Primary Objectives:• To compare Blinded Independent Committee for Radiology (BICR)-assessed objective response rate (ORR) in participants of tissue Tumor Mutational Burden-High (tTMB-H) treated with nivolumab combined with ipilimumab • To compare…
ID
Source
Brief title
Condition
- Metastases
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
BICR-assessed ORR using RECIST 1.1, and Response Assessment for Neuro-Oncology
(RANO) criteria in primary CNS tumors
Secondary outcome
Further efficacy endpoints will be assessed by BICR and the investigator and in
correlation with biomarker analysis.
Safety and tolerability will be assessed by review of Incidence of adverse
events, serious adverse events, and select adverse events
Background summary
Tumors with a high mutational burden may have a higher number of neo-antigens
which, in principle, would be expected to be more immunogenic than tumors with
comparatively low mutational burden. Therefore, high TMB has been hypothesized
to correlate with improved efficacy in patients treated with immune-oncology
(IO) therapies. This hypothesis has been supported by multiple publications
across IO therapies, tumor types, and lines of treatment. The first published
study of TMB as a biomarker of clinical outcomes was reported by Snyder et al,
where high TMB (TMB-H) was found to be associated with efficacy in metastatic
melanoma patients treated with anti-CTLA-4 therapy. Further studies by Rizvi et
al reported TMB as a biomarker of pembrolizumab efficacy in second-line NSCLC
patients. Additional studies of pembrolizumab and atezolizumab in NSCLC have
been generally consistent with these results.
This trial with nivolumab in combination with ipilimumab and nivolumab
monotherapy will include participants with refractory, metastatic or
unresectable TMB-H malignancy who have been treated with prior non-IO
therapies. In general, malignancies included in this trial are the ones that
have no standard of care after first line therapy showing an improved benefit
over best supportive care. The low prevalence of TMB-H in these tumor types
limits the feasibility of traditional large-scale randomized trials. As a
result, a high unmet medical need exists for these patients, with no less
expectation for immunotherapy activity.
The primary goal of this study is to demonstrate the clinical activity of
nivolumab in combination with ipilimumab in multiple tumor types based on the
status of TMB.
Study objective
Primary Objectives:
• To compare Blinded Independent Committee for Radiology (BICR)-assessed
objective response rate (ORR) in participants of tissue Tumor Mutational
Burden-High (tTMB-H) treated with nivolumab combined with ipilimumab
• To compare BICR-assessed ORR in participants of blood TMB-H treated with
nivolumab combined with ipilimumab
Secondary Objectives:
- To estimate the duration of response (DOR), progression free survival (PFS),
overall survival (OS) and time to response (TTR) in participants of tTMB-H
treated with nivolumab combined with ipilimumab or nivolumab monotherapy
assessed by BICR or investigator
- To estimate the duration of response (DOR), progression free survival (PFS),
overall survival (OS) and time to response (TTR) in participants of bTMB-H
treated with nivolumab combined with ipilimumab or nivolumab monotherapy
assessed by BICR or investigator
- To assess the clinical benefit rate (CBR) in participants of tTMB-H treated
with nivolumab combined with ipilimumab or nivolumab monotherapy
- To assess the clinical benefit rate (CBR) in participants of tTMB-H treated
with nivolumab combined with ipilimumab or nivolumab monotherapy
- To evaluate the safety and tolerability of NKTR 214 combined with nivolumab
and that of nivolumab monotherapy
Exploratory Objectives:
- To characterise the pharmacokinetics of ipilimumab combined with nivolumab
and that of nivolumab monotherapy
- To characterise the immunogenicity of ipilimumab combined with nivolumab
- To assess the effect of ipilimumab combined with nivolumab and that of
nivolumab monotherapy on quality of life
- To assess the effect on tumor and blood based biomarkers
Study design
The study will enroll participants diagnosed with select advanced or metastatic
solid tumors of TMB-H with either tissue (tTMB) or blood TMB (bTMB) >= 10
mut/Mb. Both tissue and blood TMB will be assessed prior to randomization.
Participants without a prior known tTMB-H status available via F1CDx assay, or
a prior known bTMB result available from Foundation Medicine, will provide
consent for pre-screening and TMB status determination, but consent for further
screening procedures and study treatment should be deferred until TMB-H status
is established. Screening process can continue when the participant is TMB-H.
Participants with a prior known result of tTMB-H via F1CDx assay or bTMB-H from
Foundation Medicine may proceed immediately with full screening procedures.
Both tissue and blood TMB will be assessed prior to randomization. Prior
results of tTMB or bTMB obtained from any other assays except the ones
described above are not acceptable, including prior result of tTMB obtained via
Foundation One assay.
Once the TMB-H status is determined, this study will consist of three phases:
screening, treatment, and follow-up.
Approximately 210 patients will be treated globally.
Participants will receive either nivolumab (240 mg) every 2 weeks combined with
ipilimumab (1 mg/kg) every 6 weeks or Nivolumab alone (480mg) every 4 weeks
until disease progression, unacceptable toxicity, withdrawal of consent, the
study ends or a maximum treatment duration of 2 years, whichever occurs first.
After treatment, all subjects will enter the follow-up phase of the study.
Subjects will have 2 visits within the first 100days after stopping treatment.
The remaining follow-up visits can be conducted over the phone and will occur
every 3 months.
Participants will be permitted to continue on nivolumab +/- ipilimumab beyond
initial defined progression, as long as they meet the protocol criteria.
Intervention
Participants will receive either nivolumab (240 mg) every 2 weeks combined with
ipilimumab (1 mg/kg) every 6 weeks or Nivolumab alone (480mg) every 4 weeks.
Both nivolumab and ipilimumab are provided by the sponsor.
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. If there is no archive
tumour tissue available or the sample was taken too long ago (more than 3
months), patients will be required to have a biopsy in order to participate. In
addition, every 12 weeks, patients will undergo radiographic assessment of
their tumors (by CT or MRI) until disease progression or treatment
discontinuation whichever occurs later. Blood will also be collected at certain
visits for research purposes (PK, 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.
Bristol-Myers Squibb B.V. Orteliuslaan 1000
Utrecht 3528 BD
NL
Bristol-Myers Squibb B.V. Orteliuslaan 1000
Utrecht 3528 BD
NL
Listed location countries
Age
Inclusion criteria
a) Participants with a refractory, metastatic, or unresectable
histologically or cytologically
confirmed solid malignant tumor with TMB-H who are refractory to standard local
therapies, or for which no standard treatment is available., b)Either a
formalin-fixed, paraffin-embedded (FFPE) tissue block or unstained tumor tissue
sections, obtained within 9 months and no additional intervening therapy
(excluding
palliative therapy) prior to enrollment, with an associated pathology report,
must be
submitted to the core laboratory for inclusion. Biopsy should be excisional,
incisional or
core needle. Fine needle aspiration is unacceptable for submission., c) The IRT
must be provided with the results of both tissue and blood TMB-H testing for
eligible participants prior to randomization. Both results are utilized for
stratification purposes.
d) Prior TMB-H results obtained with F1CDx assay (tissue) or assay from
Foundation Medicine (blood) are acceptable for eligibility purposes. When these
prior results are not available, tissue and / or blood samples must be provided
for central TMB-H testing, and results must be available prior to
randomization.
i) Participants must have either tTMB or bTMB >= 10 mut/Mb (tTMB >= 10 mut/Mb or
the
new cutoff value of bTMB determined by the 1st interim analysis). Should one of
the
two populations (tTMB-H or bTMB-H) reach the targeted sample size before the
other,
then enrollment will continue only with participants for the other TMB-H
population.
ii) TMB results obtained from any other methodologies are not acceptable for
eligibility.
d) Participants must have measurable disease for response assessment as per
RECIST 1.1 for solid tumors other than CNS, and RANO criteria for primary CNS
malignancies.
Exclusion criteria
a) Active brain metastases or leptomeningeal metastases. Participants with
brain metastases are eligible if these have been treated and there is no MRI
evidence of progression for at least 8 weeks after treatment is complete and
within 28 days prior to first dose of study treatment administration.
b) There must also be no requirement for immunosuppressive doses of systemic
corticosteroids (> 10 mg/day prednisone equivalents) for at least 2 weeks prior
to study treatment administration. Stable dose of anticonvulsants is allowed.
c) Patient who received whole brain radiation therapy are not eligible.
d) Participants who received prior treatment with an anti-PD-1, anti-PD-L1,
anti-PD-L2, anti CD137, or anti-CTLA-4 antibody, or any other antibody or drug
specifically targeting T-cell co-stimulation or checkpoint pathways
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 | EUCTR2016-002898-35-NL |
| CCMO | NL67171.031.18 |
| Other | U1111-1185-1326 |