 Female patients who are pregnant/breastfeeding 16 Adults of reproductive potential and their partners who are not using effective birth control methods. Adequate contraception must be used throughout the trial and for 8 weeks after the last dose of study drug, by both sexes. 17 Women of childbearing potential must have negative urine/serum pregnancy test within 7 days prior to administration of everolimus) 18 Patients who received prior treatment with an mTOR inhibitor (e.g sirolimus, temsirolimus,everolimus) 19 Patients with a know hypersensitivity to everolimus or other rapamycins (e.g sirolimus, temsirolimus) or to its excipients 20 History of non- compliance to medical regimens 21 Patients unwilling, or unable to comply with the protocol 22 Previous radiopeptide therapy within the last 6 months.
Outcome results
None listed