Primary Objective1. To evaluate the antitumor activity of pembrolizumab in combination with chemotherapy compared with saline placebo in combination with chemotherapy using PFS per RECIST 1.1 as assessed by BICR of imaging.2. To evaluate the…
ID
Source
Brief title
Condition
- Respiratory and mediastinal neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary endpoint of the trial is PFS per RECIST 1.1 by central imaging
vendor review.
Overal Survival, defined as time from randomization to death due to any cause.
Secondary outcome
Objective Response Rate (ORR) - RECIST 1.1 assessed by BICR
Duration of Response (DOR) - RECIST 1.1 assessed by BICR
Background summary
Lung cancer accounted for an estimated 13% of total cancer diagnoses,
representing 1.8 million new cases in 2012. Mortality from lung cancer in 2012
amounted to 1.6 million deaths globally: the leading cause of cancer death in
men and the second leading cause in women. NSCLC accounts for approximately 85%
of all lung cancer cases, with the majority being non-squamous.
Progress has been made in the clinical management of early stage NSCLC by
establishing comprehensive, multi-modality treatment regimens; however, the
prognosis for advanced disease has not improved substantially. With an overall
5-year survival rate of 9% to 13% the treatment of NSCLC remains a highly unmet
medical need. Cytotoxic chemotherapies as single agents or in combination have
served as the mainstay of treatment for decades with platinum containing
doublets conferring the greatest advances in overall survival gains. As noted
in section 4.1.4, platinum and pemetrexed therapy has become a relative
standard option for non-squamous NSCLC.
Molecular profiling has, however, established a definite role for EGFR and ALK
directed therapy in a small subset of NSCLC patients. The EGFR tyrosine kinase
inhibitors gefitinib, erlotinib and afatinib have demonstrated marked
superiority over chemotherapy in patients with activating EGFR mutations. In
addition, agents which overcome resistance to initial therapy are also in
development. Similarly, ALK inhibitors crizotinib and ceritinib have shown
significant activity in ALK-rearranged NSCLC with more agents in development.
Interestingly, the ALK inhibitors are also active in a rare subgroup of ROS-1
rearranged NSCLC patients.
This study will, therefore, be restricted to non-squamous NSCLC subjects in
whom EGFR or ALK directed therapy is not indicated. Importantly, subjects will
not be selected by PD-L1 expression status, although this is a stratification
factor.
Study objective
Primary Objective
1. To evaluate the antitumor activity of pembrolizumab in combination with
chemotherapy compared with saline placebo in combination with chemotherapy
using PFS per RECIST 1.1 as assessed by BICR of imaging.
2. To evaluate the antitumor activity of pembrolizumab in combination with
chemotherapy compared with saline placebo in combination with chemotherapy
using OS.
Secundary Objective
1. To evaluate the antitumor activity of pembrolizumab in combination with
chemotherapy compared with saline placebo in combination with chemotherapy
using ORR per RECIST 1.1 as assessed by BICR.
2. To evaluate the antitumor activity of pembrolizumab in combination with
chemotherapy compared with saline placebo in combination with chemotherapy
using DOR per RECIST 1.1 as assessed by BICR.
3. To evaluate the safety and tolerability profile of pembrolizumab in
combination with pemetrexed/platinum chemotherapy.
Study design
This is a worldwide, randomized, active-controlled, parallel-group, multi-site,
double-blind trial of intravenous (IV) pembrolizumab (also known as MK-3475)
combined with platinum-pemetrexed chemotherapy versus saline placebo combined
with platinum-pemetrexed chemotherapy in subjects with advanced or metastatic
non-squamous non-small cell lung cancer (NSCLC) who have not previously
received systemic therapy for advanced disease and in whom EGFR or ALK-directed
therapy is not indicated.
Intervention
• Arm 1: Pembrolizumab 200 mg + pemetrexed 500 mg/m2 (with vitamin
supplementation) + cisplatin 75 mg/m2 OR carboplatin AUC 5 all on Day 1 Q3W
for 4 cycles followed by pembrolizumab 200 mg + pemetrexed 500 mg/m2 every 3
weeks (Q3W) until progression.
• Arm 2: Saline placebo + pemetrexed 500 mg/m2 (with vitamin supplementation) +
cisplatin 75 mg/m2 OR carboplatin AUC 5 all on Day 1 Q3W for 4 cycles followed
by saline placebo + pemetrexed 500 mg/m2 Q3W until progression.
Study burden and risks
The patient will receive the study drug every 3 weeks for up to 24 months.
Additional treatment is possible (under certain conditions) for an extra year.
The patient will visit the doctor every week or every 3 weeks. The first visit
a tumor biopsy will take place (if necessary). Each visit, a physical
examination will be performed, and blood samples will be taken. Volume will
range from 3 -49.5 ml per visit. The patient will also fill in two
questionnaires each visit, namely a 'quality-of-life questionnaire' (EORTC QLQ
C30) and a questionnaire which asked about the health of the patient (eEuroQoL
EQ-50).
The patient may experience physical and I or psychological discomfort with some
of the procedures performed during a visit, such as blood sampling, the IV
line, ECG, CT scan, MRI and tumor biopsy.
The main side effect reported with the use of MK3475 are fatigue, itching,
rash, frequent or excessive bowel movements, joint pain and nausea.
Waarderweg 39
Haarlem 2031 BN
NL
Waarderweg 39
Haarlem 2031 BN
NL
Listed location countries
Age
Inclusion criteria
•Have a histologically-confirmed or cytologically-confirmed diagnosis of stage
IV (M1a or M1b AJCC 7th edition) nonsquamous NSCLC., • Have confirmation that
EGFR or ALK-directed therapy is not indicated., •Have measurable disease based
on RECIST 1.1 as determined by the local site investigator/radiology
assessment. Target lesions situated in a previously irradiated
area are considered measurable if progression has been demonstrated in such
lesions.
•Have not received prior systemic treatment for their advanced/metastatic
NSCLC. Subjects who received adjuvant or neoadjuvant therapy are eligible if
the adjuvant/neoadjuvant therapy was completed at least 12 months prior to the
development of metastatic disease., •Have provided tumor tissue from locations
not radiated prior to biopsy; formalin-fixed specimens after the subject has
been diagnosed with metastatic disease will be preferred for determination of
PD-L1 status prior to randomization. Biopsies obtained prior to receipt of
adjuvant chemotherapy will be permitted if recent biopsy is not feasible., •Be
18 years of age or older on day of signing informed consent. , • Have a life
expectancy of at least 3 months., •Have a ECOG performance status of 0 or 1,
•Have adequate organ function as indicated by the laboratory values specified
in the protocol , •If female of childbearing potential, have a negative urine
or serum pregnancy test within 72 hours prior to receiving the first dose of
study medication. If the urine test is positive or cannot be confirmed as
negative, a serum pregnancy test will be required., •If female of childbearing
potential, be willing to use an adequate method of contraception as outlined in
the protocol, for the course of the study through 120 days after the last dose
of study medication or through 180 days after last dose of chemotherapeutic
agents as specified in the protocol. , •If male subject with a female
partner(s) of child-bearing potential, must agree to use an adequate method of
contraception as outlined in the protocol, starting with the first dose of
study therapy through 120 days after the last dose of study therapy or through
180 days after last dose of chemotherapeutic agents as specified in the
protocol. Males with pregnant partners must agree to use a condom; no
additional method of contraception is required for the pregnant partner.,
•Subject has voluntarily agreed to participate by giving written informed
consent/assent for the trial. The subject may also provide consent/assent for
Future Biomedical Research. However, the subject may participate in the main
trial without participating in Future Biomedical Research.
Exclusion criteria
•Has predominantly squamous cell histology NSCLC. Mixed tumors will be
categorized by the predominant cell type; if small cell elements are present,
the subject is ineligible., •Is currently participating and receiving study
therapy or has participated in a study of an investigational agent and received
study therapy or used an investigational device within 4 weeks prior to
administration of pembrolizumab., •Before the first dose of trial treatment:
a)Has received prior systemic cytotoxic chemotherapy for metastatic disease
b)Has received antineoplastic biological therapy (e.g., erlotinib, crizotinib,
cetuximab)
c)Had major surgery <3 weeks prior to first dose, •Received radiation
therapy to the lung that is >30 Gy within 6 months of the first dose of
trial treatment, •Completed palliative radiotherapy within 7 days of the first
dose of trial treatment, •Is Expected to require any other form of
antineoplastic therapy while on study, • Has Received a live-virus vaccination
within 30 days of planned treatment start. Seasonal flu vaccines that do not
contain live virus are permitted., •Has clinically active diverticulitis,
intra-abdominal abscess, GI obstruction, abdominal carcinomatosis, •Has a known
history of prior malignancy except if the patient has undergone potentially
curative therapy with no evidence of that disease recurrence for 5 years since
initiation of that therapy., • Has known active central nervous system (CNS)
metastases and/or carcinomatous meningitis. Subjects with previously treated
brain metastases may participate provided they are clinically stable for at
least 2 weeks and, have no evidence of new or enlarging brain metastases and
also are off steroids 3 days prior to dosing with study medication. Stable
brain metastases by this definition should be established prior to the first
dose of study medication. Subjects with known untreated asymptomatic brain
metastases may participate but will require regular imaging of the brain as a
site of disease., •Previously had a severe hypersensitivity reaction to
treatment with another mAb., •Has a known sensitivity to any component of
cisplatin, carboplatin or pemetrexed, •Has active autoimmune disease that has
required systemic treatment in past 2 years (i.e. with use of disease modifying
agents, corticosteroids or immunosuppressive drugs). Replacement therapy
(e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy
for adrenal or pituitary insufficiency, etc.) is not considered a form of
systemic treatment., •Is on chronic systemic steroids. Subjects with asthma
that require intermittent use of bronchodilators, inhaled steroids, or local
steroid injections would not be excluded from the study., •Is unable to
interrupt aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs), other
than an aspirin dose <= 1.3 g per day, for a 5-day period (8-day period for
long-acting agents, such as piroxicam)., •Is unable or unwilling to take folic
acid or vitamin B12 supplementation., •Had prior treatment with any other
anti-PD-1, or PD-L1 or PD-L2 agent or an antibody targeting other
immuno-regulatory receptors or mechanisms. Has participated in any other
MK-3475 trial and has been treated with MK-3475., Examples of such antibodies
include (but are not limited to) antibodies against IDO, PD-L1, IL-2R, GITR,
•Has an active infection requiring therapy, •Has known history of Human
Immunodeficiency Virus (HIV) (known HIV 1/2 antibodies positive)., •Has known
active Hepatitis B or C. Active Hepatitis B is defined as a known positive
HBsAg result. Active Hepatitis C is defined by a known positive Hep C Ab
result and known quantitative HCV RNA results greater than the lower limits of
detection of the assay., for more exclusion criteria please refer to the
protocol
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 | EUCTR2015-003694-15-NL |
| ClinicalTrials.gov | NCT02578680 |
| CCMO | NL55723.056.15 |