The primary objective is to compare the overall survival (OS) between the 2 treatment arms (tremelimumab and placebo) in subjects with unresectable malignant mesothelioma.Secondary objectives are:- to estimate and compare OS rate at 18 months…
ID
Source
Brief title
Condition
- Other condition
Synonym
Health condition
inoperabel maligne mesothelioom
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary endpoint is OS which is defined as the time from randomization
until death due to any cause.
Secondary outcome
The secondary efficacy endpoints include OS rate at 18 months, durable DCR,
PFS, PROs, ORR, and duration of response, based on modified Response Evaluation
Criteria in Solid Tumors (RECIST) for pleural mesothelioma and RECIST criteria
v1.1 for peritoneal mesothelioma.
The safety endpoints include adverse events (AEs) and serious adverse events
(SAEs) changes from baseline in clinical laboratory evaluations,
electrocardiograms (ECGs), and vital signs. Adverse events and SAEs will be
assessed for severity and relationship to investigational product.
The immunogenic potential of tremelimumab will be analyzed and the
pharmacokinetics of tremelimumab will be assessed.
Background summary
Patients with pleural or peritoneal malignant mesothelioma who fail first-line
treatment have a significant unmet medical need given their poor prognosis,
lack of any approved agent in this disease setting, and absence of a clinically
meaningful OS benefit with existing salvage regimens. Mesothelioma resulting
from asbestos exposure may have an immune-mediated component and so an agent
such as tremelimumab that blocks CTLA-4 may lead to enhanced T cell immune
function and antitumor activity.
The research hypothesis is that in subjects with unresectable pleural or
peritoneal malignant mesothelioma receiving best supportive care, tremelimumab
will reduce the risk of death by approximately 29% (hazard ratio = 0.71) over
placebo while maintaining an acceptable safety profile. A reduction in the risk
of death by 29% will be both statistically significant and clinically
meaningful, as there are no available therapies that offer an OS benefit in
second- or third-line pleural or peritoneal malignant mesothelioma.
Study objective
The primary objective is to compare the overall survival (OS) between the 2
treatment arms (tremelimumab and placebo) in subjects with unresectable
malignant mesothelioma.
Secondary objectives are:
- to estimate and compare OS rate at 18 months between the 2 treatment arms;
- to estimate and compare durable disease-control rate (DCR) , progression-free
survival (PFS), overall response rate (ORR) and duration of response between
the 2 treatment arms,
- to evaluate the effect of tremelimumab on patient-reported outcomes
(PROs),including disease-related symptoms, pain symptoms, and time to
deteriorationof diseae-related symptoms
- to describe the safety and tolerability of tremelimumab in treated subjects,
- to evaluate the immunogenicity of tremelimumab in treated subjects;
- and to describe the pharmacokinetics (PK) of tremelimumab in treated subjects.
Exploratory objectives are:
* To estimate and compare durable DCR, PFS, ORR, and duration of response based
on immune related response criteria (irRC) between the 2 treatment arms;
* To examine health-related QoL, disease-related symptoms, pain, and health
status in subjects with durable clinical activity;
* To examine biomarkers and their association with tremelimumab treatment and
clinical outcome.
Study design
This is a Phase 2b, randomized, double-blind, placebo-controlled study in
adults with unresectable pleural or peritoneal malignant mesothelioma who have
progressed after previous receipt of 1 or 2 prior systemic treatment regimens
that included pemetrexed (or other anti-folate) in combination with a platinum
agent. For subjects in whom pemetrexed was contraindicated or not tolerated or
not an approved therapy (eg, peritoneal mesothelioma), prior therapy with a
first-line platinum-based regimen is required. Though the number of subjects
not receiving prior pemetrexed is expected to be small, the proportion of such
subjects enrolled in the study will be capped at 20%. Subjects will be
randomized in a 2:1 ratio to receive either tremelimumab or placebo.
Randomization will be stratified by the European Organization for Research and
Treatment of Cancer (EORTC) status (low-risk vs high-risk), line of therapy
(second vs third), and anatomical site (pleural vs peritoneal). Approximately
564subjects will be enrolled at approximately 180 study centers in multiple
countries.
If at the time of the second interim analysis or at the time of final analysis,
the study demonstrates evidence of clinical benefit with a favorable
benefit-risk profile, subjects receiving placebo will be given the option to
*cross-in* to receive tremelimumab treatment (subject to a decision by the
Sponsor in discussion with the IDMC). See Appendix 8 in the protocol for
details. Additionally, subjects on the tremelimumab arm who are receiving
clinical benefit at the time of the interim or final analyses can continue to
receive treatment with tremelimumab.
Intervention
Tremelimumab is to be administered as an intravenous (IV) solution of 10 mg/kg
at a rate of 250 mL/hr. Subjects will receive one dose of investigational
product every 4 weeks (Q4W) for 6 doses, followed by doses every 12 weeks
(Q12W) unless permanent discontinuation criteria are met.
Study burden and risks
During the trial the patient performs 18 visits to the hospital. During these
visits physical examination, vital signs will be measured and blood will be
collected, no more than 50 mL per visit. Questionnaires for pain, lung disease
(LCSS) and general health (EQ-5D) will be completed as well as ECGs . CT or MRI
is done at screening and visit 5 and every 3 months or earlier if clinically
indicated by the investigator. Also pulse oximetry will be measured at each
visit
The study medication may cause some side effects. Some of these side effects
could be inflammatory events. These events are caused by the activation of the
body*s immune system by tremelimumab and cause inflammation in different body
organs. The most commonly affected organs are gastrointestinal tract, skin,
liver, and endocrine system.
The most frequently reported adverse events (all grades of severity: mild to
severe) in subjects receiving tremelimumab as a single agent/monotherapy
included the following in decreasing order of frequency: diarrhea ( in approx 1
out of 2 subjects), fatigue, nausea, rash in approx 1 out of 3 subjects),
itchiness, decreased appetite, vomiting (in approx 1 out of 4 subjects),
fever,cough, constipation, abdominal pain, headache, difficulty of breathing (
in approx 1 out of 3-8 subjects), and decreased weight ( in approx 1 out of 10
subjects). Of these events, diarrhea, rash and itchiness) have an established
association with the administration of tremelimumab.
Approximately half of the subjects experienced adverse events that were severe
.The most frequent of these severe adverse events reported were (in decreasing
order of frequency): diarrhea (in approx 1 out of 8 subjects), fatigue (in
approx 1 out of 20 subjects), inflammation of the large intestine (colitis),
disease progression, difficulty of breathing, dehydration/nausea/vomiting,
abdominal pain, decreased appetite, and body weakness (in approx 1 out of 30-50
subjects).
The most frequent treatment-related adverse events (in more than 1 out of 20
subjects) were diarrhea, rash, itchiness, fatigue, nausea, vomiting, decreased
appetite, headache, fever, abdominal pain and inflammation of the large
intestine (colitis).
In addition you may experience:
- Decreased blood platelet count with symptoms such as unexpected bruising,
bleeding from the nose or gums, blood in vomit or stools, or red spots under
the skin
- Inflammation of the pancreas (also known as pancreatitis) with symptoms such
as abdominal pain, nausea, vomiting and tenderness when touching the abdomen or
laboratory abnormality
- Inflammation of the liver with symptoms such as abdominal swelling,
distention or bloating, diarrhea, discolored urine and stool, loss of appetite,
tiredness and lethargy, nausea with or without vomiting, yellowing of the skin
and whites of the eyes (jaundice)
- Hormonal secreting glands: symptoms can be non-specific and vary depending on
cause, and can include, but not limited to, headaches, nausea, vomiting,
fatigue, dizziness, weakness, tiredness, mood alterations, poor appetite,
weight fluctuations and possibly sexual dysfunction.
Intravenous administration can cause slight discomfort or bruising at the site
where the needle is inserted and may also cause lightheadedness and fainting,
infection, and excessive bleeding. Obtaining blood may sometimes cause pain at
the site where the blood is drawn, bruising, occasional lightheadedness and,
rarely, fainting. Repeated blood draws may lead to anemia.
The risks from a CT (or CAT) and/or MRI x-rays include exposure to radiation
and possible reaction to the dye used in the procedure.
One MedImmune Way
Gaithersburg MD 20878
US
One MedImmune Way
Gaithersburg MD 20878
US
Listed location countries
Age
Inclusion criteria
Subjects must meet all of the following criteria:
- Histologically and/or cytologically confirmed pleural or peritoneal malignant mesothelioma. ;- Disease not amenable to curative surgery;;- Age 18 and over at the time of consent;;- ECOG Performance status 0-1;;- Progressed after receipt of 1-2 prior systemic treatments for advanced disease that include a first-line pemetrexed (or anti-folate)-based regimen in combination with platinum agent;;- Recovered from all toxicities associated with prior treatment;- Measurable disease;- Adequate bone marrow, hepatic, and renal function ;- Negative screening test results for human immunodeficiency virus (HIV), hepatitis A, B and C. ;- Written informed consent and any locally required authorization (eg, HIPAA in the USA, EU Data Privacy Directive authorization in the EU) obtained from the subject/legal representative prior to performing any protocol-related procedures, including screening evaluations;;- Females of childbearing potential who are sexually active with a nonsterilized male partner must use a highly effective method of contraception for 28 days prior to the first dose of investigational product, and must agree to continue using such precautions for 6 months after the final dose of investigational product;;- Nonsterilized males who are sexually active with a female partner of childbearing potential must use a highly effective method of contraception from Day 1 through 90 post last dose.
Exclusion criteria
Any of the following would exclude the subject from participation in the study:
- Subjects who failed more than 2 prior systemic treatment regimens for advanced malignant mesothelioma;
- Received any prior monoclonal antibody against CTLA-4, programmed cell death 1 (PD1) or programmed cell death 1 ligand 1 (PD-L1);
- History of chronic inflammatory or autoimmune disease;
- Active, untreated central nervous system (CNS) metastasis;
- Any serious uncontrolled medical disorder or active infection that would impair the subject's ability to receive investigational product, such as conditions associated with frequent diarrhea
- History of other malignancy unless the subject has been disease-free for at least 3 years. Non-invasive cancer history (such as carcinoma in situ [CIS] that has been resected) is allowed;
- Pregnant or breast feeding at time of consent;
- Any condition that would prohibit the understanding or rendering of information and consent and compliance with the requirements of this protocol;
- Active or history of diverticulitis. Note that diverticulosis is permitted;
- Active or history of inflammatory bowel disease (eg, colitis,
Crohn's), irritable bowel disease, celiac disease or other serious gastrointestinal chronic conditions associated with diarrhea. Active or history of systemic lupus erythematosis or Wegener's granulomatosis;
- History of sarcoidosis syndrome;
- Currently receiving systemic corticosteroids or other
immunosuppressive medications;
- Subjects should not be vaccinated with live attenuated vaccines within one month prior to starting tremelimumab treatment;
- The last dose of prior chemotherapy or radiation therapy (with the exception of palliative radiotherapy) was received less than 2 weeks prior to randomization;
- Any unresolved toxicity NCI CTCAE Grade >- 2from previous anticancer therapy, with the exception of vitiligo and alopecia;
- Any condition that, in the opinion of the investigator, would interfere with evaluation of the investigational product or interpretation of subject safety or study results;
- Concurrent enrollment in another clinical study or receipt of an investigational product within the last 4 weeks (participation in the survival follow-up period of a study is not an exclusion criterion);
- Employees of the study site directly involved with the conduct of the study, or immediate family members of any such individuals.
- Subjects with a history of hypersensitivity to compounds of similar biologic composition to tremelimumab or any constituent of the product.
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 | EUCTR2012-003524-21-NL |
| ClinicalTrials.gov | NCT01843374 |
| CCMO | NL44425.060.13 |