To compare the long term efficacy of pasireotide LAR vs. octreotide LAR at month 6 in controlling diarrhea and/or flushing in patients with metastatic carcinoid tumors whose disease-related symptoms are inadequately controlled by the maximum…
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Source
Brief title
Condition
- Neoplastic and ectopic endocrinopathies
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary efficacy variable is the proportion of patients who receive
clinical benefit in symptom (diarrhea and/or flushing) improvement as defined
by the following subgroup specific criteria:
- Patients who over a 14 day period at baseline has diarrhea + flushing with a
daily mean number of *4 bowel movements and a total number of 5 or more
flushing episodes for which the clinical benefit response criteria in 28 days
period at month 6 is < 4 daily mean bowel movements AND * 20% reduction from
baseline in the daily mean number of bowel movements AND any reduction in total
number of flushing episodes compared to baseline
- Patients who over a 14 day period at baseline has predominantly diarrhea with
a daily mean number of *4 bowel movements and a total number of < 5 flushing
episodes for which the clinical benefit response criteria in 28 days period at
month 6 is < 4 daily mean bowel movements AND * 20% reduction from baseline in
the daily mean number of bowel movements
- Patients who over a 14 day period at baseline has predominantly flushing with
a total number of *14 flushing episode and a mean daily number of <4 bowel
movements for which the clinical benefit response criteria in 28 days period at
month 6 is * 30% reduction from baseline in the total number of flushing
episodes
Secondary outcome
Secondary efficacy variables include: objective tumor response rate (CR or PR),
disease control rate (CR, PR or SD) at month 6 based on RECIST criteria, mean
change from baseline in bowel movements alone at month 6, change from baseline
in total flushing episodes alone at month 6, proportion of patients who
achieved at least a 30% reduction in frequency of bowel movements at month 6,
time to symptom response, duration of symptom response, time to symptom
progression, and change from baseline in QoL scores at month 6.
Background summary
Somatostatin analogues are considered standard therapy for the treatment of the
disease-related symptoms of carcinoid disease. Octreotide and lanreotide are
the only two representatives of this class of compounds approved for clinical
use. These agents are known to exert their activity primarily via binding to
receptor sst2. These peptides have been shown to be effective in reducing
symptoms associated with metastatic carcinoid tumors (known as carcinoid
syndrome), specifically diarrhea and flushing.
Somatostatin analogues provide symptomatic improvement in approximately 58% to
76% of carcinoid patients. Although many patients initially respond to
treatment with these agents, adequate control cannot be achieved in
approximately 50% of patients as early as 12 to 18 months after initiation of
therapy.
There is evidence that many tumor cells become resistant to these agents by
either down-regulation of sst2 or over
expression of other sst receptors. Pasireotide may have a beneficial effect in
patients who have become resistant to these agents via its enhanced binding to
other receptor subtypes. Due to the enhanced binding of pasireotide to other
receptor subtypes, pasireotide is predicted to have a beneficial effect in
patients who have become resistant to these agents. Data from the ongoing Phase
II study in patients with metastatic carcinoid tumors further suggests that
pasireotide is active in patients refractory/resistant to Sandostatin LAR.
In addition, the requirement for both diarrhea AND flushing does not accurately
reflect the known epidemiology of Carcinoid syndrome in that
relative few patients actually have both diarrhea and flushing. Patients
generally have a predominance of either diarrhea OR flushing but not both.
Therefore, the symptom criteria, coupled with the somatostatin analogue dose
criteria, actually defined an uncommon patient population that was somewhat
counter to the natural presentation of the disease and current treatment
practices. Therefore, the inclusion criteria in this study defines 3 subgroups
of patients: diarrhea and flushing; predominantly diarrhea and predominantly
flushing.
A reduction in the frequency of bowel movements and/or bouts of flushing is
deemed clinically meaningful as either symptom alone interferes with daily
activities and impacts the quality of life.
The purpose of this randomized, multicenter, Phase III study is to compare the
efficacy of pasireotide LAR and octreotide LAR in patients whose
disease-related symptoms are inadequately controlled by currently available
somatostatin analogues.
Study objective
To compare the long term efficacy of pasireotide LAR vs. octreotide LAR at
month 6 in controlling diarrhea and/or flushing in patients with metastatic
carcinoid tumors whose disease-related symptoms are inadequately controlled by
the maximum approved dose of a somatostatin analogues.
Study design
This is a phase III, multicenter, randomized, blinded, efficacy and safety
study of pasireotide
LAR vs. octreotide LAR in patients with metastatic carcinoid tumors whose
disease-related symptoms are inadequately controlled on a maximum approved dose
of a currently available somatostatin analogue. Patients will be randomized 1:1
and stratified according to disease location (midgut vs. other).
The study will have a screening, blinded treatment phase, follow-up and a
treatment extension phase.
The treatment and evaluation period for this study is 6 months, patients will
be considered to have completed the study after the 6 month evaluation has been
performed. Treatment may be terminated prior to 6 months if symptom control is
not maintained, unacceptable toxicity occurs, or the patient decides to
discontinue study participation.
Patients who are receiving clinical benefit from pasireotide LAR and who are
not experiencing unacceptable toxicity are permitted to continue treatment
after the 6 month treatment period.
Patients who were randomized to octreotide LAR and who are not receiving
clinical benefit from this treatment may be offered the option to receive
pasireotide LAR treatment.
Intervention
Study drug: pasireotide LAR (long-acting release) i.m. 60mg depot injection
every 28 days and pasireotide s.c. as rescue medication.
Active control: octreotide LAR i.m., 40mg depot injection every 28 days and
octreotide s.c. as rescue medication.
Study burden and risks
Toxicity of pasireotide LAR or octreotide LAR. Site of the injections may cause
local pain and some discomfort (swelling, redness)
Radiation exposure of CT-scans.
Obtaining blood samples may cause some discomfort, bruising, bleeding from the
site of sampling, formation of a blood clot, and, in rare cases, infection.
Raapopseweg 1
6824 DP Arnhem
NL
Raapopseweg 1
6824 DP Arnhem
NL
Listed location countries
Age
Inclusion criteria
1. Patients with histopathologically confirmed metastatic carcinoid tumors of the digestive system 2. Patients must have inadequate control of symptoms (i.e. diarrhea and/or flushing) while receiving treatment with the maximum approved dose of a currently available somatostatin analogue for at least a 3 months prior to study entry. Inadequate control is defined by the following groups:
- Diarrhea and Flushing group (D+F): patients with a daily mean of * 4 bowel movements and a total of * 5 flushing episodes over a two-week period (14 days) while receiving treatment with the maximum approved dose of a currently available somatostatin analogue for at least a 3 month period prior to study entry (as specified in Table 4-1 in protocol).
- Predominantly Diarrhea group (D): patients with a daily mean of * 4 bowel movements and a total number of < 5 flushing episodes over a two-week period (14 days) while receiving treatment with the maximum approved dose of a currently available somatostatin analogue for at least a 3 month period prior to study entry (as specified in Table 4-1in protocol).
- Predominantly Flushing group (F): patients with * 14 flushing episodes and a daily mean of < 4 bowel movements over a two-week period (14 days) while receiving treatment with the maximum approved dose of a currently available somatostatin analogue for at least a 3 month period prior to study entry (as specified in Table 4-1 in protocol).
3. Patients must observe the following intervals between the last injection of their previous treatment and the first injection of study drug:
* octreotide LAR <= 28 days
* octreotide s.c <= 8 hours
* lanreotide Autogel <= 28 days
* lanreotide SR <= 14 days
4. Measurable or evaluable disease per RECIST
5. Karnofsky Performance status * 60%
6. Patients with a known history of impaired fasting glucose or diabetes mellitus may be included, however blood glucose and antidiabetic treatment must be monitored closely throughout the study.
7. Baseline lab values for adequate organ function:
* Absolute neutrophil count *1.5 × 10^9/L
* Hemoglobin *9 g/dL
* Platelets *100 × 10^9/L
* Hepatic: Serum bilirubin * upper limit of normal (ULN), Aspartate aminotransferase
and alanine aminotransferase, *3 × ULN without liver metastases, *5 × ULN if
documented liver metastases.
* Renal: Serum creatinine *1.5 mg/dL, calculated creatinine clearance *40 mL/min
Exclusion criteria
1. Patients who have received a somatostatin analogue higher than the maximum approved
dose within 3 months of Visit 1. (This exclusion criteria is not applicable to patients who
are receiving short acting formulation.)
2. Patients receiving radiolabeled somatostatin analogue therapy within the 3 months or any cytotoxic chemotherapy or interferon therapy within the 4 weeks prior to recording baseline symptoms.
3. Major surgery/surgical therapy for any cause within 1 month or surgical therapy of loco-regional metastases within the last 3 months before recording baseline symptoms
4. Hepatic artery embolization, chemoembolization or radioembolization (yttrium 90 microspheres) within the last 6 months (1 month if there are other sites of measurable disease), or patients who have undergone cryoablation or radiofrequency ablation of hepatic metastasis within the last 2 months before recording baseline symptoms
5. Radiotherapy for any reason within the last 4 weeks (side effects must have been recovered before recording baseline symptoms).
6. Patients who are unwilling to follow dietary restrictions within 3 days of urinary 5-HIAA sample collection or require medications that would interfere with urinary 5-HIAA measurement
7. Patients with known malabsorption syndrome, short bowel or chologenic diarrhea not
controlled
8. Patients who are not biochemically euthyroid
9. Diabetic patients on antidiabetic medications with a HbA1C > 8% (fasting)
10. Patients with symptomatic cholelithiasis
11. Any of the following cardiac abnormalities:
* QTcF at screening > 450 msec
* History of syncope or family history of idiopathic sudden death
* Sustained or clinically significant cardiac arrhythmias
* Risk factors for Torsades de Pointes such as hypokalemia, hypomagnesemia, cardiac
failure, clinically significant/symptomatic bradycardia, or high-grade AV block
*Concomitant disease(s) that could prolong QT such as autonomic neuropathy (caused
by diabetes, or Parkinson's disease), HIV, cirrhosis, uncontrolled hypothyroidism or
cardiac failure
* Concomitant medication(s) known to increase the QT interval
12. Additional active malignant disease within the last five years (with the exception of basal cell carcinoma or carcinoma in situ of the cervix)
13. The presence of active or suspected acute or chronic uncontrolled infection or with a history of immunocompromise, including a positive HIV test result. A HIV test will not be required.
14. Patients with abnormal coagulation (PT or APTT 30% above normal limits)
15. Female patients who are pregnant or lactating, or are of childbearing potential and not practicing a medically acceptable method of birth control. Male patients who are sexually active are required to use condoms during the study and for three months afterwards. Female partners of these male patients must use a secondary barrier contraception.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2007-000739-25-NL |
| ClinicalTrials.gov | NCT00690430 |
| CCMO | NL26265.042.09 |