The primary objective of the study is to confirm that at least 1 or more doses of telotristat etiprate compared to placebo is effective in reducing the change from baseline in the number of daily bowel movements (BMs) averaged over the 12-week…
ID
Source
Brief title
Condition
- Malignant and unspecified neoplasms gastrointestinal NEC
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary objective of the study is to confirm that at least 1 or more doses
of telotristat etiprate compared to placebo is effective in reducing the change
from baseline in the number of daily BMs averaged over the 12-week double-blind
portion of the trial (Treatment Period) in patients with carcinoid syndrome not
adequately controlled to current SSA therapy.
Secondary outcome
The secondary objectives of this study are:
To assess the effects of telotristat etiprate versus placebo over the 12-week
double-blind portion of the study in patients who are not adequately controlled
to current SSA therapy as determined by:
* Change from baseline in stool consistency averaged across all time points
* Change from baseline in the number of cutaneous flushing episodes
* Change from baseline in abdominal pain averaged across all time points
* Durability, defined as the proportion of responders with >=30% reduction in
daily number of BMs for >=50% of time over the double-blind portion of the study
* Change in the frequency of rescue short-acting SSA used to treat
bowel-related CS symptoms
Background summary
Currently, no approved therapy exists for the treatment of symptoms driven by
underlying serotonin pathophysiology of CS in patients whose disease is not
adequately controlled to SSA therapy. In the placebo-controlled study, the 250
and 500 mg tid dose levels showed clinical improvement in BM frequency over the
4 weeks. Clinical improvement in BM frequency was sustained to at least 12
weeks in the open-label LX1606.203 study. In utilizing a placebo group
receiving standard of care as a concurrent comparator arm, evaluation of
telotristat etiprate, as an add-on therapy to SSAs for up to 12 weeks, may be
performed without placing the patient at undue risk. (See Protocol LX1606.301
section 3.4 Rationale for Study Design and Control Groups)
Study objective
The primary objective of the study is to confirm that at least 1 or more doses
of telotristat etiprate compared to placebo is effective in reducing the change
from baseline in the number of daily bowel movements (BMs) averaged over the
12-week double-blind portion (Treatment Period) of the trial in patients with
carcinoid syndrome not adequately controlled to current SSA therapy
Study design
The study will be conducted as a Phase 3, randomized, placebo controlled,
parallel-group, multicenter, double-blind study in patients with CS not
adequately controlled to SSA therapy to evaluate 2 oral dose levels of
telotristat etiprate, 250 and 500 mg 3 times daily (tid), versus placebo.
Patients will enter into a Screening/Run-in Period of at least 3 weeks to
establish baseline symptoms. During the Run-in Period, patients will continue
to receive stable-dose SSA therapy in order to establish baseline
characteristics and symptomatology. For the purposes of this study, stable-dose
SSA therapy is defined as long acting release (LAR) or Depot SSA therapy or a
continuous subcutaneous infusion via a pump at the same dose level and
frequency for at least 3 months prior to the Run-in Period. In addition,
therapy with rescue, short-acting SSA will be permitted. Only those who
complete the Screening/Run-in Period and are 75% compliant with diary entries
will be considered eligible for the Treatment Period of the study.
Following the Screening/Run-in Period, patients will be randomly assigned
(1:1:1) on Day 1 to receive 1 of 2 dose levels of telotristat etiprate (250 or
500 mg) or placebo given 3 times daily (tid). A blinded titration period will
occur during the first 7 days. During the titration period, all patients will
be administered 2 tablets tid; given as 1 x 250 mg tablet plus 1 placebo tablet
or 2 placebo tablets. After 7 days, patients will receive their assigned dose
levels for 11 weeks. All patients must remain on their baseline dose of SSA
therapy during the Treatment Period.
Added comments based on METc MMC questions (20FEB2013)
• ABR question K2 English summary Study design Placebo: There will be 2
different doses of the study drug -250 mg and 500 mg. Each of these will be
administered 3 times a day. In order to keep the blinding the placebo will also
be administered 3 times a day. In this way all subjects will actually take 2
tablets 3 times a day.
• ABR question K2 English summary Study design Dosage: The dose groups in the
previous phase 2 studies were 150, 250, 350, and 500 mg given three times
daily. Lexicon has chosen 2 of these dose groups to further evaluate.
Added comments based on METc MMC questions (08MAY2013)
Overall, while the Sponsor believes that the 500 mg TID dose will prove to have
superior efficacy, the Sponsor wishes to emerge from this Phase 3 study with
confidence that dose response has been explored, and that a potentially useful
dose (250 mg TID) has been fully assessed.
Based on the Sponsor's assessment of the evidence thus on dose response, the
500 mg TID dose is most likely to be optimal. The best evidence for the
optimal dose is found in the LX1606.203 study. The progression of most
patients to the top dose of TE (500 mg TID) in this study suggests that this
dose is the most effective of any of the tested doses in reducing symptoms, and
also that the TE was well tolerated throughout. Starting from smaller doses,
patients progressed, per the study design, successively to the next dose, if
they had not yet achieved clinically relevant improvement in symptoms at that
dose, and if they had not experienced a dose-limiting toxicity. Of the 14
patients who completed the 12-week treatment period. 12 (86%) progressed to the
500 mg TID dose. With increasing doses during the 8 weeks of the
dose-escalation period, the mean number of BMs per day improved successively,
and improvements were then maintained for the remaining four weeks of the
treatment period, during which doses remained stable. No dose-limited toxicity
was reported, and no patient was discontinued due to an adverse event. Most
patients continued on to the extension phase, which is still ongoing.
An additional arm was added to the LX1606.301 trial in order to gain additional
information on dose response in a larger trial. The specific 250 mg TID dose
was chosen for several reasons. First, in both Phase 2 studies, this dose
showed a clear clinical response in reducing stool frequency and in reducing
urinary 5-HIAA levels. Second, since 250 mg is half the 500 mg dose, there is
natural convenience in titration between the two doses. Further, the
availability of the 250 mg dosage form will make it possible to titrate to the
500 mg TID gradually, as is recommended to reduce nausea.
Intervention
Three arms are used and there will be 2 different doses of Telotristat
etiprate and an placebo
- arm 1: 2 tablets with 250 mg Telotristat etiprate will be administered 3
times a day
- arm 2: 2 tablets with 500 mg Telotristat etiprate will be administered 3
times a day
- arm 3: 2 tablets of Placebo will be administered 3 times a day
In this way all patients will actually take 2 tablets 3 times a day.
Study burden and risks
Taking part in this study may or may not make your health better. Study doctors
hope LX1606 will be helpful in treating carcinoid syndrome compared to the
standard treatment; there is no proof of this yet. We do know that the
information from this study will help study doctors learn more about LX1606 as
a treatment for carcinoid syndrome. This information could help future
carcinoid syndrome patients.
Technology Forest Place 8800
The Woodlands TX 77381
US
Technology Forest Place 8800
The Woodlands TX 77381
US
Listed location countries
Age
Inclusion criteria
1.Patients >=18 years of age at the time of the Screening visit;2.Histopathologically-confirmed, well-differentiated metastatic NET with extent documented by computed tomography (CT), magnetic resonance imaging (MRI), or radionuclide imaging;3.A documented history of CS, and currently experiencing an average of >=4 bowel movements per day during the Run-in Period. Confirmation of eligibility will be determined by measuring the mean number of bowel movements;4.Currently receiving a stable-dose SSA therapy. For the purposes of this study, stable-dose SSA therapy is defined as long acting release (LAR) or Depot SSA therapy or a continuous subcutaneous infusion via a pump. Patients must have been receiving the same dose level and frequency for at least 3 months prior to entering the Run-in Period.;5.Minimum dose of LAR or Depot SSA therapy (higher dose or more frequent intervals will fulfill the minimum dose requirement). SSA therapy must be approved for use in CS in the patient*s country of residence or prescribers* country of practice.
a.Octreotide LAR at 30 mg every 4 weeks
b.Lanreotide Depot at 120 mg every 4 weeks
c.Patients who cannot tolerate SSA therapy at a level indicated above will be allowed to enter at their highest tolerated dose;6.Patients of childbearing potential must agree to use an adequate method of contraception (defined as having a failure rate of < 1% per year) during the study and for 12 weeks after the Follow-up visit. Adequate methods of contraception for patients or partner include condoms with spermicide gel, diaphragm with spermicide gel, coil (intrauterine device), surgical sterilization, vasectomy, oral contraceptive pill, depot progesterone injections, progesterone implant, and abstinence during the study and for 12 weeks after the Follow-up Visit.;a. Childbearing potential is defined as those who have not undergone surgical sterilization, or those who are not considered postmenopausal. Postmenopause is defined as absence of menstruation for at least 2 years. If necessary, follicle-stimulating hormone (FSH) results >50 IU/L
at Screening are confirmatory in the absence of a clear postmenopausal history.;7.Ability and willingness to provide written informed consent prior to participation in any study-related procedure
Exclusion criteria
Patients who meet any of the following criteria will be excluded from participating in the study: ;1.Presence of diarrhea attributed to any condition(s) other than CS(including, but not limited to fat malabsorption or bile acid malabsorption) ;2.Presence of more than 12 watery bowel movements per day associated with volume contraction, dehydration, or hypotension compatible with a *pancreatic cholera*-type clinical syndrome, as judged by the Investigator;3.Positive stool examination for enteric pathogens, pathogenic ova or parasites, or Clostridium difficile at Screening;4.Karnofsky Performance Status <=60% ;5.Clinical laboratory values for hematology (at Screening):;a.Absolute neutrophil count (ANC) <=1500 cells/mm3; or
b.Platelets <=750,000 cells/mm3; or
c.Hemoglobin (Hgb) <=9 g/dL for males and <=8 g/dL for females;6.Hepatic laboratory values (at Screening) such that:;a.Aspartate transaminase (AST), or alanine aminotransferase (ALT):
•>=5.5 x upper limit of normal (ULN) if patient has documented history of hepatic metastases; or
•>=2.5 x ULN if patient does not have documented history of hepatic metastases
b.Total bilirubin >1.5 x ULN (unless patient has a documented history of Gilbert*s Syndrome); or
c.Alkaline phosphatase (ALP) >=5 x ULN, if total bilirubin is >ULN
•No upper limit on the ALP value if the total bilirubin is <=ULN;7.Serum creatinine >=1.5 x ULN;8.Treatment with any tumor directed therapy including, but not limited to: interferon, chemotherapy, mTOR inhibitors <=4 weeks prior to Screening; or hepatic embolization, radiotherapy, radiolabelled SSA, and/or tumor debulking <=12 weeks prior to Screening;9.Major surgery defined as procedures requiring general anesthesia or major regional anesthesia within 8 weeks prior to Screening;10.A history of short bowel syndrome (SBS);(See Protocol LX1606.301 section Exclusion Criteria)
Clinically significant cardiac arrhytmia, bradycardia or tachycardia that would compromise patient safety or the outcome of the study.
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 | EUCTR2012-003460-47-NL |
| ClinicalTrials.gov | NCT01677910 |
| CCMO | NL43019.015.12 |