1) Objective: To compare the overall survival (OS) of previously-treated subjects with NSCLC in the strongly positive PD-L1 stratum treated with MK-3475 compared to docetaxel.2) Objective: To compare progression-free survival (PFS) per RECIST 1.1 by…
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Source
Brief title
Condition
- Respiratory and mediastinal neoplasms malignant and unspecified
- Respiratory tract neoplasms
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Overall Survival, (OS)
Progression Free Survival, (FPS)
Secondary outcome
Overall Response Rate (ORR)
response duration per RECIST 1.1 based on blinded independent radiologists*
review.
Background summary
While docetaxel is an accepted second-line standard of care for patients with
NSCLC, the objective response rate is about 5-10%, median progression-free
survival is about 3 months, and the median overall survival is about 7.5 months
[62, 63, 64]. Improvements in OS are needed since no one with progressive
NSCLC is cured. A large surgical series of resected NSCLC specimens revealed
that about 25% of squamous and adenocarcinoma have tumor infiltrating
lymphocytes (TILs) present [68]. These TILs often contain CD8+ T cells [68].
The presence of increased CD8+ cells in the tumor sets the stage for an
immune-based response against the tumor if inhibition of the immune system can
be abrogated. Indeed, in a study of ipilimumab, an anti-CTLA4 monoclonal
antibody, combined with first-line carboplatin and paclitaxel, a post-hoc
subset analysis identified an improvement in OS that favored patients with
squamous histology compared to placebo plus carboplatin and paclitaxel (HR 0.48
[95% CI 0.22-1.03]). Results were not as favorable for patients with
nonsquamous histology (HR 1.17 [95% CI 0.74-1.86]). These findings have led to
the initiation of a Phase III trial in the same population with ipilimumab.
The Phase I trial of nivolumab demonstrated that patients with tumors
expressing PD-L1 using a 5% cut point for the 5H1 anti-PD-L1 mAb for IHC were
more likely to respond to anti-PD-1 therapy (9/25 patients) than patients with
tumors that did not express PD-L1 (0/17 patients). Specifically, of the ten
lung tumors for which tumor tissue was available, five expressed PD-L1, and
only one of those five was a responder; none of the patients with PD-L1
negative tumors experienced an objective response per RECIST [65]. The
activity of anti-PD-1 monoclonal antibodies in previously treated patients
with NSCLC seems promising.
Therefore, this study will compare monotherapy MK-3475 with standard of care
docetaxel in patients with NSCLC. Overall survival and PFS are the primary
endpoints of the trial, and are accepted regulatory endpoints for this
disease.
Details regarding specific benefits and risks for subjects participating in
this clinical trial may be found in the accompanying Investigators Brochure
(IB) and Informed Consent documents.
Study objective
1) Objective: To compare the overall survival (OS) of previously-treated
subjects with NSCLC in the strongly positive PD-L1 stratum treated with MK-3475
compared to docetaxel.
2) Objective: To compare progression-free survival (PFS) per RECIST 1.1 by
independent radiologists* review of previously-treated subjects with NSCLC in
the strongly positive PD-L1 stratum treated with MK-3475 compared to docetaxel.
3) Objective: Evaluate safety and tolerability profile of MK-3475 in
previously-treated subjects with NSCLC in the strongly positive PD-L1 stratum.
Study design
This is a multi-center, worldwide, randomized, adaptively designed Phase II/III
trial of intravenous (IV) MK-3475 at two dosing schedules versus docetaxel in
subjects with non-small cell lung cancer (NSCLC) with PD-L1 positive tumors who
have experienced disease progression after platinum-containing systemic
therapy. Approximately 520-920 subjects will be enrolled in this trial to
examine the efficacy compared to docetaxel in an enriched population.
Subjects will be randomized in a 1:1:1 ratio to receive MK-3475 at 10 mg/kg
every 3 weeks (Q3W), 2 mg/kg Q3W, or docetaxel at 75 mg/m2 Q3W (Figure 1).
Because this is an adaptively designed trial, the total number of patients
randomized will depend upon demonstration of sufficient objective responses at
interim analysis 1 in an MK-3475 arm in the stratum of subjects whose tumors
test strongly positive for PD-L1. Assignment to MK-3475 or docetaxel will be
unblinded. Subjects will be stratified by Eastern Cooperative Oncology Group
(ECOG) Performance Scale (0 vs. 1), and geographic region of the enrolling site
(East Asia vs. non-East Asia) prior to randomization.
Subjects will be evaluated every 9 weeks (63 ± 7 days) with radiographic
imaging to assess response to treatment. Investigators will make all
treatment-based decisions using the Immune-Related Response Criteria (irRC).
All imaging obtained on study will be submitted for independent radiologists*
review; they will assess the images using Response Evaluation Criteria in Solid
Tumors (RECIST) 1.1 for determination of overall response rate (ORR) and
progression-free survival (PFS). Adverse events will be monitored throughout
the trial and graded in severity according to the guidelines outlined in the
NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.
Treatment with MK-3475 or docetaxel will continue until two years of therapy
have been administered, documented disease progression, unacceptable adverse
event(s), intercurrent illness that prevents further administration of
treatment, investigator*s decision to withdraw the subject, subject withdraws
consent, pregnancy of the subject, noncompliance with trial treatment or
procedure requirements, or administrative reasons. MK-3475 treated subjects
who attain an investigator-determined confirmed complete response (CR) per irRC
may consider stopping trial treatment. These subjects will be eligible for
re-treatment for up to one year with MK-3475 after they have experienced
radiographic disease progression at the discretion of the investigator
according to the criteria in Section 7.1.5.4; this re-treatment will be the
Second Course Phase. Response or progression in the Second Course Phase will
not count towards the ORR and PFS of the primary endpoint in this trial.
After the end of treatment, each subject will be followed for a minimum of 30
days for adverse event monitoring (serious adverse events will be collected for
up to 90 days after the end of treatment). Subjects will have post-treatment
follow-up for disease status, including initiating a non-study cancer treatment
and experiencing disease progression, until death, withdrawing consent, or
becoming lost to follow-up. The primary objectives of the trial include
overall survival (OS), PFS per RECIST 1.1 by independent radiologists* review,
and safety as assessed by a variety of parameters of adverse events (AEs),
including incidence and time to first Grade 3-5 AE in the strongly positive
PD-L1 stratum. Pre-specified adverse events of clinical interest include the
following events:1) Grade * 3 diarrhea 2) Grade * 2 colitis, 3) Grade * 2
pneumonitis, 4) Grade * 3 hypo- or hyperthyroidism. Secondary objectives
include OS, and PFS and ORR per RECIST 1.1 by independent radiologists* review
in subjects whose tumors express PD-L1. Additional secondary objectives
include the analysis of ORR per RECIST 1.1 by independent radiologists* review
and per irRC by investigators* review, PFS per irRC by investigators* review,
and response duration per RECIST 1.1 by independent radiologists* review and
per irRC by investigators* review in subjects whose tumors strongly express
PD-L1. Change in tumor volume and health-related quality-of-life assessments
in subjects whose tumors strongly express PD-L1 will be pursued as exploratory
objectives.
Participation in this trial will be dependent upon supplying tumor tissue from
either a newly obtained formalin-fixed specimen, or an older formalin-fixed,
paraffin-embedded specimen from locations not radiated prior to biopsy; newly
obtained formalin-fixed specimens are strongly encouraged. If new scientific
data emerge that indicate that an existing biopsy or surgical specimen is
suboptimal for identification of patients, only new biopsies will be acceptable
for determination of PD-L1 status. The specimen will be evaluated at a central
laboratory facility for expression status of PD-L1 in a prospective manner.
Only subjects whose tumors express PD-L1 as determined by the central
laboratory facility will be eligible for randomization in this study.
This trial will use an adaptive design based on pre-specified criteria, using
an independent, external Data Monitoring Committee (DMC) to monitor safety and
efficacy. Subjects enrolled to the weakly positive PD-L1 stratum will not be
included in the populations for primary efficacy and safety analyses. Two
formal interim analyses based on the data from the randomized cohort will occur
during the conduct of this trial. The first interim analysis will be triggered
after 120 subjects in the strongly positive PD-L1 stratum have completed a
minimum of 3 months of follow-up. The primary objective of this analysis is to
stop the study for futility or to discontinue the MK-3475 at 2 mg/kg Q3W dose
if it is less effective than MK-3475 at 10 mg/kg Q3W in the strongly positive
PD-L1 stratum.
The second interim analysis is expected to occur around 1 month after all trial
subjects have been randomized. It will be conducted when 174 events of
progression per RECIST 1.1 by independent radiologists* review have occurred in
the MK-3475 at 10 mg/kg Q3W and docetaxel arms in the strongly positive PD-L1
stratum. The purpose of the second interim analysis is to demonstrate
superiority of MK-3475 in PFS in the strongly positive PD-L1 stratum and
whether the trial should be stopped for overwhelming efficacy based on OS in
the strongly positive PD-L1 stratum. In addition, the trial may be stopped
early at the recommendation of the DMC if the risk/benefit ratio to the trial
population as a whole is unacceptable. Details are described in Section 8.0 *
Statistical Analysis Plan.
If the 2 mg/kg dose arm is dropped due to lack of efficacy , per the
Investigator*s discretion the subjects can continue to be treated with MK-3475
on the 10 mg/kg dose. The efficacy and safety data from these patients will
not be used in the primary analysis, but will be used in supportive analyses.
Study burden and risks
Blood samples: drawing blood from your arm may cause pain, bruising,
lightheadedness, and rarely, infection.
IV line: may cause discomfort, irritation, mild bruising, bleeding, leakage of
drug solution, and rarely, infection, nausea, and lightheadedness.
ECG: the procedure may cause minimal discomfort during the attachment and
removal of the ECG leads to and from the skin.
CT Scan: A *Computerized Tomography* or CT scan provides multiple detailed
pictures of the inside of the body, like an MRI scan, but the CT scan uses
radiation, similar to an x-ray. CT scans may be done with or without oral or
intravenous contrast. The scan may take between 30-90 minutes to complete
depending on the areas of the body being scanned and the type of scanner.
Magnetic Resonance Imaging (MRI): Risks of MRI include claustrophobia,
discomfort due to lying still for a prolonged period of time, and other factors
which will be described to you and discussed with you at the MRI center.
Tumor Biopsy: Having biopsies performed may cause pain, bruising, bleeding,
redness, low blood pressure, swelling, and/or infection at the site of the
biopsy. An allergic reaction to the anesthetic may occur. A scar may form at
the biopsy site.
Pulmonary Function Test: A brief light-headed feeling.
Waarderweg 39
Haarlem 2031 BN
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Waarderweg 39
Haarlem 2031 BN
NL
Listed location countries
Age
Inclusion criteria
1) Be willing and able to provide written informed consent/assent for the trial.
2) Be *18 years of age on day of signing informed consent.
3) Have a life expectancy of at least 3 months.
4) Have a histologically or cytologically confirmed diagnosis of nonsmall cell lung cancer (NSCLC) and have at least one measurable lesion as defined by RECIST 1.1.
5) Have experienced investigator determined radiographic progression per RECIST 1.1 of NSCLC after treatment with at least two cycles of a platinum-containing doublet for stage IIIB/IV or recurrent disease.
a. Subjects with an EGFR mutation must also be able to demonstrate progression of disease on the EGFR tyrosine kinase inhibitor (either erlotinib or gefitinib or afatinib).
b. Subjects with an ALK translocation must also be able to demonstrate progression of disease on crizotinib in a similar manner to that above for the platinum-containing doublet.
6) Have a performance status of 0 or 1 on the ECOG Performance Scale.
7) Have provided tissue for PD-L1 biomarker analysis from a newly obtained formalin fixed tumor tissue from a recent biopsy of a tumor lesion not previously irradiated; no systemic antineoplastic therapy may be administered between the PD-L1 biopsy and initiating study medication.
8) Have resolution of toxic effect(s) of the most recent prior chemotherapy to Grade 1 or less (except alopecia). If subject received major surgery or radiation therapy of > 30 Gy, they must have recovered from the toxicity and/or complications from the intervention.
9) Have a PD-L1 positive (either strongly or weakly) tumor as determined by IHC at a central laboratory (either in the neoplastic cells themselves or in mononuclear inflammatory cells infiltrating the tumor).;Inclusion Criteria for Optional Crossover from docetaxel to MK-3475 2mg/kg arm In order to be eligible for participation in the crossover phase, the subject must:
1. Be willing and able to provide written informed consent/assent for the trial.
2. Have been randomized into the docetaxel arm of MK-3475 PN010 study and taken at least one dose of study medication
3. Have experienced disease progression (either clinical or radiographic, as assessed by the investigator) from docetaxel or other subsequent anti-cancer therapies.
4. Have a performance status of 0 or 1 on the ECOG Performance Scale.
5. Subjects with known and treated brain metastasis are eligible provided they are clinically stable, and brain metastases have been treated. Steroid use for symptom control is allowed but the total daily dose should be < or <= 10 mg of prednisone or its equivalent.
6. Have baseline imaging scan done within 30 days of the first dose of MK-3475
7. Have adequately recovered from adverse events of previous anticancer therapy.
Exclusion criteria
1) Has received prior therapy with docetaxel for NSCLC.
2) Is currently participating or has participated in a study of an investigational agent or using an investigational device within 30 days of the first dose of trial treatment.
3) Is receiving systemic steroid therapy within three days prior to the first dose of trial treatment or receiving any other form of immunosuppressive medication (corticosteroid use on study for
management of ECI-ies or as a pre-medication for docetaxel is allowed).
4) Is expected to require any other form of systemic or localized antineoplastic therapy while on trial (including maintenance therapy with another agent for NSCLC or radiation therapy).
5) Has received prior systemic cytotoxic chemotherapy, biological therapy (e.g., cetuximab), major surgery within 3 weeks of the first dose of trial treatment; received radiation therapy of > 30 Gy within 6 months of the first dose of trial treatment; received prior tyrosine kinase inhibitor therapy or palliative radiotherapy of 30Gy or less within 7 days of the first dose of trial treatment.
6) Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PDL2, anti-CD137, or anti-Cytotxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways).
7) Has a known history of prior malignancy, with the exception of basal cell carcinoma of the skin, superficial bladder cancer, squamous cell carcinoma of the skin, or in situ cervical cancer, and has undergone potentially curative therapy with no evidence of that disease recurrence for 5 years since initiation of that therapy.
8) Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by MRI for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are using no steroids for at least three days prior to study medication.
9) Has an active autoimmune disease, or a documented history of autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents.
10) Has interstitial lung disease or a history of pneumonitis.
11) Has interstitial lung disease or a history of pneumonitis that required oral or intravenous glucocorticoids to assist with management. Lymphangitic spread of the NSCLC is not exclusionary.
12) Has had an allogeneic tissue/solid organ transplant.;Exclusion Criteria for Optional Crossover from docetaxel to MK-3475 2mg/kg arm
The subject must be excluded from participating in the trial if the subject:
1. Has withdrawn consent from study (MK-3475 PN010).
2. Have active pneumonitis of Grade 2 or greater or history of pneumonitis requiring systemic steroid therapy.
3. Has received thoracic radiation therapy of > 30 Gy within 6 months
4. have active and untreated brain metastasis.
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 | EUCTR2012-004391-19-NL |
| CCMO | NL43092.056.13 |
| Other | nog niet bekend |