Primary Objectives:• To compare progression free survival (PFS) as determined by blinded independent central review (BICR) and overall survival (OS) of nivolumab combined with ipilimumab to pemetrexed plus cisplatin or carboplatin regimen as first…
ID
Source
Brief title
Condition
- Pleural disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Overall survival and the progression-free survival based on Blinded Independent
Committee Review (BICR) assessment are the primary endpoints of the study.
Secondary outcome
Secondary Endpoints:
*- Objective response rate (best overall response [BOR] is either a complete
response [CR] or partial response [PR] per adapted m-RECIST and/or RECIST 1.1
criteria
*- Disease control rate (BOR is CR, PR, or stable disease [SD])
*- PD-L1 expression level
Exploratory Endpoints:
*- Incidence rates of adverse events, serious adverse events, deaths, and
laboratory abnormalities
*- Serum concentrations of nivolumab in combination with ipilimumab
*- The improvement of the EuroWol Group*s self-reported health status measure
(EQ-5D) and EQ Vas score
*- Disease-related symptom improvement rate evaluated by mesothelioma adaption
of Lung Cancer Symptom Scale (LCSS-Meso)
Background summary
Product Development Background:
Nivolumab (Opdivo) is in clinical development for the treatment of subjects
with melanoma, non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC),
head and neck carcinoma and other tumors (eg, gastric cancer, glioblastoma
multiforme, hodgkins lymphoma, small cell lung
cancer). Opdivo as monotherapy has been approved in the US in multiple
indications, including, unresectable or metastatic melanoma and disease
progression following Ipilimumab and a BRAF inhibitor, if BRAF V600 mutation
positive; previously untreated subjects with BRAF wild-type
unresectable or metastatic melanoma; NSCLC with progression on or after
platinum-based chemotherapy; and advanced renal cell carcinoma who have
received prior anti-angiogenic therapy. The combination of nivolumab and
ipilimumab has also been approved in the US for the
treatment of previously untreated metastatic melanoma. Subjects with
unresectable malignant pleural mesothelioma (MPM) have poor prognosis and
experience limited survival benefit with standard of care platinum based
therapy. Clinical data from early trials with PD-1/PD-L1 or CTLA-4 targeted
therapies has shown promising activity in pre-treated MPM. To further improve
clinical outcomes in subjects with unresectable MPM in the first line treatment
setting, nivolumab in combination with ipilimumab is being explored in the
CA209743 clinical study.
Study objective
Primary Objectives:
• To compare progression free survival (PFS) as determined by blinded
independent central review (BICR) and overall survival (OS) of nivolumab
combined with ipilimumab to pemetrexed plus cisplatin or carboplatin regimen as
first line treatment in patients with unresectable malignant pleural
mesothelioma.
Secondary Objectives:
• To compare the objective response rate (ORR) as determined by BICR, of
nivolumab combined with ipilimumab to pemetrexed plus cisplatin or carboplatin
as first line treatment in patients with unresectable malignant pleural
mesothelioma.
• To compare the Disease Control Rate (DCR) as determined by BICR, of nivolumab
combined with ipilimumab to pemetrexed plus cisplatin or carboplatin as first
line treatment in patients with unresectable malignant pleural mesothelioma.
• To evaluate whether PD-L1 expression is a predictive biomarker for ORR, PFS,
and OS.
Exploratory Objectives:
• To assess safety and tolerability of nivolumab combination with ipilimumab,
and pemetrexed plus cisplatin or carboplatin as first line treatment in
patients with unresectable pleural mesothelioma.
• To characterize pharmacokinetics of nivolumab in combination with ipilimumab
as first line in patients with unresectable malignant pleural mesothelioma
(MPM).
• To characterize the immunogenicity of Nivolumab in combination with
ipilimumab as first line in patients with unresectable MPM
• To assess the subject*s overall health status and health utility using the
3-level version of the EQ-5D (EQ-5D-3L) visual analog scale (VAS) and utility
index, respectively.
To assess the subject*s cancer-related symptoms and quality of life using the
mesothelioma adaptation of the Lung Cancer Symptom Scale (LCSS-Meso)
Study design
Study Design:
This is an open label, randomized, Phase 3 study in adult (therapy for
diagnosed unresectable malignant pleural mesothelioma
Subjects in each arm will be stratified by
* histology: Epithelioid vs non-epithelioid
* gender: male or female
Subjects will be randomized in 1:1 and treated with one of the following
open-label treatments;
* Arm A: nivolumab administered IV over 30 minutes at 3 mg/kg every 2 weeks
combined with ipilimumab administered IV over 30 minutes at 1mg/kg every 6weeks
until progression, unacceptable toxicity, or other reasons specified in the
protocol and for a maximum treatment duration of 2 years. Treatment beyond
initial investigator-assessed and BICR confirmed progression according to
adapted modified RECIST (m-RECIST) and /or RECIST 1.1 defined progression is
permitted if the subject has investigator assessed clinical benefit and is
tolerating nivolumab.
* Arm B: pemetrexed plus cisplatin or carboplatin chemotherapy administered on
day 1 of every 21 days for up to 6 cycles. Chemotherapy treatment will
continue until disease progression, unacceptable toxicity or completion of 6
cycles, whichever comes first.
On-study tumor assessments will begin at Week 6 post randomisation (+/-7 days)
and be performed every 6 weeks
(+/-7 days) for the first 12 months and every 12 weeks (+/- 7 days) thereafter
or until disease progression, whichever occurs later.
Enrollment will end after approximately 600 subjects have been randomised.
Intervention
The medicinal interventions include nivolumab/ipilimumab combination therapy
(Arm A) and pemetrexed plus cisplatin or carboplatin chemotherapy (Arm B).
Study burden and risks
As part of the trial, patients will be expected to attend multiple clinic
visits, where they will undergo physical examinations, vital sign measurements,
blood tests for safety assessment, pregnancy testing (for females of child
bearing potential), and monitoring for adverse events. In addition patients
will undergo radiographic assessment of their tumours (by CT). CT scan of Chest
and upper abdomen, and all other known sites of disease within
28 days prior to first dose. Response will be assessed at 6 weeks (+/- 7 days)
from first dose date, then every 6 weeks (+/- 7days) for the first 12 months
(until week 48) and every 12 weeks (+/- 7 days) thereafter, or until disease
progression is confirmed, whichever occurs first.
Subjects will have pre-treatment and optional on-treatment biopsies performed.
Blood will also be collected at certain visits for research purposes
(immunogenicity and biomarker studies). The frequency of visits and number of
procedures carried out during this trial would typically be considered over and
above standard of care. These procedures are conducted by medically trained
professionals and every effort will be made to minimise any risks or discomfort
to the patient. Treatment for cancer often has side effects, including some
that are life threatening. Patients
will be instructed when to contact their treating physicians if side effects
occur and are given a patient card with detailed information
Sanderson Road Uxbridge Business Park Sanderson Road Uxbridge Business Park
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Listed location countries
Age
Inclusion criteria
-Male and female subjects (18 years of age and over).
-Histologically proven diagnosis of (MPM), thoracoscopy is highly recommended.
-Advanced unresectable disease that is not amenable to therapy with curative intent (surgery with or without chemotherapy). Subjects that refuse potentially curative surgery are ineligible.
-Available (archival and/or fresh) pathological samples for centralized PD-L1 IHC testing during the screening period. Subjects cannot be randomized until the tumor tissue for PD-L1 testing has been received at the Central Lab, however, the result of the testing is not required prior to randomization. Subjects can initiate therapy before the result of PD-L1 testing is available.
-Prior palliative radiotherapy is acceptable, but at least 14 days must have passed since the administration of the radiotherapy and all signs of toxicity must have remitted.
-ECOG Performance Status of 0-1
-Weight loss < 10% during last 3 months
-Measurable disease, defined as at least 1 lesion measured in up to two positions at three separate levels on transverse cuts of CT scan that is suitable for repeated assessment using adapted modified Response Evaluation Criteria in Solid Tumors [m-RECIST] for pleural mesothelioma
-Adequate hematological, renal and hepatic functions
Exclusion criteria
-Primitive peritoneal, pericardial and tunica vaginalis testis mesotheliomas
-Brain metastasis, except if surgically resected or treated with stereotaxic radiotherapy with no evolution within the 3 months before inclusion, and asymptomatic. In addition, subjects must be either off corticosteroids, or on a stable or decreasing dose of <=10 mg daily prednisone (or equivalent) for at least 2 weeks prior to randomization
-Prior treatment with adjuvant or neoadjuvant chemotherapy, radical pleuropneumonectomy with or without intensity modulated radiotherapy or non-palliative RT
-Prior intraoperative or intracavity chemotherapy for pleural mesothelioma
-Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways.
-History of chronic inflammatory or autoimmune disease,
-Concurrent or prior malignancy requiring or anticipated to require concurrent intervention
-Subjects with interstitial lung disease that is symptomatic or may interfere with the detection or management of suspected drug-related pulmonary toxicity.
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 | EUCTR2016-001859-43-NL |
| CCMO | NL58915.031.16 |