Phase II study evaluating the efficacy of Pasireotide long-acting release (LAR; SOM230) dose escalation in patients with refractory non-functional gastroenteropancreatic neuroendocrine tumors (GEP NETs).
Phase II study evaluating the efficacy of Pasireotide LAR (SOM230) dose escalation in patients with refractory non-functional GEP NETs
Peter MacCallum Cancer Centre
30 participants
Dec 15, 2015
Interventional
Conditions
Summary
The primary purpose of this study is to investigate the efficacy of increasing doses of Pasireotide as a potential treatment after octreotide treatment has stopped working for refractory non-functional gastroenteropancreatic neuroendocrine tumors (GEP-NETs). Who is it for? You may be eligible to participate in this study if you are aged 18 years or over and have been diagnosed with well-differentiated gastroenteropancreatic neuroendocrine tumour which has shown disease progression after at least 3 months of long-acting release octreotide 30mg/28 days. Study details: All participants in this study will receive an injection of Pasireotide once every 4 weeks. There are 3 dose levels: Level 1 = 40 mg, level 2 = 60 mg. The exact dose amount for Dose level 3 is currently being evaluated in another clinical trial and will be determined prior to this time. You will start on Dose level 1 (40 mg). Every 12 weeks you will have a CT/MRI scan. If your tumour is reducing or has not changed, you will stay on your current dose level as long as you are obtaining benefit and tolerating the treatment. If your GEP-NET has worsened, your dose will be increased to the next level. If the exact dose amount for Dose level 3 isn’t defined in time or you are on Dose level 3 and your NET has continued to worsen, then you will stop study treatment. Researchers will measure disease progression and side effects to evaluate the efficacy of Pasireotide. It is hoped that this trial will provide information on whether Pasireotide is a safe and effective second line of treatment in patients with GEP-NET for whom the standard care therapy of Octreotide is not effective. Pasireotide is being investigated as a potential treatment after octreotide treatment has stopped working. This study aims to learn about the effects that increasing doses of pasireotide have on your cancer. Pasireotide is a hormonal agent that has greater ability to bind to the surface of NETs cells compared to octreotide. In other research studies, Pasireotide has been shown to slow the growth of NETs in patients previously treated with octreotide. Researchers do not yet know if increasing the dose of pasireotide allows for greater control of NET growth. Pasireotide is an experimental treatment. This means that it is not an approved treatment for NETs in Australia. Pasireotide is being developed by Novartis for the treatment of certain hormonal disorders, including acromegaly and functioning NETs of the pancreas or the gastrointestinal tract.
Eligibility
Inclusion Criteria13
- Male or female, over 18 years
- Patients with an histologically documented diagnosis of non-functional WDNET, defined according to the last WHO classification criteria for NET of gastro-entero-pancreatic (WHO/ENET 2010), bronchial and thymic origin (WHO 2004)
- Radiologic disease progression after at least 3 months of octreotide LAR 30mg/28 days
- Measurable/evaluable disease per RECIST Version 1.1,1 (as determined by relevant imaging based on disease site (i.e. for example by multiphase MRI or triphasic CT scan for hepatic metastasis)
- ECOG PS 0-2
- Adequate organ function:
- Bone marrow: Platelets greater than or equal to 100x10^9/L, Neutrophils greater than or equal to 1.5x10^9/L, Hb greater than or equal to 9g/L
- Liver: Bilirubin less than or equal to 2.0 xUNL, INR less than or equal to 1.3, AST/ALT less than or equal to 2.5 xUNL (if no hepatic metastases) or AST/ALT less than or equal to 5.0 x UNL (if hepatic metastases).
- Renal: Serum creatinine less than or equal to 2.0 X ULN
- Females of childbearing potential must provide a negative pregnancy test at the start of the study. Female patients who are at risk of becoming pregnant must agree to use an effective method of contraception. Female patients must agree to use 2 medically acceptable methods of contraception, 1 being an oral contraceptive, dermal patch, or progestin (implantation or injection), and the other being a medically acceptable barrier method; alternatively, 2 medically acceptable barrier methods may be used. Medically acceptable barrier methods of contraception that may be used by the participant and/or his/her partner include: abstinence; diaphragm with spermicide; intrauterine device (IUD); condom together with foam, spermicide, or vaginal spermicidal suppository. Prohibited methods include the rhythm method, withdrawal, condoms alone, or diaphragm alone
- Male patients must agree that, if their partner is at risk of becoming pregnant, they will use an effective method of contraception as described above.
- Informed and written consent as per the Participant Information and Consent Form
- Compliance with trial therapy or trial-related investigations/evaluations by the patient
Exclusion Criteria18
- Patients with intermediate (Grade 2) or high grade (grade 3) NET
- SSA Naive patients
- Patients that have undergone surgery related to NET within 4 weeks prior to study entry or has surgery planned during the study
- Patients that have previously received any specific anti-tumour treatment such as chemotherapy (within the previous 4 weeks), (chemo) embolisation (within the previous 3 months), radiotherapy (within the previous 4 weeks) or interferon (within the previous 4 weeks) or PRRT within the last 6 months.
- Patients that have had a previous cancer (except basal cell carcinoma of the skin, in situ carcinoma of the cervix/uterus, thyroid microcarcinoma, or eradicated thyroid or prostate cancers). Patients with a history of cancer that was not the above mentioned case can be included if they have been treated with curative intent and have been free from disease for more than 3 years.
- Diabetic patients with poor glycemic control as evidenced by HbA1c >8%
- Patients with risk factors for torsades de pointes, i.e. patients with a baseline QTcF >450 ms in males, and >460ms in females. Or patients with uncontrolled (despite supplementation) hypokalemia or hypomagnesaemia, uncontrolled hypothyroidism, family history of long QT syndrome, or concomitant medications known to prolong QT interval
- Patients with clinically significant valvular disease
- Patients with symptomatic cholelithiasis
- Patients who have congestive heart failure (NYHA Class III or IV), unstable angina, sustained ventricular tachycardia, clinically significant bradycardia, advanced heart block, history of acute myocardial infarction less than one year prior to study entry or clinically significant impairment in cardiovascular function
- Patients with liver disease such as cirrhosis, chronic active hepatitis, or chronic persistent hepatitis, or patients with ALT/AST > 2.5 X ULN, serum bilirubin > 2.0 X ULN, in the absence of liver metastases
- Patients who have a history of alcohol or drug abuse in the 6 month period prior to receiving pasireotide
- Patients who have participated in any clinical investigation with an investigational drug within 1 month prior to dosing
- Patients with the presence of active or suspected acute or chronic uncontrolled infection
- Patients with a history of non-compliance to medical regimens or who are considered potentially unreliable or will be unable to complete the entire study
- Pregnant or lactating women
- At the time of inclusion, on-going AE considered to be related to the treatment with SSA with a severity higher than grade 1
- Patients on lower doses than octreotide LAR 30mg every 28 days.
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Interventions
This is a multicentre (5 Australian sites), prospective, open label, single-arm phase II study. Overall 30 patients with non-functional GEP NETs with radiological disease progression during treatment with octreotide 30mg every 28 days will undergo therapy with increasing doses of pasireotide subject to imaging response. The aim of this study is to evaluate the efficacy and safety of dose escalating pasireotide LAR in patients with non-functional well differentiated NETs who had progressed whilst on octreotide 30mg/q28d. There will be 2 dose levels (possibly 3) evaluated, with intra-patient dose escalation: Dose Level 1: Pasireotide LAR 40mg every 28 days Dose Level 2: Pasireotide LAR 60mg every 28 days Dose Level 3: Subject to MTD of dose escalation phase I trial from Novartis, possibly 80-90mg. (ClinicalTrials.gov identifier: NCT01364415). The mode of administration of Pasireotide will be via intramuscular injection and each dose is given as a single dose every 28 days. Patients will have there dose escalated to the next dose level only if there is evidence of disease progression. The maximum duration of treatment with Pasireotide will be two years. Patients will remain on treatment until disease progression. Patients who continue on treatment and have not progressed when the study ends, will need to complete End of STudy assessments. All doses will be given and supervised by study/hospital staff and any deviations to the study treatments will be notified to the study team.
Locations(5)
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ACTRN12615001328561